MAPT mutations found in main neurodegenerative diseases.
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{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"}]},book:{item:{type:"book",id:"6344",leadTitle:null,fullTitle:"Biological Resources of Water",title:"Biological Resources of Water",subtitle:null,reviewType:"peer-reviewed",abstract:'The book is divided into two sections and represents the current trend of research in aquatic bioresource. In the section "Biology, Ecology and Physiological Chemistry", high-impact articles are contributed on reproduction, population genetics, evolution, biodiversity, biology and ecology of different aquatic faunas. Physiological chemistry of lipid, bioactive pharmaceuticals and chemical ecological aspects of aquatic organisms were discussed. In the section entitled "Conservation and Sustainable Management", authors highlighted conservation- and management-related issues of various bioresources in different regions of the earth. The book mentions the biological, ecological, physiological and genetic significance of aquatic organisms with resource potential. The authors stressed on rational utilisation and management of bioresource ensuring minimal damage of the aquatic ecosystem. This book would provide a direction towards sustainable ecological management of bioresource.',isbn:"978-1-78923-081-9",printIsbn:"978-1-78923-080-2",pdfIsbn:"978-1-83881-416-8",doi:"10.5772/intechopen.69758",price:139,priceEur:155,priceUsd:179,slug:"biological-resources-of-water",numberOfPages:340,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"ca4f407275697c7cf547debc6b1e85a9",bookSignature:"Sajal Ray",publishedDate:"April 25th 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6344.jpg",numberOfDownloads:20204,numberOfWosCitations:29,numberOfCrossrefCitations:32,numberOfCrossrefCitationsByBook:4,numberOfDimensionsCitations:67,numberOfDimensionsCitationsByBook:5,hasAltmetrics:1,numberOfTotalCitations:128,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 16th 2017",dateEndSecondStepPublish:"July 7th 2017",dateEndThirdStepPublish:"October 3rd 2017",dateEndFourthStepPublish:"January 1st 2018",dateEndFifthStepPublish:"March 2nd 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"173697",title:"Prof.",name:"Sajal",middleName:null,surname:"Ray",slug:"sajal-ray",fullName:"Sajal Ray",profilePictureURL:"https://mts.intechopen.com/storage/users/173697/images/system/173697.jpeg",biography:"Sajal Ray received an MSc in Zoology and MPhil in Environmental Science from Calcutta University, India, and a Ph.D. from Jadavpur University, India. His thesis reported the immunotoxicity of pesticides in an economically important snail of India. As a recipient of the Fogarty Visiting Fellowship, Dr. Ray carried out his postdoctoral research in cardiac pathology at the National Institutes of Health, USA. His research interest is studying the immunological responses of molluscs, sponges, crabs, and earthworms exposed to pollutants. His team is engaged in understanding the evolutionary mechanism of immunity in phylogeny. He has presented his research at various conferences including the World Congress of Malacology, Washington DC. Dr. Ray is currently a Professor of Zoology at Calcutta University.",institutionString:"University of Calcutta",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"6",institution:{name:"University of Calcutta",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"659",title:"Aquatic Ecosystem",slug:"earth-and-planetary-sciences-marine-biology-aquatic-ecosystem"}],chapters:[{id:"58420",title:"Egg-Laying in the Cuttlefish Sepia officinalis",doi:"10.5772/intechopen.71915",slug:"egg-laying-in-the-cuttlefish-sepia-officinalis",totalDownloads:1247,totalCrossrefCites:4,totalDimensionsCites:3,hasAltmetrics:0,abstract:"This chapter reviews studies about egg-laying in the cuttlefish Sepia officinalis. Egg masses are spawned in specific mating and spawning coastal areas where mates aggregate between April and June in the English Channel and all year long in the Mediterranean Sea. Environmental cues are clearly involved in the aggregation process, but chemical communication also plays a determining role in these complex mechanisms. The successive steps of egg-laying are orchestrated by three classes of regulatory peptides: (1) neuropeptides that integrate environmental cues, (2) ovarian regulatory peptides that modulate the activity of the genital tract, and (3) sex pheromones expressed and released by the oviduct gland. After egg-laying, embryo protection is ensured for 8-10 weeks by a multilayer capsule secreted by the accessory sex glands. The oviduct gland secretes the inner layer of the egg case. The main nidamental gland secretes the main polysaccharides and glycoproteins, such as Sepia Egg Case Proteins, involved in capsule formation and in embryo protection. The accessory nidamental gland expresses specific proteins inherent in the structural organization of the gland, and hosts symbiotic bacteria. Similarly to salivary glands, this gland secretes immune factors possibly associated with gamete and/or embryo protection.",signatures:"Céline Zatylny-Gaudin and Joël Henry",downloadPdfUrl:"/chapter/pdf-download/58420",previewPdfUrl:"/chapter/pdf-preview/58420",authors:[{id:"220762",title:"Dr.",name:"Céline",surname:"Zatylny-Gaudin",slug:"celine-zatylny-gaudin",fullName:"Céline Zatylny-Gaudin"},{id:"224484",title:"Prof.",name:"Joël",surname:"Henry",slug:"joel-henry",fullName:"Joël Henry"}],corrections:null},{id:"58026",title:"Pond Snail Reproduction as Model in the Environmental Risk Assessment: Reality and Doubts",doi:"10.5772/intechopen.72216",slug:"pond-snail-reproduction-as-model-in-the-environmental-risk-assessment-reality-and-doubts",totalDownloads:1144,totalCrossrefCites:4,totalDimensionsCites:10,hasAltmetrics:1,abstract:"In European limnetic systems, the most relevant endocrine-disrupting chemicals (EDCs) of steroid type are the natural and synthetic hormones, phytosterols, pesticides, biocides and other chemicals produced by the plastic industry. Their presence in aquatic ecosystems represents a potentially adverse environmental and public health impact. Furthermore, this is a warning signal that the current handling of pharmaceuticals needs to be further improved. Nowadays, it has become clear that EDCs have specific disturbing effects on the neuroendocrine system of invertebrate and vertebrate aquatic animals, particularly gastropods. Among a latter, pond snail (Lymnaea stagnalis) has been used as the first aquatic non-arthropod test organism in studying the effect of EDCs because they are sensitive to various anthropogenic steroids, like progestogens. Investigating a variety of reproductive endpoints of Lymnaea, such as fecundity, oocyte production, egg mass production, the quality of egg masses, the shell size in development and after egg-laying, the time window of cell division in the offspring, the metabolite content of single-cell zygotes and egg albumen has concluded that progestogen contaminations in water are detrimental for reproduction and early stage development of Lymnaea. This chapter is an attempt to show whether Lymnaea reproduction, despite many altering reproductive endpoints, is a suitable model for environmental risk assessment or not.",signatures:"Zsolt Pirger, Zita Zrinyi, Gábor Maász, Éva Molnár and Tibor Kiss",downloadPdfUrl:"/chapter/pdf-download/58026",previewPdfUrl:"/chapter/pdf-preview/58026",authors:[{id:"215188",title:"Dr.",name:"Zsolt",surname:"Pirger",slug:"zsolt-pirger",fullName:"Zsolt Pirger"},{id:"215190",title:"MSc.",name:"Zita",surname:"Zrinyi",slug:"zita-zrinyi",fullName:"Zita Zrinyi"},{id:"215191",title:"Dr.",name:"Gabor",surname:"Maasz",slug:"gabor-maasz",fullName:"Gabor Maasz"},{id:"215193",title:"Prof.",name:"Tibor",surname:"Kiss",slug:"tibor-kiss",fullName:"Tibor Kiss"}],corrections:null},{id:"56944",title:"Genetic Characteristics of Southern and Northern Brook Trout (Salvelinus fontinalis) Populations at the Zone of Contact",doi:"10.5772/intechopen.70719",slug:"genetic-characteristics-of-southern-and-northern-brook-trout-salvelinus-fontinalis-populations-at-th",totalDownloads:938,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Population genetic evidence suggests differentiation among evolutionarily significant units of southern and northern Appalachian brook trout, with the zone of contact in southwestern Virginia. Before this differentiation was recognized, brook trout of northern origin were stocked throughout the southeastern United States. In order to determine this differentiation, established allozyme markers were used to classify 56 southwest Virginia populations as southern, northern, or introgressed. Variation at 4 polymorphic loci, including the diagnostic creatine kinase (CK-A2*) locus, indicated that 19 populations were of southern origin, 5 of northern origin, and 32 of mixed genetic origin. Data compiled among genetic studies of brook trout in the southern Appalachians showed that the southern/northern break is sharp, occurring at the New/Roanoke-James watershed divide. New River drainage populations exhibited the southern allele at high frequency, suggesting their historic native character as southern, with presence of northern alleles due to stocking or stream capture events. In conclusion, the present study suggests that management of southern Appalachian brook trout should include: (1) genetically cognizant planning of stocking events, (2) management of populations on a stream-by-stream basis, (3) prioritized conservation of pure southern brook trout populations, and (4) use of southern Appalachian hatchery stocks in restoration efforts.",signatures:"Joanne E. Printz, Joseph Williams and Eric M. Hallerman",downloadPdfUrl:"/chapter/pdf-download/56944",previewPdfUrl:"/chapter/pdf-preview/56944",authors:[{id:"79633",title:"Prof.",name:"Eric",surname:"Hallerman",slug:"eric-hallerman",fullName:"Eric Hallerman"},{id:"207766",title:"Ms.",name:"Joanne",surname:"Printz",slug:"joanne-printz",fullName:"Joanne Printz"},{id:"207768",title:"Mr.",name:"Joe",surname:"Williams",slug:"joe-williams",fullName:"Joe Williams"}],corrections:null},{id:"59375",title:"Alien Fish Species in France with Emphasis on the Recent Invasion of Gobies",doi:"10.5772/intechopen.73408",slug:"alien-fish-species-in-france-with-emphasis-on-the-recent-invasion-of-gobies",totalDownloads:1087,totalCrossrefCites:4,totalDimensionsCites:8,hasAltmetrics:0,abstract:"Introduction of alien species constitutes worldwide one of the major threats to biodiversity, particularly in freshwater ecosystems. In France, the number of alien aquatic plant and animal species has increased exponentially over time in freshwater ecosystems and shows no sign of decreasing. For fish only, more than 40 alien species have been either voluntary or involuntary introduced in the past decades. About two-thirds are still present today and at least 26 are naturalized. As in many European countries, the fish introduction history in France switched from voluntary introduction in the nineteenth century (aquaculture, sport fishing, and management of ecosystems) to unintentional but human-aided introductions (aquarium trade and global ship transport). The negative impacts of alien species on native species and ecosystems are most often unknown in France and needs further studies to develop a functional policy on alien species introductions and the protection of aquatic ecosystems integrity. The information gathered allow discussing the possible reasons explaining whether an alien species is able or not to establish sustainable populations in France and thereafter became invasive, such as gobies recently arrived.",signatures:"Fabrice Teletchea and Jean-Nicolas Beisel",downloadPdfUrl:"/chapter/pdf-download/59375",previewPdfUrl:"/chapter/pdf-preview/59375",authors:[{id:"190135",title:"Dr.",name:"Fabrice",surname:"Teletchea",slug:"fabrice-teletchea",fullName:"Fabrice Teletchea"},{id:"207530",title:"Dr.",name:"Jean-Nicolas",surname:"Beisel",slug:"jean-nicolas-beisel",fullName:"Jean-Nicolas Beisel"}],corrections:null},{id:"57770",title:"Ice Age Terrestrial and Freshwater Gastropod Refugia in the Carpathian Basin, Central Europe",doi:"10.5772/intechopen.71910",slug:"ice-age-terrestrial-and-freshwater-gastropod-refugia-in-the-carpathian-basin-central-europe",totalDownloads:1350,totalCrossrefCites:1,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Thanks to its unique microclimatic, geomorphological , hydrological conditions forming a mosaic-like environment present at all scales, numerous Late Tertiary and Pleistocene warmth-loving gastropod taxa managed to find refugee within the Carpathian Basin during the major-minor cold spells of the Ice Age. This complex system of refugia have been continuously functioning and evolving since the Late Tertiary through the entire Pleistocene and the Holocene. To understand the spatial and temporal evolution of refugia, detailed paleoecological investigations have been implemented, results of which are summed here. The high-grade fractal-like complexity of the environment led to the emergence of a so-called dual refugia, which is a unique feature of the Carpathian Basin. This temporally parallel but spatially differing presence of habitats for taxa of contrasting ecological needs was noted for paleotemperature gradients and temperate woodland and steppe habitat types as well. Furthermore, detailed geological and paleoecological analysis of a small Pleistocene hot-spring fed pond revealed information about the evolution of endemic thermophylous freshwater gastropod taxa within this microrefugia. This chapter is aimed to give an overview of the nature, evolution of temperate terrestrial and freshwater gastropod refugia present in the Carpathian Basin during the Ice Age.",signatures:"Pál Sümegi, Sándor Gulyás, Dávid Molnár, Katalin Náfrádi, Tünde\nTörőcsik, Balázs P. Sümegi, Tamás Müller, Gábor Szilágyi and Zoltán\nVarga",downloadPdfUrl:"/chapter/pdf-download/57770",previewPdfUrl:"/chapter/pdf-preview/57770",authors:[{id:"84791",title:"Dr.",name:"Tamás",surname:"Müller",slug:"tamas-muller",fullName:"Tamás Müller"},{id:"216563",title:"Dr.",name:"Sandor",surname:"Gulyas",slug:"sandor-gulyas",fullName:"Sandor Gulyas"},{id:"216564",title:"Prof.",name:"Pál",surname:"Sümegi",slug:"pal-sumegi",fullName:"Pál Sümegi"},{id:"216565",title:"Dr.",name:"Dávid",surname:"Molnár",slug:"david-molnar",fullName:"Dávid Molnár"},{id:"216566",title:"Dr.",name:"Katalin",surname:"Náfrádi",slug:"katalin-nafradi",fullName:"Katalin Náfrádi"},{id:"216567",title:"Ms.",name:"Tünde",surname:"Törőcsik",slug:"tunde-torocsik",fullName:"Tünde Törőcsik"},{id:"216568",title:"Mr.",name:"Balázs Pál",surname:"Sümegi",slug:"balazs-pal-sumegi",fullName:"Balázs Pál Sümegi"},{id:"216570",title:"Mr.",name:"Gábor",surname:"Szilágyi",slug:"gabor-szilagyi",fullName:"Gábor Szilágyi"},{id:"216571",title:"Prof.",name:"Zoltán",surname:"Varga",slug:"zoltan-varga",fullName:"Zoltán Varga"}],corrections:null},{id:"58001",title:"Biodiversity of Gastropod in the Southeastern Gulf of California, Mexico",doi:"10.5772/intechopen.72201",slug:"biodiversity-of-gastropod-in-the-southeastern-gulf-of-california-mexico",totalDownloads:1130,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Currently, studying the environment is important because of the phenomena that take place on the earth every day. That is why it is a priority to carry out studies that relate environmental changes to the biology of organisms. This allows us to know the interactions with the environment, and in this way solve, reduce or prevent ecological and economic problems, if they are organisms with a commercial value. The objective of this investigation is to determine ecological parameters of the gastropod community from the intertidal zone on five islands from the Gulf of California, México, to model the diversity, distribution and abundance of malacological fauna. We considered to evaluate the Shannon-Wiener diversity (H′), Pielou’s of evenness (J) and the Margalef species richness indexes, in order to evaluate through an analysis from biotic and abiotic factors, the species status that was collected from the exposed and non-exposed zone tidal. The generated data were contemplated from a year-based biodiversity project (2016–2017) on the following islands: Patos, Bledos, Bleditos, Tunosa, and Mazocahui which belong to the Ohuira lagoon in Ahome, Sinaloa, southeast of the Gulf of California, México. Likewise a status about the importance of gastropods is mentioned for the study area.",signatures:"Ruth Escamilla-Montes, Salvador Granados-Alcantar, Genaro\nDiarte-Plata, Paúl de J. Pacheco-Heredia, Juan A. Gill-León, Antonio\nLuna-González, Jesús A. Fierro-Coronado, Píndaro Álvarez-Ruíz,\nHéctor M. Esparza-Leal and Wenceslao Valenzuela-Quiñonez",downloadPdfUrl:"/chapter/pdf-download/58001",previewPdfUrl:"/chapter/pdf-preview/58001",authors:[{id:"198991",title:"Dr.",name:"Genaro",surname:"Diarte-Plata",slug:"genaro-diarte-plata",fullName:"Genaro Diarte-Plata"},{id:"199061",title:"Dr.",name:"Ruth",surname:"Escamilla-Montes",slug:"ruth-escamilla-montes",fullName:"Ruth Escamilla-Montes"},{id:"199062",title:"Dr.",name:"Antonio",surname:"Luna-González",slug:"antonio-luna-gonzalez",fullName:"Antonio Luna-González"},{id:"199065",title:"MSc.",name:"Jesús Arturo",surname:"Fierro-Coronado",slug:"jesus-arturo-fierro-coronado",fullName:"Jesús Arturo Fierro-Coronado"},{id:"199067",title:"Dr.",name:"Héctor Manuel",surname:"Esparza-Leal",slug:"hector-manuel-esparza-leal",fullName:"Héctor Manuel Esparza-Leal"},{id:"205357",title:"Dr.",name:"Salvador",surname:"Granados-Alcantar",slug:"salvador-granados-alcantar",fullName:"Salvador Granados-Alcantar"},{id:"213875",title:"Dr.",name:"Wenceslao",surname:"Valenzuela-Quiñones",slug:"wenceslao-valenzuela-quinones",fullName:"Wenceslao Valenzuela-Quiñones"},{id:"213876",title:"Dr.",name:"Píndaro",surname:"Álvarez-Ruíz",slug:"pindaro-alvarez-ruiz",fullName:"Píndaro Álvarez-Ruíz"},{id:"227451",title:"Prof.",name:"Paúl De J.",surname:"Pacheco-Heredia",slug:"paul-de-j.-pacheco-heredia",fullName:"Paúl De J. Pacheco-Heredia"},{id:"227452",title:"Prof.",name:"Juan Alexis",surname:"Gill-León",slug:"juan-alexis-gill-leon",fullName:"Juan Alexis Gill-León"}],corrections:null},{id:"57531",title:"Marine Snails of the Genus Phorcus: Biology and Ecology of Sentinel Species for Human Impacts on the Rocky Shores",doi:"10.5772/intechopen.71614",slug:"marine-snails-of-the-genus-phorcus-biology-and-ecology-of-sentinel-species-for-human-impacts-on-the-",totalDownloads:1764,totalCrossrefCites:5,totalDimensionsCites:15,hasAltmetrics:1,abstract:"In this review article, the authors explore a broad spectrum of subjects associated to marine snails of the genus Phorcus Risso, 1826, namely, distribution, habitat, behaviour and life history traits, and the consequences of anthropological impacts, such as fisheries, pollution, and climate changes, on these species. This work focuses on discussing the ecological importance of these sentinel species and their interactions in the rocky shores as well as the anthropogenic impacts to which they are subjected. One of the main anthropogenic stresses that affect Phorcus species is fisheries. Topshell harvesting is recognized as occurring since prehistoric times and has evolved through time from a subsistence to commercial exploitation level. However, there is a gap of information concerning these species that hinders stock assessment and management required for sustainable exploitation. Additionally, these keystone species are useful tools in assessing coastal habitat quality, due to their eco-biological features. Contamination of these species with heavy metals carries serious risk for animal and human health due to their potential of biomagnification in the food chain. Thus, the use of these species as bioindicators is warranted to the establishment of conservation measures targeting marine coastal environments. Climate change increases the level of environmental stress to which intertidal organisms are subjected to, affecting the functioning of biological systems at different levels of organization. Phorcus species have been widely used as indicators of the effect of climate change on local disturbances of intertidal ecosystems and geographic distribution shifts of these organisms. Further studies concerning biological parameters of Phorcus species and how they react to exploitation, pollution, and climate change will consolidate these species as indicators of large-scale ecological impacts of anthropogenic activities.",signatures:"Ricardo Sousa, João Delgado, José A. González, Mafalda Freitas and\nPaulo Henriques",downloadPdfUrl:"/chapter/pdf-download/57531",previewPdfUrl:"/chapter/pdf-preview/57531",authors:[{id:"200407",title:"MSc.",name:"Paulo",surname:"Henriques",slug:"paulo-henriques",fullName:"Paulo Henriques"},{id:"200915",title:"MSc.",name:"Ricardo",surname:"Sousa",slug:"ricardo-sousa",fullName:"Ricardo Sousa"},{id:"200916",title:"MSc.",name:"João",surname:"Delgado",slug:"joao-delgado",fullName:"João Delgado"}],corrections:null},{id:"59377",title:"Freshwater Crustaceans Decadpos: An Important Resource of Guatemala",doi:"10.5772/intechopen.73638",slug:"freshwater-crustaceans-decadpos-an-important-resource-of-guatemala",totalDownloads:1313,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Guatemala is a mega diversity country because it has several ecosystems and the physiography has a high diversity. However, the local population uses this biodiversity as a natural resource of food mainly. The country had three main drainage slopes for their rivers and aquatic reservoirs with several basins (the Gulf of Mexico, the Caribbean Sea, and the Pacific Sea). In these slopes, crayfish, freshwater prawns, and crabs compose the aquatic biological resources. Several fieldtrips were performed around these slopes in order to identify the species which were used as natural aquatic resources and verify if the diversity supports the food needs of the local population. Our findings were that the country has at least four crayfish species of genus Procambarus spp., those living in the high and middle altitude areas. Five freshwater prawn species with abbreviated larval development of genus Macrobrachium, that is, Macrobrachium cemai were also found. The bigger species of Macrobrachium was also identified on the three slopes as Macrobrachium americanum, Macrobrachium tenellum, Macrobrachium occidentale, and Macrobrachium digueti on the Pacific slope, while on the Gulf of Mexico and the Caribbean Sea, Macrobrachium carcinus, Macrobrachium acanthurus, Macrobrachium heterochirus, Macrobrachium olfersii, and Macrobrachium hobbsi were recorded, and therefore, the nonnative species Macrobrachium rosenbergii; with respect to other shrimps, Palaemon pandaliformis, Palaemonetes octaviae, and atyids as Atya scabra and Potimirim glabra were found. According to the freshwater crabs, the Pseudothelphusidae family is the best to represent in comparison with Trichodactylidae where only one population was recorded. Also, we register the uses of these species around the main markets in the country and we found two main ways: the first one is for the bigger species of freshwater prawns and crabs that are offered very expensive in kilogram and are almost offered in restaurants as exclusive dishes. The second one is more for the local consumption, and many families of fishery species that include crayfishes, freshwater prawns with abbreviated larval development, and smaller crabs, and so on, are sometimes found in the markets, with the prices being cheaper and can be bought only by the local people. Our findings show that Guatemala has an enormous potential in the crustaceans decapods for use as natural aquatic resources as protein sources at low cost, especially for the families with low economical level.",signatures:"Juan Carlos Tejeda-Mazariegos, Luis Manuel Mejía Ortíz, Marilú\nLópez-Mejía, Keith A. Crandall, Marcos Pérez-Losada and Oscar\nFrausto-Martínez",downloadPdfUrl:"/chapter/pdf-download/59377",previewPdfUrl:"/chapter/pdf-preview/59377",authors:[{id:"181100",title:"Ph.D.",name:"Luis",surname:"Mejia-Ortiz",slug:"luis-mejia-ortiz",fullName:"Luis Mejia-Ortiz"},{id:"185428",title:"Prof.",name:"Keith",surname:"Crandall",slug:"keith-crandall",fullName:"Keith Crandall"},{id:"185429",title:"Dr.",name:"Oscar",surname:"Frausto-Martinez",slug:"oscar-frausto-martinez",fullName:"Oscar Frausto-Martinez"},{id:"215819",title:"MSc.",name:"Juan C.",surname:"Tejeda-Mazariegos",slug:"juan-c.-tejeda-mazariegos",fullName:"Juan C. Tejeda-Mazariegos"},{id:"215820",title:"Dr.",name:"Marilú",surname:"López-Mejía",slug:"marilu-lopez-mejia",fullName:"Marilú López-Mejía"},{id:"215821",title:"Dr.",name:"Marcos",surname:"Perez-Losada",slug:"marcos-perez-losada",fullName:"Marcos Perez-Losada"}],corrections:null},{id:"57794",title:"Assessment of Proximate and Bioactive Lipid Composition of Black Sea Mussels (M. galloprovincialis) from Bulgaria",doi:"10.5772/intechopen.71909",slug:"assessment-of-proximate-and-bioactive-lipid-composition-of-black-sea-mussels-m-galloprovincialis-fro",totalDownloads:1115,totalCrossrefCites:5,totalDimensionsCites:6,hasAltmetrics:0,abstract:"Farmed marine mussels from genera Mytilus are important for the human diet by providing high levels of proteins, omega-3 polyunsaturated fatty acids (PUFAs), fat soluble vitamins and carbohydrates. Recently, black mussels are commercially important species from the Bulgarian Black Sea. The aim of this study was to assess the seasonal changes in proximate composition and to focus on the lipid bioactive components such as fatty acids, cholesterol, fat-soluble vitamins (A, E and D3), and carotenoids (astaxanthin, beta-carotene) in farmed mussels (M. galloprovincialis) from the northern part of the Bulgarian Black Sea coast. All analyzed samples presented high protein and low lipid content. The fatty acids (FA) profile was characterized by the highest amount of PUFA, as 22:6 omega-3 (n-3) dominated, regardless of the seasons. In all seasons, the content of n-3 was significantly higher than the omega-6 PUFA. The amounts of cholesterol were in the range 62.3 (summer) to 78 (autumn) mg 100−1 g ww. The highest amounts of vitamin D3 (3.1 μg 100−1 g ww), vitamin E (2525 μg 100−1 g ww), astaxanthin (0.470 mg 100−1 g ww), and beta-carotene (0.445 mg 100−1 g ww) were found in the summer season. The studied mussel aquaculture from Bulgaria presented a high beneficial potential in all seasons in terms of human health protection.",signatures:"Albena Merdzhanova, Diana A. Dobreva and Veselina Panayotova",downloadPdfUrl:"/chapter/pdf-download/57794",previewPdfUrl:"/chapter/pdf-preview/57794",authors:[{id:"214357",title:"Associate Prof.",name:"Albena",surname:"Merdzhanova",slug:"albena-merdzhanova",fullName:"Albena Merdzhanova"},{id:"215380",title:"Dr.",name:"Diana",surname:"Dobreva",slug:"diana-dobreva",fullName:"Diana Dobreva"},{id:"215382",title:"Dr.",name:"Veselina",surname:"Panayotova",slug:"veselina-panayotova",fullName:"Veselina Panayotova"}],corrections:null},{id:"60368",title:"Biological and Medicinal Importance of Sponge",doi:"10.5772/intechopen.73529",slug:"biological-and-medicinal-importance-of-sponge",totalDownloads:2590,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Sponges are multicellular, heterotrophic parazoan organisms, characterized by the possession of unique feeding system among the animals. They are the most primitive types of animals in existence, featuring a cell-based organization where different cells have different tasks, but do not form tissues. Sponges (Porifera) are a predominantly marine phylum living from the intertidal to the abyssal (deepest ocean) zone. There are approximately 8500 described species of sponges worldwide with a prominent role in many reef coral communities. Several ecological studies reported have shown that secondary metabolites isolated from sponges often serve defensive purposes to protect them from threats such as predator attacks, biofouling, microbial infections, and overgrowth by other sessile organisms. In the recent years, interest in marine sponges has risen considerably due to presence of high number of interesting biologically active natural products. More than 5300 different natural products are known from sponges and their associated microorganisms, and every year hundreds of new substances are discovered. In addition to the unusual nucleosides, other classes of substances such as bioactive terpenes, sterols, fatty acids, alkaloids, cyclic peptides, peroxides, and amino acid derivatives (which are frequently halogenated) have been described from sponges or from their associated microorganisms. Many of these natural products from sponges have shown a wide range of pharmacological activities such as anticancer, antifungal, antiviral, anthelmintic, antiprotozoal, anti-inflammatory, immunosuppressive, neurosuppressive, and antifouling activities. This chapter covers extensive work published regarding new compounds isolated from marine sponges and biological activities associated with them.",signatures:"Musarat Amina and Nawal M. Al Musayeib",downloadPdfUrl:"/chapter/pdf-download/60368",previewPdfUrl:"/chapter/pdf-preview/60368",authors:[{id:"213049",title:"Dr.",name:"Musarat",surname:"Amina",slug:"musarat-amina",fullName:"Musarat Amina"},{id:"213050",title:"Dr.",name:"Nawal",surname:"M. Al Musayeib",slug:"nawal-m.-al-musayeib",fullName:"Nawal M. Al Musayeib"}],corrections:null},{id:"58863",title:"Chemical Ecology of Biocompounds in Molluscs",doi:"10.5772/intechopen.72741",slug:"chemical-ecology-of-biocompounds-in-molluscs",totalDownloads:1090,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Among aquatic creatures, molluscs are one of the main phylums of marine organisms because of their vast biodiversity, nutrition advantages and their natural compounds. Chemical ecology discusses study of natural compounds in organisms, analyzes their structures and tracing their production and variation in response to environmental parameters. There are about 600 natural compounds identified, in which their metabolism are studied more in four classes of molluscs: polyplacophora, gastropoda, cephalopoda and bivalves. The main identified compounds are amino acids, lipids and fatty acids, terpens and steroids. Fatty acids and lipids are the main pre-structures for biological membranes, and their physical characteristics create membrane structure and its activities. Therefore, many cell functions depend on membrane activity and chemical composition of membrane lipids and environmental parameters as follows. Normally, the omega 6 to omega 3 ratio has moderate amounts in natural food sources. The more the ratio closer to 1, the more body metabolism could be sensitive for absorption. Environmental parameters, such as temperature, salinity, pH and food type source, could change the amount and structure of natural compounds. Biological factors such as sex type, reproduction and breeding cycles, different tissues and their activities could receive different types of natural compounds.",signatures:"Nooshin Sadjadi",downloadPdfUrl:"/chapter/pdf-download/58863",previewPdfUrl:"/chapter/pdf-preview/58863",authors:[{id:"215257",title:"Associate Prof.",name:"Nooshin",surname:"Sajjadi",slug:"nooshin-sajjadi",fullName:"Nooshin Sajjadi"}],corrections:null},{id:"59973",title:"Genetic Applications in the Conservation of Neotropical Freshwater Fish",doi:"10.5772/intechopen.73207",slug:"genetic-applications-in-the-conservation-of-neotropical-freshwater-fish",totalDownloads:1717,totalCrossrefCites:3,totalDimensionsCites:9,hasAltmetrics:0,abstract:"Neotropical fish correspond to approximately 30% of all fish species worldwide. The diversity of fish species found in Neotropical basins reflects variations in life-history strategies and exhibition of particular morphological, physiological and ecological attributes. These attributes are mainly related to different forms of feeding, life maintenance and reproduction. Today, fish populations are being threatened by anthropogenic actions that are having a visible impact on the natural state of continental aquatic ecosystems. The main causes are overfishing, non-native species introduction, reservoir-dam systems, mining, pollution and deforestation. The biology and population dynamics of the species are still unclear due to lack of research. Genetic tools can be useful resources for the conservation of Neotropical fish species in several ways. Molecular genetic markers are considered powerful tools to identify cryptic and hybrid fish and also allow the evaluation of the genetic variability and structure of populations of Neotropical ichthyofauna. Several analyses of molecular markers have been performed on Neotropical fish, including allozyme analysis, restriction fragment length polymorphisms in regions of DNA (RFLP), randomly amplified polymorphic DNA (AFLP), randomly amplified polymorphic DNA (RAPD), microsatellites, single nucleotide polymorphisms (SNPs) and mitochondrial DNA (mtDNA) markers. In order to analyse a high number of markers, next generation sequencing has allowed researchers to generate a large amount of genomic information that can be applied to the conservation of Neotropical fish.",signatures:"Vito Antonio Mastrochirico Filho, Milena V. Freitas, Raquel B.\nAriede, Lieschen V.G. Lira, Natália J. Mendes and Diogo T.\nHashimoto",downloadPdfUrl:"/chapter/pdf-download/59973",previewPdfUrl:"/chapter/pdf-preview/59973",authors:[{id:"215385",title:"Dr.",name:"Diogo",surname:"Hashimoto",slug:"diogo-hashimoto",fullName:"Diogo Hashimoto"},{id:"226741",title:"MSc.",name:"Vito",surname:"Matrochirico-Filho",slug:"vito-matrochirico-filho",fullName:"Vito Matrochirico-Filho"},{id:"226743",title:"MSc.",name:"Milena",surname:"Freitas",slug:"milena-freitas",fullName:"Milena Freitas"},{id:"226744",title:"MSc.",name:"Raquel",surname:"Ariede",slug:"raquel-ariede",fullName:"Raquel Ariede"},{id:"226745",title:"MSc.",name:"Natália",surname:"Mendes",slug:"natalia-mendes",fullName:"Natália Mendes"},{id:"226746",title:"MSc.",name:"Lieschen",surname:"Lira",slug:"lieschen-lira",fullName:"Lieschen Lira"}],corrections:null},{id:"58953",title:"Status of the Important Bioresources of Girwa River with Special Reference to Ganges River Dolphin (Platanista gangetica gangetica) in Katerniaghat Wildlife Sanctuary, Uttar Pradesh, India",doi:"10.5772/intechopen.72661",slug:"status-of-the-important-bioresources-of-girwa-river-with-special-reference-to-ganges-river-dolphin-p",totalDownloads:1193,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The Girwa River in India supports a rich variety of fauna including the endangered Ganges River Dolphin and critical endangered gharial. Due to rising conservation concerns, biologists in the country have conducted a great deal of research over the past few decades on the status of these species in its distribution range. However, in the Girwa River such studies are still lacking, both to inform conservation efforts and to help address broader concerns related to biodiversity conservation. In light of the above statement, the present study was conducted in the ca.18 km of the Girwa River in Katerniaghat Wildlife Sanctuary in Uttar Pradesh. During the survey, dolphins, crocodile and aquatic birds were encountered along most of the river with the exception of ca. 1.5 km section below the international border and a ca. 2 km section above the Girijapuri barrage. Based on the best estimate, Low-best-high figures of 27-35-41 dolphins, with an encounter rate of 1.94 dolphins/km were estimated. Besides dolphin, 65 gharial, 20 mugger crocodile and 64 species of aquatic birds were counted. Actual growth may be higher because of possible population under estimation during the present survey. Increasing anthropogenic activities such as dam and barrage, coupled with mortality in fishing nets, are likely to affect the future survival of these populations. Recommendations for management and research are made to ensure the effective conservation of these species in the Girwa River.",signatures:"Hari Singh and Sandeep Kumar Behera",downloadPdfUrl:"/chapter/pdf-download/58953",previewPdfUrl:"/chapter/pdf-preview/58953",authors:[{id:"208022",title:"Dr.",name:"Hari",surname:"Singh",slug:"hari-singh",fullName:"Hari Singh"},{id:"226724",title:"Dr.",name:"Sandeep Kumar",surname:"Behera",slug:"sandeep-kumar-behera",fullName:"Sandeep Kumar Behera"}],corrections:null},{id:"57327",title:"Closed Aquaculture System: Zero Water Discharge for Shrimp and Prawn Farming in Indonesia",doi:"10.5772/intechopen.70944",slug:"closed-aquaculture-system-zero-water-discharge-for-shrimp-and-prawn-farming-in-indonesia",totalDownloads:2527,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:0,abstract:"This chapter focuses on the development and application of zero water discharge (ZWD) system, which has become an alternative solution to conventional methods of aquaculture production. With this system, it is expected to answer many issues in aquaculture cultivation, such as environmental damage, disease outbreak, and land-use change, and to create a sustainable aquaculture cultivation system. ZWD system is an improved batch system with an emphasis on microbial manipulation in rearing tank. The principle of microbial selection is based on the role of each microbial component in nutrient cycle in the rearing tank. This chapter contains in detail how methods and stages are performed in order to conduct this system, including design of construction system, cultivation of microbial components, initial conditioning of this system, and microbial manipulation. The performance of the system was tested in crustacean culture such as white shrimp and giant freshwater prawns, and it showed that the system can increase the average survival rate of 10–20%. In addition, the technical and economic feasibility of this system was evaluated to illustrate the production efficiency upon the application of this system in the industry.",signatures:"Gede Suantika, Magdalena Lenny Situmorang, Pingkan Aditiawati,\nDea Indriani Astuti, Fahma Fiqhiyyah Nur Azizah and Harish\nMuhammad",downloadPdfUrl:"/chapter/pdf-download/57327",previewPdfUrl:"/chapter/pdf-preview/57327",authors:[{id:"216920",title:"Dr.",name:"Gede",surname:"Suantika",slug:"gede-suantika",fullName:"Gede Suantika"},{id:"220079",title:"Dr.",name:"Magdalena Lenny",surname:"Situmorang",slug:"magdalena-lenny-situmorang",fullName:"Magdalena Lenny Situmorang"},{id:"220081",title:"Dr.",name:"Pingkan",surname:"Aditiawati",slug:"pingkan-aditiawati",fullName:"Pingkan Aditiawati"},{id:"220082",title:"Dr.",name:"Dea Indriani",surname:"Astuti",slug:"dea-indriani-astuti",fullName:"Dea Indriani Astuti"},{id:"220083",title:"MSc.",name:"Fahma Fiqhiyyah Nur",surname:"Azizah",slug:"fahma-fiqhiyyah-nur-azizah",fullName:"Fahma Fiqhiyyah Nur Azizah"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"8421",title:"Invertebrates",subtitle:"Ecophysiology and Management",isOpenForSubmission:!1,hash:"524faf733c0ebf32b356f89b2148e6de",slug:"invertebrates-ecophysiology-and-management",bookSignature:"Sajal Ray, Genaro Diarte-Plata and Ruth Escamilla-Montes",coverURL:"https://cdn.intechopen.com/books/images_new/8421.jpg",editedByType:"Edited by",editors:[{id:"173697",title:"Prof.",name:"Sajal",surname:"Ray",slug:"sajal-ray",fullName:"Sajal Ray"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5899",title:"Organismal and Molecular Malacology",subtitle:null,isOpenForSubmission:!1,hash:"a7f042a23fd6991a546812db126ef875",slug:"organismal-and-molecular-malacology",bookSignature:"Sajal Ray",coverURL:"https://cdn.intechopen.com/books/images_new/5899.jpg",editedByType:"Edited by",editors:[{id:"173697",title:"Prof.",name:"Sajal",surname:"Ray",slug:"sajal-ray",fullName:"Sajal Ray"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6559",title:"Earthworms",subtitle:"The Ecological Engineers of Soil",isOpenForSubmission:!1,hash:"0780208898e98441ccea18ea373c0708",slug:"earthworms-the-ecological-engineers-of-soil",bookSignature:"Sajal Ray",coverURL:"https://cdn.intechopen.com/books/images_new/6559.jpg",editedByType:"Edited by",editors:[{id:"173697",title:"Prof.",name:"Sajal",surname:"Ray",slug:"sajal-ray",fullName:"Sajal Ray"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6883",title:"Cell Signalling",subtitle:"Thermodynamics and Molecular Control",isOpenForSubmission:!1,hash:"e4e17d85c0643c7f4d274fa9adbcc628",slug:"cell-signalling-thermodynamics-and-molecular-control",bookSignature:"Sajal Ray",coverURL:"https://cdn.intechopen.com/books/images_new/6883.jpg",editedByType:"Edited by",editors:[{id:"173697",title:"Prof.",name:"Sajal",surname:"Ray",slug:"sajal-ray",fullName:"Sajal Ray"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10738",title:"Update on Malacology",subtitle:null,isOpenForSubmission:!1,hash:"2a84e581549b3720e44e989c3c0be467",slug:"update-on-malacology",bookSignature:"Sajal Ray and Soumalya Mukherjee",coverURL:"https://cdn.intechopen.com/books/images_new/10738.jpg",editedByType:"Edited by",editors:[{id:"173697",title:"Prof.",name:"Sajal",surname:"Ray",slug:"sajal-ray",fullName:"Sajal Ray"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"304",title:"Sediment Transport in Aquatic Environments",subtitle:null,isOpenForSubmission:!1,hash:"0eb11af1d03ad494253c41e1d3c998e9",slug:"sediment-transport-in-aquatic-environments",bookSignature:"Andrew J. Manning",coverURL:"https://cdn.intechopen.com/books/images_new/304.jpg",editedByType:"Edited by",editors:[{id:"23008",title:"Prof.",name:"Andrew James",surname:"Manning",slug:"andrew-james-manning",fullName:"Andrew James Manning"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6266",title:"Marine Ecology",subtitle:"Biotic and Abiotic Interactions",isOpenForSubmission:!1,hash:"9d821ed950a497c8f50de67abf419259",slug:"marine-ecology-biotic-and-abiotic-interactions",bookSignature:"Muhammet Türkoğlu, Umur Önal and Ali Ismen",coverURL:"https://cdn.intechopen.com/books/images_new/6266.jpg",editedByType:"Edited by",editors:[{id:"99483",title:"Prof.",name:"Muhammet",surname:"Turkoglu",slug:"muhammet-turkoglu",fullName:"Muhammet Turkoglu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5765",title:"Corals in a Changing World",subtitle:null,isOpenForSubmission:!1,hash:"eed323f414d06a6bd994cc9d37ad24c4",slug:"corals-in-a-changing-world",bookSignature:"Carmenza Duque Beltran and Edisson Tello Camacho",coverURL:"https://cdn.intechopen.com/books/images_new/5765.jpg",editedByType:"Edited by",editors:[{id:"155319",title:"Emeritus Prof.",name:"Carmenza",surname:"Duque",slug:"carmenza-duque",fullName:"Carmenza Duque"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7912",title:"Biological Research in Aquatic Science",subtitle:null,isOpenForSubmission:!1,hash:"8f86a91e9a5c76a2d11a861d879bc96a",slug:"biological-research-in-aquatic-science",bookSignature:"Yusuf Bozkurt",coverURL:"https://cdn.intechopen.com/books/images_new/7912.jpg",editedByType:"Edited by",editors:[{id:"90846",title:"Prof.",name:"Yusuf",surname:"Bozkurt",slug:"yusuf-bozkurt",fullName:"Yusuf Bozkurt"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6645",title:"Seabirds",subtitle:null,isOpenForSubmission:!1,hash:"6ce1372af411b6ada3b53e881f7b85fc",slug:"seabirds",bookSignature:"Heimo Mikkola",coverURL:"https://cdn.intechopen.com/books/images_new/6645.jpg",editedByType:"Edited by",editors:[{id:"144330",title:"Dr.",name:"Heimo",surname:"Mikkola",slug:"heimo-mikkola",fullName:"Heimo Mikkola"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],ofsBooks:[]},correction:{item:{id:"79356",slug:"corrigendum-to-advancement-of-nitrogen-fertilization-on-tropical-environmental",title:"Corrigendum to: Advancement of Nitrogen Fertilization on Tropical Environmental",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/73131.pdf",downloadPdfUrl:"/chapter/pdf-download/73131",previewPdfUrl:"/chapter/pdf-preview/73131",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/73131",risUrl:"/chapter/ris/73131",chapter:{id:"71453",slug:"advancement-of-nitrogen-fertilization-on-tropical-environmental",signatures:"Elizeu Monteiro Pereira Junior, Elaine Maria Silva Guedes Lobato, Beatriz Martineli Lima, Barbara Rodrigues Quadros, Allan Klynger da Silva Lobato, Izabelle Pereira Andrade and Letícia de Abreu Faria",dateSubmitted:"October 21st 2019",dateReviewed:"November 28th 2019",datePrePublished:"March 25th 2020",datePublished:"April 8th 2020",book:{id:"8004",title:"Nitrogen Fixation",subtitle:null,fullTitle:"Nitrogen Fixation",slug:"nitrogen-fixation",publishedDate:"April 8th 2020",bookSignature:"Everlon Cid Rigobelo and Ademar Pereira Serra",coverURL:"https://cdn.intechopen.com/books/images_new/8004.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"39553",title:"Prof.",name:"Everlon",middleName:"Cid",surname:"Rigobelo",slug:"everlon-rigobelo",fullName:"Everlon Rigobelo"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"158046",title:"Dr.",name:"Elaine Maria Silva Guedes",middleName:"Guedes",surname:"Lobato",fullName:"Elaine Maria Silva Guedes Lobato",slug:"elaine-maria-silva-guedes-lobato",email:"elaine.guedes@ufra.edu.br",position:null,institution:{name:"Universidade Federal Rural da Amazônia",institutionURL:null,country:{name:"Brazil"}}},{id:"313880",title:"Dr.",name:"Barbara",middleName:null,surname:"Rodrigues Quadros",fullName:"Barbara Rodrigues Quadros",slug:"barbara-rodrigues-quadros",email:"barbara.quadros@ufra.edu.br",position:null,institution:null},{id:"313881",title:"Dr.",name:"Izabelle",middleName:null,surname:"Pereira Andrade",fullName:"Izabelle Pereira Andrade",slug:"izabelle-pereira-andrade",email:"izabelle.andrade@ufra.edu.br",position:null,institution:null},{id:"314476",title:"Dr.",name:"Allan Klynger Da Silva",middleName:null,surname:"Lobato",fullName:"Allan Klynger Da Silva Lobato",slug:"allan-klynger-da-silva-lobato",email:"allan.lobato@ufra.edu.br",position:null,institution:{name:"Universidade Federal Rural da Amazônia",institutionURL:null,country:{name:"Brazil"}}},{id:"314477",title:"Dr.",name:"Leticia Abreu",middleName:null,surname:"Faria",fullName:"Leticia Abreu Faria",slug:"leticia-abreu-faria",email:"leticia.faria@ufra.edu.br",position:null,institution:{name:"Universidade Federal Rural da Amazônia",institutionURL:null,country:{name:"Brazil"}}},{id:"314484",title:"Mr.",name:"Elizeu Monteiro Pereira",middleName:null,surname:"Junior",fullName:"Elizeu Monteiro Pereira Junior",slug:"elizeu-monteiro-pereira-junior",email:"ta.elizeujr@gmail.com",position:null,institution:{name:"Universidade Federal Rural da Amazônia",institutionURL:null,country:{name:"Brazil"}}},{id:"314489",title:"Ms.",name:"Beatriz Martinelli",middleName:null,surname:"Lima",fullName:"Beatriz Martinelli Lima",slug:"beatriz-martinelli-lima",email:"biamartinelli13@gmail.com",position:null,institution:{name:"Universidade Federal Rural da Amazônia",institutionURL:null,country:{name:"Brazil"}}}]}},chapter:{id:"71453",slug:"advancement-of-nitrogen-fertilization-on-tropical-environmental",signatures:"Elizeu Monteiro Pereira Junior, Elaine Maria Silva Guedes Lobato, Beatriz Martineli Lima, Barbara Rodrigues Quadros, Allan Klynger da Silva Lobato, Izabelle Pereira Andrade and Letícia de Abreu Faria",dateSubmitted:"October 21st 2019",dateReviewed:"November 28th 2019",datePrePublished:"March 25th 2020",datePublished:"April 8th 2020",book:{id:"8004",title:"Nitrogen Fixation",subtitle:null,fullTitle:"Nitrogen Fixation",slug:"nitrogen-fixation",publishedDate:"April 8th 2020",bookSignature:"Everlon Cid Rigobelo and Ademar Pereira Serra",coverURL:"https://cdn.intechopen.com/books/images_new/8004.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"39553",title:"Prof.",name:"Everlon",middleName:"Cid",surname:"Rigobelo",slug:"everlon-rigobelo",fullName:"Everlon Rigobelo"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"158046",title:"Dr.",name:"Elaine Maria Silva Guedes",middleName:"Guedes",surname:"Lobato",fullName:"Elaine Maria Silva Guedes Lobato",slug:"elaine-maria-silva-guedes-lobato",email:"elaine.guedes@ufra.edu.br",position:null,institution:{name:"Universidade Federal Rural da Amazônia",institutionURL:null,country:{name:"Brazil"}}},{id:"313880",title:"Dr.",name:"Barbara",middleName:null,surname:"Rodrigues Quadros",fullName:"Barbara Rodrigues Quadros",slug:"barbara-rodrigues-quadros",email:"barbara.quadros@ufra.edu.br",position:null,institution:null},{id:"313881",title:"Dr.",name:"Izabelle",middleName:null,surname:"Pereira Andrade",fullName:"Izabelle Pereira Andrade",slug:"izabelle-pereira-andrade",email:"izabelle.andrade@ufra.edu.br",position:null,institution:null},{id:"314476",title:"Dr.",name:"Allan Klynger Da Silva",middleName:null,surname:"Lobato",fullName:"Allan Klynger Da Silva Lobato",slug:"allan-klynger-da-silva-lobato",email:"allan.lobato@ufra.edu.br",position:null,institution:{name:"Universidade Federal Rural da Amazônia",institutionURL:null,country:{name:"Brazil"}}},{id:"314477",title:"Dr.",name:"Leticia Abreu",middleName:null,surname:"Faria",fullName:"Leticia Abreu Faria",slug:"leticia-abreu-faria",email:"leticia.faria@ufra.edu.br",position:null,institution:{name:"Universidade Federal Rural da Amazônia",institutionURL:null,country:{name:"Brazil"}}},{id:"314484",title:"Mr.",name:"Elizeu Monteiro Pereira",middleName:null,surname:"Junior",fullName:"Elizeu Monteiro Pereira Junior",slug:"elizeu-monteiro-pereira-junior",email:"ta.elizeujr@gmail.com",position:null,institution:{name:"Universidade Federal Rural da Amazônia",institutionURL:null,country:{name:"Brazil"}}},{id:"314489",title:"Ms.",name:"Beatriz Martinelli",middleName:null,surname:"Lima",fullName:"Beatriz Martinelli Lima",slug:"beatriz-martinelli-lima",email:"biamartinelli13@gmail.com",position:null,institution:{name:"Universidade Federal Rural da Amazônia",institutionURL:null,country:{name:"Brazil"}}}]},book:{id:"8004",title:"Nitrogen Fixation",subtitle:null,fullTitle:"Nitrogen Fixation",slug:"nitrogen-fixation",publishedDate:"April 8th 2020",bookSignature:"Everlon Cid Rigobelo and Ademar Pereira Serra",coverURL:"https://cdn.intechopen.com/books/images_new/8004.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"39553",title:"Prof.",name:"Everlon",middleName:"Cid",surname:"Rigobelo",slug:"everlon-rigobelo",fullName:"Everlon Rigobelo"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11725",leadTitle:null,title:"The Erythrocyte - A Unique Cell",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tThe Erythrocyte is unique and forms a model for studying various situations/ physiological conditions.
\r\n\tThis cell has evolved an effective defense system to counteract the challenges as it is always in an oxygen-rich environment. The evolution of hemoglobin and deformability of erythrocyte membrane adapting to its function in circulation is especially striking. Erythrocyte aging and eryptosis strike a balance - the mixed population of cells and constant recycling every 120 days is a very distinct feature. Its metabolic shunt pathways and metabolites/enzymes alter and adapt with age and changes in the microenvironment.
\r\n\tErythrocyte and its cytoskeleton responses to various situations such as infections, hypoxia, hypothermia, intrigues researchers and biologists alike. This book aims to throw light on the significance of erythrocyte and its characteristic nature and survival in different physiological situations as it plays a very crucial role.
\r\n\r\n\tThis book hopes to bring different perspectives from various aspects and provide insights into the effective mechanisms evolved by erythrocytes, to counteract the challenges faced in its oxidation environment and the further research approaches.
",isbn:"978-1-80356-732-7",printIsbn:"978-1-80356-731-0",pdfIsbn:"978-1-80356-733-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"1b6073b9ff3f8f63004943bd263cd04e",bookSignature:"Dr. Vani Rajashekaraiah",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11725.jpg",keywords:"Erythrocyte, Hemoglobin, Erythrocyte Aging, Pathways, Metabolites, Deficiencies, Membrane Changes, Band 3, Deformability, Hemolysis, Disease Conditions, Free Radical Initiators",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 24th 2022",dateEndSecondStepPublish:"May 26th 2022",dateEndThirdStepPublish:"July 25th 2022",dateEndFourthStepPublish:"October 13th 2022",dateEndFifthStepPublish:"December 12th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"3 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Vani Rajashekaraiah, Associate Professor, JAIN (Deemed-to-be University), Bangalore has 20 years of research experience in Oxidative Stress Physiology and Hematology and 16 years of teaching experience. She has authored numerous journal papers and book chapters and has one published patent. She has received CSIR research fellowship and is a Member of the Society for Free Radical Research, India.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"352876",title:"Dr.",name:"Vani",middleName:null,surname:"Rajashekaraiah",slug:"vani-rajashekaraiah",fullName:"Vani Rajashekaraiah",profilePictureURL:"https://mts.intechopen.com/storage/users/352876/images/system/352876.jpg",biography:"Teaching Experience: 16 years\n•\tAssociate Professor in Biotechnology, School of Sciences, Block I, JAIN (Deemed-to-be University), Bengaluru from May 2018 till date. (Courses: Molecular Genetics, Molecular Biology and Genetic Engineering). \n Research Experience: 20 years in the field of Oxidative Stress Physiology and hematology.\n Current Research focus: Blood Storage (erythrocytes, platelets) and Drug-induced Thrombocytopenia\n Total publications in SCOPUS / Web of Science: 27 and International book chapters: 04.\n Research guidance: 3 PhD students (completed); 3 PhD students guiding currently.\n \t \n Six years of research experience as JRF (CSIR) and SRF (CSIR) in the field of High Altitude Physiology and Biochemistry, specialization in Oxidative Stress Physiology, from August 2002 to 2008. \no\tPursued research under the guidance of Dr. S. Asha Devi, Professor, Dept. of \n Zoology, Bangalore University, Bangalore-560056, towards Ph.D in Zoology.\n Title of the thesis- “Studies on Oxidative Stress in Erythrocytes of Rats Exposed to \n Intermittent Hypobaric Hypoxia”.",institutionString:"Jain University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Jain University",institutionURL:null,country:{name:"India"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"185543",firstName:"Maja",lastName:"Bozicevic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/185543/images/4748_n.jpeg",email:"maja.b@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. Mauricio Barría",coverURL:"https://cdn.intechopen.com/books/images_new/6550.jpg",editedByType:"Edited by",editors:[{id:"88861",title:"Dr.",name:"R. Mauricio",surname:"Barría",slug:"r.-mauricio-barria",fullName:"R. 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In the normal human brains, the hippopotamus volume remains relatively stable before the age of 60, and then gradually atrophies. In Alzheimer’s disease (AD) patients, the pattern of brain atrophy follows a stereotypical pathway that initiates from the entorhinal cortex and the hippocampus, and then spreads to the medial parietal, lateral temporal and frontal regions, eventually to the neocortex. As the connections between the hippocampus and its neighboring cortical structures are selectively vulnerable to neurodegeneration in AD, hippocampal volume loss is considered an important indicator of AD neuropathology [2]. In addition, since neurogenesis in adult brain only occurs in the dentate gyrus of the hippocampus and the olfactory bulb, hippocampus atrophy in AD also alters the production of newborn neurons [3].
Tau, initially isolated as a microtubule-associated protein from the porcine brain in 1975, is predominantly expressed in the hippocampus [4, 5]. In the previous year, neurofibrillary tangles (NFTs) and a paired helical filament (PHF) protein had been identified from the brains of patients with Alzheimer’s disease (AD) [6], but it was not until 1986 that tau was discovered to be a major component of PHF [7]. Subsequently, tau was implicated in the pathogenesis of over 25 human neurological disorders (termed “tauopathies”), including Alzheimer’s disease (AD), argyrophilic grain disease (AGD), corticobasal degeneration (CBD), frontotemporal dementia (FTD), globular glial tauopathy (GGT), primary age-related tauopathy (PART), Pick’s disease (PiD) and progressive supranuclear palsy (PSP) [8, 9, 10].
As the most common neurodegenerative disease, AD is characterized by early impairments in learning and memory, followed by progressive loss of complex attention, executive function, language, orientation and self-care ability, changes in mood, loss of motivation, and impairments in thinking, behavior and/or social comportment [11]. The two major neuropathological hallmarks of AD are the extracellular deposition of β-amyloid (Aβ) plaques and the intracellular neurofibrillary tangles (NFTs) consisting of aggregated hyperphosphorylated tau [12]. NFTs pathology in AD is initiated in the locus coeruleus and transentorhinal cortex, from where it spreads to the limbic system (e.g., entorhinal cortex and hippocampus) and further to the neocortex, leading to six Braak stages [13]. The progression of cognitive decline in AD correlates with the accumulation of NFTs and loss of hippocampal volume, but not deposition of Aβ plaques [14, 15]. Since most therapies targeting Aβ failed in late-stage clinical trials for AD in the past decades, increasing research revealing the roles of tau in disease has inspired tau-targeting approaches in the treatment of AD and related tauopathies [16, 17].
This chapter reviews the expression and functions of tau in physiological conditions, the pathological changes of tau in diseases, such as genetic variants, posttranslational modifications (PTMs) and prion-like seeding and propagation. Recent advances in the development of tau-based therapies for AD and other neurodegenerative diseases are also discussed.
Human tau protein is encoded by the microtubule-associated protein tau (MAPT) gene, which locates on chromosome 17q21.31 and consists of 16 exons. In the central nervous system (CNS), the alternative splicing of exons 2, 3, and 10 gives rise to six tau isoforms with zero (0 N), one (1 N) or two (2 N) N-terminal inserts and three (3R-tau) or four (4R-tau) microtubule-binding repeats (Figure 1) [18]. The longest isoform of human brain tau consists of 441 amino acids (2N4R, tau441) with an apparent molecular weight (MW) of 46 kDa. Exons 4a and 6 are predominantly expressed in the peripheral nervous system (PNS), producing proteins of apparent MW of 110 kDa, named big tau [19].
Gene structure and expression of human MAPT gene. MAPT gene is localized to chromosome 17 and consists of 16 exons. Exons 4a, 6, and 8 are expressed in PNS. Alternative splicing of tau exon 2 (green, encodes N1) or exon 3 (yellow, encodes N2) produces isoforms with zero (0 N), one (1 N) or two (2 N) N-terminal inserts. Exons 9, 11 and 12 encode the microtubule-binding repeats R1, R3, and R4 (blue). Alternative splicing of exon 10 (red, encodes R2) generates isoforms containing four (4R-tau) or three (3R-tau) microtubule-binding repeats.
The expression of tau isoforms is developmentally and pathologically regulated. 3R-tau isoforms are expressed throughout life, including in the fetal brain, whereas 4R-tau isoforms are specifically expressed in adults, resulting in approximately equal levels of 3R-tau and 4R-tau in the adult human brain [18]. Rodent tau shares about 90% homology with human tau. Unlike humans, rodents express 3R-tau only in fetus and infant, and mainly 4R-tau in adulthood [20].
Tau pre-mRNA contains multiple cis-elements that allow the interaction of trans-acting factors like the serine and arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs), including an SC35-like enhancer, a polypurine enhancer (PPE) and an A/C-rich enhancer (ACE) at the 5′ terminus, and an exonic splicing silencer (ESS) and an exonic splicing enhancer (ESE) at the 3′ end of tau exon 10, and an intronic splicing silencer (ISS) and an intronic splicing modulator (ISM) at 5′ end of intron 10 [21]. Binding of trans-acting factors to these cis-elements either suppresses (SRSF3, SRSF4, SRSF7, SRSF11, U2AF, PTB and hnRNP G) or promotes (hTRA2-beta1, CELF3, CELF4, SRSF1, SRSF2, SRSR6, SRSF9, RNA helicase p68, RNA binding motif protein 4 and Tar DNA-binding protein 43) the inclusion of exon 10 [22].
Mutations in the MAPT gene or dysregulation of the splicing factors that alter the expression of tau exon 10 are involved in the pathogenesis of neurodegenerative diseases [21]. PiD is a prototypical 3R-tauopathy with spherical tau inclusions (Pick bodies), whereas PSP, CBD, AGD and GGT are primary 4R-tauopathies. AD, FTD and chronic traumatic encephalopathy (CTE), progressive neurodegeneration associated with repetitive mild traumatic injury, comprise both 3R and 4R-tau pathologies [23]. Studies on the amount of the six tau transcripts in AD brain have been contradictory [24, 25]. However, 4R- and 3R-tau proteins appear equally in the early-stage and some late-stage AD cases [26, 27]. In some cases of late-stage AD, 3R-tau protein is predominantly expressed in the subiculum, entorhinal cortex and area CA1 of the hippocampus [27], implying that dysregulation of tau exon 10 splicings could be related to AD progression rather than initiation.
So far, 112 mutations have been identified in human the MAPT gene, of which 13 were located in an intron (https://www.alzforum.org/mutations). Not all the mutations are pathogenic, and at least 27 benign mutations are not responsible for significant clinical symptoms. The largest number of MAPT mutations (55) is found in FTD. Second, 15 mutations are identified in AD, most of which are benign mutations causing no significant neuropathology. The rest mutations are correlated to PSP (10 mutations), Parkinson’s disease (PD) (8), PiD (7), CBD (4), AGD (1) and other tauopathies (Table 1). As genetic risk factors for neurodegenerative diseases, pathogenic tau mutations alter the protein sequence or/and the balance between 4R- and 3R-tau by changing alternative splicing [28].
Clinical Phenotype | Mutations |
---|---|
Argyrophilic grain disease | S305I |
Alzheimer’s Disease | A90V, A152T, G213R, V224G, Q230R, K280del, V287I, A297V, S318L, R406W, L410F*, S427F*, P512H* Duplication 17q21.31, IVS10 + 16 C > T |
Corticobasal Degeneration | A152T, C291R, P301T, N410H |
Frontotemporal Dementia | R5H, G55R, V75A, A152T, A239T, D252V, I260V, L266V, G272V, G273R, N279K, K280del, L284L, N296D, N296N, N296H, P301L, P301P, P301S, P301T, S305N, S305S, L315L, L315R, S320F, P332S, G335A, G335S, G335V, Q336R, V337M, E342V, S356T, V363I, P364S, G366R, K369I, E372G, G389_I392del, G389R, G389R, P397S, R406W, T427M IVS9–10 G > T, IVS9–15 T > C, IVS10 + 3 G > A, IVS10 + 4 A > C, IVS10 + 11 T > C, IVS10 + 12 C > T, IVS10 + 13 A > G, IVS10 + 14 C > T, IVS10 + 15 A > C, IVS10 + 19 C > G, IVS10 + 16 C > T |
Pick’s disease | G272V, K280del, S320F, Q336R, Q336H, K369I, G389R |
Progressive Supranuclear Palsy | R5L, A152T, L284R, S285R, N296N, N296del, G303V, S305S, D285N* IVS10 + 16 C > T |
Parkinson’s Disease | R5C, A41T, A152T, N296del, I360V, S427F*, T427M, R448* |
MAPT mutations found in main neurodegenerative diseases.
The position of this variant is about the longest isoform of peripheral tau, which is 776 amino acids in length.
Two major extended haplotypes cover the MAPT gene: H1 and H2 [29]. The frequency of the haplotypes differs between population groups; the H2 haplotype is found primarily in Caucasian and southwest Asians, but barely reported in the Chinese Han population [29, 30]. H1 haplotype was shown overrepresented in Caucasian patients with PSP [31]. Nevertheless, the relationship between MAPT haplotype and AD is still contradictory [32].
Tau is a highly water-soluble and basic protein with little secondary structure. As an intrinsically disordered protein, tau consists of a large number of serine/threonine and arginine/lysine/histidine residues, which makes the protein easy to be hyperphosphorylated. Full-length human tau (tau441) is composed of four domains: (i) an acidic amino-terminal projection domain that projects away from the surface of the microtubule, (ii) a proline-rich region required for the interaction with SH3-domain-containing proteins like tau kinases, (iii) a microtubule-binding domain involved in mediating tubulin assembly and tau aggregation, and (iv) a C-terminus (Figure 1) [33].
Human tau is highly expressed in the frontal and temporal cortices and is decreased to approximately a quarter in the cerebellum. In rodent brains, the highest levels of tau are detected in the hippocampus and entorhinal cortex. The cerebellum and olfactory bulb showed the lowest total tau level, being about 2/3 of that in the frontal cortex [5]. The expression of 3R-tau is comparable throughout different regions in the adult rat brains, such as the hippocampus, entorhinal cortex, frontal cortex, occipital-temporal cortex, parietal–temporal cortex, striatum, thalamus, olfactory bulb and cerebellum. However, the distribution of 4R-tau showed significant regional differences, with the highest levels in the entorhinal and frontal cortices and the lowest in the cerebellum. The uneven expression of tau protein in brain regions may contribute to distinct vulnerability/resistance to tau pathology [5].
In the human brain, tau is primarily expressed in neurons and also expressed at lower levels in oligodendrocytes and astrocytes [34]. In physiological conditions, tau was believed to be predominantly localized to axons, but limited in the soma and dendrites of neurons. Tau levels are comparable in gray matter and white matter in normal elderly brains, but higher in gray matter than whiter matter in AD brains [35]. Normally, tau monomer is difficult to be immunostained. Only aggregated tau or microtubule-binding tau can be detected by immunostaining. Although high levels in axons, a pre-synaptic abundance of tau is low. The mechanism for polarized neuronal distribution of tau could be (i) relocalization of tau from axon to soma may be blocked by the axon initial segment (AIS), (ii) Annexin A2 in the distal part of the axon interacts with tau and provides a sink for the redistribution of tau [16]. Under pathological conditions, endogenous tau translocates from axon to the soma and dendrite, and into the post-synapse. Early studies in AD and FTD have revealed that NFTs composed of aggregated hyperphosphorylated tau are localized in the soma and dendrites [36]. Translocation of tau depends on its interaction with microtubules [37] and are modulated through multiple mechanisms involving pathological posttranslational modification (e.g., hyperphosphorylation) and/or non-physiological overexpression of tau protein [38], imbalanced expression of tau isoforms (e.g., 2 N tau) [39] and dysregulation of extracellular signals [16]. Furthermore, tau messenger RNA (mRNA) might be recruited to the dendrite and post-synapses, resulting in local somatodendritic translation of tau protein [40, 41]. Lastly, tau is also detected in the nucleus, where it is likely to protect DNA integrity from stress [42].
Microtubules are more stable in mature neurons than in non-neuronal cells [43], probably due to posttranslational modifications of the tubulin subunits as well as their interaction with specific neuronal microtubule-associated proteins (MAP) such as tau [44]. Tau binds to the interface between tubulin heterodimers through its microtubule-binding repeats [45] and stabilizes microtubules in the test tube and cultured cells [46, 47]. 4R-tau isoforms have a stronger affinity for microtubules than 3R-tau isoforms [48] and are more prone to promote microtubule assembly [49]. Besides, tau can nucleate and bundle microtubules in vitro [50] as well as in axons of mammalian neurons [51]. Recent studies have shown that tau not only acts as a microtubule stabilizer but also positively regulates the elongation of labile domains of microtubules at the plus ends [43]. Additionally, tau is involved in mediating intracellular transport along the axon [52], synaptic structure and function, and signaling pathways in neurons [53].
In AD and other tauopathies, pathological tau would detach from microtubules, leading to decreased microtubule stability, impaired axonal transport and synaptic function [54]. First, tau is more abundant on the labile domains of microtubules to protect them from severing proteins like katanin. Under a pathological condition, hyperphosphorylated tau disassociates with the microtubules and causes rapid and selective shrinkage of microtubule labile domains [55]. Disease-associated tau mutants, like K369I, G389R found in FTD, also showed decreased associations rate with microtubules, resulting in reduced ability in promoting microtubule assembly [56]. Second, the ability of tau to regulate axonal transport alters under pathological conditions. Amino acids (aa) 2–18 of tau protein, termed the phosphatase-activating domain (PAD), activate a signaling cascade involving protein phosphatase 1 (PP1) and glycogen synthase kinase 3β (GSK-3β) that results in disruption of kinesin-1-mediated anterograde fast axonal transport. Y18 (tyrosine 18) phosphorylation of tau, which is stronger in monomers than in filaments, shows reduced inhibition of kinesin-1 and is significantly reduced in disease-associated tau species [57]. Moreover, intracellular tau aggregates have been shown to impair fast axonal transport by increasing the run length, run time and instantaneous velocity of membranous organelles [58]. Third, pathological tau accumulates on both pre- and post-synapses in the AD brain. Presynaptic accumulation of tau induces the depletion of the synaptic vesicle pool, followed by impaired synaptic transmission and plasticity [59]. On the other hand, toxic Aβ oligomers trigger N-methyl-D-aspartate receptor (NMDAR)-mediated excitotoxicity depending on the presence of endogenous tau [16].
Besides, glial tau pathology is also a common feature of many tauopathies and contributes to pathogenesis [34]. Oligodendrocytic tau pathology disrupts the maintenance of myelin sheath [60]. Although found at trace levels in astrocytes [61], tau has been shown to accumulate in astrocytic end feet directly apposed to vascular endothelial cells, and therefore impair the blood–brain barrier (BBB) integrity [62] and cause neuron degeneration without neuronal tau inclusions [63]. Filamentous recombinant tau also activates astrocytes via integrin signaling [64]. The expression and function of tau in microglia remain unclear [34]. However, microglia may regulate the uptake and exosomal secretion of tau, therefore involved in the spreading of tau pathology across the brain [65].
Tau is post-translationally modified by multiple mechanisms, including phosphorylation, ubiquitination, acetylation, methylation, glycosylation, glycation, nitration, lipoperoxidation, sumoylation and truncation [22]. Recently, up to 95 PTMs have been identified in human brains by high-resolution quantitative proteomics (Table 2) [70]. In neurodegenerative diseases, tau undergoes a series of pathological changes, such as PTMs alterations and the prion-like seeding and propagation, many of which not just accompany the diseases and indicate the pathology progression and individual heterogeneity, but are also the driving force of diseases.
Modification | Sites |
---|---|
Phosphorylation | Y29, T30, T39, S46, S56, S68, T69, T71, T102, T111, S113, T153, S185, S184, T181, T175, S191, S198, S199, S202, T205, S210, T212, S214, T217, T220, T231, S235, S237, S238, S241, S258, S262, T263, S289, S293, S305, Y310, S316, S352, S356, T361, T386, Y394, S396, S400, T403, S404, S409, S412, S413, T414, S422, S433, S435 |
Ubiquitination | K163, K180, K190, K224, K228, K234, K240, K254, K257, K259, K267, K274, K280, K281, K290, K298, K311, K317, K321, K331, K340, K343, K353, K369, K375, K383, K385, K395 |
Acetylation | K24, K44, K240, K267, K274, K280, K281, K298, K311, K317, K331, K343, K347, K353, K375, K370, K369, K385, K395 |
Methylation | K44, K67, K87, K163, K174, K180, K254, K267, K290, R406, K438 |
SUMOylation | K340 |
Nitration | Y18, Y29, Y197, Y394 |
Truncation | M1-A2, M11-E12, V10-M11, D13-H14, D25-Q26, K44-E45, T102-A103, T123-Q124, R126-M127, A152-T153, R155-G156, I171-P172, A173-K174, G186-E187, Y197-S198, P223-K224, R230-T231, S237-S238, A239-K240, R242-L243, N255-V256, S258-K259, I260-G261, N279-K280, K281-L282, S305-V306, Q307-I308, I308-V309, Y310-K311, D314-L315, H330-K331, K340-S341, N368-K369, A390-E391, E391-I392, Y394-K395, D402-T403, D421-S422 |
Tau is a phosphoprotein. Theoretically, 80 serine/threonine and 5 tyrosine residues of the longest CNS tau isoform-tau441 can potentially be phosphorylated. In the brains of normal elderly, tau contains 2–3 mol phosphate/mole of the protein [71]. Phosphorylation sites like pT231, pT181, pS404 are found with high frequency (> 50%) [70]. However, tau phosphorylation increases 2–3 times in AD brains, i.e. hyperphosphorylation [71]. At least 55 phosphorylation sites are detected on pathological tau (Table 2) [70]. Hyperphosphorylation of soluble, oligomeric and seed-competent tau all exhibit substantial patient-to-patient heterogeneity, even though certain hot spots are present in AD brains, including pT181, pT217, pT231/S235, pS262, pS396 and pS400/T403/S404 [70, 72]. Among these sites, the phosphorylation levels of pT231/S235 and pS262 are positively correlated to the seeding capacity of tau species [72].
Rodent tau exhibits approximately 90% homology with human tau. Profiling of PTMs showed modifications on up to 63 sites on tau protein in the wild-type mouse brain, of which 27 were phosphorylation sites [73]. Phosphorylation of tau at specific sites was different in the brains of human and AD model mice. For example, 3 × TG-AD mice, the commonly-used AD model which contains three mutations associated with familial AD (APP Swedish, MAPT P301L, and PSEN1 M146V), are not significantly hyperphosphorylated at pS199, pS214, pS396/S400 and pS422 as in AD brains, implying a limitation of a mouse model in studying human tau pathology [74].
Abnormal hyperphosphorylation of tau is a pivotal step in neurofibrillary degeneration in AD and other tauopathies [71]. Taking the AD brain as an example, tau can be separated into three pools according to the phosphorylation state and solubility: (i) non-hyperphosphorylated normal tau (AD-tau), (ii) hyperphosphorylated tau (AD P-tau) and (iii) polyubiquitinated, hyperphosphorylated and aggregated tau in the insoluble PHFs (PHF-tau) [75]. Hyperphosphorylation of tau induces pathology through multiple mechanisms. First, hyperphosphorylation reduces tau affinity for microtubules. Natural tau forms a “paper clip” structure, with the N- and C-terminus fold over the microtubule-binding domain to prevent self-aggregation [76]. Hyperphosphorylation changes the net charge of tau protein and alters tau conformation to expose the microtubule-binding domain, thereby facilitating self-oligomerization and aggregation. Hyperphosphorylated and/or aggregated tau detach from the microtubules and lose their ability to stabilize microtubules [71]. Besides normal, AD P-tau captures microtubule-associated proteins other than tau, such as MAP1 and MAP2 [77], leading to further disruption of microtubules. Second, hyperphosphorylated tau redistributes from axons to the somatodendritic compartment and impairs synaptic function (see Section 3.3) [16, 54]. Third, phosphorylation may change the interaction of tau with other regulatory proteins [28]. Recently, 75 proteins specifically bound to phosphorylated tau in NFTs have been identified by quantitative proteomics coupled with affinity purification-mass spectrometry; most enriches in the protein ubiquitination pathway and phagosome maturation [78]. Whether hyperphosphorylation of tau alters its affinity to these proteins and directly leads to the damage of relevant pathways deserves more extensive investigation.
Tau phosphorylation is regulated by both proline-directed [GSK-3β, cyclin-dependent-like kinase-5 (CDK5), dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) and extracellular signal-related protein kinase (Erk)] and non-proline-directed protein kinases [calcium/calmodulin activated protein kinase II (CaMKII), protein kinase A (PKA), casein kinase 1 (CK1) and microtubule affinity-regulated kinase 110 (MARK p110)] in vivo, which are activated and/or overexpressed in AD brains [22]. On the contrary, tau is dephosphorylated by protein phosphatases, in particular protein phosphatases 2A (PP2A), which is responsible for over 70% of the total tau phosphatase activity in the human brain [79]. Dephosphorylation of AD P-tau with PP2A restores tau activity in promoting microtubule assembly in vitro and diminishes AD P-tau-induced propagation of tau pathology in mouse brain [80]. In disease conditions, phosphatase activity against tau is reduced to half, further increasing the imbalance between kinase and phosphatase activities, eventually resulting in excessive phosphorylation of tau [79]. It should be noted that tau is rapidly dephosphorylated during postmortem in a site-specific manner, suggesting timely dissection and proper cooling of the brain tissues [81].
Ubiquitination, a PTM that covalently conjugated ubiquitin (a highly conserved 76 amino acid protein) to the ε-amino group of target lysine residues in a protein, is usually involved in cellular protein degradation as well as non-degradative pathways including cell signaling, mitochondrial homoeostasis and DNA damage responses [82]. Ubiquitin positive pathological aggregates are present in AD, FTD, PD, CBD and other neurodegenerative diseases [83]. Quantitative analysis of ubiquitylome in AD brain reveals 28 ubiquitination sites in tau protein, which are the most abundant PTMs except phosphorylation (Table 2) [83]. Most of these ubiquitylation sites are located in the proline-rich region and the microtubule-binding domain.
Ubiquitination of tau is catalyzed by various ubiquitin ligases (E3 ligases), for instance, the C-terminus of the Hsc70-interacting protein (CHIP), TNF receptor-associated factor 6 (TRAF6) and axotrophin/MARCH7 [22]. High molecular weight (HMW) tau extracted from AD brain is shown to be polyubiquitinated, likely through K6-, K11- or K48-linkages [83], while PHF-tau is mostly monoubiquitylated, making it insufficient to trigger the ubiquitin-proteasome system (UPS)-mediated proteolysis [84]. Both polyubiquitylation and monoubiquitylation of tau contribute to the formation of insoluble protein inclusions [85, 86].
As a natively unfolded protein, tau is degraded by ATP/ubiquitin-independent 20S proteasome in physiological conditions [87]. Misfolded tau is typically ubiquitylated and is sent to the proteasome for degradation [88]. However, misfolded oligomers and aggregates cannot be fully degraded by the proteasome, but also directly damage the proteasome activity [89]. The autophagy-lysosome system provides a more potent pathway to degrade tau aggregates, which also relies on ubiquitination modification for recognition [88]. Therefore, activating ubiquitin degradation for toxic tau species is considered as one of the potential therapeutic strategies for the treatment of AD and related tauopathies.
Acetylation is a co- or post-translational modification that utilizes acetyl-CoA as the acetyl source to modify the N-termini or specific lysine residues in proteins [84]. Tau acetylation is catalyzed by the histone acetyltransferase p300 (EP300) or CREB-binding protein (CBP), and removed by sirtuin 1 (SIRT1) and histone deacetylase 6 (HDAC6) [22]. Tau is also able to catalyze self-acetylation by using cysteine residues C291 and C322 in the R2 and R3 repeats, respectively. 4R-tau displays the higher activity of autoacetylation than 3R-tau because the latter lacks the R2 repeat [90]. 19 distinct acetylation sites have been mapped in tau protein isolated from AD brains, most of which are located within the microtubule-binding repeats and the flanking region (Table 2) [70].
The pathological effect of tau acetylation depends on specific modification sites. For example, high levels of tau acetylation are found at Lys163, Lys174, Lys180, Lys274, Lys280, Lys281 and Lys369 in AD brains, which may be related to the impairment of tau function [84]. Acetylation at these sites could prevent the polyubiquitylation and degradation of hyperphosphorylated tau, thus accelerating the accumulation of phosphorylated tau and promoting NFTs formation, accompanied by increased cognitive impairment. Acetylated tau also mislocalizes to the somatodendritic compartment and disrupts cytoskeleton dynamics, postsynaptic protein localization and receptor trafficking, consequently giving rise to synaptic plasticity deficits and memory loss [91]. Moreover, auto-acetylation of tau in C291 and C322 is coupled to its auto-proteolysis at K281-L282 and K340-S341 [90]. On the contrary, Lys259, Lys290, Lys321 and Lys353 within the KXGS motifs, which are found hypoacetylated in the AD brain, are normally acetylated to inhibit tau phosphorylation and aggregation [92].
As an intrinsically disordered protein, tau is sensitive to proteolysis. In addition to acetylation-induced auto-proteolysis, tau can be cleaved by a variety of proteases both in vitro and in vivo including a disintegrin and metallopeptidase domain 10 (ADAM-10), asparagine endopeptidase (AEP), Calpain-1, Calpain-2, Caspase-3, Caspase-6, chymotrypsin, thrombin, cathepsins, human high-temperature requirement serine protease A1 (HtrA1) and puromycin-sensitive aminopeptidase (PSA). Besides, many fragments of tau in the brain have been found with undefined proteases (Table 2) [74, 93, 94]. In NFTs, at least three site-specific cleavages of tau (N368, E391 and D421) have been identified to be correlated with the progression of Braak stages [95]. Similar cleavage sites are also detected in several mouse models of tauopathies [28]. To date, more than 50 truncated forms of tau have been identified and over 30 are present in AD brains [94].
Truncation of tau plays a crucial role in its pathology. Truncation opens up the “paper clip” tertiary structure of tau protein, increases its site-specific phosphorylation, self-aggregation and affinity to oligomeric tau derived from AD brain (AD O-Tau), and thus promotes tau capture and seeded-aggregation by AD O-Tau [28, 96]. Tau truncation alone is sufficient to trigger hyperphosphorylation and aggregation [97]. Some fragments of tau can spread transcellularly, resulting in the propagation of tau pathology [94]. Additionally, Tau truncation can also induce toxic responses like apoptosis which is independent of its function on aggregates [98].
The characteristics of tau fragments depend on their amino acid composition. The C-terminal truncation increased tau fibrillization in vitro [66], while N-terminal truncations are found more associated with hyperphosphorylated high molecular weight tau oligomers (HMW-tau) isolated from AD brains [74, 93]. Tau fragments containing the aggregation-prone elements (Table 3) are prone to assemble the protease-resistant pathological core, which has various compositions in the different tauopathies [99]. Some specific fragments are secreted from the cytosol into the interstitial fluid and further released to the cerebrospinal fluid (CSF) or plasma, making them potentially biomarkers to indicate the progression of AD and other tauopathies [100]. Early study using immunoprecipitation showed that tau in CSF is predominantly the N-terminus fragments with an apparent molecular weight of approximately 20–40 kDa [101]. A 20–22 kDa NH2-truncated form of tau (aa 26–230) identified in CSF is found to be neurotoxic due to its damages to mitochondrial oxidative phosphorylation [102]. High-resolution mass spectrometry revealed at least 19 tau fragments in the CSF, of which tau aa 156–224 is the most abundant peptide [67, 68]. Nonetheless, the prion-like seeding activity of CSF tau fragments is quite limited [69].
In addition to the above modifications, tau can also be modulated by methylation, SUMOylation, nitration, glycosylation and glycation. The contributions of these PMTs to tau pathology are mostly unelucidated.
Tau methylation mainly occurs on lysine residues in the proline-rich region and the microtubule-binding domain, and a few arginine residues [73]. Up to 11 methylation sites were found in the human brain [70]. Methylated tau is highly concentrated in NFTs particularly in late-stage AD brains [103]. Lysine methylation suppresses tau binding to the microtubule-binding domain, increases abnormal phosphorylation of tau and blocks the UPS-mediated tau degradation. However, the role of methylation on tau self-aggregation is still controversial [84].
K340 residue is the major site of tau that be modified by the small ubiquitin-like modifier protein (SUMO) [104]. SUMO-1 colocalizes with phosphorylated tau in the AD brain. Sumoylation reciprocally stimulates tau phosphorylation at T231 and S262, and competes against K340 ubiquitylation and consequently suppresses degradation [105].
Tau can be nitrated on four Tyr residues, Y18, Y29, Y197 and Y394, which are found in AD and non-AD tauopathies [106]. The effect of nitration on tau assembly depends on the specific nitration sites in vitro. Y18 nitration is reported to be associated with astrocyte activation [107].
In addition, the complexity of PTM is reflected more in the cross-talk between various modifications, not just in the types of modifications. First, a single amino acid residue could be modified by different PMTs. Taking lysine residues as an example, some of these residues in tau protein are competitively modified by ubiquitylation, methylation, acetylation, or SUMOlyation in the AD brain (Table 2). The competition between these PMTs will determine whether tau will undergo degradation or pathological transformation [84]. Secondly, PMTs at different sites cross-talk with each other. Many phosphorylation and ubiquitination sites of tau are located within the KXGS motifs in the microtubule-binding domain. Tau hyperphosphorylation is shown to facilitate ubiquitylation of NFT tau [83]. Therefore, further investigations focusing on the cross-talk between tau PMTs are required to reveal and intervene in the pathological changes of tau.
In AD brains, the progression of tau aggregation follows a stereotypical pattern of spread (the Braak stages): initiates from the locus coeruleus and transentorhinal cortex (Braak stages I and II), gradually spread to the limbic system (Braak stages III and IV) and eventually to the neocortex (Braak stages V and VI) [108]. The stereotypical transmission of tau pathology is highly correlated with the cognitive impairment in AD [13]. Remarkably, tau pathology can be induced in rodent brains by injecting aggregates isolated from AD brains, and propagating to anatomically connected brain regions, in a similar spreading pattern to that observed in AD patients [80]. Besides, injection of tau aggregates extracted from other neurodegenerative diseases, such as AGD, CBD and PSP, also recapitulated the hallmark lesions of corresponding diseases [109]. A large amount of evidence indicates that the prion-like propagation of misfolded tau may explain the diverse characteristics of tauopathies [10].
The term “prion”, originally defined by Prusiner, refers to a ‘proteinaceous infectious particle’ that causes degeneration of the CNS [110]. In addition to prion, other misfolded proteins, most notably Aβ, tau, α-synuclein and TAR DNA-binding protein 43 (TDP43), also act as proteopathic seeds to template the physiological alterations of the same protein, transmit between cells and spread to neuroanatomical connected regions, described as the ‘prion-like property’ [110].
The natively unfolded and highly soluble tau monomer contains a minimal content of ordered secondary structure, which shows little tendency to undergo aggregation [111]. An initial disruption likely changes tau conformation to obtain more β-sheet structures required for the interaction between monomers [94]. Two hexapeptide motifs of tau, 275VQIINK280 and 306VQIVYK311, are crucial for the conformational switch and filament assembly [112]. As the intrinsic cause of fibrillation, the aggregation-prone sequence elements are found in multiple tauopathies (Table 3) [10]. Once the partially folded tau monomers are stimulated, they may sequentially aggregate to form dimmers, soluble oligomers, and eventually the insoluble PHFs and NTFs [113]. The microtubule-binding domains that contain β-sheet structures assemble into the rigid core of PHFs, while the N- and C-terminus of tau protein form a ‘fuzzy coat’ surrounding the core [99]. All six isoforms of CNS tau are detected in AD PHFs [114]. Oligomeric tau and PHF-tau isolated from AD brains can serve as prion-like seeds to induce the aggregation of normal tau both in vitro and in vivo, while monomeric heat-stable and straight filament (SF)-tau showed limited prion-like properties. However, AD O-tau is the most potent toxic species to induce pathological tau aggregation and propagation in vivo [80, 96, 115, 116, 117].
Tau fibrils isolated from the brains of patients with different tauopathies show disease-specific folding. In some cases, even in the same disease, the protofilaments of tau pack in distinct ways to form different polymorphs although the conformation of tau monomer is relatively preserved [10, 118]. Tau strains from different sources exhibit variant ability in inducing aggregation in vivo. For example, both the structures of PHF and SF in AD contain eight β-sheets in a C-shaped fold, but the intermolecular organization between the two kinds of protofilament is different [119]. PHF-tau, but not SF-tau, dramatically seeds tau aggregation in vitro and triggers the propagation of tau pathology in vivo [116]. Furthermore, the induced pathology in specific cell types is related to the origin of tau species. Injection of AD pathological tau to mouse brain induces pathology only in neurons, while injection of CBD or PSP pathological tau gives rise to pathology in neurons as well as astrocytes and oligodendrocytes [120].
Truncation and hyperphosphorylation are two major PMTs that contribute to tau aggregation. Truncation of tau may expose the microtubule-binding repeats that are responsible for aggregation. Tau truncation alone is sufficient to induce site-specific phosphorylation and self-aggregates [97]. Among various truncations of tau, deletion of the first 150 aa and the last 50 aa (tau151–391) promotes its pathological characteristics most significantly. Compared with full-length tau, tau151–391 is more prone to phosphorylation, self-aggregation and seeded aggregation by AD O-tau [96]. Hyperphosphorylation alone is not sufficient to induce tau aggregation, but only when it occurs together with truncation [121]. Phosphorylation at several sites (e.g. pT231, pS235 and pS262) flanking the microtubule-binding domains inhibits tau-mediated microtubule assembly and facilitates tau aggregation into PHFs [122]. Interestingly, the phosphorylation levels of these sites are positively correlated to the seeding capacity of tau species isolated from AD patients. Notably, the effect of phosphorylation on tau seeding activity seems to be site-specific. For instance, phosphorylation levels at pS198/S199/S202 and pS400/T403/S404 show a negative correlation with tau seeding activity [72].
Mutation, dysregulation of tau alternative splicing and local contextual factors are also risks for tau aggregation [22]. Moreover, some chemical factors with strong negative charges (e.g. heparin, RNA, dextran sulphate and arachidonic acid) can induce tau aggregation in vitro [10]. Nevertheless, it should be pointed out that none of the fibrils synthesized in vitro resemble patient-derived fibrils so far, because the structures of chemical-induced tau filaments are quite different from those in diseases [118]. In addition to neurons, microglias also take up both soluble and insoluble tau [123] and are involved in promoting the spread of tau pathology [124].
Once formed in the coeruleus/subcoeruleus region, the prion-like tau seeds are transmitted from a “donor cell” to a “recipient cell” to template more aggregation, and progressively spread the pathology along synaptically connected neurons to large-scale human brain networks. Propagation of tau pathology involves the following steps: 1) uptake of tau seeds, 2) seeded aggregation, 3) secretion of new seeds and 4) transcellular transmission of the toxic seeds [125].
The proteopathic seeds released from neurons can be engulfed by interconnected neurons at the somatodendritic compartment and the axon terminals, and are transported both anterogradely and retrogradely [126]. Endocytosis is the primary pathway for the internalization of proteopathic seeds, although the specific mechanisms vary [120]. It has been reported that pathological tau could be taken up by macropinocytosis, heparan sulfate proteoglycans (HSPGs)-dependent endocytosis, clathrin-mediated endocytosis, phagocytosis and tunneling nanotubes (TNT)-dependent direct intercellular transport, of which HSPGs-mediated endocytosis is the most predominant way [127]. The mechanisms of tau uptake are mainly similar for both vesicle-bound and free proteins [126]. Diverse tau strains display different uptake efficiency. Tau trimers are the minimal fragment that can be spontaneously internalized by primary neurons, while no clear upper limit is observed [128]. However, the soluble HMW-tau isolated from AD brain is the most efficiently internalized species [129].
After internalization, tau seeds are transported to the endo-lysosomal system, and some of them are degraded in the lysosomes [130]. Due to age-related dysfunction or other unknown mechanisms [131], a part of the seeds disrupt the endosomal vesicle and enter the cytoplasm, where they template amplification of new fibrils [132]. The danger receptor galectin-8 could protect against the release of seeds by monitoring endomembrane integrity and activating autophagy [133].
Tau contains no signal peptides. But it is secreted into the culture medium, interstitial fluid or CSF in a monomeric and/or truncated non-phosphorylated form lacking the C-terminal portion in physiological conditions [125], implying a potential physiologic role. Nonetheless, the transmission of tau monomer is unlikely to mediate transcellular propagation of tau pathology [134].
The proteopathic tau seeds are released from neurons through multiple pathways, including exocytosis [135], exosome [136], synaptic vesicles [137], presynapse membrane penetration [138] or even direct translocation across neurons [139]. Truncation and hyperphosphorylation of tau or increased synaptic activity facilitate its secretion [94]. The released proteopathic seeds are taken up by postsynaptic neurons and subsequently propagate tau pathology in the interconnected cells.
So far, the US Food and Drug Administration (FDA) has granted seven prescription drugs for the treatment of AD. Three of these drugs, Donepezil (Eisai Co., Ltd., Pfizer), Galantamine (Janssen, Ortho-McNeil Pharmaceutical, Sanochemia Pharmazeutika, Shire, Takeda Pharmaceutical Company) and Rivastigmine (Novartis Pharmaceuticals Corporation), are cholinesterase inhibitors that prevent the breakdown of acetylcholine in the brain. Rivastigmine has also been approved for the treatment of PD. Applications of Donepezil in the treatment of dementia with Lewy bodies, Down’s syndrome and PD are under clinical trial. The forth drug Memantine (Forest Laboratories, Inc., H. Lundbeck, Merz Pharma) is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. The fifth drug Suvorexant (Merck), an orexin receptor antagonist, is approved for treating sleep disorders in AD. The sixth drug Tacrine is a reversible acetylcholinesterase inhibitor, but has been discontinued because of its hepatotoxicity (Pfizer, Shionogi Pharma). In 2021, Aduhelm (Aducanumab), a human IgG1 monoclonal antibody against Aβ (Biogen, Neurimmune), was approved as the first immunotherapy for AD. However, most therapies exhibit limited benefits and do not prevent or slow down the progression of the disease [122].
Based on the extensive understanding of AD pathogenesis, a large number of therapies targeting tau have been developed recently. To data, among the 137 active therapeutic clinical trials for AD, FTD and PSP, 17 targeted tau (https://www.alzforum.org/therapeutics).
Although the mechanism is not fully elucidated, tau immunotherapy, either active or passive, shows protective effects on tau pathology and cognitive performance in AD model animals and is consequently becoming an essential strategy in the development of AD therapies [17]. Two vaccines for active immunotherapy of AD, AADvac-1 which is a synthetic peptide of tau (aa 294–305) and ACI-35 which is a phosphorylated tau peptide containing pS396/S404 are now in clinical trials (Table 4) [140]. Since active immunization may increase the risk of autoimmune reaction and other disadvantages [141], passive immunization currently accounts for the majority of the immunotherapy for tau (Table 4).
Disease | Aggregation-prone elements |
---|---|
AD | 3R Q273-E380, 4R-tau: G304-E380 |
CBD | K274-E380 |
CTE | 3R-tau: K274-R379, 4R-tau: S305-R379 |
PiD | K254-F378 |
Aggregation-prone elements of tau in representative tauopathies [5, 188].
Approach | Agent | Mechanism of action | Sponsor | Clinical trial | Status |
---|---|---|---|---|---|
Active | AADvac1 | A synthetic peptide derived from tau | Axon Neuroscience SE | Phase 2 | Completed |
Active | ACI-35.030 JACI-35.054 | Synthetic tau fragment phosphorylated at pS396/S404 anchored into a lipid bilayer | AC Immune SA | Phase 1 Phase 2 | Recruiting |
Passive | ABBV-8E12 | A monoclonal antibody recognizes tau’s N-terminus | AbbVie | Phase 2 | Completed |
Passive | BIIB076 | A monoclonal anti-tau antibody | Biogen | Phase 1 | Completed |
Passive | Semorinemab | A monoclonal antibody recognizes tau’s N-terminus | Genentech, Inc. | Phase 2 | Completed |
Passive | LY3303560 | A humanized antibody against soluble tau aggregates | Eli Lilly and Company | Phase 2 | Active, not recruiting |
Passive | Lu AF87908 | A monoclonal antibody recognizes phosphorylated tau | H. Lundbeck A/S | Phase 1 | Recruiting |
Passive | JNJ-63733657 | A monoclonal antibody recognizes phosphorylated tau | Janssen Research & Development, LLC | Phase 2 | Recruiting |
Passive | Bepranemab | A monoclonal antibody recognizes tau235–250 | UCB Biopharma SRL | Phase 2 | Recruiting |
Passive | E2814 | A monoclonal antibody recognizes an HVPGG epitope of tau | Eisai Inc. | Phase 1 Phase 2 | Recruiting |
PTM | Salsalate | Inhibit tau acetylation | Adam Boxer | Phase 1 | Active, not recruiting |
PTM | LY3372689 | A inhibitor of the O-GlcNAcase | Eli Lilly and Company | Phase 1 | Completed |
PTM | ASN51 | A small-molecule inhibitor of O-GlycNAcase | Asceneuron Pty Ltd. | Phase 1 | Recruiting |
ASO | BIIB080 | An antisense oligonucleotide (ASO) targeting tau expression | Ionis Pharmaceuticals, Inc. | Phase 1 Phase 2 | Active, not recruiting |
Tau-based therapies for AD.
Passive immunotherapy is a short-term immunization administered by continuous injection of antibody that is designed specifically to pathological epitopes. Intravenously injection of tau antibody decreases both Aβ and tau pathologies in animal models, implying a therapeutic potential in the treatment of AD and related tauopathies [142]. There are 8 specific tau antibodies in clinical trials up to now. Their targets mainly focus on the N-terminus (ABBV-8E12 and Semorinemab), phosphorylation sites (Lu AF87908 and JNJ-63733657) or microtubule-binding region (Bepranemab and E2814) of tau protein (Table 4). Some antibodies (e.g. Bepranemab) also show potential in the treatment of other neurodegenerative diseases like PSP (https://www.alzforum.org/therapeutics) [143]. Of course, tau-based passive immunization also faces some challenges, of which the key problem is how to deliver the antibodies more efficiently through the blood–brain-barrier (BBB) into specific brain region with tau pathology [144].
Acetylation at specific sites of tau is shown to inhibit the degradation of hyperphosphorylated tau, obstruct synaptic plasticity and promote cognitive impairment in AD mouse models [91]. Salsalate, a non-acetylated dimer of salicylic acid commonly used as a non-steroidal anti-inflammatory drug, can inhibit acetyltransferase p300-induced tau acetylation, thus enhancing tau turnover and reducing tau levels [145]. O-GlcNAcylation negatively regulates tau phosphorylation by competing for the phosphorylation sites [146]. Two small molecular inhibitors of O-GlycNAcase (LY3372689 and ASN51) are currently undergoing clinical trials.
Hyperphosphorylation is the crucial PTM that determines the propagation of tau pathology. Inhibition of tau hyperphosphorylation has long been considered as a potential therapeutic strategy. Tau phosphorylation can be modulated by the balance between protein kinases and phosphatases. Nasal insulin and the GSK-3 inhibitor Lithium that inhibit tau phosphorylation via activating PI3K signaling, and PP2A activator Metformin aimed at tau dephosphorylation are currently under development or evaluation in clinical trials [122].
Knockout of MAPT gene induces no obvious phenotype except for behavioral deficits in aged mice [147]. Reducing the levels of endogenous tau shows protection against cognitive impairments and behavioral abnormalities in AD mice [148]. BIIB080, the first antisense oligonucleotide (ASO) targeting the translation of tau mRNAs, has just started Phase 1 and Phase 2 clinical trials. Recently, a selective protein degradation approach achieved by the proteolysis targeting chimeras (PROTACs) is utilized to decrease tau protein in the brain [82, 149]. PROTACs form a ternary complex with the target protein and ubiquitin E3 ligase. E3 ubiquitin ligase stimulates polyubiquitination of the targets and facilitates its following recognition and degradation by the 26S proteasome [149]. PROTACs targeting tau remarkably decreased tau levels and improved synaptic and cognitive functions in wildtype and AD mice [150].
In the past few years, inhibitors of tau aggregation were considered as potential therapies for AD for their roles in preventing the prion-like seeding and propagation of tau pathology. Unfortunately, the clinical trials of corresponding small molecular drugs, such as methylene blue, Rember TM, and LMTX, did not show the expected effect and are thus discontinued. NPT088, a fusion protein consisting of human-IgG 1-Fc and an active fragment binds to and remodels misfolded aggregates of tau, also exhibited no effect on brain plaques, tau aggregates or AD symptoms [151].
What’s more, the disruption of microtubules is one of the main consequences of tau-induced neurotoxicity. Therefore, stabilization of microtubules may also be a potential therapeutic approach associated with tau. However, the efficacy of microtubule stabilizers (e.g. TPI-287) in the treatment of AD still requires further evaluation.
In summary, tau-mediated microtubule dynamics and assembly play essential roles in neuronal transport and the maintenance of synaptic structure and function. In neurodegenerative diseases, tau undergoes a series of pathological changes, including mutation, abnormal alternative splicing, abnormal PTMs and prion-like seeding and propagation. Certain benefits of therapeutic approaches targeting pathological tau have emerged in the treatment of AD and related tauopathies. Recently, proteomics results indicate significant heterogeneity of tau pathology in different patients, raising the possibility that personalized approaches according to the biochemical characteristics of tau may achieve better therapeutic effects [10]. It is also worth noting that tau interacts with other risk factors of neurodegenerative diseases, such as Aβ [152], apolipoprotein E [153], α-synuclein [154], metal dysregulation [155], defective mitophagy [156], stress and inflammation [157] and so on. Therefore, further investigation of the comprehensive map of tau interactions will better reveal the pathogenesis of neurodegenerative diseases.
This work was supported by Nantong University, New York State Office for People Developmental Disabilities, the Neural Regeneration Co-innovation Center of Jiangsu Province and grant from the National Natural Science Foundation of China (Grants 81872853).
The authors declare no conflict of interest.
The temporomandibular joint (TMJ) is the movable articulation of the bone head. Its structure and morphology share common features with other synovial joints; however, it also presents particularities that make it unique. In fact, deep knowledge of the anatomy and function of the TMJ is a central challenge for clinicians and scientists, since many of the pathological conditions that affect this articulation can be explained based on its morphological and physiological aspects.
\nThe TMJ is a synovial joint composed of two articular surfaces [1, 2, 3, 4] (\nFigure 1\n). The inferior articular surface is given by the mandibular articular surface, which is part of the mandibular head. Structurally, the mandibular head is formed by two surfaces, anterior and posterior, both separated by a ridge that follows the same axis of the mandibular head [5, 6, 7]. The anterior portion of the mandibular head is relatively convex in contrast with the posterior surface which is characterized for being flat and vertical [7, 8] (\nFigure 2\n). On the other hand, the superior articular surface of the TMJ is given by the horizontal portion of the squama of the temporal bone, which is organized forming two highly relevant structures: the mandibular fossa and the articular eminence of the temporal, also called temporal condyle [1, 2, 7, 8, 9, 10, 11]. The mandibular fossa corresponds to a concave surface with its greater axis in the transverse diameter [2, 7, 8, 12] and the temporal condyle corresponds to a convex bony elevation with its major dimension at the transverse axis, formed by an anterior and posterior surfaces without a clear boundary between the two of them [8, 9, 11]. Additionally, in the TMJ, it is possible to observe an articular disc, which allows fitting the temporal condyle and the mandibular head [1, 5]. It is avascular and not innervated at its center, which coincides with the area of greatest work [2, 6, 8, 13]. Like the mandibular fossa and head, its greater dimension is at the transverse axis and adapts closely to the adjacent surfaces [2, 6, 7, 8].
\nAnatomical characteristics of the temporomandibular joint (TMJ). Sagittal section of TMJ. Mandibular head (MH) articulating with temporal condyle (TC) and mandibular fossa (MF). Between the two joint surfaces the articular disc (AD) is interposed. The middle portion of the thinner disc portion being located in the work area; the anterior articular disc is continuous with the fibers of the lateral pterygoid muscle (LP), which is also inserted into the pterygoid fossa (PF) of the mandibular condyle neck; the back of the disc is related to the vascularized tissue in the retrodiscal area (RA). TMJ localizes superior to the middle cranial fossa (MCF) and posterior to the internal auditory canal (IAC).
Anatomical characteristics of the temporomandibular joint. (A) Lateral, (B) frontal, and (C) superior view of the mandibular head. This is formed by two poles, the lateral pole (LP) and the medial pole (MP), the latter being larger. In a side view, it is possible to observe the morphology of the anterior surface (AS) (convex) and posterior surface (PS) (flat) of the mandibular head. In the lower portion of the mandibular head at its point of junction with the condylar neck (CN), the pterygoid fossa can be seen (PF), where the lateral pterygoid muscle is inserted.
Mandibular movements are limited by a number of structures, which actively or passively avoid excessive mandibular displacement and consequently limit the movements within the joint. The main protective and customizing element of the joint complex relates to the joint capsule. This structure consists of thick organized bundles of collagen fibers that are upholstered with several proprioceptors that report changes in mandibular dynamics, thereby limiting the mandibular border movements [6]. Anteriorly, the capsule is inserted in the articular eminence [7, 8]. Laterally, the capsule strongly adheres to the longitudinal root of the zygoma and is continued backwards in tympanosquamous fissure [7, 8, 14]. The medial insertion is less extensive, inserted mainly in the sphenoid spine. The inferior insertion of the capsule extends along the condyle neck as a ring that is down on the backside of condylar process neck [7, 8, 14].
\nThere is a set of ligaments that meet a similar role to the capsule, functionally and structurally reinforcing the TMJ [6, 7, 8]. The main reinforcement ligament capsule corresponds to temporomandibular ligament which is located lateral to it. From this point of insertion the temporomandibular ligament lateral band descends obliquely and posteriorly, and finally inserts onto the posterior surface of condylar neck [7]. The medial band is horizontal, presenting a similar cranial origin to the lateral band, and is inserted into the lateral side of the mandibular head [11]. Portions of the temporomandibular ligament execute a different role within the mandibular dynamics [6].
\nAdditionally, there are a number of ligaments in the TMJ that are not structural or for its reinforcement, however limit the mandibular dynamics and hence the joint function. The stylomandibular, sphenomandibular, pterygomandibular and pterygospinous ligaments meet this role [7, 14]. The stylomandibular ligament is a segment of the muscular structures and it is originated in the styloid process forming the styloid bouquet [7]. Since its origin, the stylomandibular ligament descends obliquely to finally insert on the posterior and inferior border of the ramus. In the case of the sphenomandibular ligament, this appears as a thickening of the interpterygoid fascia, which inserts cranially into the sphenoid spine and in the mandibular lingula [7, 14, 15]. Its thickness and extent varies between the individuals and in its upper portion penetrates into the middle ear throughout the petrotympanic fissure being continued as the anterior ligament of the malleus [10, 16, 17, 18]. The pterigomandibular ligament originates from the pterygoid hamulus of the medial lamina of the pterygoid process of the sphenoid bone and from that point is inserted into the lateral lip of the mandibular retromolar trigone [7]. It is inserted in the buccinator muscles anteriorly and the superior constrictor muscle of the pharynx posteriorly. Finally, the pterygoespinous ligament, like the sphenomandibular, corresponds to a thickening of the interpterygoid fascia. It is reported that this ligament may undergo calcifications, which could produce alterations in the transmission of the mandibular nerve, because of its intimate relationship with the mandibular foramen determining nerve compression [19].
\nTemporomandibular disorders (TMDs) are the most widely accepted term to designate the musculoskeletal alterations of the TMJs. All TMDs share similar signs and symptoms, traditionally described as a triad of pain (TMJs, muscles, and tooth pain), interferences during mandibular movement (frequently associated with joint noises), and/or movement range limitation [20]. Bell developed the first classification of TMDs in 1986, and it was based on an orthopedic-mechanical model [21]. This classification was composed of four major categories (masticatory pain, restriction of mandibular movements, joint interference during mandibular movements, and acute malocclusion) and identified five muscular processes (myositis, muscle spasm, myofascial pain, late-onset muscle irritation, and protective co-contraction or protective stiffness). However, it was not until 1990 that the American Academy of Craniomandibular Disorders (AACD), along with the International Headache Society (IHS), developed the first taxonomic system of classification [22]. The main contributions were the distinction of two major categories (joint disorders and muscle disorders) and the possibility of establishing multiple diagnoses.
\nIn 1992, a new taxonomic classification system was developed and termed “The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD)” [23]. This system was based on the biopsychosocial model of pain, and included the Axis I (physical assessment using reliable and well-operationalized diagnostic criteria), and Axis II (assessment of psychosocial status and pain-related disability) [23]. The main purpose of this classification system was to establish standardized criteria for research, and to provide simultaneously a physical diagnosis in order to identify other patients’ characteristics that could modify the expression and eventually the management of their TMD [22].
\nSince 2014, the new DC/TMD Axis I and Axis II provide an evidence-based assessment protocol also based on the biopsychosocial model (\nFigure 3\n) that can be directly applied in the clinical and research setting [24]. In this consensus, the information required for fulfilling the Axis I diagnostic criteria is obtained from a specified examination protocol in conjunction with the core self-report instruments that assess pain symptoms involving the jaw, jaw noise and locking, and headache. Axis II core assessment instruments assess pain disability, pain intensity, jaw functioning, parafunctional behaviors, psychosocial distress, and widespread pain. All of these incorporations and changes in the core patient assessment instrument set serve as a broad foundation for patient assessment and further research [24].
\nBiopsychosocial model of disease applied to temporomandibular disorders. Axis I refers to the severity of the patient’s biological factors, including physical disorders. Axis II refers to the severity of psychosocial and behavioral factors, including interference in functioning because of pain. Two possible types of patients are depicted, each situated according to disease severity on the respective axes: Patient A has a mechanical temporomandibular joint (TMJ) disorder without secondary factors; and patient B has a pain diagnosis and clinically significant disruption in overall function and mood.
The DC/TMD also includes changes to original RDC/TMD TMJ diagnoses. An important consideration was the low sensitivity for the diagnostic algorithms for disc displacement (DD) and degenerative joint disease (DJD) (osteoarthritis and osteoarthrosis) in RDC/TMD that can provide only provisional diagnoses [24]. This is due to the fact that some DD with reduction do not have clinically detectable noise, and the disorder will not be diagnosed using the clinical criteria (positive history of noise and the presence of clicking noises) [25]. DD with reduction is highly prevalent, and crescent data suggest that internal derangement, such as DD with reduction, is likely to progress to osteoarthritis [20, 26, 27]. However, based on the evidence, DD with reduction is probably without clinical consequences unless pain occurs with noises or functional limitations, such as limited opening or interference in mastication. Nonetheless, the DC/TMD suggests that imaging using MRI is required for a definitive diagnosis of TMJ DD [24].
\nThe differential diagnosis with the other TTMs is very important in the clinical assessment. The DC/TMD taxonomic classification for TMDs is divided in four major groups: temporomandibular joint disorders, masticatory muscle disorders, headache, and associated structures. Of these, the temporomandibular joint disorders main group includes two subtypes of joint pain, three subtypes of joint disorders, and seven different subtypes of joint disease (\nTable 1\n). The clinical procedures to evaluate DD with reduction, DD without reduction without limited opening, and DJD lead to clinical diagnoses based on procedures that exhibit low sensitivity but well to excellent specificity. Thus, for treatment decision in selective cases, confirmation of presumptive diagnostic requires imaging. In contrast, clinical algorithm for assessing DD without reduction with limited opening has good sensitivity and specificity (80 and 97%, respectively) [28], being enough with the clinical evaluation for the initial working diagnosis [24].
\n\n | \n
a. Joint Pain | \n
i. Arthralgia | \n
ii. Arthritis | \n
b. Joint Disorders | \n
i. Disc disorders | \n
1. Disc displacement with reduction | \n
2. Disc displacement with reduction with intermittent locking | \n
3. Disc displacement without reduction with limited opening | \n
4. Disc displacement without reduction without limited opening | \n
ii. Hypomobility disorders other than disc disorders | \n
1. Adhesions/adherence | \n
2. Ankylosis | \n
a. Fibrous | \n
b. Osseous | \n
iii. Hypermobility disorders | \n
1. Dislocations | \n
a. Subluxation | \n
b. Luxation | \n
c. Joint diseases | \n
i. Degenerative joint disease | \n
1. Osteoarthrosis | \n
2. Osteoarthritis | \n
ii. Systemic arthritides | \n
iii. Condylysis/idiopathic condylar resorption | \n
iv. Osteochondritis dissecans | \n
v. Ostronecrosis | \n
vi. Neoplasm | \n
vii. Synovial chondromatosis | \n
d. Fractures | \n
e. Congenital/developmental disorders | \n
i. Aplasia | \n
ii. Hypoplasia | \n
iii. Hyperplasia | \n
DC/TMD taxonomic classification for temporomandibular disorders (only TMJ disorders).
DC/TMD made some changes to the diagnostic procedures of RDC/TMD for DD and DJD. TMJ noise by history is one of the recommended criteria for the intra-articular disorders of DD with reduction and DJD. The patient’s report of any joint noise (click or crepitus) during the 30 days prior to examination should be met by the history criterion or the patient’s detection of any joint noise with jaw movements during the clinical examination. Furthermore, DD with reduction diagnosis requires examiner detection of clicking, popping, or snapping noises during examination. In DJD diagnosis requires examiner detection of crepitus (e.g., crunching, grinding, or grating noises) during the examination, and distinction between fines versus coarse crepitus is not necessary. For DD without reduction, the subtype depends on an assisted opening measurement (including the amount of vertical incisal overlap): if is <40 mm it is “with limited opening” subtype, and if is ≥40 mm it is “without limited opening” subtype. In this category, joint noise does not affect the diagnosis of DD without reduction as long as the required criteria for DD without reduction are met (\nTable 2\n) [24].
\n\n | \n
a. In last 30 days, any noise present” applicable to disc displacement with reduction with and without intermittent locking, and degenerative joint disease. | \n
b. In last 30 days, jaw locks with limited mouth opening and then unlocks” applicable to disc displacement with reduction with intermittent locking. | \n
c. “Ever has jaw lock or catch so that it would not open all the way” and “interfered with eating” applicable to disc displacement without reduction with and without limited opening. | \n
d. In last 30 days, when you opened your mouth wide, jaw locked or caught so that it would not close all the way” applicable to subluxation. | \n
\n | \n
\n | \n
1. Report by patient of any joint noise (click or crepitus). | \n
2. Click detection (# of opening/closing cycles required for click) (1 of 3). | \n
3. Click detection during lateral and protrusive movements. | \n
\n | \n
\n | \n
1. Assisted opening* < 40 mm. | \n
\n | \n
1. Assisted opening* ≥ 40 mm. | \n
\n | \n
1. Report by patient of any joint noise (click or crepitus). | \n
2. Crepitus (either fine or coarse) with palpation. | \n
DC/TMD diagnostic procedures for disc displacements and degenerative joint disease with new history-based diagnosis of subluxation.
Measurement of opening includes interincisal opening plus vertical incisal overlap.
The DJD includes osteoarthritis and osteoarthrosis (\nTable 1\n). While the DD with reduction was described as “
In summary, the DC/TMD assessment protocol has both screening and confirmatory tests for the most common Axis I physical diagnoses and for Axis II contributing factors (\nTable 3\n). However, an important remark is the poor diversity of diagnostic tools available until now. The DC/TMD raise a useful systematic imagenological and clinical diagnostic tool, but with no usefulness in the study of disease progression and/or prediction. Several studies suggest some biological markers of degenerative joint disease, such as certain cytokines or proinflammatory mediators [29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42], and could be useful in the elaboration of complementary tools for diagnostic purposes with potential in the study of disease prediction/progression. Thereby, the development of diagnostic/prognostic devices based on these molecular markers is an interesting research field that could significantly improve the precision of osteoarthritis diagnosis.
\n\n | Axis I: Physical diagnosis | \nAxis II: Psychosocial status | \n||
---|---|---|---|---|
\n | Pain diagnoses | \nJoint diagnoses | \nDistress and pain disability | \n|
Application | \nClinical or research | \nClinical | \nClinical or research | \n|
Screening test | \nTMD pain screener | \nDC/TMD for disc displacements, degenerative joint disease, and subluxation | \nPHQ-4 and GCPS | \nPHQ-9, GAD-7, PHQ-15, and GCPS | \n
Confirmatory test | \nDC/TMD for myalgia, arthralgia, and headache attributed to TMD | \nImaging: MRI for disc displacements, CT for degenerative joint disease, and panoramic radiographs, MRI, or CT for subluxation | \nConsultation with mental health provider | \nStructured psychiatric or behavioral medicine interview | \n
Clinical and research applications of selected DC/TMD Axis I and Axis II tests.
Patient Health Questionnaire-4 (PHQ-4), Graded Chronic Pain Scale (GCPS), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-15 (PHQ-15).
Computed tomography (CT) and magnetic resonance (MRI) are widely useful tools for imaging the TMJ region of TMD patients, in particular for assessing degenerative bony changes, disc position and configuration, inflammatory pathological changes in the posterior disc attachment, the presence of effusion in joint spaces, and bone marrow edematous involvement [43]. Cone beam computed tomography (CBCT) allows the visualization of the TMJ in all three planes with high resolution, minimal distortion, and great precision for identifying condylar cortical changes [44]. The TMJ imaging by CBCT also allows the evaluation of the integrity of the bony structures when a degenerative disease is suspected, and to confirm the extent and progression of any bony changes [45].
\nThe degenerative changes of bone in DJD are more frequent in the mandibular condyle than in the mandibular fossa or the articular eminence, and the characteristic pathological bony changes are erosion, osteophytes, and deformity; and adaptive bony changes are marginal proliferation, flattening, concavity, sclerosis, and sub-chondral cyst [46, 47, 48, 49]. All of these anomalies are considered, for diagnostic purposes, as signs of osteoarthritis and frequently are observed in joints with long-standing DD without reduction [47].
\nSome imaging technologies such as CT [49, 50, 51], CBCT [46, 52, 53], and MR [47, 54, 55, 56] have been widely used for diagnosing DJD such as TMJ osteoarthritis. However, is CBCT, a fairly new imaging technology, that has the possibility to create images of high diagnostic quality using lower radiation doses than CT [53]. CBCT imaging has shown to be very helpful for depicting abnormal bony changes such as the cortical margin of the surface and sub-chondral cancellous trabecular structure present in the mandibular condyle, where the conventional radiography has shown difficulties to analyze successfully [30]. Conventional tomography also has difficulties in detailed assessment of changes in the surface morphology of the condyle and fossa, due to the thickness of the slices (1.0–3.0 mm) [57].
\nAnother interesting imaging technique for the diagnosis of TMJ osteoarthritis evaluated in the evidence is the bone scintigraphy [58, 59, 60, 61]. This technique shows a correlation with signs and symptoms with very good sensitivity, specificity, and accuracy (100, 90.91, and 96.97%, respectively) [59]. Interestingly, some radiographic changes seen by follow-up CBCT, MRI, and scintigraphy suggested that osteonecrosis may be the initial phase of an osteoarthritic process [30]. Thus, knowing all the potential imaging findings of every imaging modality is very important to make right imaging diagnostics (\nTable 4\n).
\nImaging modality | \nImaging findings | \n
---|---|
Medical CT and cone beam CT | \nPathological bony changes such as erosion, osteophyte and deformity | \n
\n | Osteochondritis disseccans | \n
Static MR imaging | \nDisc positional abnormalities | \n
(1) DD without reduction | \n|
(2) DD with reduction | \n|
(3) Sideways disc displacement | \n|
\n | Joint effusion presence of marked effusion | \n
\n | A higher T2 signal of the posterior disc attachment | \n
\n | Bone marrow abnormalities | \n
(1) Bone marrow edema | \n|
(2) Bone marrow osteonecrosis | \n|
\n | Tumor involvement and inflammatory diseases into the TMJ | \n
region and the surrounding structures | \n|
\n | Autoimmune processes such as rheumatoid arthritis | \n
\n | A closer proximity between the TMJ disc and the mandibular nerve | \n
Dynamic MR imaging with contrast material | \nProminent contrast enhancement of the posterior disc attachment | \n
\n | Contrast enhancement of effusion | \n
Magnetization transfer contrast imaging | \nDetection for the edematous and ischemic changes in the muscles | \n
Magnetic resonance spectroscopy | \nAscending of insular glutamine levels by 1H MRS | \n
Functional MR imaging | \nThe regions and the network of brain activation associated with TMD | \n
Ultrasonography | \nMuscular edema by low-level contraction | \n
Bone scintigraphy | \nDetection for early changes on the osseous reaction of OA | \n
A rating of the usefulness of each imaging modality related to TMJ pain, MM pain and fatigue.
TMJ, temporomandibular joint; MM, masticatory muscle; DD, disc displacement; TMD, temporomandibular disorders; OA, osteoarthritis.
Cytokine studied | \nAuthors | \nStudy groups | \nMeasuring technique | \nOutcomes of study | \n
---|---|---|---|---|
\n | \nKaneyama et al. [33] | \nGroup 1: DID with clicking. (n = 8) | \n\n | \nGroups 1, 2 and 3 > Group 4. | \n
\n | \n | Group 2: DID with locking. (n = 52) | \n\n | \n |
\n | \n | Group 3: OA. (n = 57) | \n\n | \n |
\n | \n | Group 4: Control. (n = 7) | \n\n | \n |
\n | Kaneyama et al. [32] | \nGroup 1: DID (n = 24) | \n\n | \nNo differences among the groups. | \n
\n | \n | Group 2: OA (n = 26) | \n\n | \n |
\n | \n | Group 3: Control (n = 5) | \n\n | \n |
\n | Kaneyama et al. [35] | \nGroup 1: Control (n = 5) | \n\n | \nGroups 2, and 3 > Group 1. | \n
\n | \n | Group 2: DID (n = 41) | \n\n | \n |
\n | \n | Group 3: OA (n = 14) | \n\n | \n |
\n | Kubota et al. [36] | \nGroup 1: DID and OA (n = 22) | \n\n | \nGroups 1 > Group 2. | \n
\n | \n | Group 2: Control (n = 12) | \n\n | TMJs with OA > TMJs with DID. | \n
\n | \n | Group 3: OA of Knee (n = 10) | \n\n | \n |
\n | Takahashi et al. [39] | \nGroup 1: DID with clicking (n = 8) | \n\n | \nIL-1β presented the higher incidence. Strong correlation between the presence of IL-1β and TMJ pain in groups 1, 2, and 3. | \n
\n | \n | Group 2: DID with locking (n = 25) | \n\n | No cytokines were detected in Group 4. | \n
\n | \n | Group 3: OA (n = 18) | \n\n | \n |
\n | \n | Group 4: Control (n = 6) | \n\n | \n |
\n | Vernal et al. [40] | \nGroup 1: OA (n = 12) | \n\n | \nGroup 1 > Group 2. | \n
\n | \n | Group 2: Control (n = 6) | \n\n | \n |
\n | \nKaneyama et al. [33] | \n* | \n\n | \nGroups 1, 2 and 3 > Group 4. | \n
\n | Kaneyama et al. [32] | \n* | \n\n | \nNo differences among the groups. | \n
\n | Kaneyama et al. [35] | \n* | \n\n | \nGroups 2, and 3 > Group 1. | \n
\n | \n | \n | \n | TNF-α level was positively correlated with those of IL-6, sTNFR-I and sTNFR-II. | \n
\n | Takahashi et al. [39] | \n* | \n\n | \nTNF-α presented the lower incidence. | \n
\n | \n | \n | \n | No cytokines were detected in Group 4. | \n
\n | Vernal et al. [40] | \n* | \n\n | \nGroup 1 > Group 2. | \n
\n | \nKaneyama et al. [33] | \n* | \n\n | \nGroups 1, 2 and 3 > Group 4. | \n
\n | Kaneyama et al. [34] | \nGroup 1: Control (n = 7) | \n\n | \nIn groups 2 and 3 was significantly higher in joints with osseous changes in the condyle. | \n
\n | \n | Group 2: DID (n = 39) | \n\n | No cytokines detected in group 1. | \n
\n | \n | Group 3: OA (n = 22) | \n\n | \n |
\n | Kubota et al. [36] | \n* | \n\n | \nGroups 1 > Group 2. | \n
\n | \n | \n | \n | TMJs with OA > TMJs with DID. | \n
\n | Takahashi et al. [39] | \n* | \n\n | \nGroup 1, 2 and 3 presented at least 1 of the cytokines in 64.5% of the cases. | \n
\n | Vernal et al. [40] | \n* | \n\n | \nGroup 1 > Group 2. | \n
\n | \nKaneyama et al. [34] | \n* | \n\n | \nDetection rate of IL-17 was low, and there was no association between the concentration of IL-17 and the presence or absence of osseous changes. | \n
\n | Vernal et al. [40] | \n* | \n\n | \nGroup 1 > Group 2. | \n
\n | \nKaneyama et al. [33] | \n* | \n\n | \nGroups 1, 2 and 3 > Group 4. | \n
\n | Takahashi et al. [39] | \n* | \n\n | \nGroup 1, 2 and 3 presented at least 1 of the cytokines in 64.5% of the cases. | \n
\n | \nFang et al. [29] | \nGroup 1: DID (n = 12) | \n\n | \nGroup 2 > Group 1. | \n
\n | \n | Group 2: OA (n = 15) | \n\n | \n |
\n | \n | Group 3: Control (n = 4) | \n\n | \n |
\n | \nKaneyama et al. [34] | \n* | \n\n | \nIn groups 2 and 3 was significantly higher in joints with osseous changes in the condyle. | \n
\n | \n | \n | \n | \n |
\n | \nWakita et al. [42] | \nGroup 1: DID with reduction (n = 25) | \n\n | \nNo significance difference in RANKL concentration between group 4 compared to the rest of groups. | \n
\n | \n | Group 2: DID without reduction (n = 39) | \n\n | RANKL/ OPG ratio in group 3 was increased. | \n
\n | \n | Group 3: OA (n = 53) | \n\n | \n |
\n | \n | Group 4: Control (n = 13) | \n\n | \n |
\n | \nFang et al. [29] | \n* | \n\n | \nUndetectable in all the groups. | \n
\n | Vernal et al. [40] | \n* | \n\n | \nGroup 2 > Group 1. | \n
\n | \nKaneyama et al. [32] | \n* | \n\n | \nGroup 3 > Group 2. | \n
\n | Wakita et al. [42] | \n* | \n\n | \nGroup 4 > Groups 1, 2, and 3. | \n
\n | \n | \n | \n | RANKL/OPG ratio in group 3 was increased. | \n
Molecular mediators proposed as associated with signs and symptoms of TMJ disorders.
When the clinical diagnosis of DD with reduction or with reduction with intermittent locking needs imaging confirmation, the DC/TMD suggests positive detection of the following: “(1)
The DC/TMD criteria consider a positive diagnostic of DJD when the TMJ-CBCT is positive for at least one of the following: sub-chondral cyst(s), erosion(s), generalized sclerosis, or osteophyte(s). An important difference between RDC/TMD and DC/TMD is in flattening and/or cortical sclerosis, because while the first consider as positive findings, the second consider indeterminate findings and possible sign of normal variation, aging, remodeling, or a precursor to frank DJD [24].
\nThe great sensitivity and specificity of TMJ-CBCT in the DJD diagnoses compared with the clinical assessment was well demonstrated in the work of Bakke et al., that shows 21 TMJ-CBCTs positive for osteoarthrosis while only two were clinically positive for the disease [62]. The high frequencies of bony changes in the CBCT images of pain-free subjects in this study were in accordance with the findings of Krisjane et al. indicating that radiographic signs of osteoarthritis are a poor indicator of pain [63]. Furthermore, several studies have demonstrated that there is a poor correlation between condylar bony changes including pathological changes, adaptive changes and/or remodeling and pain symptoms in TMJ osteoarthritis [55, 56, 64, 65, 66]. These results support the idea that many times the bony changes are not associated with the clinical diagnoses (\nFigure 4\n), and that good diagnoses comprehend history of the patient, and clinical/imaging diagnostic, although, new assessment tools are necessary for accuracy of the diagnoses.
\nImagenological characteristics of the temporomandibular joint affected with osteoarthritis. (A) Sagittal CBCT images of a TMJ of a patient with DC/TMD diagnosis of osteoarthritis but without bony osteoarthritic changes (erosions and osteophytes). (B) Sagittal CBCT images of a TMJ of a patient with a DC/TMD diagnosis of osteoarthritis and with bony osteoarthritic changes (erosions and osteophyte). CBCT: Cone beam computed tomography, TMJ: temporomandibular joint, DC/TMD: diagnostic criteria for temporomandibular joint. White arrow: osteophyte; black arrow: flattening; dot pattern arrow: erosion; asterisk: sclerosis.
Finally, \nFigure 5\n shows the decision tree made in the DC/TMD consensus summarizes the algorithm made for the diagnosis of degenerative joint disease and intra-articular joint disorders with history, clinical, and imagenological features.
\nDiagnostic criteria for temporomandibular disorders (DC/TMD): diagnostic decision tree. Schematic diagnostic decision tree made to summarize the algorithm of diagnostic for intra-articular disorders (disc displacement with reduction, disc displacement with reduction with intermittent locking, disc displacement without reduction with limited opening, or disc displacement without reduction without limited opening), or degenerative joint disease (osteoarthritis or osteoarthrosis), including history, clinical examination, and imaging.
TMJ-OA is a disease having a great deal of variation in progression, symptoms, epidemiology, pathophysiology, and presentation. The rate of progression from a healthy joint to a severe TMJ-OA can vary from weeks to decades and TMJ-OA affects all of the tissues of the joint, including the articular cartilage, synovium, sub-chondral bone, capsule, ligaments, peri-articular muscles, and the sensory nerves innervating the tissues.
\nMany factors have been proposed as responsible for the TMJ-OA development, such as genetic factors, over-loading, unilateral chewing, bruxism, and internal derangement; however, the molecular basis of the TMJ-OA aetio-pathogenesis remains unclear [67, 68, 69, 70].
\nDuring TMJ-OA, a complex inflammatory response is developed, involving the synthesis of different cytokines by resident cells (e.g., synovial fibroblast, chondrocytes, and macrophages) and inflammatory cells that infiltrate the joint tissues [71, 72]. This inflammatory response could be triggered as result of the tissue breakdown and the consequent release of damage-associated molecular patterns (DAMPs), such as low molecular weight hyaluronan (LMW-HA), high-mobility group protein 1 (HMGB1), and S100 proteins [73, 74], activating resident inflammatory cells, including dendritic cells and macrophages [75]. At initial stages of the disease, functional overload induces oxidative stress that initiates cartilage disruption [76, 77] and activation of MMPs and aggrecanases, promoting the secretion of DAMPs and the activation of the immune response [75]. During the disease progression, there is a local imbalance between the expression of specific cytokines, their receptors, and regulatory soluble receptors, which may be critical in the biological activity of the cytokine network [35]. Under these conditions, both fibroblast and synovial cells are activated to express MMPs and bone-associated cytokines that control the formation/destruction of articular cartilage and bone, determining the clinical outcome of the OA-TMJ (\nFigures 6\n and \n7\n). In fact, higher levels of interleukin (IL)-1β, IL-6, IL-17, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, prostaglandin E2 (PGE2), matrix metalloproteinase (MMP)-2, MMP-9, aggrecanase-1, superoxide dismutase, substance P, and receptor-activator of nuclear factor-κB ligand (RANKL) have been detected in synovial fluid from TMJ-OA patients as compared with disc displacement with reduction (DDWR), disc displacement without reduction (DDWOR), or healthy subjects \nTable 5\n [35, 40, 42, 68, 69, 78, 79, 80, 81, 82, 83, 84, 85, 86].
\nPhases in progression of the degenerative joint disease of the temporomandibular joint. (1) Fibrocartilage and bone tissue in physiological state, (articular disc in correct position). (2) The presence of functional overload or individual susceptibility generates hypoxia and compression of the articular tissues, resulting in apoptosis of chondrocytes and fibroblasts of the fibrocartilage, and DAMP’s release, such as ATP, ROS, TIMPs, fragments of collagen and low molecular weight hyaluronic acid. In addition to cytokines and chemokines, these molecules produced by synoviocytes allow the migration of immune cells into the joint, such as dendritic cells that generate the environment leading to the polarization of T cell populations towards Th1, Th22, and Th17 phenotypes. These polarized cells in turn will allow the differentiation and activation of osteoclasts that will degrade the articular surface establishing the degenerative and destructive pathology (3).
Chemotaxis of immune cells to the subarticular space. Synoviocytes, fibroblasts and chondrocytes produce cytokines, chemokines, intracellular DAMPs, and extracellular matrix derivatives that facilitate the migration of immune cells from the bloodstream into the joint. VEGF and CCL5 facilitate the overexpression of CD44 in endothelial cells and T cells. These molecules, together with low molecular weight hyaluronic acid fragments (sandwich effect), facilitate the diapedesis of lymphocytes through the vessels, enhancing the inflammatory stage of the disease in progress.
Certain cytokines such as IL-1β, IL-6, and TNF-α has been associated with signs and symptoms of TMJ-OA, in particular, synovitis and arthralgia [39]. In addition, TNF-α and IL-6 have been described as markers of pain and successful clinical outcomes in TMDs [87, 88]. However, a study assessing the relation between the scores from a visual analog scale of pain and the levels of IL-1β, IL-6, and TNF-α reported no positive correlation [35]. Differences among different studies results could be due to variability in the selection criteria of subjects, sampling techniques, and/or analysis methods.
\nIL-17 plays a key role in the pathogenesis of rheumatoid arthritis by inducing the synoviocyte-dependent IL-6 secretion [89]. In addition, TNF-α and IFN-γ augment the IL-17 activity and IL-17 activity has been associated with synovitis, chondral degradation, and inhibition of chondrocyte proliferation [89]. The presence of IL-17 in the TMJ synovial fluid could be an important pathophysiological biomarker of TMJ-OA [40]. In fact, bone resorption associated with an increased osteoclast activity is a central phenomenon in the pathophysiology of autoimmune and inflammatory arthritis, and it is also related to IL-17 presence, mainly through T lymphocyte-associated direct and indirect regulation [90, 91]. RANKL is the main molecule involved in the direct regulation of osteoclast activity, through the direct activation of osteoclast precursors [92]. Conversely, the indirect regulation depends on the secretion of IL-17, IL-1β, and TNF-α by synoviocytes, cytokines that in turn induce the RANKL expression on synovial fibroblast and osteoblasts [92]. Recently, it has been reported that IL-17, rather than IL-12 or IFN-γ, is critical for the onset of autoimmune arthritis [91, 92]. Thereby, the role of IL-17 in bone metabolism-associated diseases has been extensively defined, and this role is mainly associated with the induction of proinflammatory cytokines, chemokines, and matrix metalloproteinases that leads pathological bone and/or cartilage damage [89, 93, 94].
\nOur recent data revealed that higher levels of IL-1β, IL-17, and IL-22, associated with the Th1, Th17, and Th22-pattern of immuno-inflammatory response, were detected in TMJ-OA as compared with DDWR. Increased cytokine levels significantly correlated with an enhancement of RANKL expression and the detection of imagenological signs of articular bone degeneration [95]. IL-22 plays a proinflammatory role through the synergistic activity with IL-1β and TNF-α [96, 97, 98] and IL-22 can indirectly induce osteoclastogenesis and bone resorption by the induction of Th17 lymphocyte activity and IL-17 production [99]. In fact, previous reports have detected over-expressed levels of IL-22 in rheumatoid arthritis synovial fibroblasts, demonstrating a pathogenic role of IL-22 in the rheumatic joint inflammation and destruction through the modulation of the IL-1β and IL-17R expression [100, 101]. In general terms, we believe that the Th1/Th17/Th22 immuno-inflammatory cell pathways, associated with the production of IL-1β, IL-17, and IL-22, play a central role in the pathogenesis of the TMJ-OA. Similarly, the role of the Th2/Th9/T regulatory cell pathways, responsible for the production of IL-4, IL-9, and TGF-β1, respectively, could be associated with TMJ-OA disease healing.
\nAt the beginning of 1980s, the existence of a suppressor T cell population was proposed, suggesting that these T cells restrict the induction or expression of effector T cells and thereby prevent and control exaggerated immune response and autoimmune disease development [102]. The modern view of suppressor cells began with the observation that the transfer of T cells depleted of the IL-2Rα+ (CD25+) cell subpopulation induced multiorgan autoimmunity in recipient mice [103]. Nowadays, suppressor T cells have been renamed and are currently known as T regulatory cells (Tregs). These cells have been isolated from mice and humans and their regulatory functions have been demonstrated not only
Natural Tregs are CD4+ T cells that develop and mature in the thymus carry out their regulatory function during normal surveillance of self-antigens [106]. On normal individuals, they represent 5–10% of the peripheral CD4+ T cell population and are characterized by the constitutive expression of high levels of CD25 and low levels of CD45RB [107]. In turn, adaptive Tregs represent CD4+ T cells that acquire their regulatory activity during activation [106]. Unlike natural Tregs, which came out from the thymus as CD4+CD25+ cells, adaptive Tregs originate from peripheral naïve T cells [106]. They are derived from CD4+CD25− T cells and show variable expression of CD25 during their mature phenotype, depending on the disease and the site of regulatory activity [108] Induced Tregs require TCR stimulation for induction of regulatory functions and have demonstrated limited proliferation
Although induced Tregs and effector Th17 cells play different roles during the immunity, reciprocal developmental pathways have been demonstrated for their generation. Naïve T cells exposed to TGF-β1 up-regulate Foxp3 and become induced Tregs; however, when cultured with TGF-β1 and IL-6, naïve T cells generate IL-17 secreting Th17 cells with pathologic activities [110, 111]. Thus, when the immune response is not activated, TGF- β1 favors the generation of induced Tregs, which suppress inflammation; however, when the inflammatory process is established, IL-6 is synthesized during the innate immune response, inhibiting the generation of Tregs and inducing the differentiation of proinflammatory of Th17 cells in presence of TGF-β1 [112]. Thus, induced Tregs and Th17 lymphocytes may arise from the same precursor cell and selective differentiation would depend on the local cytokine milieu, which would determine the predominance of either Tregs with suppressor activity or Th17 cells with pathologic activities, determining the outcome of the disease [112].
\nThe therapeutic potential of Tregs has created a lot of expectations and a large number of publications have assayed their properties either
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nOAI-PMH
\\n\\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\\n\\nPeer Review Policies
\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\\n\\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\\n\\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
\\n\\n\\n"}]'},components:[{type:"htmlEditorComponent",content:'
The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr.",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Rheinmetall (Germany)",country:{name:"Germany"}}},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. He has contributed in stochastic estimation of control area especially, in the Multiple Target Tracking and Interactive Multiple Model (IMM) research, Ball & Beam Control Problem, Robotics, Levitation Control. He has contributed in developing Algorithms for Fingerprint Matching, Computer Vision and Face Recognition. He has been supervising Pattern Recognition, Formal Languages and Distributed Processing projects for several years. He has reviewed many books on Management, Computer Science. Currently, he is an active and permanent reviewer for many international conferences and symposia and the program committee member for many international conferences.\nIn teaching he has taught the core computer science subjects like, Digital Design, Real Time Embedded System Programming, Operating Systems, Software Engineering, Data Structures, Databases, Compiler Construction. In the Engineering side, Digital Signal Processing, Computer Architecture, Electronics Devices, Digital Filtering and Engineering Management.\nApart from his Academic Interest and activities he loves sport especially, Cricket, Football, Snooker and Squash. He plays cricket for Esbjerg city in the second division team as an opener wicket keeper batsman. 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After introducing the link between PSE and parental competence, the role of PSE on parenting quality, its multiple influences, and transactional effects connected to contextual or cultural variables are discussed. The chapter addresses some key issues: (a) the levels of PSE measurement (i.e., domain- or task-specific approach), their interrelationship and magnitude as mutual predictors (study 1); (b) infant-caring, parent’s adjustment, and PSE development in the transition to parenthood (study 2); (c) parenting difficult children and the role of PSE as a “buffer” variable moderating the effects of negative child’s characteristics on parenting skills; and (d) PSE beliefs in family context, the relationships with other family measures (marital self-efficacy and stress), and their associations with children’s adjustments (study 3). Finally, in the study 4, PSE is presented as an outcome variable in a parent training. In all summarized studies, a special attention was devoted to father’s PSE as a specific factor affecting childrearing and parent’s well-being. As Bandura says, PSE is not a personality trait, but a learnable set of beliefs producing positive effects on parenting quality. Suggestions for family-based interventions enhancing PSE are discussed.",book:{id:"5605",slug:"parenting-empirical-advances-and-intervention-resources",title:"Parenting",fullTitle:"Parenting - Empirical Advances and Intervention Resources"},signatures:"Loredana Benedetto and Massimo Ingrassia",authors:[{id:"193200",title:"Prof.",name:"Loredana",middleName:null,surname:"Benedetto",slug:"loredana-benedetto",fullName:"Loredana Benedetto"},{id:"193901",title:"Prof.",name:"Massimo",middleName:null,surname:"Ingrassia",slug:"massimo-ingrassia",fullName:"Massimo Ingrassia"}]},{id:"53767",doi:"10.5772/66985",title:"Parenting Practices and the Development of Internalizing/ Externalizing Problems in Adolescence",slug:"parenting-practices-and-the-development-of-internalizing-externalizing-problems-in-adolescence",totalDownloads:1729,totalCrossrefCites:5,totalDimensionsCites:8,abstract:"This chapter examines the existing relationship between different types of parental practices and the development of internalizing and externalizing behavioral problems in adolescence. Parental involvement and parenting styles are defined and analyzed as possible parameters of adolescent problems, including bullying and victimization. Special emphasis is given to the distinction between behavioral and psychological parental control. Furthermore, issues such as parent‐adolescent conflict, locus of control, and parental values are discussed as correlates of these problems, since prior research has identified them as either risk or protective factors for child and adolescent social and emotional adaptation.",book:{id:"5605",slug:"parenting-empirical-advances-and-intervention-resources",title:"Parenting",fullTitle:"Parenting - Empirical Advances and Intervention Resources"},signatures:"Stelios N. Georgiou and Maria Symeou",authors:[{id:"193345",title:"Prof.",name:"Stelios",middleName:null,surname:"Georgiou",slug:"stelios-georgiou",fullName:"Stelios Georgiou"},{id:"197682",title:"Dr.",name:"Maria",middleName:null,surname:"Symeou",slug:"maria-symeou",fullName:"Maria Symeou"}]},{id:"67167",doi:"10.5772/intechopen.86517",title:"Aligning Human Resource Management with Knowledge Management for Better Organizational Performance: How Human Resource Practices Support Knowledge Management Strategies?",slug:"aligning-human-resource-management-with-knowledge-management-for-better-organizational-performance-h",totalDownloads:1993,totalCrossrefCites:7,totalDimensionsCites:8,abstract:"Contributing to the HR-approach to knowledge management (KM), this chapter aims at outlining the role of human resource management (HRM) in supporting KM through utilizing the theoretical and empirical literature. The article is divided into two sections. The first section presents various knowledge concepts, KM perspectives and KM strategies. This section ends up by linking these topics in a KM sequential model which helps us to track the philosophical underpinnings and perspectives of each KM strategy. The second section investigates various HR orientations and HR practices and situates their differing contextual characteristics under each KM strategy. It aligns various HR practices with different KM strategies; suggesting that HRM is most effective as a combination of practices that are consistent and sharpened in supporting each KM strategy, which is part of the organizational strategy. The debated practices are recruitment and selection, compensation management, training and development, performance management, retention management and career management. Each of those practices is speculated to alter based on the chosen KM strategy; presenting a framework that is useful for practitioners and academics alike. The review ends up by identifying some research gaps and opportunities to be carried out in future studies. Those research gaps, if addressed, will extend our understanding of KM and the supporting role HRM.",book:{id:"7808",slug:"current-issues-in-knowledge-management",title:"Current Issues in Knowledge Management",fullTitle:"Current Issues in Knowledge Management"},signatures:"Hadi El-Farr and Rezvan Hosseingholizadeh",authors:[{id:"293827",title:"Dr.",name:"Hadi",middleName:null,surname:"El-Farr",slug:"hadi-el-farr",fullName:"Hadi El-Farr"},{id:"293834",title:"Dr.",name:"Rezvan",middleName:null,surname:"Hosseingholizadeh",slug:"rezvan-hosseingholizadeh",fullName:"Rezvan Hosseingholizadeh"}]},{id:"59135",doi:"10.5772/intechopen.73540",title:"The Relationship between Parenting and Internalizing Problems in Childhood",slug:"the-relationship-between-parenting-and-internalizing-problems-in-childhood",totalDownloads:1500,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"Several types of stress factors are likely to be implied in the development, maintenance, and transmission of internalizing symptomatology: genetic/temperamental factors, cognitive factors, family factors, and societal/cultural factors. Nonetheless, family factors—especially those related to parenting—seem to be crucial during childhood, because children are nested within their families and family factors are able to indirectly influence other factors as well. The current chapter focuses on the relationship between parental style and internalizing symptoms in childhood. In the first part of the chapter, the most important studies on the topic are reviewed in detail and differences in parenting behaviors between mothers and fathers are illustrated. A discussion on the cognitive and metacognitive factors as possible pathways of the relation between parenting and childhood symptoms is also proposed. The last part of the chapter reviews studies investigating the efficacy of parental involvement in cognitive behavior therapy for children who exhibit internalizing symptoms.",book:{id:"5605",slug:"parenting-empirical-advances-and-intervention-resources",title:"Parenting",fullTitle:"Parenting - Empirical Advances and Intervention Resources"},signatures:"Simona Scaini, Sara Palmieri and Marcella Caputi",authors:[{id:"240074",title:"Dr.",name:"Simona",middleName:null,surname:"Scaini",slug:"simona-scaini",fullName:"Simona Scaini"},{id:"240906",title:"Dr.",name:"Marcella",middleName:null,surname:"Caputi",slug:"marcella-caputi",fullName:"Marcella Caputi"}]},{id:"67575",doi:"10.5772/intechopen.86757",title:"Toward Management Based on Knowledge",slug:"toward-management-based-on-knowledge",totalDownloads:1140,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"In a world overwhelmed with pervasive digital technologies, the organization is transformed and becomes a socio-technical system which is constantly renewed. Organization needs specific skills, adapted to the values and to the cultures peculiar to each location. The cooperation and the mobility become a shape of inescapable work which rests on a permanent personal and collective learning. Beyond the information handled in the digital information systems, the role of the tacit knowledge, which is in each individual’s head, cannot be ignored. A constructivist attitude replaces a determinist attitude strongly deep-rooted in our educational modes. The managers have to pass from a posture of authority and of control to a posture of incitation, of support, and of accompaniment. The notions that are introduced in this chapter result from a managerial and socio-technical vision of knowledge management. They arouse essential reflections to develop a mode of management adapted to the digital transformation of the organizations called management based on knowledge.",book:{id:"7808",slug:"current-issues-in-knowledge-management",title:"Current Issues in Knowledge Management",fullTitle:"Current Issues in Knowledge Management"},signatures:"Michel Grundstein",authors:[{id:"292425",title:"Mr.",name:"Michel",middleName:null,surname:"Grundstein",slug:"michel-grundstein",fullName:"Michel Grundstein"}]}],mostDownloadedChaptersLast30Days:[{id:"55633",title:"Parental Self-efficacy in Promoting Children Care and Parenting Quality",slug:"parental-self-efficacy-in-promoting-children-care-and-parenting-quality",totalDownloads:2117,totalCrossrefCites:9,totalDimensionsCites:14,abstract:"Parental self-efficacy (PSE) emerges as a crucial variable into exploring variability in parenting quality. After introducing the link between PSE and parental competence, the role of PSE on parenting quality, its multiple influences, and transactional effects connected to contextual or cultural variables are discussed. The chapter addresses some key issues: (a) the levels of PSE measurement (i.e., domain- or task-specific approach), their interrelationship and magnitude as mutual predictors (study 1); (b) infant-caring, parent’s adjustment, and PSE development in the transition to parenthood (study 2); (c) parenting difficult children and the role of PSE as a “buffer” variable moderating the effects of negative child’s characteristics on parenting skills; and (d) PSE beliefs in family context, the relationships with other family measures (marital self-efficacy and stress), and their associations with children’s adjustments (study 3). Finally, in the study 4, PSE is presented as an outcome variable in a parent training. In all summarized studies, a special attention was devoted to father’s PSE as a specific factor affecting childrearing and parent’s well-being. As Bandura says, PSE is not a personality trait, but a learnable set of beliefs producing positive effects on parenting quality. Suggestions for family-based interventions enhancing PSE are discussed.",book:{id:"5605",slug:"parenting-empirical-advances-and-intervention-resources",title:"Parenting",fullTitle:"Parenting - Empirical Advances and Intervention Resources"},signatures:"Loredana Benedetto and Massimo Ingrassia",authors:[{id:"193200",title:"Prof.",name:"Loredana",middleName:null,surname:"Benedetto",slug:"loredana-benedetto",fullName:"Loredana Benedetto"},{id:"193901",title:"Prof.",name:"Massimo",middleName:null,surname:"Ingrassia",slug:"massimo-ingrassia",fullName:"Massimo Ingrassia"}]},{id:"67528",title:"The Management, Sharing and Transfer of Knowledge in the Oil Districts - The Case Study of An Italian District",slug:"the-management-sharing-and-transfer-of-knowledge-in-the-oil-districts-the-case-study-of-an-italian-d",totalDownloads:1192,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Knowledge management is one of the most innovative and effective tools available to companies to manage an economic and organizational ever-changing environment. The chapter is based on an empirical study starting from the classification of oil district and aims to understand how firms’ position affect knowledge transfer process within the district. We support the idea that knowledge transfer is deeply affected by firms’ contractual power as well as by their position within the district. The companies of the industrial districts have the advantage of exploiting and sharing knowledge with each other. The literature generally holds that knowledge transfer requires a sense of equality and fairness among the firms, to create conditions in which firms will share their own knowledge for joint competitive advantage. However, empirical evidence shows that the value chains are often characterized by hierarchical relations and asymmetry between the parties: this feature is particularly evident in the oil districts. For companies attempting to acquire new information, the typologies of their intercompany collaboration and their cultural relationships are crucial.",book:{id:"7808",slug:"current-issues-in-knowledge-management",title:"Current Issues in Knowledge Management",fullTitle:"Current Issues in Knowledge Management"},signatures:"Giovanna Testa",authors:[{id:"293404",title:"Dr.",name:"Giovanna",middleName:null,surname:"Testa",slug:"giovanna-testa",fullName:"Giovanna Testa"}]},{id:"67167",title:"Aligning Human Resource Management with Knowledge Management for Better Organizational Performance: How Human Resource Practices Support Knowledge Management Strategies?",slug:"aligning-human-resource-management-with-knowledge-management-for-better-organizational-performance-h",totalDownloads:1993,totalCrossrefCites:7,totalDimensionsCites:8,abstract:"Contributing to the HR-approach to knowledge management (KM), this chapter aims at outlining the role of human resource management (HRM) in supporting KM through utilizing the theoretical and empirical literature. The article is divided into two sections. The first section presents various knowledge concepts, KM perspectives and KM strategies. This section ends up by linking these topics in a KM sequential model which helps us to track the philosophical underpinnings and perspectives of each KM strategy. The second section investigates various HR orientations and HR practices and situates their differing contextual characteristics under each KM strategy. It aligns various HR practices with different KM strategies; suggesting that HRM is most effective as a combination of practices that are consistent and sharpened in supporting each KM strategy, which is part of the organizational strategy. The debated practices are recruitment and selection, compensation management, training and development, performance management, retention management and career management. Each of those practices is speculated to alter based on the chosen KM strategy; presenting a framework that is useful for practitioners and academics alike. The review ends up by identifying some research gaps and opportunities to be carried out in future studies. Those research gaps, if addressed, will extend our understanding of KM and the supporting role HRM.",book:{id:"7808",slug:"current-issues-in-knowledge-management",title:"Current Issues in Knowledge Management",fullTitle:"Current Issues in Knowledge Management"},signatures:"Hadi El-Farr and Rezvan Hosseingholizadeh",authors:[{id:"293827",title:"Dr.",name:"Hadi",middleName:null,surname:"El-Farr",slug:"hadi-el-farr",fullName:"Hadi El-Farr"},{id:"293834",title:"Dr.",name:"Rezvan",middleName:null,surname:"Hosseingholizadeh",slug:"rezvan-hosseingholizadeh",fullName:"Rezvan Hosseingholizadeh"}]},{id:"53767",title:"Parenting Practices and the Development of Internalizing/ Externalizing Problems in Adolescence",slug:"parenting-practices-and-the-development-of-internalizing-externalizing-problems-in-adolescence",totalDownloads:1729,totalCrossrefCites:5,totalDimensionsCites:8,abstract:"This chapter examines the existing relationship between different types of parental practices and the development of internalizing and externalizing behavioral problems in adolescence. Parental involvement and parenting styles are defined and analyzed as possible parameters of adolescent problems, including bullying and victimization. Special emphasis is given to the distinction between behavioral and psychological parental control. Furthermore, issues such as parent‐adolescent conflict, locus of control, and parental values are discussed as correlates of these problems, since prior research has identified them as either risk or protective factors for child and adolescent social and emotional adaptation.",book:{id:"5605",slug:"parenting-empirical-advances-and-intervention-resources",title:"Parenting",fullTitle:"Parenting - Empirical Advances and Intervention Resources"},signatures:"Stelios N. Georgiou and Maria Symeou",authors:[{id:"193345",title:"Prof.",name:"Stelios",middleName:null,surname:"Georgiou",slug:"stelios-georgiou",fullName:"Stelios Georgiou"},{id:"197682",title:"Dr.",name:"Maria",middleName:null,surname:"Symeou",slug:"maria-symeou",fullName:"Maria Symeou"}]},{id:"59028",title:"Parent Training Interventions for Children and Adolescents with Aggressive Behavioral Problems",slug:"parent-training-interventions-for-children-and-adolescents-with-aggressive-behavioral-problems",totalDownloads:1646,totalCrossrefCites:0,totalDimensionsCites:2,abstract:"Children who display early disruptive and aggressive behavior are also at greater risk for delinquency, mood and anxiety disorders, and substance use in the long term. As is the case for many forms of childhood psychopathology, a number of factors are associated with the emergence of aggressive and disruptive behavior, including family factors. Indeed, conduct problems during childhood are usually associated with peculiar parenting practices, such as increasingly coercive cycles of harsh parenting and noncompliance exhibited by child; insensitive and nonresponsive parenting; inconsistent, severe discipline and vague commands and directions; lack of parental warmth and involvement; and absence of parental monitoring and supervision. That is why behavioral parent trainings (BPTs) represent one of the gold standard interventions for conduct problems. The main goal of BPT is to decrease coercive interchanges and, consequently, children aggressive problems by teaching parents strategies in order to apply a more effective discipline. Therefore, the putative mechanism for change in youth behavior in BPT is change in parent behavior. 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Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award, a senior member of the Institute of Electrical and Electronics Engineers (IEEE), and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null}]}},subseries:{item:{id:"1",type:"subseries",title:"Oral Health",keywords:"Oral Health, Dental Care, Diagnosis, Diagnostic Imaging, Early Diagnosis, Oral Cancer, Conservative Treatment, Epidemiology, Comprehensive Dental Care, Complementary Therapies, Holistic Health",scope:"
\r\n\tThis topic aims to provide a comprehensive overview of the latest trends in Oral Health based on recent scientific evidence. Subjects will include an overview of oral diseases and infections, systemic diseases affecting the oral cavity, prevention, diagnosis, treatment, epidemiology, as well as current clinical recommendations for the management of oral, dental, and periodontal diseases.
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Her qualifications are: a specialist in Dental Imaging and Radiology, Master in Dentistry (Periodontics) from the University of São Paulo (FORP-USP, Ribeirão Preto, SP), and Doctor (Ph.D.) in Dentistry (Stomatology Clinic) from Hospital São Lucas of the Pontifical Catholic University of Rio Grande do Sul (HSL-PUCRS, Porto Alegre, RS). She held a postdoctoral internship at the Federal University from Jequitinhonha and Mucuri Valleys (UFVJM, Diamantina, MG). She is currently a member of the Brazilian Society for Dental Research (SBPqO) and the Brazilian Society of Stomatology and Pathology (SOBEP). Dr. Marinho's experience in Dentistry mainly covers the following subjects: oral diagnosis, oral radiology; oral medicine; lesions and oral infections; oral pathology, laser therapy and epidemiological studies.",institutionString:null,institution:{name:"State University of Paraíba",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,series:{id:"3",title:"Dentistry",doi:"10.5772/intechopen.71199",issn:"2631-6218"},editorialBoard:[{id:"267724",title:"Prof.",name:"Febronia",middleName:null,surname:"Kahabuka",slug:"febronia-kahabuka",fullName:"Febronia Kahabuka",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZpJQAW/Profile_Picture_2022-06-27T12:00:42.JPG",institutionString:"Muhimbili University of Health and Allied Sciences, Tanzania",institution:{name:"Muhimbili University of Health and Allied Sciences",institutionURL:null,country:{name:"Tanzania"}}},{id:"70530",title:"Dr.",name:"Márcio",middleName:"Campos",surname:"Oliveira",slug:"marcio-oliveira",fullName:"Márcio Oliveira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRm0AQAS/Profile_Picture_2022-08-01T12:34:46.jpg",institutionString:null,institution:{name:"State University of Feira de Santana",institutionURL:null,country:{name:"Brazil"}}}]},onlineFirstChapters:{paginationCount:25,paginationItems:[{id:"82654",title:"Atraumatic Restorative Treatment: More than a Minimally Invasive Approach?",doi:"10.5772/intechopen.105623",signatures:"Manal A. 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