Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
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We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
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Throughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"5355",leadTitle:null,fullTitle:"Water Quality",title:"Water Quality",subtitle:null,reviewType:"peer-reviewed",abstract:"As concerns increase over the scarcity of water resources and the role of anthropogenic activities, water quality is evermore important. Activities ranging from agriculture to mining have had a bearing on the quality of water that they impact. Several studies assessing such impacts have been conducted at local and global scales over the years. This book, consisting of contributions by authors in various water-related fields, delves into some approaches that are used to understand and/or to improve water quality, and these include assessment of water chemistry, biomonitoring, modelling and water treatment. This book will be useful to environmental scientists, water professionals, researchers, academics and students.",isbn:"978-953-51-2882-3",printIsbn:"978-953-51-2881-6",pdfIsbn:"978-953-51-5466-2",doi:"10.5772/62562",price:139,priceEur:155,priceUsd:179,slug:"water-quality",numberOfPages:428,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"d371f1ad9fbc2b37808571c3b1cc7042",bookSignature:"Hlanganani Tutu",publishedDate:"January 18th 2017",coverURL:"https://cdn.intechopen.com/books/images_new/5355.jpg",numberOfDownloads:60163,numberOfWosCitations:246,numberOfCrossrefCitations:173,numberOfCrossrefCitationsByBook:4,numberOfDimensionsCitations:373,numberOfDimensionsCitationsByBook:4,hasAltmetrics:1,numberOfTotalCitations:792,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 2nd 2016",dateEndSecondStepPublish:"March 23rd 2016",dateEndThirdStepPublish:"June 27th 2016",dateEndFourthStepPublish:"September 25th 2016",dateEndFifthStepPublish:"October 25th 2016",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"93222",title:"Prof.",name:"Hlanganani",middleName:null,surname:"Tutu",slug:"hlanganani-tutu",fullName:"Hlanganani Tutu",profilePictureURL:"https://mts.intechopen.com/storage/users/93222/images/5112_n.jpg",biography:"Hlanganani Tutu is an associate professor in environmental chemistry at the University of the Witwatersrand, South Africa. He obtained his PhD degree in Environmental Chemistry from the same university in 2006. His research interests include geochemical modelling of solute transport, designing remediation strategies for contaminated environments, recovering value from waste and chemometric data modelling. He teaches courses in general chemistry, environmental chemistry and geochemical modelling and has supervised a number of research projects. He has published many articles in international scientific journals and chapters in books.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of the Witwatersrand",institutionURL:null,country:{name:"South Africa"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"837",title:"Hydrology",slug:"hydrology"}],chapters:[{id:"52602",title:"Ecosystem Approach to Managing Water Quality",doi:"10.5772/65707",slug:"ecosystem-approach-to-managing-water-quality",totalDownloads:1993,totalCrossrefCites:3,totalDimensionsCites:4,hasAltmetrics:1,abstract:"This chapter argues for the ecosystem approach to managing water quality, which advocates the management of water, land and the associated living resources at the catchment scale as complex social-ecological systems and proactively defend and protect the ecological health of the ecosystem for the continuing supply of ecosystem services for the benefit of society. It argues for a shift from the engineering-driven command and control approach to water resource management. Environmental water quality (EWQ) is discussed as a holistic and integrated tripod ecosystem approach to managing water quality. Water physico-chemistry, biomonitoring and aquatic ecotoxicology are discussed as and their application and limitation with respect to water quality management, particularly in South Africa, is critically evaluated. The chapter concludes with a case study illustrating the application of biomonitoring for the assessment of ecosystem health in the Swartkops River, Eastern Cape, South Africa. The macroinvertebrates-based South African Scoring System version 5 was applied at three impacted sites and one control site. Two of the three impacted sites downstream of an effluent discharge point had very poor health conditions. The urgent need for ecological restoration was recommended.",signatures:"Oghenekaro Nelson Odume",downloadPdfUrl:"/chapter/pdf-download/52602",previewPdfUrl:"/chapter/pdf-preview/52602",authors:[{id:"175580",title:"Dr.",name:"Oghenekaro Nelson",surname:"Odume",slug:"oghenekaro-nelson-odume",fullName:"Oghenekaro Nelson Odume"}],corrections:null},{id:"52384",title:"Macroinvertebrates and Fishes as Bioindicators of Stream Water Pollution",doi:"10.5772/65084",slug:"macroinvertebrates-and-fishes-as-bioindicators-of-stream-water-pollution",totalDownloads:3755,totalCrossrefCites:5,totalDimensionsCites:17,hasAltmetrics:1,abstract:"Freshwater ecosystems worldwide have been progressively deteriorated during the past decades due to an increasing human pressure that has lead to a decrease in aquatic biodiversity. Among the human activities of high impact on freshwater ecosystems is the land-use change, principally from native forests to agriculture. To evaluate the impacts of human activities on water quality, a traditional approach has considered the use of single physical-chemical parameters. However, this approach may be insufficient to fully assess the impact of these human activities on freshwaters. Therefore, there is a need for alternative tools such as the indices of biotic integrity that may provide a complement to traditional approaches. In the literature, there are several examples of biotic indicators that have shown promising results in evaluating water quality including the use of macroinvertebrates and fish diets. Here, we provide a review of the indicators of biotic integrity that included fish assemblages as well as macroinvertebrates as bioindicators. We identify pros and cons of using aquatic communities as indicators of water quality. Finally, we develop a procedure that combines fish and macroinvertebrate assemblages as bioindicators and discuss their effectiveness using illustrative examples from streams under several agricultural uses in the Mediterranean region of Chile.",signatures:"Pablo Fierro, Claudio Valdovinos, Luis Vargas-Chacoff, Carlos\nBertrán and Ivan Arismendi",downloadPdfUrl:"/chapter/pdf-download/52384",previewPdfUrl:"/chapter/pdf-preview/52384",authors:[{id:"73014",title:"Dr.",name:"Ivan",surname:"Arismendi",slug:"ivan-arismendi",fullName:"Ivan Arismendi"},{id:"186733",title:"M.Sc.",name:"Pablo",surname:"Fierro",slug:"pablo-fierro",fullName:"Pablo Fierro"},{id:"187083",title:"Dr.",name:"Claudio",surname:"Valdovinos Zarges",slug:"claudio-valdovinos-zarges",fullName:"Claudio Valdovinos Zarges"},{id:"187084",title:"Dr.",name:"Luis",surname:"Vargas-Chacoff",slug:"luis-vargas-chacoff",fullName:"Luis Vargas-Chacoff"},{id:"187085",title:"Dr.",name:"Carlos",surname:"Bertran",slug:"carlos-bertran",fullName:"Carlos Bertran"}],corrections:null},{id:"52961",title:"Calibrating and Validating the Biomonitoring Working Party (BMWP) Index for the Bioassessment of Water Quality in Neotropical Streams",doi:"10.5772/66221",slug:"calibrating-and-validating-the-biomonitoring-working-party-bmwp-index-for-the-bioassessment-of-water",totalDownloads:2032,totalCrossrefCites:3,totalDimensionsCites:6,hasAltmetrics:0,abstract:"The Biological Monitoring Working Party (BMWP) is among the most used bioassessment indices for aquatic ecosystems quality assessment, which assigns scores to each macroinvertebrate taxa according to their sensitivity to organic pollution. However, BMWP scores must be calibrated to each geographical and ecological conditions. In this study, we obtain statistically derived scores of sensitivity for macroinvertebrates taxa from Neotropical Mexican rivers, Apatlaco and Chalma-Tembembe rivers, Balsas Basin. We obtained water samples and aquatic macroinvertebrates in four sampling campaigns (dry and rainy seasons). Physicochemical parameters and the abundances of the aquatic macroinvertebrates were used for the BMWP index calibration, which was performed in steps obtaining: the physicochemical quality index (Pcq), incorporation of abundances classes of macroinvertebrates taxa in the corresponding Pcq interval and the determination of bioindication values for each macroinvertebrate family. The BMWP calibrated index was validated and tested for the geographical range extension. The BMWP scores for Chalma-Tembembe River (located in agricultural areas) showed bad polluted to regular and moderated polluted categories. The urban river zone of Apatlaco River showed: bad, very polluted to very bad categories. The BMWP calibrated is a suitable biomonitoring tool, allowing the detection of those zones that needs urgently a management and recovery plan.",signatures:"Ricardo Arturo Ruiz-Picos, Jacinto Elías Sedeño-Díaz and Eugenia\nLópez-López",downloadPdfUrl:"/chapter/pdf-download/52961",previewPdfUrl:"/chapter/pdf-preview/52961",authors:[{id:"153660",title:"M.Sc.",name:"Jacinto Elías",surname:"Sedeño-Díaz",slug:"jacinto-elias-sedeno-diaz",fullName:"Jacinto Elías Sedeño-Díaz"},{id:"186654",title:"MSc.",name:"Ricardo A.",surname:"Ruiz-Picos",slug:"ricardo-a.-ruiz-picos",fullName:"Ricardo A. Ruiz-Picos"},{id:"190562",title:"Dr.",name:"Eugenia",surname:"López-López",slug:"eugenia-lopez-lopez",fullName:"Eugenia López-López"}],corrections:null},{id:"52639",title:"Metals Toxic Effects in Aquatic Ecosystems: Modulators of Water Quality",doi:"10.5772/65744",slug:"metals-toxic-effects-in-aquatic-ecosystems-modulators-of-water-quality",totalDownloads:4253,totalCrossrefCites:21,totalDimensionsCites:47,hasAltmetrics:0,abstract:"The topic of this work was based on the assessment of aquatic systems quality related to the persistent metal pollution. The use of aquatic organisms as bioindicators of metal pollution allowed the obtaining of valuable information about the acute and chronic toxicity on common Romanian aquatic species and the estimation of the environment quality. Laboratory toxicity results showed that Cd, As, Cu, Zn, Pb, Ni, Zr, and Ti have toxic to very toxic effects on Cyprinus carpio, and this observation could raise concerns because of its importance as a fishery resource. The benthic invertebrates’ analysis showed that bioaccumulation level depends on species, type of metals, and sampling sites. The metal analysis from the shells of three mollusk species showed that the metals involved in the metabolic processes (Fe, Mn, Zn, Cu, and Mg) were more accumulated than the toxic ones (Pb, Cd). The bioaccumulation factors of metals in benthic invertebrates were subunitary, which indicated a slow bioaccumulation process in the studied aquatic ecosystems. The preliminary aquatic risk assessment of Ni, Cd, Cr, Cu, Pb, As, and Zn on C. carpio revealed insignificant to moderate risk considering the measured environmental concentrations, acute and long-term effects and environmental compartment.",signatures:"Stefania Gheorghe, Catalina Stoica, Gabriela Geanina Vasile, Mihai\nNita-Lazar, Elena Stanescu and Irina Eugenia Lucaciu",downloadPdfUrl:"/chapter/pdf-download/52639",previewPdfUrl:"/chapter/pdf-preview/52639",authors:[{id:"186964",title:"Dr.",name:"Stefania",surname:"Gheorghe",slug:"stefania-gheorghe",fullName:"Stefania Gheorghe"},{id:"194072",title:"Dr.",name:"Catalina",surname:"Stoica",slug:"catalina-stoica",fullName:"Catalina Stoica"}],corrections:null},{id:"53211",title:"Biofloc Technology (BFT): A Tool for Water Quality Management in Aquaculture",doi:"10.5772/66416",slug:"biofloc-technology-bft-a-tool-for-water-quality-management-in-aquaculture",totalDownloads:16842,totalCrossrefCites:60,totalDimensionsCites:138,hasAltmetrics:1,abstract:"Biofloc technology (BFT) is considered the new “blue revolution” in aquaculture. Such technique is based on in situ microorganism production which plays three major roles: (i) maintenance of water quality, by the uptake of nitrogen compounds generating in situ microbial protein; (ii) nutrition, increasing culture feasibility by reducing feed conversion ratio (FCR) and a decrease of feed costs; and (iii) competition with pathogens. The aggregates (bioflocs) are a rich protein-lipid natural source of food available in situ 24 hours per day due to a complex interaction between organic matter, physical substrate, and large range of microorganisms. This natural productivity plays an important role recycling nutrients and maintaining the water quality. The present chapter will discuss some insights of the role of microorganisms in BFT, main water quality parameters, the importance of the correct carbon-to-nitrogen ratio in the culture media, its calculations, and different types, as well as metagenomics of microorganisms and future perspectives.",signatures:"Maurício Gustavo Coelho Emerenciano, Luis Rafael Martínez-\nCórdova, Marcel Martínez-Porchas and Anselmo Miranda-Baeza",downloadPdfUrl:"/chapter/pdf-download/53211",previewPdfUrl:"/chapter/pdf-preview/53211",authors:[{id:"146126",title:"Dr.",name:"Maurício Gustavo Coelho",surname:"Emerenciano",slug:"mauricio-gustavo-coelho-emerenciano",fullName:"Maurício Gustavo Coelho Emerenciano"},{id:"186970",title:"Prof.",name:"Marcel",surname:"Martínez-Porchas",slug:"marcel-martinez-porchas",fullName:"Marcel Martínez-Porchas"},{id:"186971",title:"Prof.",name:"Anselmo",surname:"Miranda-Baeza",slug:"anselmo-miranda-baeza",fullName:"Anselmo Miranda-Baeza"},{id:"195101",title:"Dr.",name:"Luis Rafael",surname:"Martínez-Córdoba",slug:"luis-rafael-martinez-cordoba",fullName:"Luis Rafael Martínez-Córdoba"}],corrections:null},{id:"53001",title:"Modelling Impact of Adjusted Agricultural Practices on Nitrogen Leaching to Groundwater",doi:"10.5772/66324",slug:"modelling-impact-of-adjusted-agricultural-practices-on-nitrogen-leaching-to-groundwater",totalDownloads:1604,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The aim of the research was to determine how changes in the management of agricultural land (cultivation techniques, fertilisation, type of crop and crop rotation) influence on the leaching of nitrogen from the soil profile. Research was conducted in the Drava River plain in Slovenia. The impact of 31 different scenarios of potential change in agricultural land management was evaluated using the Soil and Water Assessment Tool (SWAT) model. The research was located on the shallow aquifer with alluvial bedrock composite from carbonate and silicate layers, which is the main source of drinking water in the area. The results of the SWAT model version 2009 showed that with the constant climate and land management technology, the magnitude of nitrogen leaching from the soil profile is mainly influenced by soil properties. The most drastic effect on the increase of nitrogen leaching showed vegetable production technology, followed by cereals (corn, wheat and barley). Vegetable production even in ecological production by Slovenian standards can result in similar leaching potential as conventional farming, due to unfavourable conditions originating from soil properties (shallow soil profile). Effects of grassland production may lead to 76–98% reduction in nitrogen loss from soil profile in comparison to current practices.",signatures:"Matjaž Glavan, Andrej Jamšek and Marina Pintar",downloadPdfUrl:"/chapter/pdf-download/53001",previewPdfUrl:"/chapter/pdf-preview/53001",authors:[{id:"61187",title:"Prof.",name:"Marina",surname:"Pintar",slug:"marina-pintar",fullName:"Marina Pintar"},{id:"82604",title:"Dr.",name:"Matjaž",surname:"Glavan",slug:"matjaz-glavan",fullName:"Matjaž Glavan"},{id:"193694",title:"BSc.",name:"Andrej",surname:"Jamšek",slug:"andrej-jamsek",fullName:"Andrej Jamšek"}],corrections:null},{id:"52670",title:"Modeling Agricultural Land Management to Improve Understanding of Nitrogen Leaching in an Irrigated Mediterranean Area in Southern Turkey",doi:"10.5772/65809",slug:"modeling-agricultural-land-management-to-improve-understanding-of-nitrogen-leaching-in-an-irrigated-",totalDownloads:1894,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Nitrogen (N) cycle dynamics and its transport in the ecosystem were always an attracting subject for the researchers. Calculation of N budget in agricultural systems with use of different empirical statistical methods is common practice in OECD and EU countries. However, these methodologies do not include climate and water cycle as part of the process. On the other hand, big scale studies are labor and work intensive. As a solution, various computer modeling approaches have been used to predict N budget and related N parameters. One of them is internationally established Soil and Water Assessment (SWAT) model, which was developed especially for modeling agricultural catchments. The aim of this study was to improve understanding of N leaching with simulation of agricultural land management (fertilization, irrigation, and plant species) in hydrological heavily modified watershed with irrigation-depended agriculture under Mediterranean climate. The study was conducted in Lower Seyhan River Plain Irrigation District (Akarsu) of 9495 ha in Cukurova region of southern Turkey. Intensive and extensive water and nitrogen monitoring data (2008–2014), soil properties, cropping pattern, and crop rotation were used for the SWAT model build, calibration, and validation of the model.",signatures:"Ebru Karnez, Hande Sagir, Matjaž Gavan, Muhammed Said\nGolpinar, Mahmut Cetin, Mehmet Ali Akgul, Hayriye Ibrikci and\nMarina Pintar",downloadPdfUrl:"/chapter/pdf-download/52670",previewPdfUrl:"/chapter/pdf-preview/52670",authors:[{id:"61187",title:"Prof.",name:"Marina",surname:"Pintar",slug:"marina-pintar",fullName:"Marina Pintar"},{id:"82604",title:"Dr.",name:"Matjaž",surname:"Glavan",slug:"matjaz-glavan",fullName:"Matjaž Glavan"},{id:"186540",title:"Prof.",name:"Mahmut",surname:"Çetin",slug:"mahmut-cetin",fullName:"Mahmut Çetin"},{id:"186541",title:"Prof.",name:"Hyriye",surname:"Ibrikci",slug:"hyriye-ibrikci",fullName:"Hyriye Ibrikci"},{id:"186543",title:"Dr.",name:"Ebru",surname:"Karnez",slug:"ebru-karnez",fullName:"Ebru Karnez"},{id:"186544",title:"MSc.",name:"Hande",surname:"Sağir",slug:"hande-sagir",fullName:"Hande Sağir"},{id:"186545",title:"BSc.",name:"Muhammet Said",surname:"Gölpinar",slug:"muhammet-said-golpinar",fullName:"Muhammet Said Gölpinar"},{id:"194134",title:"Mr.",name:"Mehmet Ali",surname:"Akgul",slug:"mehmet-ali-akgul",fullName:"Mehmet Ali Akgul"}],corrections:null},{id:"53503",title:"Identification of Seawater Quality by Multivariate Statistical Analysis in Xisha Islands, South China Sea",doi:"10.5772/66227",slug:"identification-of-seawater-quality-by-multivariate-statistical-analysis-in-xisha-islands-south-china",totalDownloads:1646,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Xisha waters are considered to be in pristine condition, while facing the fast increasing stress under anthropogenic activities. Water quality around Yongxing Island (YX) has been measured in May, 2012. The results show that the water quality is of the first class standards as compared to the water quality of China, with insignificant difference among the monitoring stations. Robust principal component analysis (PCA) was used to identify the spatial pattern of water quality. YX is characterized by high DO, salinity, and Chl-a with low nutrients, indicating phytoplankton photosynthesis is stronger in YX island waters than the rest of the study areas. Beidao (BD) is characterized by high NH4-N and COD, and low pH, implying that these areas may have higher organic matter decomposition than rest of the areas. The water quality monitoring stations should cover spatially and temporally around Xisha waters for protecting the marine environment.",signatures:"Mei-Lin Wu, Jun-De Dong and You-Shao Wang",downloadPdfUrl:"/chapter/pdf-download/53503",previewPdfUrl:"/chapter/pdf-preview/53503",authors:[{id:"187030",title:"Dr.",name:"Meilin",surname:"Wu",slug:"meilin-wu",fullName:"Meilin Wu"}],corrections:null},{id:"53668",title:"Relationship between Land Use and Water Quality and its Assessment Using Hyperspectral Remote Sensing in Mid- Atlantic Estuaries",doi:"10.5772/66620",slug:"relationship-between-land-use-and-water-quality-and-its-assessment-using-hyperspectral-remote-sensin",totalDownloads:2378,totalCrossrefCites:2,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Mid-Atlantic coastal waters are under increasing pressures from anthropogenic disturbances at various temporal and spatial scales exacerbated by the climate change. According to the National Oceanic Atmospheric Association (NOAA), 10 of the 22 estuaries in the Mid-Atlantic, including the Chesapeake Bay, exhibit high levels of eutrophic conditions while seven, including Delaware Bay, exhibit low conditions. Chesapeake Bay is the largest estuarine system in the United States and undergoes frequent eutrophication and low dissolved oxygen events. Although substantially lower in nutrients compared to other Mid-Atlantic Estuaries, the biological, chemical, and ecological status of the Delaware Bay has changed in the past few decades due to high coastal tourism, increased local resident populations, and agricultural activities which have increased nutrient inputs into this shallow coastal bay. As stated by the Academy of Natural Sciences, although the nutrient load has reduced since the Clean Water Act, years of nutrient accumulation, contaminations, and sedimentation have impacted estuarine systems substantially, long-term monitoring is lacking, and ecological responses are not well quantified. Eutrophication within the Bays has degraded water quality conditions advanced by sedimentation. Understanding the quality of the water in any aquatic ecosystem is a critical first step in order to identify characteristics of that ecosystem and draw conclusions about how well adapted the system is in terms of anthropogenic activity and climate change. Determining water quality in intertidal creeks along the Chesapeake and Delaware coastlines is important because land cover is constantly changing. Many of these tidal creeks are lined with forested riparian buffers that may be intercepting nutrients from running off into the waterways. Identifying water conditions, coupled with the marsh land cover, provides a strong foundation to see if the buffer systems are providing the ecosystem services they are designed to provide. Our primary goal in this chapter is to provide research findings on the application of the hyperspectral remote sensing to monitor specific land-use activities and water quality. Along with hyperspectral remote sensing, our monitoring was coupled with the integration of remotely sensed data, global positioning system (GPS), and geographic information system (GIS) technologies that provide a valuable tool for monitoring and assessing waterways in the Mid-Atlantic Estuaries.",signatures:"Gulnihal Ozbay, Chunlei Fan and Zhiming Yang",downloadPdfUrl:"/chapter/pdf-download/53668",previewPdfUrl:"/chapter/pdf-preview/53668",authors:[{id:"189520",title:"Dr.",name:"Gulnihal",surname:"Ozbay",slug:"gulnihal-ozbay",fullName:"Gulnihal Ozbay"},{id:"189529",title:"Dr.",name:"Chunlei",surname:"Fan",slug:"chunlei-fan",fullName:"Chunlei Fan"},{id:"195038",title:"Dr.",name:"Zhiming",surname:"Yang",slug:"zhiming-yang",fullName:"Zhiming Yang"}],corrections:null},{id:"52622",title:"Review of the Impact on Water Quality and Treatment Options of Cyanide Used in Gold Ore Processing",doi:"10.5772/65706",slug:"review-of-the-impact-on-water-quality-and-treatment-options-of-cyanide-used-in-gold-ore-processing",totalDownloads:3015,totalCrossrefCites:4,totalDimensionsCites:6,hasAltmetrics:0,abstract:"Cyanide has been widely used in several industrial applications such as electroplating photography, metal processing, agriculture, food and the production of organic chemicals, plastics, paints and insecticides. The strong affinity of cyanide for metals such as gold and silver makes it suitable for selective leaching of these metals from ores. Cyanide is highly toxic; hence, there is a need to regulate and limit the amount of cyanide that may be discharged into the environment. Technologies focusing on the use of physical, chemical and biological methods have been developed to reduce the concentration of cyanide and cyanide compounds in wastewaters to permissible limits. This chapter reviews the current and emerging technologies for treatment of cyanide from wastewaters generated in gold mining processes.",signatures:"Benias C. Nyamunda",downloadPdfUrl:"/chapter/pdf-download/52622",previewPdfUrl:"/chapter/pdf-preview/52622",authors:[{id:"186506",title:"Dr.",name:"Benias",surname:"Nyamunda",slug:"benias-nyamunda",fullName:"Benias Nyamunda"}],corrections:null},{id:"52632",title:"A Comparative Study of Modified and Unmodified Algae (Pediastrum boryanum) for Removal of Lead, Cadmium and Copper in Contaminated Water",doi:"10.5772/65745",slug:"a-comparative-study-of-modified-and-unmodified-algae-pediastrum-boryanum-for-removal-of-lead-cadmium",totalDownloads:1856,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The presence of heavy metals in water is of concern due to the risk toxicity. Thus there is need for their removal for the safety of consumers. Methods applied for removal of heavy metals include adsorption, membrane filtration and co-precipitation. However, studies have revealed adsorption is highly effective technique. Most adsorbents are expensive or require extensive processing before use and hence need to explore for possible sources of inexpensive adsorbents. This research work investigated the use an algal biomass (pediastrum boryanum) as an adsorbent for removal of Lead, Cadmium and Copper in waste water in its raw and modified forms. The samples were characterized with FTIR and was confirmed a successful modification with tetramethylethlynediamine (TMEDA). Sorption parameters were optimized and the material was finally applied on real water samples. It was found that the sorption was best at lower pH values (4.2-6.8). Sorption kinetics was very high as more that 90% of the metals were removed from the solution within 30 minutes. The adsorption of copper fitted into the Langmuir adsorption isotherm indicating a monolayer binding mechanism. Cadmium and lead fitted best the Freundlich adsorption mechanism. Sorption of lead and cadmium was of pseudo-second order kinetics, confirming a multisite interaction whereas copper was pseudo-first order indicating a single site adsorption. The adsorption capacity did not improve upon modification but the stability of the material was improved and secondary pollution of leaching colour was alleviated. This implies that the modified material is suitable for application on the removal of metals from water.",signatures:"John Okapes Joseph, Isaac W. Mwangi, Sauda Swaleh, Ruth N.\nWanjau, Manohar Ram and Jane Catherine Ngila",downloadPdfUrl:"/chapter/pdf-download/52632",previewPdfUrl:"/chapter/pdf-preview/52632",authors:[{id:"187156",title:"Dr.",name:"Isaac",surname:"Mwangi",slug:"isaac-mwangi",fullName:"Isaac Mwangi"}],corrections:null},{id:"52601",title:"Aspects on the Accumulation of Trace Metals in Various Environmental Matrices (Water, Soil, Plant and Sediments): Case Study on Catchment Area of the Somes River, Romania",doi:"10.5772/65700",slug:"aspects-on-the-accumulation-of-trace-metals-in-various-environmental-matrices-water-soil-plant-and-s",totalDownloads:1506,totalCrossrefCites:3,totalDimensionsCites:6,hasAltmetrics:0,abstract:"A study was carried out to determine the accumulation of trace metals in water, sediments, and soil from several locations in the Transylvania region (Romania), using the inductively coupled plasma mass spectrometry (ICP‐MS) technique. A significant number of metals (range of several μg L−1) were identified, the toxic metal concentrations in mostly of the investigated waters being within the permissible limits. A seasonal variation in the metal content was also observed. Comparison of the metal concentrations to samples of sediment, soil, and vegetation coming from the surrounding areas of the same water reservoir revealed a higher accumulation of rare and toxic metals in sediments than in soil and vegetation.",signatures:"Cezara Voica, Andreea Maria Iordache, Roxana Elena Ionete and\nIoan Ștefănescu",downloadPdfUrl:"/chapter/pdf-download/52601",previewPdfUrl:"/chapter/pdf-preview/52601",authors:[{id:"186087",title:"Ph.D.",name:"Cezara",surname:"Voica",slug:"cezara-voica",fullName:"Cezara Voica"},{id:"187102",title:"Dr.",name:"Roxana",surname:"Ionete",slug:"roxana-ionete",fullName:"Roxana Ionete"},{id:"194297",title:"Dr.",name:"Andreea Maria",surname:"Iordache",slug:"andreea-maria-iordache",fullName:"Andreea Maria Iordache"},{id:"194298",title:"Prof.",name:"Ioan",surname:"Ștefanescu",slug:"ioan-stefanescu",fullName:"Ioan Ștefanescu"}],corrections:null},{id:"52259",title:"Formulating Specific Water Quality Criteria for Lakes: A Malaysian Perspective",doi:"10.5772/65083",slug:"formulating-specific-water-quality-criteria-for-lakes-a-malaysian-perspective",totalDownloads:1753,totalCrossrefCites:0,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Monitoring water quality of inland water bodies such as lakes, reservoirs and ponds throughout Malaysia is important to ensure that these water bodies can be managed sustainably for their ecosystem functioning and services. Determining the quality of these water bodies for different uses is limited due to the unavailability of specific criteria or standards for such water bodies in the country. The aim of this study is to develop national water quality criteria and guidance values for lakes to enhance the water quality of the water bodies in Malaysia. The work is based on a literature review and a consensus among experts from the various stakeholders’ consultative sessions. The criteria were divided into four specific uses which aim at protecting the health of human and aquatic life. The criteria and standards are targeted for non‐regulatory purposes to promote lake quality monitoring by various stakeholders. More than 20 parameters were identified in the lake criteria to determine the classification. The identification of parameters and limits for the standards, however, was limited by data availability and appropriate understanding of the water body characteristics. The role of the criteria and their limitation was also discussed.",signatures:"Zati Sharip and Saim Suratman",downloadPdfUrl:"/chapter/pdf-download/52259",previewPdfUrl:"/chapter/pdf-preview/52259",authors:[{id:"186369",title:"Dr.",name:"Zati",surname:"Sharip",slug:"zati-sharip",fullName:"Zati Sharip"},{id:"193709",title:"Dr.",name:"Saim",surname:"Suratman",slug:"saim-suratman",fullName:"Saim Suratman"}],corrections:null},{id:"52710",title:"Integrated Approaches in Water Quality Monitoring for River Health Assessment: Scenario of Malaysian River",doi:"10.5772/65703",slug:"integrated-approaches-in-water-quality-monitoring-for-river-health-assessment-scenario-of-malaysian-",totalDownloads:2172,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Current practice of determining river water quality in Malaysia is based mainly on physicochemical components. Perhaps, owing to the lack of information on habitat requirements and ecological diversity of aquatic macroinvertebrates and on unearthly taxonomic key of benthic macroinvertebrates in this region makes it less popular than conventional methods. The study took place in three rivers in the state of Johor, Southern Peninsula of Malaysia, which exhibited different degrees of disturbances and physical properties, namely Sungai Ayer Hitam Besar, Sg Berasau, and Sg Mengkibol. Benthic macroinvertebrates were sampled using rectangular dipnet with frame dimension 0.5 m × 0.3 m. Although physicochemical elements such as water temperature, pH, and dissolved oxygen (DO) were measured using a YSI Professional Plus handheld multiparameter instrument, other parameters such as biochemical oxygen demand (BOD5), chemical oxygen demand (COD), total suspended solid (TSS), and ammoniacal nitrogen (NH3N) were tested using the procedure of APHA Standard Method. The study found that the status of water quality varies among the three rivers. A multivariate analysis, the canonical correspondence analysis (CCA), was applied to elucidate the relationships between biological assemblages of species and their environment using PAST (version 2) software. The present findings reveal that human-induced activities are the ultimate causes of the alteration in macroinvertebrate biodiversity.",signatures:"Salmiati, Nor Zaiha Arman and Mohd Razman Salim",downloadPdfUrl:"/chapter/pdf-download/52710",previewPdfUrl:"/chapter/pdf-preview/52710",authors:[{id:"12268",title:"Prof.",name:"Mohd Razman",surname:"Salim",slug:"mohd-razman-salim",fullName:"Mohd Razman Salim"},{id:"186018",title:"Dr.",name:"Salmiati",surname:"Salmiati",slug:"salmiati-salmiati",fullName:"Salmiati Salmiati"},{id:"187052",title:"Dr.",name:"Nor Zaiha",surname:"Arman",slug:"nor-zaiha-arman",fullName:"Nor Zaiha Arman"}],corrections:null},{id:"52992",title:"Assessment of Impacts of Acid Mine Drainage on Surface Water Quality of Tweelopiespruit Micro-Catchment, Limpopo Basin",doi:"10.5772/65810",slug:"assessment-of-impacts-of-acid-mine-drainage-on-surface-water-quality-of-tweelopiespruit-micro-catchm",totalDownloads:2446,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"This research aimed to contribute to current literature for Tweelopiespruit micro-catchment, Limpopo Basin, by trending SO42−, Cl−, Ca2+, Mg2+, Na+, K+, Fe, pH and EC, for points F1S1, F2S2, W1S3, F6S7, F8S9, F10S11 and F11S12, as identified by the Department of Water and Sanitation, South Africa, for years 2003 to 2008. Results showed that pollutant concentrations generally increased downstream, which questioned their possible sources since pollution generally attenuates towards downstream. A possible explanation was that groundwater (polluted with the effluent) could be decanting from various places, thus contributing to the increase in concentrations, in places. This could potentially add value to existing efforts, which aim to halt and reverse impacts of acid mine drainage (AMD) in the micro-catchment and possibly in the Goldfields (a highly negatively impacted environment), which incorporates the Cradle of Humankind. Conclusions reached could provide invaluable options for alternative technological or methodological approaches that could be adopted for the treatment of AMD. This is critical to South Africa?s water quality trending and sustainability of this ecosystem, especially because the Tweelopiespruit micro-catchment supports humans and a variety of wildlife like giraffe, within the preserve of the Krugersdorp Game Reserve (KGR) and also its outer boundaries.",signatures:"Bloodless Dzwairo and Munyaradzi Mujuru",downloadPdfUrl:"/chapter/pdf-download/52992",previewPdfUrl:"/chapter/pdf-preview/52992",authors:[{id:"171648",title:"Prof.",name:"Bloodless",surname:"Dzwairo",slug:"bloodless-dzwairo",fullName:"Bloodless Dzwairo"},{id:"194127",title:"Dr.",name:"Munyaradzi",surname:"Mujuru",slug:"munyaradzi-mujuru",fullName:"Munyaradzi Mujuru"}],corrections:null},{id:"53816",title:"The Behaviour of Natural and Artificial Radionuclides in a River System: The Yenisei River, Russia as a Case Study",doi:"10.5772/65743",slug:"the-behaviour-of-natural-and-artificial-radionuclides-in-a-river-system-the-yenisei-river-russia-as-",totalDownloads:1741,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The Yenisei River is one of the largest rivers in the world. There is Mining and Chemical Combine (MCC) of Rosatom located at Krasnoyarsk, on the bank of the River Yenisei, 50 km downstream of the city of Krasnoyarsk. Since 1958 MCC used river’s water for cooling of industrial nuclear reactors for the production of weapon plutonium—238Pu. Besides the pollution caused by industry-related radionuclides, pollution by natural radionuclide—uranium and its isotopes— are also investigated. Besides the natural uranium isotopes (234U, 235U, 238U), exclusive artificial isotope—236U was also found. Yenisei water was also polluted by high tritium content: from 4 Bq/L (back road value) to 200 Bq/L (some sample of water). The total amount of radionuclides investigated was about 20 radioisotopes. These radionuclides have different physical and chemical properties, different half-lives, and so on. Thus, the data on artificial radionuclides entering the Yenisei River water were obtained by long-term monitoring, which is likely to be connected with the activity of the industrial enterprises located on the river’s banks of the studied area.",signatures:"Lydia Bondareva, Valerii Rakitskii and Ivan Tananaev",downloadPdfUrl:"/chapter/pdf-download/53816",previewPdfUrl:"/chapter/pdf-preview/53816",authors:[{id:"186817",title:"Dr.",name:"Lydia",surname:"Bondareva",slug:"lydia-bondareva",fullName:"Lydia Bondareva"},{id:"193899",title:"Prof.",name:"Valerii",surname:"Rakitskii",slug:"valerii-rakitskii",fullName:"Valerii Rakitskii"},{id:"193900",title:"Prof.",name:"Ivan",surname:"Tananaev",slug:"ivan-tananaev",fullName:"Ivan Tananaev"}],corrections:null},{id:"52943",title:"Processes and the Resulting Water Quality in the Medium-Size Turawa Storage Reservoir after 60-Year Usage",doi:"10.5772/66226",slug:"processes-and-the-resulting-water-quality-in-the-medium-size-turawa-storage-reservoir-after-60-year-",totalDownloads:1635,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:0,abstract:"The characteristics of water in the Turawa reservoir, one of the important storage reservoirs in Poland, were thoroughly studied. The reservoir and also the rivers flowing into the reservoir were monitored in the period 2004–2006 with respect to the basic physico-chemical parameters determining the quality of water such as water temperature, specific conductance, pH, biochemical oxygen demand (BOD5) and chemical oxygen demand (CODMn), water hardness, content of typical ions (sodium, potassium, sulphates, phosphates and chlorides), heavy metals, and so on. The observed seasonal and long-term changes of the parameters measured were discussed and the processes responsible for the changes suggested. The causes of the observed deterioration of the ecological status of the Turawa reservoir were given and the remedial operations proposed. The latter included improvement in the management of solid wastes and wastewater in the area, reducing the runoff of nutrients in the catchment, decrease in discharge of pollutants into the rivers flowing into the reservoir, removal of bottom sediments and also increasing the average water table and decreasing its fluctuations. The effect of the remedial operations will be further studied.",signatures:"Marek Ruman, Żaneta Polkowska and Bogdan Zygmunt",downloadPdfUrl:"/chapter/pdf-download/52943",previewPdfUrl:"/chapter/pdf-preview/52943",authors:[{id:"187026",title:"Dr.",name:"Marek",surname:"Ruman",slug:"marek-ruman",fullName:"Marek Ruman"},{id:"194472",title:"Prof.",name:"Bogdan",surname:"Zygmunt",slug:"bogdan-zygmunt",fullName:"Bogdan Zygmunt"},{id:"194473",title:"Prof.",name:"Żaneta",surname:"Polkowska",slug:"zaneta-polkowska",fullName:"Żaneta Polkowska"}],corrections:null},{id:"53194",title:"Impact of Wastewater on Surface Water Quality in Developing Countries: A Case Study of South Africa",doi:"10.5772/66561",slug:"impact-of-wastewater-on-surface-water-quality-in-developing-countries-a-case-study-of-south-africa",totalDownloads:7655,totalCrossrefCites:64,totalDimensionsCites:123,hasAltmetrics:1,abstract:"Wastewater effluents are major contributors to a variety of water pollution problems. Most cities of developing countries generate on the average 30–70 mm3 of wastewater per person per year. Owing to lack of or improper wastewater treatment facilities, wastewater and its effluents are often discharged into surface water sources, which are receptacles for domestic and industrial wastes, resulting to pollution. The poor quality of wastewater effluents is responsible for the degradation of the receiving surface water body. Wastewater effluent should be treated efficiently to avert adverse health risk of the user of surface water resources and the aquatic ecosystem. The release of raw and improperly treated wastewater onto water courses has both short‐ and long‐term effects on the environment and human health. Hence, there should be proper enforcement of water and environmental laws to protect the health of inhabitants of both rural and urban communities. This study reports major factors responsible for the failing state of wastewater treatment facilities in developing countries, which includes poor operational state of wastewater infrastructure, design weaknesses, lack of expertise, corruption, insufficient funds allocated for wastewater treatment, overloaded capacities of existing facilities, and inefficient monitoring for compliance, among others.",signatures:"Joshua N. Edokpayi, John O. Odiyo and Olatunde S. Durowoju",downloadPdfUrl:"/chapter/pdf-download/53194",previewPdfUrl:"/chapter/pdf-preview/53194",authors:[{id:"187867",title:"Dr.",name:"Joshua",surname:"Edokpayi",slug:"joshua-edokpayi",fullName:"Joshua Edokpayi"},{id:"189690",title:"Prof.",name:"John",surname:"Odiyo",slug:"john-odiyo",fullName:"John Odiyo"},{id:"194678",title:"Dr.",name:"Olatunde",surname:"Durowoju",slug:"olatunde-durowoju",fullName:"Olatunde Durowoju"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"911",title:"Water Stress",subtitle:null,isOpenForSubmission:!1,hash:"639300ffd325d217a7b6ec2261ff26e0",slug:"water-stress",bookSignature:"Ismail Md. Mofizur Rahman and Hiroshi Hasegawa",coverURL:"https://cdn.intechopen.com/books/images_new/911.jpg",editedByType:"Edited by",editors:[{id:"110740",title:"Dr.",name:"Ismail M.M.",surname:"Rahman",slug:"ismail-m.m.-rahman",fullName:"Ismail M.M. 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Mofizur Rahman, Zinnat Ara Begum and Hiroshi Hasegawa",coverURL:"https://cdn.intechopen.com/books/images_new/5284.jpg",editedByType:"Edited by",editors:[{id:"110740",title:"Dr.",name:"Ismail M.M.",surname:"Rahman",slug:"ismail-m.m.-rahman",fullName:"Ismail M.M. 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Challenges and Opportunities in Cognitive Semiotics and Aesthetics",slug:"mind-and-matter-challenges-and-opportunities-in-cognitive-semiotics-and-aesthetics",publishedDate:"April 6th 2022",bookSignature:"Asun López-Varela Azcárate",coverURL:"https://cdn.intechopen.com/books/images_new/10978.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"302731",title:null,name:"Asun",middleName:null,surname:"López-Varela Azcárate",slug:"asun-lopez-varela-azcarate",fullName:"Asun López-Varela Azcárate"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"420861",title:"Dr.",name:"Filippo",middleName:null,surname:"Silvestri",fullName:"Filippo Silvestri",slug:"filippo-silvestri",email:"filippo.silvestri@uniba.it",position:null,institution:null}]}},chapter:{id:"78886",slug:"between-madness-and-literature-by-michel-foucault-from-a-philosophical-point-of-view-of-language",signatures:"Filippo Silvestri",dateSubmitted:"June 21st 2021",dateReviewed:"September 8th 2021",datePrePublished:"October 8th 2021",datePublished:"April 6th 2022",book:{id:"10978",title:"Mind and Matter",subtitle:"Challenges and Opportunities in Cognitive Semiotics and Aesthetics",fullTitle:"Mind and Matter - 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1. Introduction
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All the cell functions accomplished by the living cell are dependent on a sophisticated network of protein filaments with different compositions, distributions and roles into the cell, forming an integrated meshwork known as the cytoskeleton. However, the most striking feature of the cytoskeleton concerns its ability to respond to signals and conditions to which cells are submitted, taking part of adaptive cell response to different stimuli. The cytoskeleton is an end point of signaling pathways adapting cells to immediate or long‐lasting behaviors in healthy and sick organisms.
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Cytoskeleton of most animal cells is constituted by three interconnected filament subsystems: microfilaments (MFs), microtubules (MTs) and intermediate filaments (IFs). Compelling evidence from the last decades has brought convincing understanding for the highly regulated and interconnected interactions between the cytoskeletal elements giving support to sculpting and maintaining cell shape and sustaining all kinds of morphological alterations or internal organization, as well as their implications for the behavior of animal cells. Figure 1 demonstrates the organization of the cytoskeleton in neurons.
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Figure 1.
Distribution of cytoskeletal constituents into neurons. Neuronal cytoskeleton is composed by microfilaments, microtubules, and intermediate filaments. The microtubules are nucleated at the centrosome, then released and delivered to either the dendrites or the axon. Neurofilaments are abundant in axons and the spacing of neurofilaments is sensitive to the level of phosphorylation. The microfilaments are dispersed within the cells and they are most abundant near the plasma membrane.
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A cohort of accessory proteins and signaling machinery regulates the dynamic turnover of the cytoskeleton. Although each type of filament has specific cell distribution, molecular constituents and equilibrium, the coordinated intertwining among the different networks provides the force for a number of coherent processes in response to all kinds of intra‐ and extracellular stimuli leading responses so decisive as cell survival or death [1].
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This chapter initiates with a brief introduction about the structure and function of IFs, emphasizing those from neural cells. However, the main purposes of the chapter are the experimental evidence of our laboratory that the roles of IFs are beyond protection from mechanical and nonmechanical stress. They might be the end point of misregulated‐signaling mechanisms in neurotoxic conditions adapting their dynamics, in concert with the other cytoskeletal fibers, to cell survival or death.
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2. Intermediate filaments
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2.1. Molecular architecture of intermediate filaments
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IFs are flexible, rod‐shaped fibers averaging 10 nm in diameter, a size that is intermediate between MFs and MTs. They are ubiquitous constituents of the structural scaffold of the eukaryotic cells and considered mechanical integrators of cytomatrix [2]. These cytoskeletal filaments are widespread expressed in practically all animal cell types and are the most diverse cytoskeletal protein family, encoded by an estimated 70 IF genes in the humans. IFs have been grouped into six sequence homology classes (SHC) according to the degree of sequence identity: acidic keratins (SHC group I); basic keratins (SHC group II); desmin, vimentin and other mesenchymal IF proteins, such as glial fibrillary acidic protein (GFAP) (SHC group III); neurofilament proteins (SHC group IV); and lamins (SHC group V).
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IF building blocks are fibrous proteins stabilized by multistranded left‐handed coiled coils giving rise to a rope‐like structure. Their structures are constituted by a long central α‐helical region, also designed rod domain, with a distinct number of equally sized coiled coils forming segments flanked by non‐α‐helical N‐terminal (the head domain) and C‐terminal domains (the tail domain). Both head and tail domains are highly varying in size and sequence, thus, the functional and molecular heterogeneity of IF proteins are a consequence of the highly variable non‐α‐helical end domains of subunits.
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The central rod domain of IF subunits is α‐helical rod highly charged, with a role in the first phase of IF assembly. By contrast, the head domain enriched in basic amino acids is essential for the formation of tetramers (the polymerization units) and complete IF assembly.
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The non‐α‐helical tail domain can vary drastically between different IF proteins. This domain is not essential for the assembly of cytoplasmic IFs but plays a significant role in filament width control. The functional role of the tail domain is particularly important in the neurofilaments, the neuronal‐specific IFs, as discussed below.
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Overall, the assembly of subunits giving rise to functional IFs is a complex and multistep process with individual specificities among the different representatives of this molecularly heterogeneous family. Taking into account the in vitro polymerization of vimentin, filament assembly starts with the formation of parallel, in‐register dimers. These dimers spontaneously associate laterally into antiparallel, half‐staggered tetramers. Tetramers aggregate into higher‐order oligomers to form unit length filaments (ULFs) that undergo reorganization and elongation by longitudinal annealing to form immature IFs. The final step is radial compaction of the filaments from approximately16 nm to a diameter of 10–12 nm [3].
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Different from the other IFs, NFs comprise three subunits with different molecular masses and distributions into the filament. They are formed by light, medium and heavy molecular mass NF triplet proteins (NF‐L, NF‐M and NF‐H), respectively. NF‐L can self‐assemble forming the core of the filament. NF‐M and NF‐H are peripherally disposed on the filament, with their long and flexible tails rich in highly charged domains and multiple phosphorylation sites, radially projecting out from the filament backbone when NF‐M and NF‐H co‐assemble with the short‐tail NF protein NF‐L. Interestingly, NF‐H and NF‐M by their own are not able to assemble into filaments, but by contrast, self‐assembled NF‐L yields normal looking 10‐nm filaments. These side arms of NF‐M and NF‐H contain multiple phosphorylation sites regulating the interactions of NFs with each other and with other cytoskeletal structures [4].
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2.2. Roles of intermediate filaments in neural cell function
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Neurons are highly specialized in the transmission and processing of electrical and chemical signals. A functional nervous system is dependent of a proper axonal array, which in turn is critically dependent upon the organization of the axonal cytoskeleton. Five main subunit proteins form the neuronal specific NFs: the group IV NF‐L, NF‐M and NF‐H triplet proteins, α‐internexin and the group III peripherin. Mature filaments are composed of several combinations of these five subunits. In most differentiated neurons, α‐internexin expression precedes that of the NF triplet and declines somewhat postnatally, while the expression of the NF triplet sharply rises. Neurofilaments found in perikarya, dendrites and axons differ considerably in their organization and function. Perikarial NFs form a meshwork around the nucleus. In the axons of mature neurons, a large number of longitudinally oriented and phosphorylated NFs play a fundamental role increasing the diameter of myelinated axons and consequently nerve conductivity. Neurofilaments present in dendrites are less abundant and less phosphorylated than those of axons.
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Neurofilaments are transported from the cell body, where they are synthesized, to be delivered along the axon by a mechanism called axonal transport. The motors implicated in the anterograde transport are kinesins, while the retrograde transport is mediated in association with dynein, the same motor proteins involved in the fast axonal transport along MTs [4].
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The multiple roles of cytoskeletal proteins in the neural cells imply that there is an underlying cytoskeletal pathology associated with several neurodegenerative processes. The major neurodegenerative diseases are characterized by the presence of inclusion bodies in implicated neurons. These inclusion bodies all contain elements of the cytoskeleton. In addition, mutations and/or accumulations of NFs are frequently observed in several human neurodegenerative disorders including amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease, Charcot‐Marie‐Tooth, giant axonal neuropathy, neuronal intermediate‐filament inclusion disease and diabetic neuropathy [5]. Multiple factors can potentially induce the accumulation of NF, including deregulation of NF gene expression, NF mutations, defective axonal transport, abnormal posttranslational modifications and proteolysis [4]. Beyond their association with neural damage in inherited or age‐dependent neurodegenerative diseases, studies from our laboratory indicated that the disruption of NF homeostasis is a response to toxic agents and abnormally accumulated metabolites in rat brain.
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Astrocytes are important cytoarchitectural elements of the CNS; however, during the past few years, molecular and functional characterization of astroglial cells indicates that they have a much broader function than only support the neurons in the brain. Compelling evidence supports that astrocytes have specialized functions in inducing and regulating the blood‐brain barrier (BBB), glutamate uptake, synaptic transmission, plasticity and metabolic homeostasis of the brain [6]. Astrocytes express 10 different isoforms of glial fibrillary acidic protein (GFAP), the specific astrocytic IF, together with vimentin, nestin and synemin. However, GFAP is the main IF protein expressed in mature astrocytes, where it helps maintaining mechanical strength, as well as cell shape. However, recent evidence has shown that GFAP plays a role in a variety of additional astrocyte functions, such as cell motility/migration, cell proliferation, glutamate homeostasis, neurite outgrowth and injury/protection [7].
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Astrocytes are also involved in a wide range of CNS pathologies, including trauma, ischemia and neurodegeneration. In such situations, the cells change both their morphology and their expression of many genes leading to activation of astroglia, or astrogliosis. It is accepted that the increase of IFs with accompanying cellular hypertrophy and an abnormal apparent increase in the number of astrocytes characterize astrogliosis. However, upregulation of IF proteins, in particular GFAP, but also vimentin and nestin, two IF proteins abundantly expressed in immature astrocytes, is regarded as the hallmark of astrogliosis [7]. In this regard, the most remarkable evidence of the relevance of GFAP in the physiological roles of astrocytes in maintaining normal brain function is Alexander disease, a fatal disorder in which GFAP mutations might compromise the astrocyte stress response [8].
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3. Protein phosphorylation in signaling transduction
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Phosphorylation is the most widespread type of posttranslational modification of the intracellular signaling proteins. Phosphorylation of proteins occurs within seconds or minutes of a regulatory signal, typically an extracellular signal.
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Phosphorylation is an enzymatic process in which the introduction of a phosphoryl group to specific amino acid residues of a protein is catalyzed by protein kinases and the removal of phosphoryl groups is catalyzed by protein phosphatases. For phosphorylation to be useful in the regulation of a protein activity, it is important to be a reversible process, in which the phosphorylated form of the protein could restore its original dephosphorylated form when signal ends, functioning therefore as a molecular switch. The addition of a phosphoryl group to the side chain of a Ser, Thr, or Tyr residue introduces a bulky, charged group into a polar region. The oxygen atoms of a phosphoryl group can hydrogen bond with one or several groups in a protein, commonly the amide groups of the peptide backbone at the α‐helix start or the charged guanidinium group of an Arg residue influencing the functionality of the protein [9].
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3.1. Phosphorylation of intermediate‐filament proteins
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Phosphorylation, glycosylation and transglutamination take part in the multiple mechanisms of IF regulation. However, phosphorylation/dephosphorylation is a major regulatory mechanism orchestrating IF dynamics. Phosphorylation sites of IF subunits are located on their head and tail domains and phosphorylation plays a major role in regulating the structural organization and function of these cytoskeletal proteins in a cell‐ and tissue‐specific manner [10].
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Amino‐terminal phosphorylation regulates the assembly/disassembly equilibrium of type III and IV IFs. Second messenger‐dependent protein kinases add phosphate groups on the amino‐terminal head domain on GFAP, vimentin and NF‐L. Specific phosphorylating sites for cAMP‐dependent protein kinase (PKA), Ca2+/calmodulin‐dependent protein kinase II (PKCaMII) and protein kinase C (PKC) are associated with IF disassembly; however, the action of the protein phosphatases 1, 2A and 2B (PP1, PP2A and PP2B), respectively, removes phosphate and restores the IF ability to polymerize [11].
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Otherwise, the main phosphorylation sites on NF‐M and NF‐H are located in Lys‐Ser‐Pro (KSP) repeat regions of the tail domain of these subunits. The KSP repeats are phosphorylated by proline‐directed kinases such as Cdk5, the mitogen‐activated protein kinases (MAPK) such as Erk1/2, JNK, p38MAPK as well as glycogen synthase kinase 3 (GSK3). Phosphorylation of these KSP sites regulates the interactions of NFs with each other and with other cytoskeletal structures, since the tail domain of NF‐M and NF‐H protrudes laterally from the filament backbone to form “side‐arms” when phosphorylated. These lateral interactions are central in the formation of a cytoskeletal lattice that supports the mature axon. Moreover, carboxyl‐terminal phosphorylation of NF‐M and NF‐H subunits has long been considered to regulate their axonal transport rate and in doing so to provide stability to mature axons [12]. The axonal transport of NFs results from binding to the fast motor proteins kinesin and dynein intermitted with prolonged pauses. It is known that carboxyl‐terminal phosphorylation of NF‐H progressively restricts the association of NFs with kinesin and stimulates its interaction with dynein. This event could represent one of the mechanisms by which aberrant carboxyl‐terminal phosphorylation would slow NF axonal transport. Both the maintenance of axonal caliber and axonal transport are dependent on the adequately phosphorylated NF subunits. Consequently, abnormally hyperphosphorylated NF subunits, commonly found in several neurodegenerative diseases, are intimately associated with neural dysfunction and considered a hallmark of neurodegeneration. In addition, demyelinating diseases might be associated with hypophosphorylated NFs, compromised axonal transport and decreased axonal diameter, since the phosphorylation of NFs occurs in close proximity to myelin sheaths, which release signals needed to induce phosphorylation of NFs in mature axons [13].
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In the next sections, we discuss the recent findings from our laboratory indicating that signaling mechanisms involved in the regulation of IF phosphorylation/dephosphorylation are important targets of neurotoxins, metabolites accumulating in neurodegenerative diseases as well as thyroid hormones, emphasizing the relevance of cytoskeletal homeostasis on the brain function/dysfunction. To assess the effects of the neurotoxicants on the phosphorylation level of IF proteins, we developed an approach to measure the in vitro incorporation of radioactive phosphate (32P‐orthophosphate) into these proteins [14]. In order to shed light onto the signaling cascades targeted by them, we used pharmacological and immunological approaches, specific enzyme inhibitors, channel blockers, or glutamate antagonists as well as monoclonal antibodies directed to signaling cascades or specific phosphorylation sites. We conclude that misregulated cell signal transduction interferes with the phosphorylation/dephosphorylation of IFs disrupting the homeostasis of the cytoskeleton of astrocytes and neurons and this is associated with cell dysfunction and neurodegeneration in experimental models of neurotoxicity. Figure 2 corresponds to a schematic representation of the consequences of misregulated NF phosphorylation for neuronal function.
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Figure 2.
Schematic representation of disrupted neurofilament phosphorylation. The hyperphosphorylation of neurofil-aments can change the cytoskeleton architecture and lead to neurofilament aggregation in perikarya and in axon accounting for cell damage.
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3.2. Central roles of Ca2+ and glutamate receptors on the regulation of cytoskeletal dynamics in neural cells
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Changes in the cytoplasmic free Ca2+ concentration constitute one of the main pathways by which information is transferred from extracellular signals received by animal cells to intracellular sites. However, an augmented Ca2+ influx through the NMDA receptor or voltage‐dependent calcium channels (VDCCs) can be responsible for the activation of lethal metabolic pathways in neural cells. Overactivation of glutamate receptors produces neuronal membrane depolarization. This causes the influx of Ca2+ into the cytoplasm and subsequently triggers cascade events leading to excitotoxic neuronal death. Excitotoxicity is recognized as a major pathological process of neuronal death in neurodegenerative diseases involving the CNS. In this regard, compelling findings point to the cytoskeleton as an end point of excitotoxic mechanisms.
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Different toxins and stress conditions are implicated in the misregulation of intracellular Ca2+‐dependent processes in cells and different cell types exhibit a diverse range of transient responses to their stimuli. Exposure of tissue slices to neurotoxicants or metabolites in toxic concentrations triggers the activation of ionotropic and metabotropic glutamate receptors as well as L‐VDCC and the endoplasmic reticulum (ER) Ca2+ channels. These receptors and channels activate several intracellular‐signaling complexes altering cell behavior in a spatiotemporally regulated manner. Metabolism of cyclic nucleotides, membrane phospholipids as well as endogenous enzymatic regulators are the key biochemical steps coordinating cell response to an extracellular stimulus [15].
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Calcium is a critical regulator of cytoskeletal dynamics. Dysregulation of Ca2+ homeostasis is an important event in driving the disruption of assembly/disassembly equilibrium as well as the interaction of cytoskeletal proteins with regulatory proteins or cell organelles. In particular, IF proteins are directly regulated by Ca2+ levels, which crosslink signaling cascades and connect physiological or pathological extracellular signals with the IF cytoskeleton influencing multiple aspects of cell behavior. Consequently, abnormally elicited Ca2+ signals provoking misregulation of key phosphorylation cascades are able to disrupt cytoskeletal homeostasis and this is commonly associated with the cell damage.
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4. Toxicity of diphenyl ditelluride on the cytoskeleton of neural cells
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Many processes in the organic synthesis, vulcanization of rubber and in metal‐oxidizing solutions to tarnish metals, such as silver, extensively use tellurium. Diphenyl ditelluride (PhTe)2 is the simplest of the aromatic, diorganoyl ditelluride compounds used in organic synthesis. Indeed, developmental exposure to (PhTe)2 is teratogenic and is associated with long‐term behavioral and neurochemical changes in rats. Until recently, the general toxicity of (PhTe)2 was considered to be exclusively related to the oxidation of thiol‐containing proteins (for review, see [16]). However, compelling evidence from our laboratory points to an important role played by signaling mechanisms involved in regulating IF phosphorylation/dephosphorylation as target of (PhTe)2 neurotoxicity. In addition, we evidence a remarkable role of Ca2+ mediating these actions secondary to glutamate receptors and L‐VDCC activation.
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The neurotoxicity of (PhTe)2 is spatiotemporally regulated, consistent with the window of susceptibility of signaling cascades as well as the structural and functional heterogeneity of neurons in different brain regions. In this regard, exposure of cortical slices from 18‐ and 21‐day‐old rats to (PhTe)2 shows unaltered phosphorylation of IF proteins, while IFs of acute cortical slices from younger pups (9 and 15 days old) are hypophosphorylated. Activated ionotropic glutamate receptors, L‐VDCC and ryanodine channels result in PP1‐mediated hypophosphorylation of GFAP and NF subunits pointing to the cortical cytoskeleton as a preferential target of the action of phosphatases in this window of vulnerability. Activation of PP1 is modulated by dopamine and cyclic AMP‐regulated neuronal phosphoprotein 32 (DARPP‐32), an important endogenous Ca2+‐mediated inhibitor of PP1 activity. Depending on the site of phosphorylation, DARPP‐32 is able to produce opposing biochemical effects, that is, inhibition of PP1 activity or inhibition of protein kinase A (PKA) activity [17]. Decreased cAMP and PKA catalytic subunits support that (PhTe)2 disrupts the cytoskeletal‐associated phosphorylating/dephosphorylating system of neurons and astrocytes through PKA‐mediated inactivation of DARPP‐32, promoting PP1 release and hypophosphorylation of IF proteins of those neural cells [18]. Regarding neurons, hypophosphorylation of IF proteins could be associated with cell dysfunction since decreased phosphorylation of KSP repeats in the carboxyl‐terminal domains of NF‐M and NF‐H correlates with impaired axonal transport and increased NF‐packing density.
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In contrast with younger rats, hippocampal slices of 21‐day‐old rats acutely exposed to (PhTe)2 result in hyperphosphorylated IFs. Hippocampal IF hyperphosphorylation is partially dependent on L‐VDCC, NMDA and ER Ca2+ channels. The signal evoked by (PhTe)2 is also transduced through metabotropic glutamate receptors on the plasma membrane, leading to the activation of phospholipase C (PLC) that produces the intracellular messengers inositol 1,4,5‐trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds to specific receptors on the ER changing the conformation of IP3 receptors and opening the channel. Released Ca2+ and DAG directly activate PKCaMII and PCK, resulting in the hyperphosphorylation of some of the critical amino acid residues in the carboxyl‐terminal tail domain of NF‐L known to interfere with filament assembly. In addition, the activation of Erk1/2 and p38MAPK results in hyperphosphorylation of KSP repeats of NFM. Interestingly, PKCaMII and PKC are upstream of MAPK activation implying in a significant cross‐talk among signaling pathways elicited by (PhTe)2 that connect the glutamate metabotropic cascade with the activation of Ca2+ channels. The final molecular result is the extensive phosphorylation of amino‐ and carboxyl‐terminal sites on IF proteins and deregulated cytoskeletal homeostasis [19].
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4.1. Diphenyl ditelluride disrupts the cytoskeleton and provokes neurodegeneration in acutely injected young rats
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The in vivo exposure to (PhTe)2, in which the neurotoxicant reaches the brain via systemic circulation, also results in different susceptibilities of the IF proteins from neural cells. This can be evidenced in cerebral cortex and hippocampus of 15‐day‐old rats acutely injected with a toxic dose of (PhTe)2 (0.3 µmol/kg body weight) [20]. Cortical hyperphosphorylation of neuronal and glial IF proteins is an early and persistent event up to 6 days after injection, accompanied by increased levels of GFAP and NF‐L. Upregulated gene expression as well as GFAP and vimentin hyperphosphorylation could be a response to injury and take part in the program of reactive astrogliosis, as further demonstrated in striatum [21] and cerebellum [22] of (PhTe)2‐injected rats. In addition, hippocampal IFs are not responsive to the insult until weaning. A strong evidence supports an important role of astrocytes in a more severe cortical than hippocampal damage following the in vivo (PhTe)2 insult. This supports a direct action of the neurotoxicant on intracellular signaling pathways and highlights the relevance of the interplay between glial and neuronal cells to adapt the cellular metabolic response to the insult even when the brain connections are only partially preserved, as shown in acute brain slices.
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Of importance, neurodegeneration is part of the deleterious in vivo effects of (PhTe)2 toxicity, as demonstrated in the striatum [23] and cerebellum [22] of (PhTe)2‐injected rats. Neurodegeneration is associated with alterations in Ca2+ homeostasis and glutamatergic neurotransmission, upstream of inhibited Akt and activated caspase 3. We therefore propose that excitotoxicity is a main mechanism of neurodegeneration caused by this compound in the developing rat brain. On the other hand, most of the actions of (PhTe)2 disrupting the homeostasis of the cytoskeleton in neural cells are mediated by high Ca2+ levels. Moreover, a link among disrupted IF homeostasis, activated astrocytes and neuronal apoptosis in (PhTe)2‐injected rats has been demonstrated by immunohistochemical approaches. In addition, MAPK pathway might be a link between altered IF equilibrium and neural cell damage, since MAPK is implicated in IF hyperphosphorylation and neurodegeneration as well in the brain structures attained by (PhTe)2 toxicity. Further supporting the cytoskeleton as an end point of neurotoxicity, hyperphosphorylated NFs can inhibit their proteolytic breakdown by calpain, a Ca2+‐activated protease. In addition, abnormally phosphorylated NFs accumulate in the perikarya and the phospho‐NF aggregates can thus become cytotoxic by the enduring impairment of axonal transport of NFs (see Figure 2). The increased time the NF spent in the cell body is thought to result in further aberrant phosphorylation and may prevent them from entering the axon, resulting in a deleterious feedback loop [24].
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In summary, we propose that complex and integrated actions mediate the (PhTe)2 toxicity directed to the cytoskeleton of neural cells. These molecular mechanisms induce spatiotemporal responses of the cells because of the different windows of susceptibility of the developmental brain. Nonetheless, the Ca2+ ‐initiated events highlight a role for this neurotoxicant as a disruptor of the cytoskeleton.
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5. Cytoskeleton as a target of amino acids and their metabolites
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Misregulated cytoskeletal homeostasis is among the molecular mechanisms underlying the neural cell dysfunction in brain tissue exposed to high levels of amino acids and/or their metabolites. In humans, several neurological impairments are associated with enzymatic deficiencies or defects in proteins involved in cellular metabolism of neural cells, causing accumulation of metabolic intermediates associated with neuronal damage. We discuss some aspects of the molecular mechanisms underlying the disruption of cytoskeletal homeostasis in response to branched‐chain keto acids (BCKAs) derived from leucine, isoleucine and valine. We also addressed the effects of homocysteine and quinolinic acid (QUIN), a metabolite of tryptophan metabolism, directed to the cytoskeleton.
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5.1. Branched chain α‐keto acids and the cytoskeleton of neural cells
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The branched‐chain ketoacids, α‐ketoisocaproic acid (KIC), α‐keto‐β‐methylvaleric acid (KMV) and α‐keto‐isovaleric acid (KIV) are produced from the respective branched‐chain amino acids (BCAAs) leucine, isoleucine and valine, in the reaction catalyzed by the branched‐chain α‐keto acid dehydrogenase (BCKAD) complex. A deficiency of the BCKAD complex is an inherited metabolic disease known as maple syrup urine disease (MSUD) which lead to the accumulation of BCAAS and BCKAs in tissues and body fluids resulting in dramatic cerebral symptoms [25].
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Curiously, cortical slices of young rats exposed to high levels of the BCAAs individually preserve the homeostasis of the cytoskeleton. On the other hand, their respective keto acids provide an interesting example of the fine‐tune regulation of the cytoskeleton, since KIC [26] and KMV [27] were differently deleterious to the homeostasis of the cytoskeleton. KIC and KMV alter the dynamics of IF proteins of astrocytes and neurons through different transduction mechanisms dependent on excessive intracellular Ca2+ influx, while KIV appears not to be involved in the disruption of the IF cytoskeleton [28].
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The effect of KIC is outlined by hypophosphorylation of GFAP, NF‐M and NF‐L in very young rats (up to 12 days of age) changing to hyperphosphorylation of the same proteins later in development (17 days of age). Nonetheless, both responses of the cytoskeletal‐associated phosphorylating system are regulated by Ca2+ currents through the NMDA and L‐VDCC, as well as by the intracellular Ca2+storage release from the ER, leading to a differential activation of protein phosphatases or kinases [28]. These paradoxical findings provide an interesting insight into the differential susceptibility of cortical IF cytoskeleton to the exposure to pathological levels of this metabolite. The different vulnerabilities of the cytoskeleton of cortical cells during development might be ascribed to the temporal maturation mediated by a multitude of developmental processes and signaling pathways. It is conceivable that they are associated with the pathological role of the developmentally regulated glutamate receptors in neural cells since the expression patterns of glutamate receptor subunit genes change during the ontogeny of the brain. Distinct regional and temporal patterns of the expression of types and subtypes of the glutamate ionotropic receptors during ontogeny may possibly explain the different signaling pathways targeting the cytoskeleton of cortical neural cells during development.
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Interestingly, KMV disturbs the IF‐associated cytoskeletal phosphorylation only in 12‐day‐old rats without changing the phosphorylation level of these proteins in younger or older animals, showing a specific window of vulnerability of cytoskeleton to KMV insult in the cerebral cortex of developing brain. Strikingly, this effect was dependent on intracellular Ca2+ concentrations; however, in this case ɣ‐amino butyric acid A and B (GABAA and GABAB, respectively) rather than glutamate receptors were involved in this action. This is in agreement with GABAA and GABAB receptors mediating the induction and maintenance of Ca2+ levels [27].
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Overall, we propose that BCKAs in supra‐physiological concentrations disrupt the cytoskeleton of rat brain through misregulation of the phosphorylating system associated with the IF cytoskeleton. We evidenced developmentally regulated mechanisms in which Ca2+‐mediated excitotoxicity plays a critical role in destabilizing the cytoskeleton that may ultimately disrupt normal cell function and viability. Although evidence from animal models should be taken with caution, we can propose that the disrupted cytoskeleton is part of the physiopathology of MSUD.
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5.2. Hyperhomocysteinemia and the cytoskeleton of neural cells
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Homocysteine (Hcy) is a sulfur‐containing amino acid generated during methionine metabolism. Genetic mutations impairing Hcy metabolism cause accumulation of this amino acid attaining high levels in blood, leading to severe hyperhomocysteinemia and brain damage. Otherwise, along with genetic factors, mild‐moderate hyperhomocysteinemia is associated with nutritional imbalance and hormonal factors. Mild hyperhomocysteinemia, which markedly enhance the vulnerability of neuronal cells to excitotoxicity and oxidative imbalance, is also common in older people, constituting an independent risk factor for stroke and cognitive impairment [29].
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Various existing experimental evidences from our group link hyperhomocysteinemia and cytoskeletal misregulation, supporting that disrupted cytoskeleton could be an end point of neural dysfunction in this neurometabolic disorder. Experiments with brain slices acutely exposed to mild Hcy levels (100 μM) showed greater vulnerability of hippocampal cytoskeleton as compared with cortical one. Moreover, a window of vulnerability of the cytoskeleton of hippocampal cells is evidenced, since misregulated phosphorylation is detected only at postnatal day 17 [30], reflecting an altered activity of the endogenous phosphorylating system associated with the IFs in this brain structure. As expected, NMDA receptors, L‐VDCC and extracellular Ca2+influx result in PKC and PKCaMII activation. The prevention of Hcy action through the inhibition of PKC and MEK, a step that is upstream of MAPK cascade (Raf‐1/MEK/MAPK), is consistent with an effect at the level of the monomeric GTPase Raf‐1, supporting a role for PKC phosphorylating and activating Raf‐1 in the Hcy‐induced modulation of the cytoskeleton.
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In contrast with hypophosphorylation found in hippocampal slices, the chemically induced chronic hyperhomocysteinemia differently alters the signaling mechanisms directed to the cytoskeleton, producing PP1‐, PP2A‐ and PP2B‐mediated hypophosphorylation of NF subunits and GFAP in hippocampal slices of 17‐day‐old rats without affecting the cerebral cortex [31] through glutamate and Ca2+‐mediated mechanisms. Further evidence that homocysteine targets the cytoskeleton came from cytoskeletal reorganization in primary astrocytes and neurons exposed to homocysteine [32]. Dramatically altered actin cytoskeleton in primary astrocytes exposed to 100 μM Hcy is consistent with the role of actin as a main determinant of cell morphology. Concomitant disrupted GFAP meshwork underlies the remodeled actin cytoskeleton and altered cell morphology. These findings provide further evidence of the cross‐talk among the different cytoskeletal subsystems and the roles played by the toxic levels of Hcy.
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Therefore, taking into account our experimental evidence it is conceivable that disturbed cell signaling is an important determinant of the disrupted homeostasis of the cytoskeleton as a whole, with widespread consequences on cell function that could be associated with human hyperhomocysteinemia.
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6. Cytoskeleton is a target of quinolinic acid neurotoxicity
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Quinolinic acid is a neuroactive metabolite of the kynurenine pathway normally found in nanomolar concentrations in human brain and cerebrospinal fluid (CSF). QUIN is antagonist of NMDA receptor and it has a high in vivo potency as an excitotoxin supporting involvement in the pathogenesis of a variety of human neurological diseases. The neurotoxicity of QUIN results from complex mechanisms including presynaptic receptors, energetic dysfunction, oxidative stress, transcription factors and behavior [33]. We experimentally demonstrate that the disruption of the cytoskeleton, in particular, misregulation of the phosphorylation system associated with the IFs, is a target of QUIN toxicity in injected rat striatum, tissue slices and primary astrocytes and neurons in culture.
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6.1. Effects of intrastriatally injected quinolinic acid on the cytoskeleton of neural cells
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Acute intrastriatal injection of QUIN (150 nmol/0.5 μL) in adolescent rats (30 days old) provokes NF‐L and GFAP hyperphosphorylation 30 min after infusion, evidencing the susceptibility of the cytoskeleton of both neurons and astrocytes in the early events of QUIN toxicity. Hyperphosphorylated NF‐LSer55 destabilizes the NF structure and this might represent an early step in the pathophysiological cascade of deleterious events exerted by QA in rat striatum. Experimental insights to get light on the molecular mechanisms underlying this effect point to NMDA‐mediated Ca2+ events and oxidative stress upstream of activated second messenger‐dependent protein kinases PKA, PKC and PKCaMII, but not MAPKs after QUIN infusion [34].
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A link between misregulation of cell‐signaling mechanisms, disruption of IF phosphorylation and cell damage as part of QUIN toxicity becomes more evident analyzing the long‐lasting effect of the acute intrastriatal injection of QUIN in adolescent rats on the dynamics of the phosphorylating system until 21 days after injection [35]. The acutely injected QUIN alters the homeostasis of IF phosphorylation in a selective manner, progressing from striatum to cerebral cortex and hippocampus. Twenty‐four hours after QUIN injection, the IFs are hyperphosphorylated in the striatum. This effect progresses to cerebral cortex causing hypophosphorylation at day 14 and appears in the hippocampus as hyperphosphorylation at day 21 after QUIN infusion, PKA and PKCaMII mediating this effect. However, MAPKs (Erk1/2, JNK and p38MAPK) are hyperphosphorylated/activated only in the hippocampus, suggesting different signaling mechanisms in these two brain structures during the first weeks after QUIN infusion. Also, PP1 and PP2B‐mediated hypophosphorylation of the IF proteins in the cerebral cortex 14 days after QUIN injection reinforces the selective signaling mechanisms in different brain structures. Increased GFAP immunocontent in the striatum and cerebral cortex 24 h and 14 days after QUIN injection, respectively, suggests reactive astrocytes in these brain regions. Yet, we observe biochemical and histopathological alterations in the striatum, cortex and hippocampus, as well as altered behavioral tests in response to the long‐lasting exposure to QUIN through glutamate and Ca2+‐mediated mechanisms. Thus, it is tempting to propose that the long‐lasting deleterious effect of intrastriatal QUIN injection could be due to the fact that QUIN interferes with the highly regulated signaling mechanisms targeting the cytoskeleton in the immature brain [36].
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6.2. Insight into the molecular basis of quinolinic acid action toward the cytoskeleton
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Studies in acute brain slices further support the role of glutamatergic signaling and Ca2+ overload disturbing the cytoskeletal equilibrium downstream of QUIN exposure. Moreover, this experimental approach brings light on the cell‐specific mechanisms targeting the cytoskeleton in astrocytes and neurons when the cell connections are partially preserved. In astrocytes, the QUIN action is mainly due to increased Ca2+ influx through NMDA and L‐VDCC. In neuronal cells, QUIN acts through the activation of metabotropic glutamate receptors and influx of Ca2+ through NMDA receptors and L‐VDCC, as well as Ca2+ release from intracellular stores. These mechanisms then set off a cascade of events including the activation of PKA, PKCaMII and PKC, which phosphorylate head domain sites on GFAP and NFL. Moreover, Cdk5 is activated downstream of mGluR5, phosphorylating the KSP repeats on NFM and NFH. Metabotropic glutamate receptors type 1 (mGluR1) is upstream of PLC, which, in turn, produce DAG and IP3 promoting hyperphosphorylation of KSP repeats on the tail domain of NFM and NFH [37].
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6.3. The cytoskeleton of astrocytes and neurons responds differently to quinolinic acid toxicity
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The susceptibility of the cytoskeleton to toxic levels of QUIN is also detectable in isolated astrocytes and neurons growth in primary cultures [38]. In astrocytes, Ca2+‐mediated glutamate mechanisms target the endogenous phosphorylating system, since metabotropic glutamate receptors and Ca2+ influx through NMDA receptors are upstream of PKA, PKCaMII and PKC activation, provoking GFAP hyperphosphorylation. Interestingly, the misregulated phosphorylation system leads to a reversible and dramatically altered actin cytoskeleton with concomitant change of morphology to fusiform and/or flattened cells with retracted cytoplasm and disruption of the GFAP meshwork [39] supporting the dynamic behavior of the cytoskeleton.
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Interestingly, neurons show greater vulnerability to QUIN than astrocytes (10×). Neurons exposed to QUIN presented PKA‐ and PKC‐mediated hyperphosphorylation of NF subunits. These effects are also downstream of ionotropic and metabotropic glutamate signaling and Ca2+ influx through NMDA receptors and L‐VDCC. The misregulated signaling pathways disrupt the neuronal cytoskeleton, evaluated by altered neurite/neuron ratios and neurite outgrowth. It is important to consider that microtubules play a central role in cell polarity [40]. In particular, microtubules are the main determinants of neuronal polarity and regulation of microtubule dynamics includes tubulin posttranslational modifications [40] and phosphorylation of microtubule‐associated proteins (MAPs), whose binding to microtubules is essential for neurite formation [41]. As an example, activated GSK‐3β leads to increased phosphorylation of some MAPs, destabilizing microtubules with consequence for neurite stabilization [42]. Therefore, the neurite destabilization could derive from both NFs and microtubules disruption.
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Interestingly, we found a protective role of astrocyte‐conditioned medium on the disrupted neuronal cytoskeleton and morphometric alterations, suggesting that QUIN‐induced trophic factors secreted by astrocytes are able to modulate signaling mechanisms targeting the neuronal cytoskeleton. More interestingly, co‐cultured astrocytes and neurons preserve their cytoskeletal organization and cell morphology together with unaltered activity of the phosphorylating system associated with the cytoskeleton. In other words, co‐cultured astrocytes and neurons tightly and actively interact with one another reciprocally protecting themselves against QUIN injury [38]. This evidence raise the question about the role played by the activated microglia eliciting signals essential to destabilize the astrocytic and neuronal cytoskeleton but this hypothesis remains to be clarified.
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All together, we conclude that among the multiple mechanisms through which accumulated QUIN is able to induce cell damage, our experimental evidence points to Ca2+‐mediated mechanisms directed to the cytoskeletal disruption as an end point of QUIN toxicity. Both in vivo and ex vivo approaches clearly demonstrate a wide spectrum of misregulated signaling mechanisms downstream of QUIN action directly affecting the cytoskeleton and disrupting cell homeostasis. We also provide evidence that impaired physiological equilibrium of the signaling cascades directed to the cytoskeleton underlies QUIN cytotoxicity and is associated with neurodegeneration. The in vitro results showing disorganized cytoskeleton and altered cell morphology further support the cytoskeleton as a hallmark of stress condition that could be implicated in the human brain disorders associated with high QUIN levels.
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7. Cytoskeleton of neural cells is a target of thyroid hormones
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Thyroid hormones are essential for the development and function of central nervous system. In brain, these hormones are essential for myelination [43, 44], neuritogenesis [45], synaptic plasticity [46–48], IF phosphorylation [49–54], cell differentiation and maturation [55]. Considering the role of these hormones on brain development, thyroid diseases might account for brain injury as well as alteration in mood and cognition [56].
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The classical mechanism of thyroid hormone action involves the modulation of nuclear receptors by 3,5,3′‐triiodo‐l‐thyronine (T3). The nuclear receptors are ligand‐dependent transcription factors, which are involved in the genomic‐dependent effects of thyroid hormones. However, there are numerous physiological effects of these hormones that cannot be mediated by the genome‐like mechanism, due the short time frame in which the response occurs. Nongenomic actions of thyroid hormones are defined as events that (i) do not primarily involve the cell nucleus, (ii) are rapid in onset (minutes or a few hours) relative to transcription and translation and (iii) do not require gene transcription and protein synthesis [57]). These events are triggered by rapid/nongenomic responses that are frequently associated with secondary messenger‐signaling pathways.
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7.1. Insight into the molecular basis of genomic and nongenomic action of thyroid hormones toward the cytoskeleton of neural cells
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The first evidence of nongenomic actions of thyroid hormones targeting the cytoskeleton demonstrated the thyroxine‐dependent modulation of actin polymerization in cultured astrocytes. Thyroxine (T4) was involved in the conversion of soluble actin to a fibrous form through nongenomic mechanism [58].
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While many of the T3 actions are mediated by genomic‐dependent mechanisms, T4 and reverse 3,3′,5′‐triiodothyronine (reverse T3, rT3) exert direct, The nongenomic effects in neural cells. Both T4 and rT3 hormones control actin polymerization in cultured astrocytes without affecting gene expression. The authors suggested that these events might contribute to thyroid hormone\'s influence on brain development. Subsequently, the same research group showed that both T4 and rT3, but not T3, directly regulate the F‐actin content of elongating neurites of cerebellar neurons. These results provide a molecular mechanism for the influence of thyroid hormones on brain development that is independent of regulated gene expression [59].
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Trentin and Moura Neto [60] demonstrated that T3 altered the organization of GFAP in cerebellar astrocytes in culture. GFAP filaments that normally spread in the cytoplasm of astrocytes became organized around the cell nucleus. In addition, Zamoner and coworkers [51] showed that both T3 and T4 induced GFAP phosphorylation and reorganization in glioma C6 cells through the inhibition of RhoA GTPase. The modulation of GFAP was accompanied by increased proliferation of glioma cells. Taking together, these results suggest that thyroid hormones may be important regulators of astrocyte growth and differentiation.
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Despite the evidence that nongenomic actions of thyroid hormones initiated at the plasma membrane via integrin αVβ3 [57, 61], the complexity of the processes underlying the differential mechanisms of action to thyroid hormones suggests the existence of multiple binding sites for these hormones. In this context, it has been previously demonstrated that both T3 and T4 may modulate the GABAergic system and induce PKA‐ and PKCaMII‐mediated hyperphosphorylation of vimentin, GFAP, NF‐M and NF‐L in cerebral cortex from very young rats (up to 10 days of age) [50]. However, only T4 caused hyperphosphorylation of the same proteins later in development (15 days of age) through GABA‐independent mechanisms [49]. These paradoxical findings provide an interesting insight into the differential susceptibility of cortical IF cytoskeleton to thyroid hormone exposure.
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Calcium‐dependent mechanisms play a central role on the thyroid hormone‐induced modulation of the phosphorylating system associated with IFs. Zamoner and colleagues [49] demonstrated that the nongenomic mechanisms underlying the effects T4 targeting the IF‐associated phosphorylating system in cerebral cortex from 15‐day‐old rats are dependent on extracellular Ca2+ influx through VDCC, as well as Ca2+ release from ER stores.
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Taking into account that in rat the myelination peak is coincident with postnatal day 15 and that this is a period of intense synaptogenesis, the NF hyperphosphorylation induced by T4 in cerebral cortex from 15‐day‐old rats appears to be correlated to synaptogenesis and myelination (for review, see [53]).
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In summary, we could suggest that nongenomic actions of T4 targeting the cytoskeleton of glial cells and neurons might account for neuronal cell migration, myelination, synaptogenesis and synaptic plasticity. Moreover, the modulation of NF phosphorylation by thyroid hormone may control axonal caliber.
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7.2. Hypothyroidism and the cytoskeleton of neural cell
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The effects of thyroid hormones in central nervous system during development include the modulation of the cytoskeleton dynamics. Hypothyroidism in the developing rat brain is associated with oxidative stress and aberrant intraneuronal accumulation of NFs in the perikaryon of Purkinje neurons (see Figure 2). The authors suggested that the neuron alterations observed in the developing hypothyroid brain are comparable to those seen in neurodegenerative diseases [62]. Corroborating these findings, it has been shown that the effects of hypothyroidism on neuronal cytoskeleton involve the developmental modulation of specific isoforms of protein expression, which induce stoichiometric imbalance between the NF triplet [52]. In addition, thyroid hormone deficiency induces a delay and a partial arrest of astrocyte differentiation, supported by the decreased expression of GFAP both in cortical [52] and in hippocampal astrocytes [54], which was accompanied by downregulation of the astrocyte glutamate transporters. These findings are associated with the extracellular signal‐regulated kinase (ERK)1/2 and c‐jun terminal kinase (JNK) activation. NF hyperphosphorylation might account for the aberrant intraneuronal accumulation of these cytoskeletal structures previously described [62].
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Our research group demonstrated the hyperphosphorylation of tail KSP repeats on NF‐H in hypothyroid cortical and hippocampal neurons [52, 54]. The carboxyl‐terminal phosphorylation of NF‐H progressively restricts association of NFs with kinesin, the axonal anterograde motor protein and stimulates its interaction with dynein, the axonal retrograde motor protein [63]. This event could represent one of the mechanisms by which carboxyl‐terminal phosphorylation would slow NF axonal transport.
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Taking into account our experimental evidence, we propose that the consequences of congenital hypothyroidism to neural cells involve IF hyperphosphorylation, misregulation of glutamate‐glutamine cycle, oxidative stress and glutamate excitotoxicity. These events suggest a compromised astroglial defense system that is probably playing a role in the physiopathology of the neurological dysfunction of hypothyroidism (Figure 3).
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Figure 3.
Role of glutamate excitotoxicity on intermediate‐filament dynamics and cell damage. Congenital hypothyroidism leads to glutamate excitotoxicity, calcium overload, and oxidative stress. These events are related to intermediate‐filament (GFAP and NF) hyperphosphorylation and neural cell damage.
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8. General conclusion
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Studies of our group on the endogenous phosphorylating system associated with the IF proteins of neural cells point to a critical role of disrupted cytoskeleton in response to a variety of signals both in physiological and in pathological conditions. Our findings highlight the IFs as a preferential target of the signal transduction pathways. Importantly, a large body of evidence shows a link among misregulation of cell‐signaling mechanisms, disruption of IF phosphorylation and cell damage in response to different stress signals. While the exact signaling pathways regulating NF phosphorylation remains elusive, there is increasing evidence that known signal transduction cascades are involved. These actions can be initiated by the activation of NMDA‐, L‐VDCC, or G protein‐coupled receptors and the signal is transduced downstream of Ca2+ mobilization or monomeric GTPase activation through different kinase/phosphatase pathways, regulating the dynamics of the cytoskeleton. Figure 4 summarizes the calcium‐associated mechanisms triggered by thyroid hormones, quinolinic acid, (PhTe)2, BCKAs and homocysteine targeting IF phosphorylation in neural cells.
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Figure 4.
Summary of calcium‐associated mechanisms triggered by thyroid hormones, quinolinic acid, diphenyl ditelluride, branched‐chain keto acids, and homocysteine targeting intermediate‐filament phosphorylation in neural cells. Calcium influx through the NMDA receptor or voltage‐dependent calcium channels (VDCC) can be responsible for the activation of lethal metabolic pathways in neural cells. Augmented intracellular Ca2+ levels might be associated with the modulation of diverse cell‐signaling pathways and exhibit a diverse range of responses to their stimuli.
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Despite the focus on the misregulation of IF dynamics in response to signaling mechanisms downstream of metabolites and neurotoxicants, we should consider that cytoskeleton is a complex meshwork of interconnecting filaments [1]. In this regard, the morphological alterations demonstrated in primary cells in culture mainly reflect the reorganization of the meshwork of filaments. Taking into account our findings, we propose that misregulation of kinase/phosphatase cascades downstream of stressors could disrupt the cytoskeleton as a whole and this might be an important determinant of neural dysfunction associated with the action of neurotoxicants and in neurometabolic conditions.
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\n',keywords:"intermediate filament, cytoskeleton, cell signaling, calcium, neurotoxicity",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/53691.pdf",chapterXML:"https://mts.intechopen.com/source/xml/53691.xml",downloadPdfUrl:"/chapter/pdf-download/53691",previewPdfUrl:"/chapter/pdf-preview/53691",totalDownloads:1271,totalViews:480,totalCrossrefCites:0,totalDimensionsCites:2,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:68,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"March 16th 2016",dateReviewed:"November 15th 2016",datePrePublished:null,datePublished:"May 17th 2017",dateFinished:"December 29th 2016",readingETA:"0",abstract:"In this chapter, we deal with the current knowledge and important results on the cytoskeletal proteins and their differential regulation by kinases/phosphatases and Ca2+‐mediated mechanisms in developmental rat brain. We focus on the misregulation of the phosphorylating system associated with intermediate filament proteins of neural cells and its relevance to cell and tissue dysfunction. Taking into account our findings, we propose that intermediate‐filament proteins are dynamic structures whose regulation is crucial for proper neural cell function. Given their relevance, they must be regulated in response to extracellular and intracellular signals. The complexity and connection between signaling pathways regulating intermediate‐filament dynamics remain obscure. In this chapter, we get light into some kinase/phosphatase cascades downstream of membrane receptors disrupting the dynamics of intermediate filaments and its association with neural dysfunction. However, intermediate filaments do not act individually into the neural cells. Our results evidence the importance of misregulated cytoskeletal crosstalk in disrupting cytoskeletal dynamics and cell morphology underlying neural dysfunction in experimental conditions mimicking metabolic diseases and nongenomic actions of thyroid hormones and as an end point in the neurotoxicity of organic tellurium.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/53691",risUrl:"/chapter/ris/53691",book:{id:"5382",slug:"cytoskeleton-structure-dynamics-function-and-disease"},signatures:"Ariane Zamoner and Regina Pessoa-Pureur",authors:[{id:"186612",title:"Dr.",name:"Regina",middleName:null,surname:"Pessoa-Pureur",fullName:"Regina Pessoa-Pureur",slug:"regina-pessoa-pureur",email:"rpureur@ufrgs.br",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Federal University of Rio Grande do Sul",institutionURL:null,country:{name:"Brazil"}}},{id:"187776",title:"Dr.",name:"Ariane",middleName:null,surname:"Zamoner",fullName:"Ariane Zamoner",slug:"ariane-zamoner",email:"arianezps@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Intermediate filaments",level:"1"},{id:"sec_2_2",title:"2.1. Molecular architecture of intermediate filaments",level:"2"},{id:"sec_3_2",title:"2.2. Roles of intermediate filaments in neural cell function",level:"2"},{id:"sec_5",title:"3. Protein phosphorylation in signaling transduction",level:"1"},{id:"sec_5_2",title:"3.1. Phosphorylation of intermediate‐filament proteins",level:"2"},{id:"sec_6_2",title:"3.2. Central roles of Ca2+ and glutamate receptors on the regulation of cytoskeletal dynamics in neural cells",level:"2"},{id:"sec_8",title:"4. Toxicity of diphenyl ditelluride on the cytoskeleton of neural cells",level:"1"},{id:"sec_8_2",title:"4.1. Diphenyl ditelluride disrupts the cytoskeleton and provokes neurodegeneration in acutely injected young rats",level:"2"},{id:"sec_10",title:"5. Cytoskeleton as a target of amino acids and their metabolites",level:"1"},{id:"sec_10_2",title:"5.1. Branched chain α‐keto acids and the cytoskeleton of neural cells",level:"2"},{id:"sec_11_2",title:"5.2. Hyperhomocysteinemia and the cytoskeleton of neural cells",level:"2"},{id:"sec_13",title:"6. Cytoskeleton is a target of quinolinic acid neurotoxicity",level:"1"},{id:"sec_13_2",title:"6.1. Effects of intrastriatally injected quinolinic acid on the cytoskeleton of neural cells",level:"2"},{id:"sec_14_2",title:"6.2. Insight into the molecular basis of quinolinic acid action toward the cytoskeleton",level:"2"},{id:"sec_15_2",title:"6.3. The cytoskeleton of astrocytes and neurons responds differently to quinolinic acid toxicity",level:"2"},{id:"sec_17",title:"7. Cytoskeleton of neural cells is a target of thyroid hormones",level:"1"},{id:"sec_17_2",title:"7.1. Insight into the molecular basis of genomic and nongenomic action of thyroid hormones toward the cytoskeleton of neural cells",level:"2"},{id:"sec_18_2",title:"7.2. 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Thyroid hormone receptor alpha plays an essential role in the normalisation of adult‐onset hypothyroidism‐related hypoexpression of synaptic plasticity target genes in striatum. J Neuroendocrinol. 2009;21(1):49–56.'},{id:"B49",body:'Zamoner A, Heimfarth L, Loureiro SO, Royer C, Mena Barreto Silva FR, Pessoa‐Pureur R. Nongenomic actions of thyroxine modulate intermediate filament phosphorylation in cerebral cortex of rats. Neuroscience. 2008;156(3):640–52.'},{id:"B50",body:'Zamoner A, Funchal C, Heimfarth L, Silva F, Pessoa‐Pureur R. Short‐term effects of thyroid hormones on cytoskeletal proteins are mediated by GABAergic mechanisms in slices of cerebral cortex from young rats. Cell Mol Neurobiol. 2006;26(2):209–24.'},{id:"B51",body:'Zamoner A, Funchal C, Jacques‐Silva MC, Gottfried C, Mena Barreto Silva FR, Pessoa‐Pureur R. Thyroid hormones reorganize the cytoskeleton of glial cells through Gfap phosphorylation and Rhoa‐dependent mechanisms. 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Neuroreport. 1995;6(2):293–6.'},{id:"B61",body:'Bergh JJ, Lin HY, Lansing L, Mohamed SN, Davis FB, Mousa S, et al. Integrin alphaVbeta3 contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen‐activated protein kinase and induction of angiogenesis. Endocrinology. 2005;146(7):2864–71.'},{id:"B62",body:'Rahaman SO, Ghosh S, Mohanakumar KP, Das S, Sarkar PK. Hypothyroidism in the developing rat brain is associated with marked oxidative stress and aberrant intraneuronal accumulation of neurofilaments. Neurosci Res. 2001;40(3):273–9.'},{id:"B63",body:'Motil J, Chan WK, Dubey M, Chaudhury P, Pimenta A, Chylinski TM, et al. Dynein mediates retrograde neurofilament transport within axons and anterograde delivery of NFs from perikarya into axons: regulation by multiple phosphorylation events. Cell Motil Cytoskeleton. 2006;63(5):266–86.'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Ariane Zamoner",address:null,affiliation:'
Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Brazil
Department of Biochemistry, Institute of Basic Sciences of Health, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
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1. Introduction
Pediatric robotic surgery offers unique challenges within this rapidly advancing field. There has been a slow rate of uptake within most pediatric surgical centers around the world due to both finance, and difficulties associated with equipment primarily designed for adults. The ergonomics required for the da Vinci® master–slave-type platform currently challenge the small working space in very small children.
Currently, there are three options for surgical treatment for a wide variety of pathologies in the pediatric population, open surgery (traditional) and MIS, which include: conventional laparo-thoracoscopic surgery and RAS.
Minimally invasive techniques are applicable in more than 60% of abdominal and thoracic operations in children, and according to evidence-based data and ethical principles can be used properly [1].
In 1994, the first robotic system used in the urological practice known as AESOP was introduced. Later, the evolution of these devices would bring the Zeus system and finally the Da Vinci system while continuously increasing their precision and effectiveness [2].
Since these initial reports, robotic surgery has seen widespread application within the adult population, especially in urologic and gynecologic procedures. As is often the case for new devices, technology, and therapeutic options in surgery, the application of robotic surgery for children has occurred more slowly than in adults. This caution is due in part to technical limitations with developing appropriately sized instruments for the pediatric patient; however, in recent years broader implementation has been seen [3, 4, 5, 6].
In April 2001, Meininger et al. [7] published the first cases of RAS in children. The first of these two Nissen fundoplication procedures was reported as occurring in July 2000 [7, 8, 9, 10]. Shortly afterward, the first robotic urological procedure in a child was undertaken in March 2002 by Peters et al. (personal communication, July 2002) who performed a pyeloplasty using the da Vinci® [11, 12]. Since then to date, more than 70 different surgical techniques have been published [13, 14].
Currently, the only robotic system that is approved for pediatric use is the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, CA) [7]. The da Vinci robot is well suited for children of all ages, including infants and newborns, using careful preoperative planning, this allows the da Vinci to be used for numerous procedures in small children [14, 15].
The evolution of conventional laparoscopic surgery highlights the transitory stages that follow adoption and diffusion of surgical innovation [16, 17, 18]. RAS was introduced to the specialty of pediatric surgery following initial case reports in the early 21st century. Subsequently, this promising surgical technology has undergone a formative 10-year period of introduction, development, early dispersion, exploration and preliminary assessment [13].
Cundy et al. [13], performed a 2013 systematic literature search for all reported cases of RAS in children during an 11-year period. During this time, 2,393 procedures in 1,840 patients were reported and the most prevalent gastrointestinal, genitourinary, and thoracic procedures were fundoplication, pyeloplasty, and lobectomy, respectively.
Due to the limitations of conventional laparoscopic surgery in pediatric patients, expert pediatric surgeons should only perform the more complex or reconstructive laparoscopic techniques [19].
There have been few reports that have been published about robotic general pediatric surgery [20, 21, 22, 23, 24, 25, 26, 27, 28, 29]. Thus, far, the largest number of procedures and publications have been produced about robotic urological pediatric surgery [11, 12, 13, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45]. Trends in the literature indicate that pediatric RAS is continuing to be globally utilized [11, 13, 30, 31, 32, 33, 34, 35, 43, 44, 45, 46].
The safety of RAS in children is reported to be similar to open procedures, and the outcomes are at least equivalent to conventional laparoscopy [47]. Robotic surgery on smaller children and infants require special considerations when discussing robotic surgery [48].
Numerous case reports, case series, and comparative studies have unequivocally demonstrated that robotic surgery in children is safe [13].
In systematic investigations of databases of pediatric RAS, the global surgical conversion rate was 4.7% [22], and a net overall surgical conversion rate of 2.5% was reported [13]. In published studies of pediatric RAS, transoperative complications are infrequent, and in the postoperative period, the frequency varies from 0 to 15% [22, 49, 50, 51].
2. Characteristics, advantages, benefits, limitations and applications of robotic surgery
2.1 Characteristics
In RAS robotic devices are used, such as the Da Vinci system from Intuitive Surgical, which has a miniaturized camera and the surgeon operates seated at a console close to the patient (telesurgery), with three-dimensional and magnified images of the operative field, and manipulates articulated instruments controlled by their hands and feet; It is supported by a second surgeon positioned next to the patient at the exposure of the operative field, with retraction, suction and exchange of instruments in the arms of the robot. There is greater precision than in open surgery and conventional laparo-thoracoscopic surgery [52].
2.2 Advantages
RAS enables more refined hand-eye coordination, superior suturing skills, better dexterity, and precise dissection. It is achieved by the characteristics of robotic surgical platforms that include motion scaling, greater optical magnification, 3D, and stereoscopic vision, increased articulated instrument tip dexterity, tremor filtration, operator-controlled camera movement, and elimination of the fulcrum effect [13], all of this translates into greater safety for patients and advantages for the surgeon.
Robotic instruments were specifically designed to mimic human wrist movements, allow 7 degrees of freedom of movement, and can be particularly advantageous for newborns, infants, and young children, as well as, certain hard-to-reach anatomical areas [29, 46]. By operating seated at the console, surgical fatigue and tremors are reduced [53].
2.3 Benefits
Robotic enhancements offer improvements in the technical capacity of human performance for surgery within spatially restricted workspaces in children [13]. Less time is required to acquire the right skills and confidence with RAS, “The learning curve is shorter” [46, 54, 55, 56]. Robotic assistance will allow more pediatric surgeons to perform a greater volume of minimally invasive procedures [57].
It also has a real benefit for the pediatric patient in terms of: minimizing operative trauma, minimal scarring, less postoperative pain, less need for opioids, less bleeding and transfusions, fewer complications, less risk of infection, shorter hospitalization, and quick return to daily activities, this also benefits parents [46, 47, 58].
2.4 Limitations
There are limitations in RAS, this includes, access to the patient by the anesthesiologist is limited after the robot is docked, changes to patient position or access to the patient requires detachment of the robot, and patients must remain entirely paralyzed when the robot is docked [59].
In addition, RAS frequently requires Trendelenburg or reverse Trendelenburg steeper positioning, which has hemodynamic consequences. This situation can typically be mitigated by adequate volume expansion [60].
Infants are typically more susceptible to the respiratory effects of pneumoperitoneum than older children or adults, abdominal insufflation decreases respiratory compliance and increases airway pressures, and the instilled CO2 can cause hypercapnia and acidosis [61].
The primary disadvantage of robotic surgical technology in pediatric surgery is related to the size of the surgical robot and its associated instruments [4, 5, 46], the robotic instruments are only available in 2 sizes, 8 mm and 5 mm. Similarly, robotic endoscopes (lens) are currently only available as 12.0 mm and 8.5 mm.
The cost analysis for the use of the robot is not strictly measured by numerical cost in dollars, but should be considered as value equating to quality (as defined by positive outcomes/cost). Naturally, there is the initial cost of purchasing and maintaining the robot itself, as well as the increased costs from the disposable robotic equipment and the longer operative times [4]. It should be noted other factors associated with the robotic portion of a procedure, such as increased operating room or anesthesia time, staff training, and cost of marketing campaigns [62].
In contrast, patient and parent satisfaction, as well as emotional and professional benefits, should also be considered when evaluating cost/satisfaction of this type of investment [63]. One study found that it takes at least 3 to 5 cases per week in a program to demonstrate a net gain from robotic surgery [64].
Other cost analyses suggest that robotic surgeries are more expensive than those associated with laparoscopic or open surgery [65, 66]. However, RAS is associated with a 2% decrease in anastomotic leaks [67, 68]. This reduces hospitalization and costs of managing the resulting surgical morbidity, and benefits the earlier return of the patient to the workforce [66]. In addition, by preferably performing difficult and complex cases in which robotic surgery adds value to patient care; it should be a solution with the best profitability in hospitals that have a robotic system. In some countries such as in Latin America, costs represent a great inconvenience for the advancement of robotic surgery in children, especially in private hospitals.
A short hospital stay, prudent use of instruments, reduced operating room times, and competent robotic equipment reduce costs [69]. Therefore, future comparative analyses of outcomes in children should include financial factors such as loss of human capital, parents [70].
2.5 Applications
Robotic surgery has been used in almost all pediatric surgical subspecialties, including urology, general surgery (gastrointestinal-hepatopancreatobiliary), thoracic, oncology, and otorhinolaryngology. Among pediatric disciplines, robotic surgery is used most frequently in urology.
The best indications for robotic surgery are procedures that require a small surgical field, fine and precise dissection, and secure intracorporeal sutures [71]. The RAS have special application in complex and reconstructive surgery, for these procedures, from the open technique; surgeons often jump to RAS [14]. RAS in otorhinolaryngology with the application of the transoral approach is particularly useful in masses of the tongue base [72]. Furthermore, RAS has performed a wide spectrum of surgical procedures in children [13].
3. Urologic robotic surgery
To date, the application of MIS in pediatric urology has evolved over more than 30 years [73]. Urology has the highest acceptance of robotic surgery within pediatrics. The first use of robotics in children was a pyeloplasty for ureteropelvic junction (UPJ) obstruction, because the ureteropelvic anastomosis was a technical challenge using conventional laparoscopic surgery [11, 12].
In a systematic bibliographic search that was carried out of all the published cases of pediatric robot-assisted urological surgery between 2003 and 2016. A total of 151 publications that reported 3688 procedures in 3372 patients were identified. The most reported procedures were pyeloplasty (1923), ureteral reimplantation (1120), heminephrectomy (136), and nephrectomy or nephroureterectomy (117). There were 16 countries and 48 institutions represented in this literature [6].
We will approach the surgical urological pathology of the child based on the anatomy of the urinary tract as follows, i. Upper urinary tract, ii. Lower urinary tract and iii. Miscellaneous procedures.
3.1 RAS on the upper urinary tract
3.1.1 Nephrectomy
In pediatric patients, complete or partial nephrectomies are indicated more frequently for benign diseases and less frequently for malignant diseases. Indications for RAS nephrectomy for benign diseases are multicystic dysplastic kidney disease, kidney exclusion due to various pathologies, such as UPJ obstruction, reflux nephropathy, among others, indications of malignant tumors, particularly Wilms tumor are increasing legitimizing itself through corresponding treatment protocols, and surgery performed while adhering strictly to oncological surgical rules [74].
In nephrectomy, the initial step is the dissection and exposure of the renal pedicle, its ligation and cutting. The next step, the kidney is completely freed from its surrounding tissue. Subsequently, the dissection of the ureter is performed, in the case of radical nephroureterectomy it should be performed up to the bladder. The kidney is extracted through the umbilical access, in case of nephrectomy due to tumor, the use of a collection bag is mandatory, and it is removed through a Pfannenstiel incision, and finally lymph node sampling is crucial for surgical staging and guiding subsequent treatment.
3.1.2 Partial nephrectomy
Ureteral duplication is the most common congenital abnormality of the urinary tract. Partial nephrectomy for benign indication is performed for the resection of a deficient or non-functional fraction of a duplex system and can cause or be associated with obstruction and hydronephrosis, dysplasia, megaureter, ureterocele, and vesicoureteral reflux. Heminephroureterectomy is performed in cases with a reflux system [73]. It is recommended before surgery, to place a stent in the ureter to be preserved (for easy identification during dissection). If the ureter of the remaining fraction is to be reimplanted or if an ectopic ureter is to be followed in the deep pelvis, the robot is repositioned between the patient’s legs and redocked [75].
3.1.3 Pyeloplasty
Robot-assisted pyeloplasty is the most common procedure performed robotically in pediatric patients, both within urology and overall [76]. The excellent experience with robot-assisted pyeloplasty has challenged other approaches as a new standard for the treatment of UPJ obstruction.
Dismembered pyeloplasty (Anderson-Hynes) includes resection of the UPJ and reduction of the renal pelvis. In the technique, the ureter is incised and spatulated laterally to provide sufficient ureteral wall length to achieve a wide side-to-side anastomosis. Once the anterior layer of the pelvic-ureteral anastomosis has been sutured, an antegrade transanastomotic double-J stent is passed. J-Vac transabdominal drainage was used in the surgical bed.
Patients undergoing robotic pyeloplasty have a shorter hospital stay, and less need for analgesics; however, there is no difference in the success rate of robotic pyeloplasty in comparison to the other two approaches [77, 78, 79].
In robotic pyeloplasty the learning curve is much shorter. This allows some surgeons to transition from the open pyeloplasty to the robotic approach without any prior laparoscopic experience with this technique [80].
Pyeloplasty in infants less than 10 kg has been performed successfully. A multi-institutional study of 60 infants less than 12 months old with a 91% success rate and an 11% complication rate, which is similar to other studies on larger children and adults [81]. The foregoing supports the personal experience of the author.
Also, the retroperitoneal robotic approach is indicated mainly for patients with previous abdominal surgery, when adhesion syndrome is suspected, and it has been validated for pyeloplasty and other techniques in this anatomical area [82].
3.1.4 Ureteroureterostomy
The procedures performed included pyeloureterostomy for incomplete duplication and lower pole UPJ obstruction and ipsilateral ureteroureterostomy along with distal ureterectomy for obstruction in a dysplastic upper pole with ureteral, ectopia, for the treatment of duplex anomalies and reconstruction of obstructed dilated ureteral segments [83]. This can also be applied to the lower ureter in duplex systems where it helps to avoid reimplantation of disparate ureters in the same tunnel. Also, transperitoneal robotic ureteroureterostomies have been reported for mid ureteric strictures and also for the correction of retrocaval ureters [84, 85]. Also with robotic assistance, the removal of a large ureteric stone at any level with the placement and closure of a stent is a relatively simple affair, using the Mikulicz procedure to close the ureterotomy or a spatulate anastomosis.
3.1.5 Ureterocalicostomy
Ureterocalicostomy is a potential, and technically feasible option in patients with UPJ obstruction and significant lower pole caliectasis which is often reserved for patients with a failed pyeloplasty and a minimal pelvis, or patients with an exaggerated intrarenal pelvis [86]. An ureterocalicostomy is a procedure in which the ureter is sutured to the lowermost calyx of the kidney. It is a salvage operation, which should be in the arsenal of every surgeon operating the UPJ [87]. The robotic approach is a good option.
3.2 RAS on the lower urinary tract
3.2.1 Extravesical ureteral reimplantation
The most performed procedure in the lower urinary tract in children is the antireflux ureteral reimplantation [13]. Indications for the surgical treatment of pediatric vesicoureteral reflux include severe urinary tract infections while taking continuous antibiotics prophylaxis, renal scarring, and worsening or non-resolution vesicoureteral reflux. Robotic ureteral reimplantation can be done by an extravesical or intravesical approach and, of these approaches, the extravesical is much more widely reported [88, 89]. The extravesical procedure is a ureteral reimplantation according to the well-established technique of Lich-Gregoir, for achieving an antireflux mechanism. This technique is an accepted alternative to endoscopic treatment and open reimplantation techniques in pediatric patients [73]. However, open surgery remains the gold standard for ureteral reimplantation [90].
The long-term results of the antireflux procedure are evaluated in terms of preservation of differential renal function, absence of urinary tract infections, and adequate urinary drainage, with a follow-up of more than one year [91]. In a prospective study of children undergoing robot extravesical ureteral reimplantation at eight academic centers from 2015 to 2017, 143 patients (199 ureters). The majority of ureters (73.4%) had grade III or higher vesicoureteral reflux preoperatively. Radiographic resolution was present in 93.8% of ureters. Robotic ureteral reimplantation should be considered as one of several viable options for management of vesicoureteral reflux in children [92].
3.2.2 Appendico-vesicostomy and continent catheterizable channels
3.2.2.1 Appendicovesicostomy (Mitrofanoff)
Complete bladder emptying in children with bladder emptying dysfunction (neuropathic bladder) is achieved with clean intermittent catheterization (CIC). In 1980, Mitrofanoff described his technique of a continent appendicovesicostomy for patients when transurethral CIC cannot be carried out for any reason. When medical therapy fails in the neuropathic bladder, the surgery aims to preserve upper tract function and social continence. A cystostomy with a continent opening easy to catheterize and associated with a closure of the vesical neck, was the objective. The tip of the appendix opened into the bladder at the end of an antireflux submucosal tunnel and the other end hemmed to the skin. The bladder neck is usually closed in the same operation. The continence of the vesicostomy is total and the comfort obtained is excellent [93].
The surgical technique is analogous to the Lich-Gregoir technique, to create an antireflux mechanism. The appendicocutaneostomy can be placed in the umbilicus or in the right lower abdominal quadrant [73]. Robotic continence procedures have been shown to be a safe and effective alternative [94]. An important point is to assess whether a simultaneous bladder augmentation is performed [95].
In patients with neurogenic bowel and bladder secondary to spinal dysraphism who tend to have multiple limb spasms and spinal scoliosis, RAS is a good option [96]. Complex lower urinary tract reconstruction defined as reconstruction of the bladder neck or catheterizable continent ducts, or both, as well as the creation of an antegrade Malone continence enema, for better management of constipation [97].
3.2.3 Augmentation cystoplasty
Augmentation cystoplasty often performed in the context of other reconstructive procedures such as appendicovesicostomy or bladder neck reconstruction. The procedure of bladder augmentation can be performed using a mega-ureter when nephrectomy is anticipated. At present day, the ileocystoplasty represents the currently accepted standard of care [73]. In robotic technique, a 20 cm segment of ileum is selected and isolated. Intestinal continuity is restored, and in the postoperative, the bladder is drained with a suprapubic tube, a urethral catheter and another catheter through the Mitrofanoff channel [98]. Another tissue option for bladder augmentation is the sigmoid colon, this technique significantly improved urodynamic parameters, such as bladder accommodation and filling pressure in children with myelomeningocele-associated neurogenic bladder [99].
3.3 Pediatric urology miscellaneous procedures
The miscellaneous pediatric urology procedures are some surgeries in the pelvic area, a narrow field that is ideal for the robotic approach. There are reports from RAS of; symptomatic bladder diverticulum excision [36], symptomatic or malignant urachal cyst excision [100], posterior urethral diverticula excision, mainly after surgical reconstruction of imperforate anus [101], prostatic utricle removal, is a malformation due to incomplete regression of Müllerian ducts [102], and varicocele cure, a condition that has a significant association with infertility [103].
4. General surgery (gastrointestinal and hepatopancreatobiliary)
RAS in general surgery, and thoracic surgery have not yet reached the magnitude that it has in pediatric urology. Robotic procedures that have been reported include, fundoplication, cholecystectomy, choledochal cysts resection, hepatectomy, colectomies, proctectomy with ileal pouch-anorectal anastomosis [104]. Other techniques are, Thal fundoplication and salpingo-oophorectomy [8], Soave pull-through procedure for Hirschsprung’s disease [105]. Others that are less common, RAS for the treatment of duodenal obstruction, such as the Ladd cure in intestinal malrotation, the duodenojejunostomy for superior mesenteric artery syndrome [106], the repair of congenital duodenal atresia [107], and gastroduodenal obstruction due to trichobezoar [14].
Hepatopancreatobiliary RAS in children inevitably involves high complexity, such as Kasai portoenterostomies and choledochal cyst resection [108, 109]. Furthermore, liver resection, robot-assisted generally indicated for treatment of tumors [110].
4.1 Fundoplication
Fundoplication is the most widely performed and reported robotic-assisted surgery in pediatric general and thoracic surgery [3].
When comparing conventional laparoscopic primary fundoplication and RAS in children, there were no differences between the two groups in terms of operative time, length of hospital stay, conversions, and complications. The conclusion is that RAS is a safe alternative to conventional laparoscopic surgery [111]. Regarding the advantages of RAS, a systematic review of primary fundoplication showed that postoperative complications are reduced in the robotic group. Because in the RAS there is greater dexterity and precision in the subphrenic space, than with laparoscopy [112]. In addition, RAS plays an important role in difficult cases, such as obese patients, large hiatal hernias, and redo fundoplication [113, 114]. On the other hand, with conventional laparoscopy, only skilled pediatric surgeons resolve difficult cases [114].
4.2 Choledochal cyst resection
Choledochal cyst resection and reconstructive Roux-en-Y hepaticojejunostomy are technically complex and, only in Southeast Asian centers there is extensive experience in the laparoscopic technique. In the rest of the pediatric centers of the world, most of this surgeries are performed with the open technique [115].
In 2006, the first pediatric RAS choledochal cyst resection was reported [116]. Since that time and up to 2019, several authors have reported cohorts of 1 to 39 pediatric patients undergoing RAS choledochal cyst resection [109]. A recent publication informed 70 cases with RAS and 70 cases by conventional laparoscopy, and concluded that RAS choledochal cyst excision and hepaticojejunostomy were associated with better short-term intraoperative and postoperative outcomes, and proved the safety and feasibility of RAS in children with choledochal cysts [117].
The ideal treatment for children with choledochal cyst, nowadays, is MIS, laparoscopic, through expert pediatric surgeons or RAS, in institutions where technology is available. But, if one or another situation is not present, the author recommends continuing with the open approach to offer children the greatest safety and effectiveness [109].
4.3 Kasai procedure
The Kasai procedure can be ideal for RAS because it is a complex technique, it has an ideal instrumentation to dissect the hepatic portal and find the portal plate [118]. To date, there are very few reported cases of Kasai operation for RAS for biliary atresia. The experience is larger with conventional laparoscopy, especially in Southeast Asian countries, where the pathology is more frequent than in other latitudes of the world [115].
4.4 Pancreatic pathology
There are very few publications of pancreatic pathology in children treated with RAS, we find only case reports about: tumor enucleation, distal pancreatectomy, subtotal pancreatectomy, and pancreaticoduodenectomy. The traditional open surgeries have been largely replaced by MIS, including laparoscopic surgery and RAS.
RAS distal spleen-sparing pancreatectomy is safe and feasible in pediatric patients with insulinoma [119]. Also, robotic enucleation is indicated in small neuroendocrine tumors of the pancreas. This technique provides the dual benefits of minimal invasiveness and good preservation of the pancreatic parenchyma. The experience has demonstrated the feasibility and safety of the RAS enucleation, with an excellent curative effect for pediatric insulinoma [120, 121].
4.5 Soave pull-through
Hirschsprung’s disease (HSCR) has also been shown to benefit from robotic surgery, the outcome of totally robotic soave pull-through for HSCR is promising. This technique is particularly suitable for older HSCR patients, even those requiring a redo surgery, and represents a valid alternative for HSCR patients. In cases of total colonic aganglionosis, for the hepatic angle or only recto sigmoid, RAS has been used and its versatility has been confirmed. The published results are promising, continence scored from excellent to good in all patients who could be evaluated in this regard [105]. In the first series of infants less than 6 kg who underwent the Swenson RAS, morbidity did not increase [122].
4.6 Treatment of duodenal obstruction
Superior mesenteric artery syndrome is a rare condition that results from intermittent functional obstruction of the third part of the duodenum. The diagnostic criteria are clinical, radiological and endoscopic. The classic approach has been open surgery [123]. There are case reports of robotic Roux-en-Y duodenojejunostomy as a surgical option for the treatment of this condition [106, 124].
Robotic repair of congenital duodenal atresia may help overcome the obstacles presented by the use of traditional rigid laparoscopic instruments, due to the difficulty in constructing a precise duodenal anastomosis, with robotic surgery the procedure is relatively straightforward [107]. About gastroduodenal obstruction due to trichobezoar in children and laparoscopy, we found several reports. We operated with RAS on a 12-year-old girl weighing 23 kg with pica and psychological disorder, with success and without postoperative morbidity [14].
4.7 Various procedures in general surgery
4.7.1 Cholecystectomy
Elective robot-assisted cholecystectomy is relatively prevalent in the literature [13]. Multiport robotic cholecystectomy and single-site robotic cholecystectomy are the approach options. Robotic cholecystectomy is safe and effective and serves as an excellent introductory procedure for pediatric surgeons considering the development of a pediatric robotic surgery program, useful for training [125].
4.7.2 Splenectomy
Splenectomy remains the mainstay of treatment for the sequelae of pediatric hereditary hematologic disorders. These conditions can lead to splenomegaly, medically refractory cytopenias, and dependence on transfusions. Laparoscopic splenectomy is the standard of surgical care. Robot-assisted splenectomy is an option and is associated with a shorter length of hospital stay compared to laparoscopic splenectomy [126].
4.7.3 Gynecological surgery
There are case reports and series documenting a variety of robotic gynecological surgeries in children with favorable results. Procedures consisted of ovarian cystectomies, oophorectomies for ovarian masses, and salpingo-oophorectomy for gonadal dysgenesis [127]. In addition, robotic resection of mature cystic teratoma and mucinous ovarian tumor. It is an easy and safe technique in selected patients and also for the treatment of complex gynecological diseases [128]. Surgeries in the pelvis have a reduced field of work and are ideal for the robotic approach.
4.7.4 Heller’s cardiomyotomy for achalasia
Achalasia is rare in children. Surgical options include open, laparoscopic, and robotic approaches, and Heller’s myotomy remains the treatment of choice. Concomitant partial posterior fundoplication is suggested for all patients. Heller’s robotic myotomy for esophageal achalasia in children has been shown to be safe and effective. Both laparoscopic and robotic esophageal myotomy are comparable in their results. However, robotic surgery is superior in terms of avoiding mucosal perforation, this complication occurred in 16% of patients in the laparoscopic group [129, 130, 131].
4.7.5 Management for anorectal malformations
Anorectal pull-through for anorectal malformations, with the robotic technology assists the pediatric surgeon by increasing dexterity and precision of movement. This is important in anorectal malformations surgery, where the dissection of the fistula and the pull-through of the rectum into the muscular complex are crucial to achieve continence in future. RAS permits easier closure of the fistula, improves reconstruction technique, and minimizes trauma to important surrounding structures, providing better visualization of the muscular complex. Robotic anorectal pull-through makes use of fundamental concepts learned from decades of high-anorectal malformation open repair, and combines them with modern advances in surgical instrumentation and techniques [132].
5. Thoracic robotic surgery
The global experience in thoracoscopic surgery in children is more than 30 years compared to robot-assisted thoracic surgery (RATS). The learning curve of thoracoscopy is longer compared to RAS. Thoracic MIS reduces the risk of thoracic and spinal deformities after lung resection in children. Lobectomy is one of the robotic techniques most frequently performed in children [133].
Early publications on RATS in children reported having performed cardiovascular techniques such as patent ductus arteriosus (PDA) closure and vascular ring section [134, 135]. Le Bret, et al. [134] in 2000, 56 children operated on for PDA surgical closure, 28 cases with thoracoscopy and 28 cases with robotic approach. They used the ZEUS robotic surgical system (Computer Motion, Inc., Goleta, CA. USA). Their results were comparable in both approaches.
Cundy et al. [13], in a systematic search in the literature of reported cases of robotic surgery in children of 2393 procedures, thoracic procedures accounted for 3.2% (77 surgeries and 12 different techniques), and the conversion rate was 10% in thoracic procedures. In this report, the five most frequent RATS procedures are: lobectomy (18), thymectomy (14), benign mass excision (9), diaphragmatic plasty (8), and malignant tumor resection (5).
There are three series reported with a greater number of cases, each with 11 RATS in children (total 33), in order of frequency the procedures include: tumor masses resection (8), lobectomy (7), diaphragmatic plication (4), diaphragmatic plasty (3), esophageal atresia correction (3), bronchogenic cysts resection (3) and unique procedures of segmentectomy, esophageal duplication resection, pleural and lung biopsies, gastric tube/esophagoplasty and Heller myotomy. Overall, there were 6 (18%) conversions to open surgery in neonatal patients and (3) 9% postoperative complications. The neonatal thorax represents the greatest obstacle in the adaptation of the 5 or 8 mm robotic platform instruments [20, 133, 136]. In RATS, children weighing more than 4 kg are more easily treated [15].
5.1 Pulmonary lobectomy
The most common RATS in children is lobectomy. The first publication on robotic lobectomy, including pediatric cases, was by Park et al. [137], in 2006. Series with few cases of segmental lung resections and lobectomies have been published with excellent results with conversions mainly on the first attempt [14, 15, 133, 136]. Addressing the disadvantages of RATS lobectomy, a prolonged total operative time was reported, but without having a negative effect, since it did not increase the postoperative morbidity and mortality of patients [138].
5.2 Congenital diaphragmatic hernia repair
Congenital diaphragm abnormalities, including eventration and Morgagni and Bochdalek diaphragmatic hernias, have been successfully repaired through the use of conventional MIS. However, some reports have shown a high recurrence rate for some defects. Robotic surgery is the alternative to close diaphragmatic hernias more efficiently [139].
Some authors prefer the thoracic approach to repair Bochdalek’s diaphragmatic hernia, but infants weighing less than 2.5 kg are better treated with the abdominal approach. The author performed one case of Morgagni’s diaphragmatic hernia and another case of Bochdalek’s diaphragmatic hernia via the abdominal route. Robotic assistance allows the surgeon to more easily reach this area to suture diaphragmatic defects [139].
Acquired anomalies, such as diaphragmatic paralysis, can also be resolved with RATS [14, 139].
5.3 Thymectomy
Radical thymectomy is the comprehensive treatment of myasthenia gravis. The feasibility and effectiveness of robotic thymectomy is evident in this cohort study [140]. In addition, performing the “early thymectomy” (performed within a year of diagnosis) resulted in higher remission rates compared to “late thymectomy” [141], including minimizing the adverse effects of immunosuppression in pediatric patients [142].
In recent studies including 49 children, thoracoscopic thymectomy was also safe for children with juvenile myasthenia gravis (JMG) [143, 144]. Two other studies with 9 and 18 children, reported the same results [145, 146]. Robotic thymectomy is a safe procedure, complications were low, and without mortality. Thymectomy should be offered as a part of multimodal therapy for treating children and adolescents with acetylcholine receptor antibody-Positive JMG [146].
5.4 Other robotic thoracic procedures
There are RATS publications of other specific procedures, such as tracheopexy for the treatment of severe tracheomalacia [147], and reports of pediatric cases of resection of a bronchogenic cyst [148, 149].
6. Oncologic robotic surgery
Presently, the use of MIS in patients with cancer is progressing. However, the role of MIS in children with solid neoplasms is less clear than it is in adults. Although the use of diagnostic MIS to obtain biopsy specimens for pathology is accepted in pediatric surgical oncology, there is limited evidence to support the use of MIS for the resection of malignancies (solid tumors) in the thorax and abdomen in children [150].
Open surgery remains the main technique for the resection of solid tumors in children. RAS offers technical and ergonomic advantages that can make MIS more achievable in this environment, allowing benefits for both the patient and the surgeon. Reduced postoperative recovery time and faster initiation of adjuvant therapy are the most important benefits for the patient [104].
A systematic search of multiple electronic databases, of 23 publications, reported 40 cancer cases in total. The indications for surgery were more than 20 different pathologies. One third of the tumors were malignant. Most of the procedures involved abdominal or retroperitoneal tumors in adolescent patients. Oncological adverse events were two isolated events, one tumor spillage and one residual disease. The evidence is limited to case reports and small case series only. Pediatric cancer surgery is an area of opportunity for robotic surgery. Its technical challenges create the opportunity to develop robotic approaches that meet the challenges of complex cancer procedures [151].
6.1 Thoracic tumors
As an anecdote, the robot appears to be well adapted to complex mediastinal dissection and has been used in excision of left ventricular myxoma [152], and in excision of complex massive leiomyoma of the esophagus [153]. The robot offered excellent visualization and ease of resection. The other case of complex massive retrocardiac esophageal leiomyoma was successfully removed using RAS. In the latter case, intraoperative esophagoscopy and transillumination were useful adjuncts to identify the esophagus and develop a safe extramucosal dissection plane.
There is a publication with five pediatric patients with a mean age of 9.8 years and weight of 41.5 kg, who underwent robotic resection of a mediastinal thoracic mass, including a ganglioneuroma, ganglioneuroblastoma, teratoma, germ cell tumor, and a large inflammatory mass of unclear etiology. The application of RATS in malignant solid tumors in children in selected cases is an option, but oncological surgical principles should be applied [154].
6.2 Abdominal tumors
There are mostly individual case reports for robot-assisted abdominal oncological surgery in children.
Neuroblastoma is the most common extracranial solid tumor in children and the most common malignancy in infants. Complete resection is curative in low-stage disease. Robotic surgery can skeletonize abdominal blood vessels in the tumor and cut the tumor into pieces, including stage IV retroperitoneal neuroblastoma [155, 156].
Juvenile cystic adenomyoma is the focal presence of ectopic endometrial glands and stroma within the uterine myometrium. Another case, a 15-year-old adolescent girl underwent RAS of a 4 cm cyst, and the uterus was closed in four layers, the postoperative period was uneventful [157].
Management of rhabdomyosarcoma. A 22-month-old, 8-kg boy with an embryo-rhabdomyosarcoma in the urinary bladder and prostate, the treatment was a robot-assisted radical cystoprostatectomy, and the postoperative course was uneventful [158]. Another application of RAS is in the dissection of retroperitoneal lymph nodes in selected pediatric and adolescent patients with paratesticular rhabdomyosarcoma or germ cell tumor of the testicle, a report of a case of each of these conditions, they were treated with good results. The robotic approach to extended lymph node dissection is suitable [159].
Robotic partial nephrectomy has been reported in appropriately selected children with renal cell carcinoma. However, there are limited reports of laparoscopic or robotic partial nephrectomy for cancer surgery in children. RAS allows for an oncologically sound resection of partial nephrectomy, as well as extended lymph node dissection [160].
Robotic adrenalectomy is an increasingly used procedure in patients with a variety of surgical adrenal lesions, including adenomas, aldosteronomas, pheochromocytomas, and adrenal gland metastases. Emerging literature also supports the role of RAS in partial adrenalectomy [161]. With robotic partial adrenalectomy, successful preservation of adrenocortical function is achieved [162].
RAS is an emerging technique for the treatment of pancreatic neoplasms. Robotic spleen-preserving distal pancreatectomy for a solid pseudopapillary tumor in pediatric patient, can be considered in younger patients presenting with a solid pseudopapillary tumor in the distal pancreas, and its use as an alternative to open pancreatectomy [163]. A report with 15 adolescents with pancreatic head tumor treated with MIS. Pancreaticoduodenectomy was performed, 10 cases with conventional laparoscopic surgery and 5 cases with RAS. The pathological diagnoses were solid pseudopapillary neoplasms (8), neuroendocrine neoplasms (3), intraductal papillary mucinous neoplasm (1), cystic fibroma (1), serous cystadenoma (1), Ewing’s sarcoma (1). Six patients presented postoperative complications. The median follow-up was 37 months. The patient with Ewing’s sarcoma was diagnosed with liver metastasis 41 months after surgery and died 63 months after surgery. All other patients survived without a tumor [164].
Robotic gynecological surgery in girls with ovarian disease, the ideal is to maintain the morphology of the ovary, which is beneficial for the recovery of postoperative ovarian function, especially in benign diseases. In centers where robotic surgery is available, ovarian tumors are a suitable entry procedure [128].
Robotic surgery can also be used in supportive care in pediatric oncology including placement of gastrostomy tubes and ovarian transposition [104].
The fundamental oncological principles of no tumor spillage and total resection of tumor margins can be adhered to by RAS; a specific concern being the lack of haptics having an impact on the surgeon’s ability to differentiate cancerous from healthy tissue. However, it has been noted that the loss of tactile feedback is, very well compensated for by the excellent optical system [158]. Cancer patients are necessarily followed for recurrences, and only long-term prospective studies of robotic resections can guarantee adherence of the RAS to oncological principles.
Contraindications in children for MIS in tumors, including robotic surgery, are large or fragile tumors that carry a high risk of fracture and tumor spillage, significant adhesions from previous operations, and significant deterioration of respiratory or cardiovascular physiology [104].
7. Otorhinolaryngology
Pediatric robotic surgery has been used least frequently in otorhinolaryngology [72]. Until now, the majority of RAS applications in otorhinolaryngology is a transoral approach, particularly useful in masses of the base of the tongue. Open surgery can facilitate access to the oropharyngeal region, including the base of the tongue, but can lead to the morbidity of splitting the lip and jaw or require pharyngotomy. As a result, the robotic transoral approach is being used [165]. In the near future, we believe that transoral robotic surgery may become the gold standard.
In a publication of pediatric cases of robotic transoral surgery, with 41 patients, with age between 2 months and 19 years, the techniques were, lingual tonsillectomies (16), lingual and lingual based tonsillectomies (9), 2 malignant diseases in the oropharynx (high-grade undifferentiated sarcoma and biphasic synovial sarcoma), a thyroglossal duct cyst at the base of the tongue, laryngeal cleft cysts (11), a posterior glottic stenosis, and a surgery for congenital true vocal cord paralysis. A minor intraoperative complication occurred. No patient required postoperative tracheostomy. Conversion index was 9.8% [166].
8. Author’s experience in robotic surgery
From March 2015 to January 2021, since the beginning the prospective registry of the casuistry has been carried out. We have performed 258 robot-assisted laparoscopic and thoracoscopic surgeries (RALTS) in 227 patients (224 children and 3 adults), in a public hospital and two private hospitals in Mexico City. The demographic data of the patients are, in relation to gender, 52.4% male and 47.6% female. The average and range of age, weight and height of the patients were, age 79.5 months (2 to 204), weight 26.8 kg (4.4 to 102) and height 114.5 cm (55 to 185), the smallest patient was 2 months old, 4.4 kg in weight and 57 cm in height, a left pyeloplasty was performed. The adult patients were 31, 63 and 64 years old.
We grouped our RALTS into gastrointestinal-hepatobiliary 123 (47.68%), urological 117 (45.35%), thoracic 10 (3.87% and oncological 8 (3.1%). We have performed 46 different techniques, globally our conversion rate is 3.1%, the hemotransfusion rate is 4.2%, the mean postoperative stay is 2.5 days, and the mean follow-up is 40 months.
From the group of gastrointestinal-hepatobiliary robotic surgery, in order of frequency, the techniques performed were: primary fundoplication 50 (41.67%), redo fundoplication 20 (15.83%), gastrostomy 17 (14.16%), cholecystectomy 14 (11.67%), biliodigestive 7 (5%), being 5 resections of choledochal cysts with hepaticojejunostomy, a Kasai operation and a hepaticojejunostomy to manage the lesion of the left hepatic duct. Splenectomy 6 (5%), Malone operation 2 (1.67%) and various techniques 7 (5%), of single cases, duodenoplasty and adhesiolysis, gastric trichobezoar extraction, drainage of recurrent retrohepatic abscess after appendectomy, gastric antrum membrane resection, gastrojejunostomy de-derivation, and Ladd’s Cure. In this group of gastro-intestinal-hepatobiliary robotic surgery, the conversion rate was 3.25%, intraoperative complications 1.6%, and postoperative complications 4%. In this group of RAS 14 different techniques were performed.
From the robotic urological surgery group, in order of frequency, the techniques performed were: pyeloplasty 26 (22.2%), ureteral reimplantation 21 (17.94%), nephrectomy 20 (17.1%), Mitrofanoff operation 8 (6.8%), nephroureterectomy 7 (6%), ureterostomy de-derivation and ureteral neo-reimplantation 5 (4.3%), nephro-cystolithotomy 5 (4.3%), varicocelectomy 5 (4.3%), release of extrinsic UPJ obstruction 4 (3.4%), inguinal hernioplasty 3 (2.56%) and various techniques 13 (11.1%) of single cases, ureteroureterostomy, augmentation cystoplasty, bladder neck closure, heminephroureterectomy, perirenal abscess drainage, colostomy closure, enterovesical fistula closure, Mitrofanoff review, ureterostomy and ureteropyelography, bilateral gonadectomy, duplicated ureter ureterostomy, hysterosalpingectomy, bladder wall biopsy. In this robotic urologic surgery group, the conversion rate was 0.85%, intraoperative complications 0.85%, and postoperative complications 1.7%. In this group of RAS 20 different techniques were performed.
In the robotic thoracic surgery group, in order of frequency, the techniques performed were: lobectomy 4 (40%), diaphragmatic plication or plasty 4 (40%), a bronchogenic cyst resection (10%) and a pleural biopsies (10%). In this robotic thoracic surgery group, the conversion rate was 20% and postoperative complications 10%. In this group of RAS 5 different techniques were performed.
In the robotic oncological surgery group, the techniques performed were adrenalectomy 2 (for adenoma and another for pheochromocytoma) and single techniques of, anterior mediastinal teratoma resection, Ewing tumor resection, Wilms tumor stage 3 resection in horseshoe kidney, partial gastrectomy for carcinoid tumor, retroperitoneal lipoma resection and conservative resection of ovarian cyst. In this robotic cancer surgery group, the conversion rate was 12.5%, and there were no complications. In this group of RAS 8 different techniques were performed. The cases of adult patients were pheochromocytoma, adrenal adenoma and carcinoid tumor.
Previously, we published our experience with RALTS, the first 186 surgeries [14], the first 4 cases of choledochal cyst resection [109], redo Nissen fundoplication [114] and in thoracic surgery [133].
9. Implementation of a pediatric robotic surgery program
9.1 Planning
The success of a pediatric robotic surgery program (PRSP) depends on a well-structured plan. Implementing a PRSP requires institutional support and requires a comprehensive, detail-oriented plan that takes into account training, supervision, cost, and cases volume. Given the lower prevalence of robotic surgery in children, in many cases it may be more feasible to implement pediatric robotic surgery within an adult robotic surgery program. The pediatric surgery team determines its goals for volume expansion, surgical case selection, surgeons training, and surgical innovation within the specialty. In addition to the clinical model, a robust economic model that includes marketing must be present, especially in private hospitals [167].
9.2 Development of the program
The development of a robotic surgery program is associated with significant initial costs due to the initial investment in the robotic surgical system [168]. Adequate surgical volume is essential for both feasibility and ensuring adequate results for patients [64]. The surgeon should start with less complex index cases and gradually progress to more advanced reconstructive procedures with growing experience [61].
Less complex cases, such as a fundoplication, are excellent robotic training cases not only for surgeons and anesthesia personnel, but also for technical and nursing personnel assisting in the operating room [169].
Additionally, robotic cholecystectomy is a suitable procedure for first few surgeries when pediatric surgeons are beginning robotic surgery [125]. It is imperative to have a core group of specific personnel familiar with robotic procedures to increase efficiency. Adequate and systematic performance of the entire team in simple cases, then translates into better performance in more complex cases.
It is estimated that approximately 100 cases are required to obtain consistent results in pediatric robotic surgery cases by a surgical team [167]. The learning curve for each procedure varies, but is shorter than with laparoscopy, for example for robotic pyeloplasty there are 15 to 20 cases, to obtain similar results and surgical success [170]. Experience shows that in complex or reconstructive techniques, surgeons using the open approach switch to the robot-assisted approach, such as pyeloplasty, ureteral reimplantation, biliodigestive and pulmonary lobectomy, among others.
9.3 Robotic pediatric surgery team
There are three main actors involved in the implementation of a pediatric robotic surgery program: i. Surgeons and anesthetists, ii. Nurses and iii. Administration [168].
Successful robotic surgery is mentioned as requiring four elements, i. Good understanding of the surgical procedure, ii. Excellent surgical skills, iii. Frequent teamwork training, and iv. Trocar placement [171]. Adequate surgical volume is critical both for feasibility and to ensure good patient outcomes. Cases should be performed once a week to maintain surgical skill and advance to more advanced reconstructive procedures.
There has been a growing role for simulation and surgical training. Currently, the robotic surgery simulators available for training are the Mimic and da Vinci simulators. The simulators evaluate the skills in the different tasks that the surgeon performs. It is desirable that surgeons have previous experience in conventional laparo-thoracoscopy.
9.4 Training, accreditation and credentialing
Training and accreditation. In the present, the certification process to be a robotic surgeon depends on the manufacturer. Intuitive Surgical (Sunnyvale, CA, USA), the manufacturers of the da Vinci Surgical System, have a separate training program that takes surgeons from console setup to the monitoring phase for initial cases with support from a proctor.
This process should be more structured and create a curriculum for robotic surgeons, this is essential for the training and objective evaluation of future robotic surgeons. Defining results, specific training tasks and their validation; as well as, establishment of measurements and approval criteria to improve the quality of robotic surgery should be included in the plan [172]. Academic organizations and hospital institutions can lead the implementation of a structured curriculum.
An accreditation proposal for the robotic surgeon is the following; After the intuitive surgery training program (step 1), then do the first five cases with a co-surgeon (step 2), who has the dual role of preceptor and supervisor, assesses the surgeon who is learning and also imparts new skills and takes control of the operative case if the clinical situation warrants it (the tutor allows the trainee to gain robotic experience safely in the first index cases). This is followed by 6 to 10 cases in which the tutor / supervisor is a bedside assistant (step 3). The preceptor/supervisor reports the findings to the Institution’s Robotics Committee on the skills and progress of the trainee, evaluating whether the independent practice can be continued by the surgeon (step 4), based on the favorable evaluation of the preceptor [167].
The author’s experience supports this accreditation proposal so that the learning curve of the surgeon, who is starting his foray into robotic surgery, is a satisfactory experience for him, and the patient is offered the greatest security from the stage of the curve of learning.
9.5 Program information data log
Data collection is very important. Collecting, analyzing, and presenting data prospectively to Institutional colleagues, at a minimum, allow objective analysis of results for comparative studies against other approaches, as well as to publish them.
10. The future of robotic surgery in children
Recently, the Senhance Robotics System (Transenterix, Morrisville, NC) has begun offering 3 mm instrument sizes, which could make robotic surgery more technically feasible for even the smallest pediatric patient. Although not currently approved for use in pediatric surgery, the Transenterix platform, was evaluated in an experimental study where surgeons were able to successfully perform intracorporeal and knotted sutures in body cavities as small as 90 ml, and the instruments could be inserted directly without the need for ports, reducing the required distance between ports [5]. This Transenterix platform has haptic feedback.
With advancing technology and the demand for more compact robotic platforms, the future for robotic surgery will doubtlessly result in a reduction of instrument size and an improvement in haptic feedback. This puts the pediatric patient in particular, the newborn at the forefront. Reconstructive surgery such as esophageal and intestinal anastomosis, all of which require a delicate and more magnified approach will benefit enormously from these advances. The pediatric and neonatal patient must be at the forefront of research into the future of robotic surgery [173].
We are at a dawn of a new age in surgery, as we witness the dramatic growth in robotic surgery. The proliferation and commercialization of new robotic surgical systems over the next few years will drive competition, lower cost, and accelerate the adoption of these technologies [174].
Artificial intelligence. More sophisticated systems will track the surgeon’s movements and patient data and synchronize with outcomes data to provide us with early warning systems for complications. One more interesting aspect is how these systems will participate in the surgical decision-making process in real time. We are already gathering data on tissue perfusion, helping us decide on the appropriate location for an anastomosis. Additionally, using artificial intelligence, real-time data will be collected from many sources, including electronic medical records, anesthesia monitoring systems, video images, and surgeon data for making decisions that we will increasingly rely on [174].
Digital surgery (Surgery 4.0), the next frontier of surgery, is defined as the convergence of surgical technology, real-time data and artificial intelligence. Following previous waves of disruption, which saw the transition from open (Surgery 1.0) to laparoscopic surgery (Surgery 2.0), and from laparoscopic surgery to robotic surgery (Surgery 3.0), the digital paradigm in surgery is bringing unprecedented changes to the century-old field. The power of linked data and advancements in artificial intelligence are beginning to make a real impact in the way surgeries are performed, reducing well-documented variability in surgical process and outcomes.
Companies, investors, surgeons and health systems are racing to accelerate the digitization of surgery in order to dramatically improve patient outcomes whilst reducing cost and inefficiencies; improve patient access; reduce inequities between populations; improve quality; and deliver more personalized surgical care, and the digital surgery is the next apex in surgery [175].
Verb Surgical is building a digital surgery platform that combines robotics, advanced visualization, advanced instrumentation, data analysis, and connectivity. Surgery 4.0 or digital, which seeks to achieve less invasive and smarter interventions, “marks the beginning of a true democratization of the discipline”. The Verb Surgical platform will be an option in the near future of digital surgery [175, 176].
11. Conclusions
In this chapter, in relation to robot-assisted surgery, its definition, characteristics, advantages, benefits, limitations and applications in children are addressed. As well as, the surgical areas of its application in the pediatric population, which include urological, general, thoracic, oncological and otorhinolaryngological surgery.
To date, there are multiple publications that demonstrate that robotic surgery in children is safe and effective, and it is important to offer children its benefits. However, a frequent conclusion of published studies on robotic surgery in children is the impossibility of carrying out comparative studies with all the scientific rigor, which makes it impossible to reach solid conclusions about the advantages and benefits in the pediatric population.
Robotic surgery preferably applied to difficult and complex cases adds value to patient care, and is an important balancing factor against the apparently higher cost (main drawback), compared to open and laparo-thoracoscopic surgery.
The author included his results in pediatric robotic surgery, which compared to other series of similar published cases; the experience is favorable and encouraging.
Globally, to date, few pediatric surgeons have adopted the robot-assisted surgery, as opposed to more pediatric urologists who have benefited more children. To date, in malignant tumors in children, robotic surgery has been applied less.
Recommendations for the implementation of a pediatric robotic surgery program are included. With robotic assistance, it is important to mention that the learning curve is shorter than with laparo-thoracoscopic surgery. It is necessary for each institution to establish the curriculum for the accreditation and credentialing of the robotic surgeon. A proposal is included.
The future will be fascinating with upcoming advancements in robotic surgical systems, the use of artificial intelligence, and digital surgery.
Acknowledgments
I thank the Pediatricians, Pediatric Surgery Residents and Pediatric Surgeons of the Department of Pediatrics of the Hospital Militar de Especialidades de la Mujer y Neonatología, for their collaboration in the referral of patients for treatment with robotic surgery, and your participation in the surgical teams or as trainees. As well as, the Pediatric Surgeons of the Hospital Angeles Lomas and the Hospital Español of Mexico City, who participated in the surgical teams as trainees.
Conflict of interest
The author declares to be Proctor of the da Vinci Surgical System and sometimes receives salary for advice to Surgeons in their first robotic procedures. In relation to the execution of this manuscript, no economic financing was received.
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Robotic surgery is performed with robotic devices, for example the Da Vinci system from Intuitive Surgical, which has a miniaturized camera capable of image magnification, a three-dimensional image of the surgical field, and the instruments are articulated with 7 degrees of freedom of movement, and the surgeon operates in a sitting position at a surgical console near the patient. Robotic surgery has gained an enormous surge in use on adults, but it has been slowly accepted for children, although it offers important advantages in complex surgeries. The areas of application of robotic surgery in the pediatric population include urological, general surgery, thoracic, oncological, and otorhinolaryngology, the largest application has been in urological surgery. There is evidence that robotic surgery in children is safe and it is important to offer its benefits. Intraoperative complications are rare, and the frequency of postoperative complications ranges from 0–15%. Recommendations for the implementation of a pediatric robotic surgery program are included. The future will be fascinating with upcoming advancements in robotic surgical systems, the use of artificial intelligence, and digital surgery.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75621",risUrl:"/chapter/ris/75621",signatures:"Mario Navarrete-Arellano",book:{id:"10569",type:"book",title:"Latest Developments in Medical Robotics Systems",subtitle:null,fullTitle:"Latest Developments in Medical Robotics Systems",slug:"latest-developments-in-medical-robotics-systems",publishedDate:"September 15th 2021",bookSignature:"Serdar Küçük",coverURL:"https://cdn.intechopen.com/books/images_new/10569.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83969-383-0",printIsbn:"978-1-83969-382-3",pdfIsbn:"978-1-83969-384-7",isAvailableForWebshopOrdering:!0,editors:[{id:"5424",title:"Dr.",name:"Serdar",middleName:null,surname:"Küçük",slug:"serdar-kucuk",fullName:"Serdar Küçük"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"342759",title:"Dr.",name:"Mario",middleName:null,surname:"Navarrete-Arellano",fullName:"Mario Navarrete-Arellano",slug:"mario-navarrete-arellano",email:"drcirugiaroboticamx@gmail.com",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342759/images/15279_n.png",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Characteristics, advantages, benefits, limitations and applications of robotic surgery",level:"1"},{id:"sec_2_2",title:"2.1 Characteristics",level:"2"},{id:"sec_3_2",title:"2.2 Advantages",level:"2"},{id:"sec_4_2",title:"2.3 Benefits",level:"2"},{id:"sec_5_2",title:"2.4 Limitations",level:"2"},{id:"sec_6_2",title:"2.5 Applications",level:"2"},{id:"sec_8",title:"3. Urologic robotic surgery",level:"1"},{id:"sec_8_2",title:"3.1 RAS on the upper urinary tract",level:"2"},{id:"sec_8_3",title:"3.1.1 Nephrectomy",level:"3"},{id:"sec_9_3",title:"3.1.2 Partial nephrectomy",level:"3"},{id:"sec_10_3",title:"3.1.3 Pyeloplasty",level:"3"},{id:"sec_11_3",title:"3.1.4 Ureteroureterostomy",level:"3"},{id:"sec_12_3",title:"3.1.5 Ureterocalicostomy",level:"3"},{id:"sec_14_2",title:"3.2 RAS on the lower urinary tract",level:"2"},{id:"sec_14_3",title:"3.2.1 Extravesical ureteral reimplantation",level:"3"},{id:"sec_15_3",title:"3.2.2 Appendico-vesicostomy and continent catheterizable channels",level:"3"},{id:"sec_15_4",title:"3.2.2.1 Appendicovesicostomy (Mitrofanoff)",level:"4"},{id:"sec_17_3",title:"3.2.3 Augmentation cystoplasty",level:"3"},{id:"sec_19_2",title:"3.3 Pediatric urology miscellaneous procedures",level:"2"},{id:"sec_21",title:"4. General surgery (gastrointestinal and hepatopancreatobiliary)",level:"1"},{id:"sec_21_2",title:"4.1 Fundoplication",level:"2"},{id:"sec_22_2",title:"4.2 Choledochal cyst resection",level:"2"},{id:"sec_23_2",title:"4.3 Kasai procedure",level:"2"},{id:"sec_24_2",title:"4.4 Pancreatic pathology",level:"2"},{id:"sec_25_2",title:"4.5 Soave pull-through",level:"2"},{id:"sec_26_2",title:"4.6 Treatment of duodenal obstruction",level:"2"},{id:"sec_27_2",title:"4.7 Various procedures in general surgery",level:"2"},{id:"sec_27_3",title:"4.7.1 Cholecystectomy",level:"3"},{id:"sec_28_3",title:"4.7.2 Splenectomy",level:"3"},{id:"sec_29_3",title:"4.7.3 Gynecological surgery",level:"3"},{id:"sec_30_3",title:"4.7.4 Heller’s cardiomyotomy for achalasia",level:"3"},{id:"sec_31_3",title:"4.7.5 Management for anorectal malformations",level:"3"},{id:"sec_34",title:"5. Thoracic robotic surgery",level:"1"},{id:"sec_34_2",title:"5.1 Pulmonary lobectomy",level:"2"},{id:"sec_35_2",title:"5.2 Congenital diaphragmatic hernia repair",level:"2"},{id:"sec_36_2",title:"5.3 Thymectomy",level:"2"},{id:"sec_37_2",title:"5.4 Other robotic thoracic procedures",level:"2"},{id:"sec_39",title:"6. Oncologic robotic surgery",level:"1"},{id:"sec_39_2",title:"6.1 Thoracic tumors",level:"2"},{id:"sec_40_2",title:"6.2 Abdominal tumors",level:"2"},{id:"sec_42",title:"7. Otorhinolaryngology",level:"1"},{id:"sec_43",title:"8. Author’s experience in robotic surgery",level:"1"},{id:"sec_44",title:"9. Implementation of a pediatric robotic surgery program",level:"1"},{id:"sec_44_2",title:"9.1 Planning",level:"2"},{id:"sec_45_2",title:"9.2 Development of the program",level:"2"},{id:"sec_46_2",title:"9.3 Robotic pediatric surgery team",level:"2"},{id:"sec_47_2",title:"9.4 Training, accreditation and credentialing",level:"2"},{id:"sec_48_2",title:"9.5 Program information data log",level:"2"},{id:"sec_50",title:"10. The future of robotic surgery in children",level:"1"},{id:"sec_51",title:"11. Conclusions",level:"1"},{id:"sec_52",title:"Acknowledgments",level:"1"},{id:"sec_55",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Ure B. Enthusiasm, evidence and ethics: the triple E of minimally invasive pediatric surgery. J Pediatr Surg. 2013;48(1):27-33. Doi: 10.1016/j.jpedsurg.2012.10.013'},{id:"B2",body:'Passerotti C, Peters CA. Pediatric robotic–assisted laparoscopy: adescription of the principle procedures. Sci World J. 2006;6:2581-2588. 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Doi: 10.1016/j.suc.2020.01.001'},{id:"B175",body:'https://www.digital.health/digital-surgery'},{id:"B176",body:'https://www.tynmagazine.com/que-es-la-cirugia-digital/ (Date Nov, 20, 2019)'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Mario Navarrete-Arellano",address:"drcirugiaroboticamx@gmail.com",affiliation:'
Hospital Central Militar and Hospital Angeles Lomas, Mexico City, Mexico
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The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.
",metaTitle:"Our story",metaDescription:"The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.",metaKeywords:null,canonicalURL:"/page/our-story",contentRaw:'[{"type":"htmlEditorComponent","content":"
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\\n\\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\\n\\n
The IntechOpen timeline
\\n\\n
2004
\\n\\n
\\n\\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\\n\\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\\n
\\n\\n
2005
\\n\\n
\\n\\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\\n
\\n\\n
2006
\\n\\n
\\n\\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\\n
\\n\\n
2008
\\n\\n
\\n\\t
Downloads milestone: 200,000 downloads reached
\\n
\\n\\n
2009
\\n\\n
\\n\\t
Publishing milestone: the first 100 Open Access STM books are published
\\n
\\n\\n
2010
\\n\\n
\\n\\t
Downloads milestone: one million downloads reached
\\n\\t
IntechOpen expands its book publishing into a new field: medicine.
\\n
\\n\\n
2011
\\n\\n
\\n\\t
Publishing milestone: More than five million downloads reached
\\n\\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\\n\\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\\n\\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\\n
\\n\\n
2012
\\n\\n
\\n\\t
Publishing milestone: 10 million downloads reached
\\n\\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\\n
\\n\\n
2013
\\n\\n
\\n\\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\\n
\\n\\n
2014
\\n\\n
\\n\\t
IntechOpen turns 10, with more than 30 million downloads to date.
\\n\\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\\n
\\n\\n
2015
\\n\\n
\\n\\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\\n\\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\\n\\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\\n\\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\\n
\\n\\n
2016
\\n\\n
\\n\\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\\n
\\n\\n
2017
\\n\\n
\\n\\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\\n\\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\n\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\n\n
The IntechOpen timeline
\n\n
2004
\n\n
\n\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\n\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\n
\n\n
2005
\n\n
\n\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\n
\n\n
2006
\n\n
\n\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\n
\n\n
2008
\n\n
\n\t
Downloads milestone: 200,000 downloads reached
\n
\n\n
2009
\n\n
\n\t
Publishing milestone: the first 100 Open Access STM books are published
\n
\n\n
2010
\n\n
\n\t
Downloads milestone: one million downloads reached
\n\t
IntechOpen expands its book publishing into a new field: medicine.
\n
\n\n
2011
\n\n
\n\t
Publishing milestone: More than five million downloads reached
\n\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\n\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\n\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\n
\n\n
2012
\n\n
\n\t
Publishing milestone: 10 million downloads reached
\n\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\n
\n\n
2013
\n\n
\n\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\n
\n\n
2014
\n\n
\n\t
IntechOpen turns 10, with more than 30 million downloads to date.
\n\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\n
\n\n
2015
\n\n
\n\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\n\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\n\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\n\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\n
\n\n
2016
\n\n
\n\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\n
\n\n
2017
\n\n
\n\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\n\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
\n
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Medicine",slug:"cardiology-and-cardiovascular-medicine"},numberOfBooks:1,numberOfSeries:0,numberOfAuthorsAndEditors:44,numberOfWosCitations:22,numberOfCrossrefCitations:20,numberOfDimensionsCitations:43,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicId:"988",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"5504",title:"Renin-Angiotensin System",subtitle:"Past, Present and Future",isOpenForSubmission:!1,hash:"66b46ee5dfa426cb08d97d2f261e5e0e",slug:"renin-angiotensin-system-past-present-and-future",bookSignature:"Anna Naidenova Tolekova",coverURL:"https://cdn.intechopen.com/books/images_new/5504.jpg",editedByType:"Edited by",editors:[{id:"143727",title:"Prof.",name:"Anna",middleName:"Naydenova",surname:"Tolekova",slug:"anna-tolekova",fullName:"Anna Tolekova"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:1,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"55894",doi:"10.5772/intechopen.69513",title:"The Function of Renin and the Role of Food-Derived Peptides as Direct Renin Inhibitors",slug:"the-function-of-renin-and-the-role-of-food-derived-peptides-as-direct-renin-inhibitors",totalDownloads:1491,totalCrossrefCites:2,totalDimensionsCites:10,abstract:"Food proteins contain active peptide fragments encrypted within their structure that can exert beneficial effects on human health above and beyond their expected nutritional value. Among many types of food-derived peptides, peptides with antihypertensive activity have received the most significant attention due to the prevalence of hypertension and its associated complications with pharmacological interventions. One strategy for the selection of potential food-derived antihypertensive peptides is to search for in vitro renin inhibitory activity. Thus far, various food protein-derived peptides and protein hydrolysates have shown in vitro renin inhibitory capacity. Many of these peptides have induced antihypertensive effects when orally administered to spontaneously hypertensive rats, and also, antihypertensive effects in hypertensive humans have been reported. Indeed, the results indicate that antihypertensive food protein-derived peptides may be acting at the same time via multiple pathways at the protein level as well as at the gene level modulating the renin-angiotensin system. Important knowledge on structure-function parameters of peptides is increasing constantly, which can greatly enhance the production and processing of peptides with high physiological efficacy. By means of novel nutrigenomic approaches, it is possible and, in future, perhaps essential to investigate the impact of peptides on the expression of genes and hence endeavor to optimize the nutritional and health effects delivered by peptides. Novel technologies are available to standardize and stabilize the concentrations of active peptides in the products in down-stream processing. The existing data provide strong potential for developing new added-value products with scientifically approved health effects for consumers. This review provides an overview of food-derived peptides that may mediate the antihypertensive activities through inhibiting renin, one of the key enzymes in renin-angiotensin system, and reviews also the safety and applicability aspects of the these peptides.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Anne Pihlanto and Sari Mäkinen",authors:[{id:"191941",title:"Ph.D.",name:"Anne",middleName:null,surname:"Pihlanto",slug:"anne-pihlanto",fullName:"Anne Pihlanto"},{id:"192566",title:"Dr.",name:"Sari",middleName:null,surname:"Mäkinen",slug:"sari-makinen",fullName:"Sari Mäkinen"}]},{id:"53100",doi:"10.5772/66076",title:"Signaling Pathways of Cardiac Remodeling Related to Angiotensin II",slug:"signaling-pathways-of-cardiac-remodeling-related-to-angiotensin-ii",totalDownloads:1740,totalCrossrefCites:6,totalDimensionsCites:8,abstract:"Heart failure affects more than 23 million people worldwide, and its prognosis remains poor. Hypertension is one of the most prominent human health problem and places individuals at a higher risk for heart failure. Several factors interplay the development of hypertension contributing for decompensated heart hypertrophy. The renin-angiotensin system (RAS) has been shown to be the foremost regulator of blood pressure. Many evidences have pointed out the importance of RAS and its key mediator, angiotensin II (Ang II), on signaling pathways involved in cardiac remodeling. The Ang II-induced hypertrophic effects seem to be related to increased reactive oxygen species (ROS). Under oxidative stress conditions, as those observed in hypertension and heart failure, the matrix metalloproteinases (MMP) is activated. Ang II is connected with TNF-α and TGF-β by ROS-NF-κB-MMP mechanisms, which are involved in heart failure. The rationale of the present chapter is structured on the progression of heart failure related to Ang II, TNF-α and TGF-β by common signaling pathways. Pharmacotherapeutics approaches to the heart failure abound, but the mortality rates remain high. This chapter will also describe molecular mechanisms involved in heart failure highlighting that TGF-β and/or TNF-α inhibitors could contribute to treatment to this serious clinical condition.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Carolina Baraldi Araujo Restini, Arthur F. Engracia Garcia, Henrique\nMelo Natalin, Guilherme Melo Natalin and Elen Rizzi",authors:[{id:"178144",title:"Dr.",name:"Carolina",middleName:null,surname:"Baraldi A. Restini",slug:"carolina-baraldi-a.-restini",fullName:"Carolina Baraldi A. Restini"},{id:"193457",title:"Dr.",name:"Henrique",middleName:null,surname:"Melo Natalin",slug:"henrique-melo-natalin",fullName:"Henrique Melo Natalin"},{id:"193458",title:"Dr.",name:"Arthur",middleName:null,surname:"Feierabend Engracia Garcia",slug:"arthur-feierabend-engracia-garcia",fullName:"Arthur Feierabend Engracia Garcia"},{id:"193459",title:"Dr.",name:"Guilherme",middleName:null,surname:"Melo Natalin",slug:"guilherme-melo-natalin",fullName:"Guilherme Melo Natalin"},{id:"193460",title:"Dr.",name:"Elen",middleName:null,surname:"Rizzi",slug:"elen-rizzi",fullName:"Elen Rizzi"}]},{id:"54072",doi:"10.5772/65919",title:"Local Renin-Angiotensin System at Liver and Crosstalk with Hepatic Diseases",slug:"local-renin-angiotensin-system-at-liver-and-crosstalk-with-hepatic-diseases",totalDownloads:1784,totalCrossrefCites:3,totalDimensionsCites:7,abstract:"The systemic renin-angiotensin system mainly regulates blood pressure and maintains kidney function. Recent studies have realized that renin-angiotensin system (RAS) has been found in many tissues, such as heart, liver, and kidney. Although RAS in heart and kidney has been well documented, the RAS in the liver has been evaluated in a few studies. Therefore, this chapter will be assessed it. Based on findings, RAS in the liver has presented almost all of its components, such as angiotensin-I (Ang-I), angiotensin-II (Ang-II), angiotensin-converting enzyme (ACE), angiotensin type-1 receptor (AT1), angiotensin type-2 receptor (AT2), named as classical RAS. Expect these components, the local RAS has had alternative pathway components, including angiotensin-converting enzyme 2 (ACE2) and chymase. Classical RAS has an opposite effect of alternative RAS. Although these local RAS might not be such a crucial for the tissue, it could be a more vital function under pathophysiologic conditions. The chapter the local RAS in the liver the under both physiologic and pathophysiologic conditions is highlighted.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Eylem Taskin and Celal Guven",authors:[{id:"192567",title:"Prof.",name:"Eylem",middleName:null,surname:"Taskin",slug:"eylem-taskin",fullName:"Eylem Taskin"},{id:"195229",title:"Dr.",name:"Celal",middleName:null,surname:"Guven",slug:"celal-guven",fullName:"Celal Guven"}]},{id:"54082",doi:"10.5772/67016",title:"Regulation of the Renin-Angiotensin-Aldosterone System by Reactive Oxygen Species",slug:"regulation-of-the-renin-angiotensin-aldosterone-system-by-reactive-oxygen-species",totalDownloads:1887,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"Angiotensin II (Ang II), the major effector of the renin-angiotensin-aldosterone system (RAAS), stimulates the production of reactive oxygen species (ROS) which are critically involved in Ang II-induced effects. Noteworthy, accumulating evidence indicates that ROS also regulate the activation of RAAS, contributing to the fine-tuning of this system under physiological conditions or to the amplification of the deleterious signaling in several pathologies. This chapter aims at giving an overview of the role of ROS in the regulation of expression, secretion and/or activity of several RAAS components.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Manuela Morato, Marta Reina-Couto, Dora Pinho, António Albino-\nTeixeira and Teresa Sousa",authors:[{id:"140800",title:"Prof.",name:"António",middleName:null,surname:"Albino-Teixeira",slug:"antonio-albino-teixeira",fullName:"António Albino-Teixeira"},{id:"142410",title:"Prof.",name:"Teresa",middleName:null,surname:"Sousa",slug:"teresa-sousa",fullName:"Teresa Sousa"},{id:"193340",title:"Prof.",name:"Manuela",middleName:null,surname:"Morato",slug:"manuela-morato",fullName:"Manuela Morato"},{id:"193341",title:"M.D.",name:"Marta",middleName:null,surname:"Reina-Couto",slug:"marta-reina-couto",fullName:"Marta Reina-Couto"},{id:"193342",title:"Prof.",name:"Dora",middleName:null,surname:"Pinho",slug:"dora-pinho",fullName:"Dora Pinho"}]},{id:"53588",doi:"10.5772/66997",title:"Renin-Angiotensin System on Reproductive Biology",slug:"renin-angiotensin-system-on-reproductive-biology",totalDownloads:1349,totalCrossrefCites:1,totalDimensionsCites:4,abstract:"In the female reproductive system, angiotensin II (ANG II) is a potential signaling molecule involved in ovarian follicle development, which acts through two transmembrane receptors. Within the ovarian follicle, there appear to be species differences in the precise pattern of localization of AGTR2 protein and it has an important role in in vitro maturation of oocytes in mammals. The infusion of ANG II induced ovulation in rabbits and the use of ANG II antagonists inhibited ovulation in rabbits, rats, and cattle. In fetal ovaries, AGTR2 protein was detected in ovigerous cords and preantral follicles throughout porcine and bovine gestation. In the oviduct, ANG II is responsible for the orchestration of the transport of gametes. In the male reproductive system, there is considerable evidence for the local synthesis of components of renin-angiotensin system (RAS) in male reproductive tissues. The roles of RAS in local processes at these sites are still uncertain, although there is evidence for involvement in tubular contractility, spermatogenesis, sperm maturation, capacitation, acrosomal exocytosis, and fertilization.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Anthony C.S. Castilho, Patrícia K. Fontes, Fernanda F. Franchi,\nPriscila H. Santos and Eduardo M. Razza",authors:[{id:"191450",title:"Associate Prof.",name:"Anthony",middleName:"César Souza",surname:"Castilho",slug:"anthony-castilho",fullName:"Anthony Castilho"},{id:"191848",title:"M.Sc.",name:"Patricia",middleName:"Kubo",surname:"Fontes",slug:"patricia-fontes",fullName:"Patricia Fontes"},{id:"191860",title:"MSc.",name:"Fernanda",middleName:null,surname:"Franchi",slug:"fernanda-franchi",fullName:"Fernanda Franchi"},{id:"191862",title:"MSc.",name:"Priscila",middleName:null,surname:"Santos",slug:"priscila-santos",fullName:"Priscila Santos"},{id:"191906",title:"MSc.",name:"Eduardo",middleName:null,surname:"Razza",slug:"eduardo-razza",fullName:"Eduardo Razza"}]}],mostDownloadedChaptersLast30Days:[{id:"53100",title:"Signaling Pathways of Cardiac Remodeling Related to Angiotensin II",slug:"signaling-pathways-of-cardiac-remodeling-related-to-angiotensin-ii",totalDownloads:1740,totalCrossrefCites:6,totalDimensionsCites:8,abstract:"Heart failure affects more than 23 million people worldwide, and its prognosis remains poor. Hypertension is one of the most prominent human health problem and places individuals at a higher risk for heart failure. Several factors interplay the development of hypertension contributing for decompensated heart hypertrophy. The renin-angiotensin system (RAS) has been shown to be the foremost regulator of blood pressure. Many evidences have pointed out the importance of RAS and its key mediator, angiotensin II (Ang II), on signaling pathways involved in cardiac remodeling. The Ang II-induced hypertrophic effects seem to be related to increased reactive oxygen species (ROS). Under oxidative stress conditions, as those observed in hypertension and heart failure, the matrix metalloproteinases (MMP) is activated. Ang II is connected with TNF-α and TGF-β by ROS-NF-κB-MMP mechanisms, which are involved in heart failure. The rationale of the present chapter is structured on the progression of heart failure related to Ang II, TNF-α and TGF-β by common signaling pathways. Pharmacotherapeutics approaches to the heart failure abound, but the mortality rates remain high. This chapter will also describe molecular mechanisms involved in heart failure highlighting that TGF-β and/or TNF-α inhibitors could contribute to treatment to this serious clinical condition.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Carolina Baraldi Araujo Restini, Arthur F. Engracia Garcia, Henrique\nMelo Natalin, Guilherme Melo Natalin and Elen Rizzi",authors:[{id:"178144",title:"Dr.",name:"Carolina",middleName:null,surname:"Baraldi A. Restini",slug:"carolina-baraldi-a.-restini",fullName:"Carolina Baraldi A. Restini"},{id:"193457",title:"Dr.",name:"Henrique",middleName:null,surname:"Melo Natalin",slug:"henrique-melo-natalin",fullName:"Henrique Melo Natalin"},{id:"193458",title:"Dr.",name:"Arthur",middleName:null,surname:"Feierabend Engracia Garcia",slug:"arthur-feierabend-engracia-garcia",fullName:"Arthur Feierabend Engracia Garcia"},{id:"193459",title:"Dr.",name:"Guilherme",middleName:null,surname:"Melo Natalin",slug:"guilherme-melo-natalin",fullName:"Guilherme Melo Natalin"},{id:"193460",title:"Dr.",name:"Elen",middleName:null,surname:"Rizzi",slug:"elen-rizzi",fullName:"Elen Rizzi"}]},{id:"54072",title:"Local Renin-Angiotensin System at Liver and Crosstalk with Hepatic Diseases",slug:"local-renin-angiotensin-system-at-liver-and-crosstalk-with-hepatic-diseases",totalDownloads:1784,totalCrossrefCites:3,totalDimensionsCites:7,abstract:"The systemic renin-angiotensin system mainly regulates blood pressure and maintains kidney function. Recent studies have realized that renin-angiotensin system (RAS) has been found in many tissues, such as heart, liver, and kidney. Although RAS in heart and kidney has been well documented, the RAS in the liver has been evaluated in a few studies. Therefore, this chapter will be assessed it. Based on findings, RAS in the liver has presented almost all of its components, such as angiotensin-I (Ang-I), angiotensin-II (Ang-II), angiotensin-converting enzyme (ACE), angiotensin type-1 receptor (AT1), angiotensin type-2 receptor (AT2), named as classical RAS. Expect these components, the local RAS has had alternative pathway components, including angiotensin-converting enzyme 2 (ACE2) and chymase. Classical RAS has an opposite effect of alternative RAS. Although these local RAS might not be such a crucial for the tissue, it could be a more vital function under pathophysiologic conditions. The chapter the local RAS in the liver the under both physiologic and pathophysiologic conditions is highlighted.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Eylem Taskin and Celal Guven",authors:[{id:"192567",title:"Prof.",name:"Eylem",middleName:null,surname:"Taskin",slug:"eylem-taskin",fullName:"Eylem Taskin"},{id:"195229",title:"Dr.",name:"Celal",middleName:null,surname:"Guven",slug:"celal-guven",fullName:"Celal Guven"}]},{id:"54082",title:"Regulation of the Renin-Angiotensin-Aldosterone System by Reactive Oxygen Species",slug:"regulation-of-the-renin-angiotensin-aldosterone-system-by-reactive-oxygen-species",totalDownloads:1887,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"Angiotensin II (Ang II), the major effector of the renin-angiotensin-aldosterone system (RAAS), stimulates the production of reactive oxygen species (ROS) which are critically involved in Ang II-induced effects. Noteworthy, accumulating evidence indicates that ROS also regulate the activation of RAAS, contributing to the fine-tuning of this system under physiological conditions or to the amplification of the deleterious signaling in several pathologies. This chapter aims at giving an overview of the role of ROS in the regulation of expression, secretion and/or activity of several RAAS components.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Manuela Morato, Marta Reina-Couto, Dora Pinho, António Albino-\nTeixeira and Teresa Sousa",authors:[{id:"140800",title:"Prof.",name:"António",middleName:null,surname:"Albino-Teixeira",slug:"antonio-albino-teixeira",fullName:"António Albino-Teixeira"},{id:"142410",title:"Prof.",name:"Teresa",middleName:null,surname:"Sousa",slug:"teresa-sousa",fullName:"Teresa Sousa"},{id:"193340",title:"Prof.",name:"Manuela",middleName:null,surname:"Morato",slug:"manuela-morato",fullName:"Manuela Morato"},{id:"193341",title:"M.D.",name:"Marta",middleName:null,surname:"Reina-Couto",slug:"marta-reina-couto",fullName:"Marta Reina-Couto"},{id:"193342",title:"Prof.",name:"Dora",middleName:null,surname:"Pinho",slug:"dora-pinho",fullName:"Dora Pinho"}]},{id:"54743",title:"Role of the Renin-Angiotensin System in Healthy and Pathological Pregnancies",slug:"role-of-the-renin-angiotensin-system-in-healthy-and-pathological-pregnancies",totalDownloads:1355,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Introduction: Pregnancy is a physiological process that necessitates many cardiovascular and hemodynamic adaptations to ensure the survival of the foetus and well‐being of the mother. The renin‐angiotensin system (RAS) has been suggested as key player in many of these changes as it is critical for blood pressure control as well as fluid and salt homeostasis in the non‐pregnant state.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Émilie Pepin, Shahin Shabanipour Dehboneh, Nozha Raguema,\nMaedeh Talebi Esfandarani and Julie L. Lavoie",authors:[{id:"191471",title:"Dr.",name:"Julie",middleName:"L.",surname:"Lavoie",slug:"julie-lavoie",fullName:"Julie Lavoie"},{id:"197626",title:"Dr.",name:"Émilie",middleName:null,surname:"Pépin",slug:"emilie-pepin",fullName:"Émilie Pépin"},{id:"197627",title:"MSc.",name:"Shahin",middleName:null,surname:"Shabanipour Dehboneh",slug:"shahin-shabanipour-dehboneh",fullName:"Shahin Shabanipour Dehboneh"},{id:"197628",title:"MSc.",name:"Nozha",middleName:null,surname:"Raguema",slug:"nozha-raguema",fullName:"Nozha Raguema"},{id:"197629",title:"MSc.",name:"Maedeh",middleName:null,surname:"Talebi Esfandarani",slug:"maedeh-talebi-esfandarani",fullName:"Maedeh Talebi Esfandarani"}]},{id:"53588",title:"Renin-Angiotensin System on Reproductive Biology",slug:"renin-angiotensin-system-on-reproductive-biology",totalDownloads:1349,totalCrossrefCites:1,totalDimensionsCites:4,abstract:"In the female reproductive system, angiotensin II (ANG II) is a potential signaling molecule involved in ovarian follicle development, which acts through two transmembrane receptors. Within the ovarian follicle, there appear to be species differences in the precise pattern of localization of AGTR2 protein and it has an important role in in vitro maturation of oocytes in mammals. The infusion of ANG II induced ovulation in rabbits and the use of ANG II antagonists inhibited ovulation in rabbits, rats, and cattle. In fetal ovaries, AGTR2 protein was detected in ovigerous cords and preantral follicles throughout porcine and bovine gestation. In the oviduct, ANG II is responsible for the orchestration of the transport of gametes. In the male reproductive system, there is considerable evidence for the local synthesis of components of renin-angiotensin system (RAS) in male reproductive tissues. The roles of RAS in local processes at these sites are still uncertain, although there is evidence for involvement in tubular contractility, spermatogenesis, sperm maturation, capacitation, acrosomal exocytosis, and fertilization.",book:{id:"5504",slug:"renin-angiotensin-system-past-present-and-future",title:"Renin-Angiotensin System",fullTitle:"Renin-Angiotensin System - Past, Present and Future"},signatures:"Anthony C.S. Castilho, Patrícia K. Fontes, Fernanda F. Franchi,\nPriscila H. Santos and Eduardo M. 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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, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for 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:"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:null},{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:"Beijing University of Technology",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:"Lakhno Igor Victorovich 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.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of 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 a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), 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 DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. 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: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{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:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{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:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{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:"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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We welcome chapters presenting research on the many applications of multi-agent studies including, but not limited to, the following key areas: machine learning for multi-agent systems; modeling swarms robots and flocks of UAVs with multi-agent systems; decision science and multi-agent systems; software engineering for and with multi-agent systems; tools and technologies of multi-agent systems.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",keywords:"Collaborative Intelligence, Learning, Distributed Control System, Swarm Robotics, Decision Science, Software Engineering"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:{id:"25",title:"Environmental Sciences",doi:"10.5772/intechopen.100362",issn:"2754-6713",scope:"
\r\n\tScientists have long researched to understand the environment and man’s place in it. The search for this knowledge grows in importance as rapid increases in population and economic development intensify humans’ stresses on ecosystems. Fortunately, rapid increases in multiple scientific areas are advancing our understanding of environmental sciences. Breakthroughs in computing, molecular biology, ecology, and sustainability science are enhancing our ability to utilize environmental sciences to address real-world problems. \r\n\tThe four topics of this book series - Pollution; Environmental Resilience and Management; Ecosystems and Biodiversity; and Water Science - will address important areas of advancement in the environmental sciences. They will represent an excellent initial grouping of published works on these critical topics.
",coverUrl:"https://cdn.intechopen.com/series/covers/25.jpg",latestPublicationDate:"April 13th, 2022",hasOnlineFirst:!1,numberOfOpenTopics:4,numberOfPublishedChapters:9,numberOfPublishedBooks:1,editor:{id:"197485",title:"Dr.",name:"J. Kevin",middleName:null,surname:"Summers",fullName:"J. Kevin Summers",profilePictureURL:"https://mts.intechopen.com/storage/users/197485/images/system/197485.jpg",biography:"J. Kevin Summers is a Senior Research Ecologist at the Environmental Protection Agency’s (EPA) Gulf Ecosystem Measurement and Modeling Division. He is currently working with colleagues in the Sustainable and Healthy Communities Program to develop an index of community resilience to natural hazards, an index of human well-being that can be linked to changes in the ecosystem, social and economic services, and a community sustainability tool for communities with populations under 40,000. He leads research efforts for indicator and indices development. Dr. Summers is a systems ecologist and began his career at the EPA in 1989 and has worked in various programs and capacities. This includes leading the National Coastal Assessment in collaboration with the Office of Water which culminated in the award-winning National Coastal Condition Report series (four volumes between 2001 and 2012), and which integrates water quality, sediment quality, habitat, and biological data to assess the ecosystem condition of the United States estuaries. He was acting National Program Director for Ecology for the EPA between 2004 and 2006. He has authored approximately 150 peer-reviewed journal articles, book chapters, and reports and has received many awards for technical accomplishments from the EPA and from outside of the agency. Dr. Summers holds a BA in Zoology and Psychology, an MA in Ecology, and Ph.D. in Systems Ecology/Biology.",institutionString:null,institution:{name:"Environmental Protection Agency",institutionURL:null,country:{name:"United States of America"}}},subseries:[{id:"38",title:"Pollution",keywords:"Human activity, Pollutants, Reduced risks, Population growth, Waste disposal, Remediation, Clean environment",scope:"
\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
",annualVolume:11966,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",editor:{id:"110740",title:"Dr.",name:"Ismail M.M.",middleName:null,surname:"Rahman",fullName:"Ismail M.M. Rahman",profilePictureURL:"https://mts.intechopen.com/storage/users/110740/images/2319_n.jpg",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"201020",title:"Dr.",name:"Zinnat Ara",middleName:null,surname:"Begum",fullName:"Zinnat Ara Begum",profilePictureURL:"https://mts.intechopen.com/storage/users/201020/images/system/201020.jpeg",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorThree:null,editorialBoard:[{id:"252368",title:"Dr.",name:"Meng-Chuan",middleName:null,surname:"Ong",fullName:"Meng-Chuan Ong",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRVotQAG/Profile_Picture_2022-05-20T12:04:28.jpg",institutionString:null,institution:{name:"Universiti Malaysia Terengganu",institutionURL:null,country:{name:"Malaysia"}}},{id:"63465",title:"Prof.",name:"Mohamed Nageeb",middleName:null,surname:"Rashed",fullName:"Mohamed Nageeb Rashed",profilePictureURL:"https://mts.intechopen.com/storage/users/63465/images/system/63465.gif",institutionString:null,institution:{name:"Aswan University",institutionURL:null,country:{name:"Egypt"}}},{id:"187907",title:"Dr.",name:"Olga",middleName:null,surname:"Anne",fullName:"Olga Anne",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBE5QAO/Profile_Picture_2022-04-07T09:42:13.png",institutionString:null,institution:{name:"Klaipeda State University of Applied Sciences",institutionURL:null,country:{name:"Lithuania"}}}]},{id:"39",title:"Environmental Resilience and Management",keywords:"Anthropic effects, Overexploitation, Biodiversity loss, Degradation, Inadequate Management, SDGs adequate practices",scope:"
\r\n\tThe environment is subject to severe anthropic effects. Among them are those associated with pollution, resource extraction and overexploitation, loss of biodiversity, soil degradation, disorderly land occupation and planning, and many others. These anthropic effects could potentially be caused by any inadequate management of the environment. However, ecosystems have a resilience that makes them react to disturbances which mitigate the negative effects. It is critical to understand how ecosystems, natural and anthropized, including urban environments, respond to actions that have a negative influence and how they are managed. It is also important to establish when the limits marked by the resilience and the breaking point are achieved and when no return is possible. The main focus for the chapters is to cover the subjects such as understanding how the environment resilience works, the mechanisms involved, and how to manage them in order to improve our interactions with the environment and promote the use of adequate management practices such as those outlined in the United Nations’ Sustainable Development Goals.
",annualVolume:11967,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/39.jpg",editor:{id:"137040",title:"Prof.",name:"Jose",middleName:null,surname:"Navarro-Pedreño",fullName:"Jose Navarro-Pedreño",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRAXrQAO/Profile_Picture_2022-03-09T15:50:19.jpg",institutionString:"Miguel Hernández University of Elche, Spain",institution:null},editorTwo:null,editorThree:null,editorialBoard:[{id:"177015",title:"Prof.",name:"Elke Jurandy",middleName:null,surname:"Bran Nogueira Cardoso",fullName:"Elke Jurandy Bran Nogueira Cardoso",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRGxzQAG/Profile_Picture_2022-03-25T08:32:33.jpg",institutionString:"Universidade de São Paulo, Brazil",institution:null},{id:"211260",title:"Dr.",name:"Sandra",middleName:null,surname:"Ricart",fullName:"Sandra Ricart",profilePictureURL:"https://mts.intechopen.com/storage/users/211260/images/system/211260.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}}]},{id:"40",title:"Ecosystems and Biodiversity",keywords:"Ecosystems, Biodiversity, Fauna, Taxonomy, Invasive species, Destruction of habitats, Overexploitation of natural resources, Pollution, Global warming, Conservation of natural spaces, Bioremediation",scope:"
\r\n\tIn general, the harsher the environmental conditions in an ecosystem, the lower the biodiversity. Changes in the environment caused by human activity accelerate the impoverishment of biodiversity.
\r\n
\r\n\tBiodiversity refers to “the variability of living organisms from any source, including terrestrial, marine and other aquatic ecosystems and the ecological complexes of which they are part; it includes diversity within each species, between species, and that of ecosystems”.
\r\n
\r\n\tBiodiversity provides food security and constitutes a gene pool for biotechnology, especially in the field of agriculture and medicine, and promotes the development of ecotourism.
\r\n
\r\n\tCurrently, biologists admit that we are witnessing the first phases of the seventh mass extinction caused by human intervention. It is estimated that the current rate of extinction is between a hundred and a thousand times faster than it was when man first appeared. The disappearance of species is caused not only by an accelerated rate of extinction, but also by a decrease in the rate of emergence of new species as human activities degrade the natural environment. The conservation of biological diversity is "a common concern of humanity" and an integral part of the development process. Its objectives are “the conservation of biological diversity, the sustainable use of its components, and the fair and equitable sharing of the benefits resulting from the use of genetic resources”.
\r\n
\r\n\tThe following are the main causes of biodiversity loss:
\r\n
\r\n\t• The destruction of natural habitats to expand urban and agricultural areas and to obtain timber, minerals and other natural resources.
\r\n
\r\n\t• The introduction of alien species into a habitat, whether intentionally or unintentionally which has an impact on the fauna and flora of the area, and as a result, they are reduced or become extinct.
\r\n
\r\n\t• Pollution from industrial and agricultural products, which devastate the fauna and flora, especially those in fresh water.
\r\n
\r\n\t• Global warming, which is seen as a threat to biological diversity, and will become increasingly important in the future.
",annualVolume:11968,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/40.jpg",editor:{id:"209149",title:"Prof.",name:"Salustiano",middleName:null,surname:"Mato",fullName:"Salustiano Mato",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLREQA4/Profile_Picture_2022-03-31T10:23:50.png",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorTwo:{id:"60498",title:"Prof.",name:"Josefina",middleName:null,surname:"Garrido",fullName:"Josefina Garrido",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRj1VQAS/Profile_Picture_2022-03-31T10:06:51.jpg",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorThree:{id:"464288",title:"Dr.",name:"Francisco",middleName:null,surname:"Ramil",fullName:"Francisco Ramil",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003RI7lHQAT/Profile_Picture_2022-03-31T10:15:35.png",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorialBoard:[{id:"220987",title:"Dr.",name:"António",middleName:"Onofre",surname:"Soares",fullName:"António Soares",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNtzQAG/Profile_Picture_1644499672340",institutionString:null,institution:{name:"University of the Azores",institutionURL:null,country:{name:"Portugal"}}}]},{id:"41",title:"Water Science",keywords:"Water, Water resources, Freshwater, Hydrological processes, Utilization, Protection",scope:"
\r\n\tWater is not only a crucial substance needed for biological life on Earth, but it is also a basic requirement for the existence and development of the human society. Owing to the importance of water to life on Earth, early researchers conducted numerous studies and analyses on the liquid form of water from the perspectives of chemistry, physics, earth science, and biology, and concluded that Earth is a "water polo". Water covers approximately 71% of Earth's surface. However, 97.2% of this water is seawater, 21.5% is icebergs and glaciers, and only 0.65% is freshwater that can be used directly by humans. As a result, the amount of water reserves available for human consumption is limited. The development, utilization, and protection of freshwater resources has become the focus of water science research for the continued improvement of human livelihoods and society.
\r\n
\r\n\tWater exists as solid, liquid, and gas within Earth’s atmosphere, lithosphere, and biosphere. Liquid water is used for a variety of purposes besides drinking, including power generation, ecology, landscaping, and shipping. Because water is involved in various environmental hydrological processes as well as numerous aspects of the economy and human society, the study of various phenomena in the hydrosphere, the laws governing their occurrence and development, the relationship between the hydrosphere and other spheres of Earth, and the relationship between water and social development, are all part of water science. Knowledge systems for water science are improving continuously. Water science has become a specialized field concerned with the identification of its physical, chemical, and biological properties. In addition, it reveals the laws of water distribution, movement, and circulation, and proposes methods and tools for water development, utilization, planning, management, and protection. Currently, the field of water science covers research related to topics such as hydrology, water resources and water environment. It also includes research on water related issues such as safety, engineering, economy, law, culture, information, and education.
",annualVolume:11969,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/41.jpg",editor:{id:"349630",title:"Dr.",name:"Yizi",middleName:null,surname:"Shang",fullName:"Yizi Shang",profilePictureURL:"https://mts.intechopen.com/storage/users/349630/images/system/349630.jpg",institutionString:"China Institute of Water Resources and Hydropower Research",institution:{name:"China Institute of Water Resources and Hydropower Research",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"216491",title:"Dr.",name:"Charalampos",middleName:null,surname:"Skoulikaris",fullName:"Charalampos Skoulikaris",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRMsbQAG/Profile_Picture_2022-04-21T09:31:55.jpg",institutionString:null,institution:{name:"Aristotle University of Thessaloniki",institutionURL:null,country:{name:"Greece"}}},{id:"300124",title:"Prof.",name:"Thomas",middleName:null,surname:"Shahady",fullName:"Thomas Shahady",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002kuIgmQAE/Profile_Picture_2022-03-18T07:32:10.jpg",institutionString:null,institution:{name:"Lynchburg College",institutionURL:null,country:{name:"United States of America"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/113153",hash:"",query:{},params:{id:"113153"},fullPath:"/profiles/113153",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()