Xenobiotic metabolizing enzymes genes regulate via AhR pathway.
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"84",leadTitle:null,fullTitle:"Theory and Applications of CT Imaging and Analysis",title:"Theory and Applications of CT Imaging and Analysis",subtitle:null,reviewType:"peer-reviewed",abstract:"The x-ray computed tomography (CT) is well known as a useful imaging method and thus CT images have continuingly been used for many applications, especially in medical fields. This book discloses recent advances and new ideas in theories and applications for CT imaging and its analysis.\nThe 16 chapters selected in this book cover not only the major topics of CT imaging and analysis in medical fields, but also some advanced applications for forensic and industrial purposes. These chapters propose state-of-the-art approaches and cutting-edge research results.",isbn:null,printIsbn:"978-953-307-234-0",pdfIsbn:"978-953-51-6427-2",doi:"10.5772/616",price:139,priceEur:155,priceUsd:179,slug:"theory-and-applications-of-ct-imaging-and-analysis",numberOfPages:302,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"1c2713601b49dbbc072998268cdc16eb",bookSignature:"Noriyasu Homma",publishedDate:"April 4th 2011",coverURL:"https://cdn.intechopen.com/books/images_new/84.jpg",numberOfDownloads:53254,numberOfWosCitations:30,numberOfCrossrefCitations:18,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:35,numberOfDimensionsCitationsByBook:1,hasAltmetrics:0,numberOfTotalCitations:83,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 18th 2010",dateEndSecondStepPublish:"June 15th 2010",dateEndThirdStepPublish:"September 20th 2010",dateEndFourthStepPublish:"November 19th 2010",dateEndFifthStepPublish:"February 2nd 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"3411",title:"Prof.",name:"Noriyasu",middleName:null,surname:"Homma",slug:"noriyasu-homma",fullName:"Noriyasu Homma",profilePictureURL:"https://mts.intechopen.com/storage/users/3411/images/1650_n.jpg",biography:"Dr. Noriyasu Homma received a BA, MA, and PhD in electrical and communication engineering from Tohoku University, Japan, in 1990, 1992, and 1995, respectively. \nFrom 1995 to 1998, he was a lecturer at the Tohoku University, Japan. He is currently an associate professor of the Cyberscience Center at the Tohoku University. From 2000 to 2001, he was a visiting professor at the Intelligent Systems Research Laboratory, University of Saskatchewan, Canada. His current research interests include neural networks, complex and chaotic systems, soft-computing, cognitive sciences, medical systems and brain sciences. 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At the North of the old African continent, craton and shields having more than two billion years, Tunisia, Algeria and northern Morocco underwent a complex geodynamic and structural evolution during the Mesozoic and Cenozoic times (Dercourt et al., 1985; Bouillin, 1986; Frizon de Lamotte et al., 2009). This evolution resulted in the development of varied paleogeographic fields, in relation with the Tethyan and Atlantic movements. Its end led to the genesis of the North-African alpine orogen (Dercourt et al., 1985; Martinez et al., 1990) formed by the Maghrebid and Atlassic domains (Fig. 1).
Tunisia occupies the eastern part of this orogen, located at the north of a large Saharan platform, developed on the stable African craton, not deformed during the alpine cycle and bounded by a major structural lineament « South Atlassic fault » composed of complex overlapping folds trending NE-SW, E-W and NW-SE (Caire,1971; Zargouni, 1985; Turki, 1988; Zouari et al., 1990; Ben Ayed, 1993; Boukadi, 1994; Bédir, 1995; Bouaziz, 1995; Zouari, 1995; Bouaziz et al., 1999, 2002; Abbès, 2004; Zouaghi et al., 2005a, b, 2011; Ouali, 2007; Melki et al, 2010).
Structures of the North African margin were usually subject of discussion. This domain could be considered as a passive margin, close to the oceanic opening, characterized by a strong subsidence marked by accumulations of prograding deposits (Dercourt et al., 1985; Biju-Duval et al., 1976). For others, it is a transform margin related to displacements of the African plate compared to the Eurasian plate. These movements generated opening of the Paleo-Tethys (Arthaud and Thomas, 1977). The Africa-Europe relative motions would be at the origin of the recent ocean floor spreading of the Mediterranean (Taponnier, 1977; Reading, 1980; Olivet et al., 1982; Alvarez et al., 1984; Ricou, 1994).
The study area belongs to the North African margin and the northern edge of the Saharan platform. Studies undertaken on Paleo-Tethys show the development of deformed and subsiding zones between the cratonic blocks and the basins (Caire, 1974; Arthaud and Thomas, 1977; Aubouin and Debelmas, 1980; Bernoulli and Lemoine, 1980; Durand-Delga and Fonrbote, 1980; Bousquet and Philip, 1981; Dercourt et al., 1992). The geodynamic aspects at the Mediterranean scale are the origin of the tectonic mechanisms responsible for the structural evolution of the study area during the Mesozoic and Cenozoic periods. These aspects correspond to: (1) Permian-Triassic Tethyan rifting. Mesozoic divergence between the blocks continues and results in opening of the central Atlantic and the Tethys ligure and development of the Mesogea following the fragmentation of the Pangea super-continent, which generates the Gondwana to the South and the Laurasia to the North. An extensional tectonic event was consequently generated during the beginning of Mesozoic times, recorded in the African and European margins. (Biju-Duval, 1980; Dercourt et al., 1985 and 1992). (2) During the Cenozoic times, blocks located on both sides of the Mediterranean Basin converge, involving compressional phases, which induced formation of the European alpine chains and the Maghrebides (Bouillin, 1977, 1986).
The tectonic polyphasage in North Africa domains presents one of the most discussed subjects from an area to another. Some interpretations concerning the role of inherited features, halokinesis and later inversion, showed by outcrop studies, remain still not well argued even if the majority of authors agree with the influence of the ante-Triassic basement on the sedimentary lapout. In this work we try to study the geometry and structural evolution of the various morphostructural units during extensional and contractional periods.
The studies carried out on outcropping strata and on well data of southern Tunisia allow to identify the lithostratigraphic series from Paleozoic to the Quaternary one. However, there are some divergences between the authors concerning the age of various geological Formations (Burollet, 1956; Fournié, 1978; M’Rabet, 1987). The sedimentary series show lateral variations of thickness and facies and local gaps. In this section we try to describe and discuss briefly the sedimentary history of the study area.
The Paleozoic outcrops in the Tebaga mountain is represented only by Permian deposits. In addition the Paleozoic has been crossed by many petroleum wells in Saharan platform of Tunisia where various units have been identified. (Busson, 1969, 1970a, b; Ben Ismail, 1982, 1991). During the Paleozoic periods, the Saharan field is characterized by clayey detrital and sandy facies indicating a continental to margino-continental deposition (Fig. 2) with a general tendency to marine platform towards the North in the Djeffara domain (Bellini and Massa, 1980). For the southern Atlas, no information exists yet concerning the Paleozoic. But based on its lithostratigraphy, the Early Paleozoic could be marked by a progradational series followed by a transgressive interval corresponding to the clays of Silurian-Devonian known in the Saharan field (Busson, 1969, 1970a, b; Ben Ismail, 1982).
Except the Triassic, which keeps a relative homogeneity of facies from the South to the North (Kamoun et al., 2001), the Mesozoic paleogeographic scheme is characterized by a marginal platform environment with continental influence marked by detrital, carbonate-evaporite and evaporite to the South and by a marine deposition (clayey, more carbonated-clay, less evaporitic and sandy) to the North.
In Tunisia the Jurassic rarely outcrops and is classically represented by three carbonated members of the Nara Formation (Burollet, 1956; Soussi, 2002) (Fig. 2), indicating deposition in a moderate deep marine of external platform in central Tunisia. Towards the South, in the Saharan platform, presence of detrital and evaporite layers indicate fluvio-deltaic and lagunal internal platform under a restricted and confined marine environment. (Ben Ismail, 1982; Chandoul et al., 1993 ; Kamoun et al., 1999).
Geological (
Lithostratigraphic correlation of Paleozoic to Cenozoic series highlighted in the petroleum wells, showing thickness and facies variation between structures of southern Tunisia
The Cretaceous, which largely outcropped can be subdivided into two great mega-units: the first essentially clastic until Aptian corresponds to the lower Cretaceous fluvial and deltaic to marine environments (Marie et al., 1984; M’Rabet, 1987; Ben Youssef, 1999; Azaïez et al., 2007 ; Lazzez et al., 2008; Guellala, 2010; Zouaghi et al., 2011); the second represented by carbonates, clays and rare evaporitic layers, corresponds to the Late Cretaceous (Marie et al., 1984; Fakraoui, 1990; Abdallah et al., 2000). The southern part of Tunisia belongs to sub-continental field of Saharan platform, where the sedimentation rate is low to null in some localities of the vast stable platform (Burollet, 1956; Bishop, 1975; Ben Ferjani et al., 1990; Negra, 1994; Chaabani, 1995; Zouaghi et al., 2011).
The Paleogene represented by clays, carbonates and evaporites is identified in the Gafsa-Metlaoui phosphate basin (Sassi, 1974; Chaabani, 1995), showing varied thicknesses. The Saharan platform domain and the Chotts zone, already emerged since the end of the Cretaceous, are deprived of Paleogene sedimentation (Fig. 2). The Cenozoic is represented in the Saharan domain by the Neogene-Quaternary continental sandy and silty deposits (Zargouni, 1985; Fakraoui, 1990; Addoum, 1995). The marine deposition has evolved to continental since the end of the Cretaceous. In the Atlassic domain, the marine environment continued at least until the end of the Eocene. It is marked by the clayey, carbonated and evaporite series of the Paleogene and changed to frankly continental detrital sedimentation during the Neogene and Quaternary periods.
Placed within the Maghrebin framework, Tunisia occupies a privileged geological position in the African structuring. It belongs to the old African frame by its southern Saharan part, and to the alpine field by its northern area. The boundary between these two domains is marked by the South-Atlassic morphostructural master fault system (Fig. 3).
The southern Atlas, extension of the western Saharan Atlas in Algeria, includes mountains of the Gafsa area trending E-W to NE-SW and NW-SE (Burollet, 1956; Boltenhagen, 1985; Zargouni, 1985; Abdeljaoued and Zargouni, 1985; Boukadi, 1994; Zouari, 1995; Bédir, 1995; Bédir et al.; 2001, Hlaiem, 1999; Bouaziz et al, 2002; Zouaghi et al., 2005a, b, 2009, 2011). These chains consist of overlapping folds poured to the South and separated by synclines filled with Neogene and Quaternary deposits (Fig. 1).
Structural map, showing location of the master trending faults and folds. Rhombic structures are highlighted between the northwest-southeast and east-west right-steeping, dextral strike-slip faults (
NW-SE interpreted seismic section L1 crossing the Gantass and northern range of the Chotts. The reduction of thickness and unconformities are related to rejuvenation of master faults associated with Triassic evaporate risings
The Metlaoui tectonic bundle, which is made from West to East by the Bliji, Alima, Oum El Khecheb and Stah anticlines, is extended to the West in Algeria by the Mandra anticlines and is truncated to the East by the Gafsa master strike-slip fault. The Gafsa fold belt generally trending NW-SE is composed by the Moulares, Bou Ramli and Ben Younes anticlines and is crossed by the N120 Gafsa master dextral wrench fault (Zargouni, 1985; Zargouni et al., 1985; Boukadi, 1994; Bédir, 1995; Zouari, 1995; Boutib and Zargouni, 1998; Zouaghi et al., 2005a, b, 2009) (Fig. 1). The Orbata fold belt located at the East of Gafsa town is constituted by the Orbata and Bou Hedma anticlines, which are often asymmetric with sigmoidal shape (Boukadi et al., 1998 ; Bensalem et al., 2009). The Bou Hedma structure is affected to the West by the Mech dextral strike-slip fault. Between the Metlaoui and Orbata chains and northern range of the Chotts are located the Gantass, Sehib, Berda, Chemsi and Ben Kheir separated overlapping folds (Figs. 3 and 4).
The Chotts fold belt, which includes northern and southern chain of Chotts separated by the Chott El Fedjedj depocenter, is the most external structure of the Atlassic domain (Rabia, 1985; Zargouni, 1985; Abdeljaoued and Zargouni, 1985; Fakraoui, 1990; Ben Ayed, 1993; Bouaziz, 1995; Hlaiem, 1999). The eastern end of this fold belt is affected by several faults; the most significant one is that of Bir Oum Ali. The Hadifa diapir appears to be composed by Triassic saliferous located in the eastern end of northern chain of the Chotts shows the Triassic halokinesis in the study area.
These folded structures, located in northern edge of the Saharan platform, are affected and truncated by faults trending NW-SE and E-W (Fig. 3). They are often anchored on these lineaments and are characterized by axial virgations and echelon along a WSW- ENE axial direction (Rabia, 1985; Zargouni, 1985; Fakraoui, 1990; Ben Ayed, 1993; Bouaziz, 1995). The great anticline structures are asymmetric and marked by faulted southern side with steep dip (Fig. 4).
Located on the northern edge of the African craton, this domain is composed of a Precambrian substratum surmounted by a thick Paleozoic cover (Figs. 4 and 5). However, Dahar field, high since the Carboniferous times is unconformably overlain by Mesozoic deposits on the Medenine Upper Permian, which is the only Paleozoic outcrop in Tunisia (Busson, 1967; Burollet and Desforges, 1982; Bouaziz, 1986; Ben Ayed, 1993; Bouaziz, 1995; Bouaziz et al., 1999). Except the upper Permian marine deposits of the Tebaga, the Precambrian and Paleozoic are recognized, in southern Tunisia by deep petroleum wells (Fig. 2). Mesozoic series of Dahar slightly tilted towards the West, have not recorded the Alpine and Atlassic shortening phases. To the East, the Djeffara plain, bounded by a NW-SE network of normal faults (Castany, 1954) and marked by Carboniferous and Permian high subsidence related to NE-SW extension (Ben Ayed, 1993; Bouaziz, 1995). The Talemzane Arch is the most significant structure appreciably trending E-W, corresponds to substratum of the Saharan platform and generated following the Hercynian tectonic phase (Busson, 1970a, b). On both sides of the Talemzane Arch, the Mesozoic strata, Triassic in particular, rest with angular unconformity on the eroded Paleozoic (Busson, 1967). This ridge extends from the Algerian Sahara crossing the Dahar structure of Southern Tunisian and constitutes the northern edge of the Ghedames basin and the limit between the Saharan craton and the extensive Mesogean domain to the North.
Study of seismic lines (Figs. 5, 6 and 8) shows that the transitional zone between the little deformed Saharan platform and the Atlassic folded zone, being complex with deep E-W direction in the Djerid Chotts area. This zone corresponded to a major lineament represented by North-Saharan faults and flexures separating the northern subsiding domain with relatively thick sedimentary cover in the Chotts and Gafsa basins from the southern domain with thin sediments.
The Chotts structures contain the Chott Djerid and El Fedjedj depocenters, which are bounded by the North and South chains. The Chotts domain generally trends E-W extending from the Gulf of Gabes in the East to the Nefta-Tozeur zone in the West of Chott Djerid.
On both sides of the chain of Chotts, the thicknesses and facies changed (Figs. 2 and 4). These significant and abrupt variations testify of pronounced subsidence in the Chotts furrow, controlled by normal faults during the Mesozoic times. The synsedimentary activity seems to be accompanied by Triassic halokinetic activity during the Jurassic and Early Cretaceous (Figs. 4, 5 and 8). Triassic saliferous facies moved and caused a local thickness variation of overlying series near the normal faults, inducing therefore an early structuring of the northern chain of Chotts.
Seismic section L2 of the Chott El Fedjaj, showing two positive flower fault structures trending east-west and evolution of Mesozoic series under faulting change and halokinesis of northern and southern range of the Chotts
The early halokinesis and its influence on the Chotts structuring was also observed in areas of the southern Atlas of Tunisia (Bédir, 1995; Boukadi and Bédir, 1996; Zitouni, 1997; Boukadi et al., 1998; Hlaiem, 1999; Bédir et al., 2000, 2001; Ben Timzal, 2000; Tanfous-Amri et al., 2005; Zouaghi et al., 2005a, b, 2007 ; Azeiez et al., 2007) and in the Saharan Atlas of Algeria (Vially et al., 1994). Thicknesses of the Mesozoic and Cenozoic series increase gradually from the Saharan platform to the Chotts depocenters (Figs. 5 and 6).
Study of seismic sections shows that the Djerid basin could has a half-graben geometry bounded to the North by a major fault of northern chain of the Chotts (Figs. 5 and 6). Towards the East, the Chott El Fedjej seems to correspond to a graben structure limited to the South and to the North by fault systems. In this area, seismic reflectors emphasize migration of depocenter from North to South since the Triassic until the Early Cretaceous. This inversion would be related to the synsedimentary tectonic and halokinetic activity of the Chotts faults during the extensional intervals. Inversion of structures has continued during Late Cretaceous and Neogene.
The Hercynian unconformity defined by toplap structures of the eroded Paleozoic series is related to intense erosion which succeeded the Hercynian orogenesis (Figs.4-6). The aggradational/retrogradational onlaps mark the transgression of Early Triassic composed by sandy-clay, showing an angular unconformity. The seismic reflector, tilted to the North by slight slope, is characterized by continuous reflections and high amplitude.
Seismic section L3 of the Djerid Chott, illustrating distribution of major unconformities and their evolution towards the northern Chotts east-west strike-slip fault and associated Triassic salt intrusion (see
The top of the Jurassic Nara dolomite formation is marked by moderate continuous and high amplitude seismic doublet (Fig. 6). This reflector is sealed by progradational downlaps of the overlying Neocomian fluvial continental series. This unconformity marked the change from a marine carbonate platform deposition to a fluvial continental one related to a regional marine regression, which reached central Tunisia.
The Late Barremian-Early Aptian erosional surface, which is observed on the entire Saharan platform, is defined by moderate to well continuous and high amplitude reflections forming locally seismic doublets (Figs. 4 and 6). The toplaps correspond to erosional truncation of the Barremian-Neocomian upper detrital series that are onlapped by Aptian to Cenomanian aggradational/retrogradational transgressive carbonates and clays to the South. The occurrence of this regional erosional surface could explained by an uplifting generated by a tectonic deformation and a sea level fall.
The upper Cretaceous unconformity is characterized by basal toplaps, corresponding to upper strata of Senonian truncated by post-Cretaceous erosion. It is marked by moderate continuous and high amplitude reflections followed by the Neogene-Quaternary sandy-clay continental series deposed in angular unconformity by onlap structures (Fig. 6). Absence of all Paleogene strata indicates general elevation of the Saharan platform at the end of Cretaceous related to the Late Cretaceous-Eocene compressional tectonics associated with sea level falls.
Previous synthesis works described the geodynamic evolution of the southern margin of Maghrebid Tethys and established approximate models showing the relation between current structuring and the ancient Hercynian and later-Hercynian events. The outcrops results (Zargouni, 1985; Delteil et al., 1991; Boukadi, 1994; Zouari, 1995) seem agree with those elaborate in subsurface (Ben Ismail, 1991; Bédir, 1995; Zitouni, 1997; Jallouli and Mickus, 2000; Gabtni et al., 2005; Zouaghi et al., 2005a, b, 2009; Gabtni, 2006). These tectonic models, particularly related to the Tertiary and Quaternary deformations were used for deduce the geodynamic evolution of the Mesozoic basins.
Extensional tectonics started with the Carboniferous-Permian times known in the Dahar plateau and the Djeffara plain of South-East Tunisia (Bishop, 1975; Ben Ferjani et al., 1990\n\t\t\t\t\tBouaziz, 1995; Bouaziz et al., 1999, 2002). This extensional event continued and accentuated during Mesozoic periods in relation with the sub-meridian Tethyan extensional framework, which affected the whole of the North-African margin. The relatively thick sedimentary strata of Triassic, Jurassic and Early Cretaceous in the Chotts area, the Gulf of Gabes, and the Gafsa area (Figs. 2, 4-6) testify to an active subsidence during these periods.
Triassic structuring seems to be inherited from the Paleozoic. Mechanisms of the opening are accompanied by thick sedimentary sequences and probably volcanic in subsiding grabens with installation of progradational systems tracts of Early to Middle Triassic sandy-clay and carbonate sequences. The evaporites and salts of the upper Triassic sequences seem to be accumulated on down sides of faults bordering grabens. The Triassic NNW-SSE to NW-SE oriented extension (Bouaziz et al., 2002) is associated with the alkaline magmatism documented from petroleum well data in the Chotts basin (Laaridhi-Ouazaa, 1994). Basin structuring and sedimentary lapout of the Triassic have been described in Algerian outcrops (Bouillin, 1977; Vila, l980; Obert, l984, 1986; Kazi Tani, 1986). This kinematic corresponds to the beginning of opening of the Tethys and the central Atlantic and therefore separation of Africa from Eurasia. This event coincides with the beginning of the anti-clockwise rotational migration of African plate towards the East (Olivet et al., 1982, Dercourt et al., 1985).
During the Jurassic and Early Cretaceous, the synsedimentary and halokinetic activity of faults, probably developed since Triassic, persists in relation with N-S extensional stage (Fig. 7). This activity involved formation of the pre-existing structures.
The opening of basins, which began with the Triassic has continued and accentuated during the Jurassic where the grabens and subsiding depocenters in southern Atlas showed a geodynamic mechanism similar to that prevailed with the Triassic. Synchronism between the opening of basins and the Jurassic halokinetic rising has accentuated the paleogeographic differentiation, which characterized by progradational deposits on sides of Rim Synclines (Figs. 4 and 5) and by carbonated reefal platforms appeared since the Jurassic.
The Early Cretaceous is marked by a notable change in the tectonic structuring, induced by the reorientation of tectonic extensional stress and sedimentary evolution. This change is fossilized by general unconformity marked by lower Cretaceous progradational downlaps of Sidi Khalif Formation above the Jurassic carbonates (Figs. 4-6). This discordance has been also highlighted in Algeria by Vila (1980) and Obert (1984, 1986). The opening movements observed during the Triassic and Jurassic, are clearly decreased and even sealed during the Early Cretaceous around the majority of Atlassic blocks. The deep fault network starts to undergone deviations of some directions following the strike-slip movements, the rotations of blocks and the rising of the Triassic intrusions and domes across master fault intersections (Zouaghi, 2008; Zouaghi et al., 2005b, 2011).
The Jurassic and lower Cretaceous kinematics show an influence of extensional stresses trending near NNW-SSE (Fig. 7), which is well integrated in the context of the Tethyan openings (Vila, 1980; Olivet et al., 1982; Obert, 1984, 1986; Dercourt et al., 1985).
During Late Cretaceous several complex deformations have been showed controlled by both extensional and compressional stages. The highlighted structures indicate irregularity of the tectonic and sedimentary mode in Tunisia. These intervals are marked by major Triassic evaporite extrusion indicating the saliferous movements and diapirism well characterized in northern Tunisia (Perthuisot, 1978; Vila, 1980). These deformations result in thickness and facies variations associated with unconformities and gaps recorded in middle and upper Cretaceous strata (Figs. 4-6 and 8) highlighted in many localities of the Tunisian Atlas. The end of the Late Cretaceous corresponds to the beginning of the compressional stresses marked by installation of several anticlines. This extensional stress change to strike-slip movements caused deposition of thick Albian-Cenomanian black shales rocks in the subsiding blocks and reefal carbonated platforms on the high blocks. Regionally, this evolution is related to the bringing together of the African plate with the Iberia to the West and Eurasia to the East, under the effect of its rotation but also related to the East-West relative movement of these plates (Olivet et al., 1982; Dercourt et al., 1985; Guiraud and Bosworth, 1997).
Effect of the regional tectonic stress field on the geodynamic evolution integrating strike-slip movements, basin geometry, filling and Triassic halokinesis
With the beginning of Tertiary times and especially since the Eocene until Quaternary, the compressional events were largely highlighted in the Tunisian areas. These periods are marked by principal tectonic phases of compression trending NW-SE to N-S, which are related to the mechanisms of collision between the African and European plates.
The Eocene corresponds to the final emergence of the Saharan Platform, which started since the Late Cretaceous with the development of the Gafsa-Metlaoui intracontinental folds and synclines. During this period, the Saharan domain that is marked by absence of the Paleogene Sediments, is exposed to erosive action assigning upper strata of the Early Cretaceous (Figs. 4 and 6). Formation of the Eocene folded structures, are locally accompanied by the opening of grabens along the strike slip fault corridors (Ben Ayed, 1993; Melki et al., 2010; Zouaghi et al., 2010). The contractional regional constraint is still NW-SE generating transpressional dextral strike-slip movements on lineaments trending N90 and N120 (Figs. 3 and 7).
The Eocene contractional events detected on the southern Tunisian margin are related to formation of the alpine arc following collision of Europe with the Apulia margin and the accentuation of the Africa-Europe bringing together (Olivet et al., 1982; Dercourt et al., 1985)
At Late Miocene, contractional tectonics become more evident and fossilized by development of folded structures and infilling of the intracontinental basins in southern Atlas (Figs. 4, 5 and 8). The structures previously started by the halokinesis since the Jurassic are reactivated and accentuated during these compressional deformations. The NW-SE upper Miocene contractional events could be correlated to the processes of Africa and Europe bringing together and its collision. The Tortonian major contractional phase, which induces thrust sheets of the North African margin, is well documented (Vila, 1980; Obert, 1984, 1986).
The Quaternary is marked by complex structures resulting from the combined effect of the tectonic polyphasage dominated by the N-S contractional stress (Fig. 7) and saliferous tectonics. We think that it is the result of a combination of a cover tectonic style and deep basement movements.
The Atlassic folds and synclines seem to be evolved under three contractional tectonic events. The first, known as Pyrenean dated end Cretaceous-Eocene has NW-SE (N120 to N140) dominant paleo-stress, the second of Late Miocene named Alpine trending NW-SE, and the third corresponds to post-Villafranchian phase oriented N-S. Some authors have showed another minor and local contractional event dated of Late Pliocene and characterized by N150 to N160 direction of shortening (Zargouni, 1985; Fakraoui, 1990; Addoum, 1995; Bouaziz, 1995).
During the compressional events a local extensional episodes were highlighted. In particularly the Middle Miocene (Langhian-Serravalian) phase trending NE-SW, which induced the opening of the grabens of central Tunisia (Philip et al., 1986; Ben Ayed, 1993; Chihi, 1995; Zouaghi, 2008; Zouaghi et al., 2010, 2011). The N-S post-Villafranchian compressional phase, which largely marked the Atlassic structuring, is associated with normal faults in the Khenchla depression of the eastern Saharan Atlas (Addoum, 1995). In southern Atlas the Eocene-Paleocene phosphate series of the Gafsa-Metlaoui basin shows existence of synsedimentary normal faults (Bouaziz, 1995) that coexist sometimes with other reverse faults (Ben Ayed, 1993; Melki et al., 2010).
Seismic section L4 across the El Fedjaj Chott, showing folding and wrench salt-intrusion at the intersection of the northeast-southwest Tebaga-Fatnassa and northwest-southeast Hadifa master lineaments
The main works established on the kinematic of deformation in the Atlassic domain (Creusot et al., 1992 ; Creusot et al., 1993 ; Outtani et al., 1995 ; Addoum, 1995) show the coexistence of two modes of folding; the first corresponds to the folds formed on inherited faults of the infra-Triassic basement, where the ancient extensional structures are reactivated and evolved to reverse faults during the compressional deformations; the second model of propagation folds was also highlighted.
Because the oblique position of the preexistent faults compared to the direction of tectonic stress (Fig. 7), formation of folds becomes more complex because of the strike-slip fault movements (Letouzey, 1990; Ben Ayed, 1993). This kinematic of deformation results in the positive flower-structures organized into overlapping fold belts recognized at the southern Atlas, the most known are the Metlaoui chains, the Chotts chains and the Gafsa chains. In fact, formation of the Atlassic chains was generated by interaction between the major effect related to reactivation in transcurrent and inversion of the old basement faults (thick-skinned style) and a surface effect related to decollement and overfolding of the supra-Triassic cover (thin-skinned style) (Hlaiem, 1999; Zouaghi et al., 2005b; Bensalem et al., 2009). Moreover the early halokinesis during Jurassic and Early Cretaceous associated with the synsedimentary activity of some normal faults contributed to pre-structuring and guiding the genesis of Atlassic fold belts.
Lithostratigraphic column of the study area reveals the existence of several Formations, which could constitute potential levels of decollement of the overlying cover at the time of folding. Although the main level of decollement remains the Triassic evaporites (Hlaiem, 1999; Zouaghi et al., 2005b; Bensalem et al., 2009), the Cretaceous clays and sandy-clays are locally considered as levels of secondary detachments (Outtani et al., 1995).
The seismic reflection sections suggest a model of broken folds on break-thrusting associated with reverse deep-seated faults in the Triassic. We suggest than these folds are controlled by the basement inherited extensional structures (Figs. 4, 5 and 9).
The kinematic study on seismic lines allows to propose folded structures associated with reverse deep-seated faults reaching the Triassic strata (Figs. 4 and 8). Position and orientation of existing structures would be related to the position of ancient normal faults, which controlled genesis and evolution of the folds structures and associated reverses faults during the compressional events.
Thickness variations on sides of the master faults, which bounded the basins in southern Atlas during the Jurassic and Lower Cretaceous, suggest the existence of normal fault generated during the rifting and extensional phases and caused subsidence increasing (Figs. 5 and 6). The resulted in steps structuring seem to be in agreement with the Knowledge model, which characterizes the North Africa passive margin (Biju-Duval, 1980; Ben Ayed, 1993; Bédir, 1995; Zouaghi, 2008; Zouaghi et al., 2011).
The deep master faults, which are associated with the anticline structures could have a role in the structuring of the cover since the extensional periods by their synsedimentary and halokinetic activity inducing local structural anomalies marked by variations of thicknesses and facies, unconformities, pinching outs and gaps of depositions (Figs. 8 and 9). These inherited faults could influence the localization of the future Atlassic chains before starting of the compressional deformations (Vially et al., 1994).
Block diagram imaging the strain partitioning and resulted folds during the Cenozoic transpressional inversion of Chotts inherited structures
In addition to the role of Triassic halokinesis during the extensional periods that consist in a pre-structuring of the chains, the inherited normal faults would be reactivated and reversed and therefore control the evolution of folds during the contractional times. According to the seismic data we suggest that anticlines structures of southern Atlas are comparable to broken folds on break thrusts (Fig. 9). The slope is generated by the rejuvenation of pre-existing basement faults.
Study of major unconformities using the seismic reflections had permitted to identify the principal tectono-sedimentary events, which marked the history of infilling and deformation of the Chotts basins during the Mesozoic and Cenozoic periods. In spite of the local tectonic history, eustatism has marked Saharan craton, in particular during the great falls of sea level. The history of deposition of Chott domain recorded the combined effect of the tectonic deformation and eustatic change, which marked the Saharan platform.
The significant thickening of the Mesozoic series from the South to the North indicates a high subsidence in the Chotts areas controlled by master faults of the Chotts. The southern range of Chotts is characterized by a reduced Mesozoic sedimentation on the platform, which corresponded to a relatively resistant butte rests on the ante-Mesozoic substratum of the northern side of the Talemzane Arch. Increase of thickness in the distal zone to the North, suggests a reduction of deposition space to the South.
Deposition in the Saharan intra-cratonic and marginal basin suggests effect of the Chotts faults related to the regional geodynamic evolution of the peri-tethyan platforms in North Africa.
During the Cenozoic compressive phases trending NW-SE to N-S, rejuvenation of the major faults of Chotts is marked by dextral strike-slip movements, which generate the overlapping fold belts and overthrust folds on the cover of the North chain of Chotts. Structures resulted from deep tectonic deformations as Thick-skinned style and from tectonics of cover as Thin-skinned style are marked by folding and decollement of the sedimentary cover. The southern sides of the majority of chains are vertically straightened sometimes inverted, and transpressive structures are associated with reverse faults. The overlapping folds, which characterize the southern Atlas chains result from dextral strike-slip motion trending near E-W at the level of the basement.
Evolution of the structures around the tectonic blocks of Southern Tunisia from the Jurassic to the Neogene is guided by the rejuvenation of deep crustal lineaments trending E-W and NW-SE and have controlled geometry and evolution of the following sedimentary deposits.
Tectonic deformations have induced halokinesis along master inherited faults. Intersection of these faults during regional extensional and contractional events in the Triassic subsalt basement caused its vertical rising. Interaction of folding and salt diapirism accentuates overthrusting along strike-slip faults.
The strike-slip faults delimited the asymmetric tectonic blocks and differently moved during the geological history. The extensional and transtensional movements during the Triassic, Jurassic and Early Cretaceous, then contractional and transpressional from the end of Late Cretaceous, induced opening of quadratic basins and formation of platforms then closing of the basins and migration of subsiding depocenters, resulting sometimes in blocking stages with compressions following the ancient structural inheritances. The reorientations of the regional stresses along major tectonic discontinuities appear to be induced by movements of the African plate compared to the Eurasia and Iberia (Olivet et al., 1982; Dercourt et al., 1985). Thus we highlight the effects of the principal tectonic events related to the migration of the African plate since the Triassic-Jurassic rifting and the geodynamic answers to these movements at times of shortening on the Tunisian margin.
The study is based on subsurface data set recorded during exploration and production surveys. It has been partly supported by national and international geological and geophysical projects and research programs on southern Atlas of Tunisia. We thank the ETAP, AGIP, SHELL, CPG and ONM companies for its coordinations and helps.
We thank reviewers and editors of the book for comments and suggestions on an early version of the chapter.
Six decades ago, researchers made extensive studies to answer a puzzling question. That was how administrating exogenous substances such as polycyclic aromatic hydrocarbons (PAHs) had a potent induction on xenobiotic-metabolizing enzymes in rats’ livers [1, 2]. It was finally Alan Poland and his colleagues who finally answered this question in the early 1970s. Poland discovered a novel hepatic protein in complex with the polycyclic aromatic hydrocarbons compound, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [2]. The new protein was bound to TCDD in a potent affinity and was isolated from hepatic cytosolic fractions of mice C57BL/6, a mice model strain for studying aromatic hydrocarbon responsiveness. This protein was later termed as the aryl hydrocarbon receptor (AhR) [2] and was identified as a ligand-activated transcription factor.
Later studies showed that AhR is expressed in several tissues including but not limited to; liver, lung, placenta, and heart and different cell types throughout the developmental periods of organ growth [3]. Further knockout studies in mice revealed essential functions for AhR in multiple physiological and pathophysiological pathways [4, 5, 6]. This accumulated knowledge over the last decades defined AhR as an environmental sensor for air pollutants and as a ligand-activated transcriptional factor, which regulates the expression of various genes, including enzymes responsible for xenobiotic metabolism [7].
AhR-mediates the toxicity of uncountable xenobiotics, and their triggered toxicity is accompanied by an overexpression and overactivation of AhR in cells. Thus, it increases the pathophysiological functions of AhR and could develop cancer in different organs such as the breast and liver. In addition, it can also lead to cardiovascular diseases, among other diseases [8, 9]. Thus, targeting AhR with a small molecule agonist/antagonist could efficiently inhibit several of the important hallmarks of various cancers [10].
Computational modeling and computer simulations continue to be an important tool for studying various biological mechanisms and for analyzing the interactions between biomolecular entities (
AhR is a member of the basic helix–loop–helix (bHLH)-PER- ARNT-SIM (PAS) family of transcription factors. The “PAS” term is an abbreviation for three proteins, namely, the Drosophila circadian rhythm protein period (Per), the mammalian AhR nuclear translocator (ARNT), and Drosophila neurogenic protein single-minded (Sim) [7, 14, 15]. Human AhR is a 848 amino acid with a molecular weight of ~96 kDa [16]. It includes two PAS domains, namely PAS A and PAS B, and interacts with the Aryl hydrocarbon nuclear tranlocator (ARNT) protein. Moreover, the PAS B domain involves two interactions sites: a ligand-binding site in which a bound ligand can modulate the AhR activity; and a direct binding interface for the HSP 90-chaperone protein. Additionally, AhR includes a basic helix loop helix motif located near its N-terminal domain, which is responsible for DNA binding as well as contributing to other protein–protein interactions. Finally, the transactivation (
AhR domain structure and sub-domains’ functions.
The AhR PAS B domain can interact with both exogenous and endogenous chemicals from various origins. These interactions can induce different effects on AhR activity, leading to a wide range of physiological and toxicological downstream consequences. For example, several studies showed that environmental pollutants have been associated with developing cardiovascular diseases, cancer, and other diseases through AhR modulation [7, 17, 18]. Exogenous AhR ligands include various aromatic hydrocarbon molecules such as dioxins. One can be exposed to such ligands through contaminated food or environmental pollutants. Following exposure, their interaction with AhR can lead to several toxic effects, including organ dysfunctions, immunotoxicity, and carcinogenicity. On the other hand, endogenous AhR ligands are usually metabolic derivatives derived from cellular processes such as 6-Formylindolo (3,2- b) carbazole (FICZ). The interaction of these ligands with AhR is part of a normal functional response through AhR modulation [7, 19, 20].
AhR is an essential protein that contributes to countless biological pathways to establish its physiological role in developing the immune system and regulating xenobiotic enzymes [7, 15, 21]. AhR knockout mice models showed abnormal female reproductive functions and impairment in managing blood pressure [7]. The overactivation and constitutive activation of AhR have been associated with the initiation, promotion, progression, and invasion of cancer cells. For example, activating AhR by exogenous AhR ligands can have several effects, which includes inducing cell proliferation in the G1-S phase, silencing tumor suppressor genes, and activating proto-oncogenes in cancer cell lines.
Earlier findings showed that the exogenous AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD promoted the degradation of cell–cell adhesion and expansion of cancer cells’ motility by separating the Src kinase from the AhR protein complex. Furthermore, the activation of AhR via environmental pollutants can lead to a significant induction of xenobiotic-metabolizing enzymes, including CYP1A, which produces reactive intermediate metabolites and reactive oxygen species to promote tumor growth [14, 22]. In a nutshell, AhR resembles a machinery of genes, which controls xenobiotic-metabolizing enzymes in phases I and II, as shown in Table 1. Also, known AhR agonists such as TCDD and β -naphthoflavone have been shown to induce cellular hypertrophic actions on H9c2 cardiomyoblast cells. This was correlated with an increase in the levels of numerous cytochrome P450 genes, which could overcome by using an AhR antagonist [31].
Metabolism phase | Gene | Reference |
---|---|---|
Phase I | CYP1A1 | [23] |
Phase I | CYP1A2 | [24] |
Phase I | CYP1B1 | [25] |
Phase I | CYP2S1 | [26] |
Phase II | NQO1 NAD(P)H: Quinine oxidoreductase 1 | [27] |
Phase II | GSTA1 Glutathione transferase A1/2 | [28] |
Phase II | UGT1A6 Uridine diphosphate glucuronosyltransferase 1A6 | [29] |
Phase II | ALDH3A1 Aldehyde dehydrogenase 3A1 | [30] |
Xenobiotic metabolizing enzymes genes regulate via AhR pathway.
On the positive side, experiments on a mouse model of induced colitis showed that the endogenous AhR agonist (FICZ), which has a strong binding affinity towards AhR, could block IL-6 and claudin-2 expression, and prevent any induced disorders in the intestinal barrier function through AhR activation [32]. Further protein knockout studies showed that AhR ligands play a fundamental role in autoimmune diseases through regulating Tregs and TH17 cell differentiation in the immune system. For example, FICZ inhibited Treg and TH17 cell development, accelerating experimental autoimmune encephalomyelitis in mice models [21, 33].
AhR is generally expressed in its inactive form in the cytoplasm as part of a protein complex encompassing a dimer heat shock protein, co-chaperone p23, an AhR-interacting protein, called AIP, and the protein kinase SRC (see Figure 2). The PAS B domain within AhR binds to one monomer of the HSP90 dimer and the second HSP90 monomer interacts with the AhR basic helix–loop–helix domain (bHLH) as well as with the PAS A domain [34]. As shown in Figure 2, the bHLH domain within AhR is also crucial for DNA binding in a process initiated by the binding of an AhR ligand within the PAS B domain and its interaction with the co-chaperone P23. Binding to P23 stabilizes AhR in the cytoplasm, protecting it from proteasomal degrading, and also maintains the PAS B domain of AhR in a unique conformation, suitable for strong ligand binding [35, 36].
Canonical pathway of aryl hydrocarbon receptor.
Once an AhR ligand binds to the PAS B domain, it forms an AhR-ligand complex, including p23, SRC, and AIP (see Figure 2). This complex is transformed into an active state and then translocated inside the nucleus. Then in the nucleus, all complex components dissociate from the AhR-ligand complex, excluding an agonist and AhR protein. Subsequently, AhR forms an active heterodimer with ARNT and creates an AhR–ARNT complex. This complex is then recruited to the DNA via the Dioxin response element (DRE), exhibiting a common DNA compromise motif (5′-TNGCGTG-3). This canonical AhR pathway increases the expression of various genes, including the principal ones in xenobiotic metabolism, AhR repressor (AHRR), and other genes [36].
Resolving the full-length three-dimensional structure of AhR has been a challenging exercise for the last two decades. Unfortunately, despite the many efforts towards this goal, there is no complete structure for the whole AhR protein. However, as discussed below, there are a few structures, which describe the number AhR domains. Although these structures do not reveal the exact overall AhR architecture, they can still provide useful information on the function of these separate domains. Giving computational modeling a favorable vantage point to construct reliable hypotheses for the full-length AhR organization for rational drug development and drug screening campaigns.
The first AHR 3D structure was reported in 2013 for the mouse PAS A domain (residues 110 to 267) at a resolution of 2.55 Å (PDB ID: 4M4X) (see Figure 3). This X-ray diffraction-based PAS A homodimer structure was obtained from recombinant
The upper figure represents crystal structure of homodimer mouse AhR-PAS a obtained from protein databank [
Two more additional AhR structures were revealed in 2017 (see Figure 4). The two structures comprise multiple AhR domains and show a clear interaction between AhR and its dimerization partner, ARNT, as well as its interaction with two DNA strands. The two structures (PDB IDs: 5V0L and 5NJ8) [39, 40] were resolved at a resolution of 4.0 and 3.35 Å, respectively and revealed the complex formation among the bHLH and PAS A domains from human AhR and their interactions with ARNT and DNA. However, due to the observed high flexibility of the AhR PAS B domain and the transactive domain (C- terminal), none of these two subdomains were included in this architecture. However, both structures clearly explain the protein–protein interactions (PPI) and show clear interface regions for these interactions between the individual domains within AhR as well as their interactions with ARNET and DNA.
Crystal structure of human aryl hydrocarbon receptor in heterodimer with aryl hydrocarbon nuclear translocator and recruit on DNA in dioxin element response [
As shown in Figure 4, the first PPI interface is between the AhR-ARNT heterodimer with the two DNA strands. This interaction is mediated by DRE Ser36, His39, and Arg40 from the AhR bHLH domain and His79, Asp83, Arg86, and Arg87 from ARNT, as well as thymine and guanine from the DNA. The second PPI interface is between AhR and ARNT through different regions within the two proteins. These regions involve many hydrophobic interactions from both proteins and comprise residues Leu47, Leu50, Leu53, Val74, and Leu70 from the AhR bHLH domain and residues Ile109, Leu112, Val136, and Met139 in ARNT. The third PPI interface involves interactions between residues from the PAS A domain in both AhR and ARNT, mediated by residues Phe117, Leu118, Ala121, Leu122, Tyr137, Val126, Phe266, and Ile268 from AhR. The fourth, and final PPI interface encompasses the interdomain interactions between the AhR bHLH and AhR PAS A domains, through residues Phe136, Ser151, Ile154, and Leu246 from the PAS A domain and Phe56, Val60, Leu72, Ala79, and Phe82 from the bHLH domain.
The wealth of structural information described above on AhR provides an excellent opportunity to apply various computer-based simulations to study the dynamicity and structural organization of the various AhR domains. The applications of such computational tools not only can yield much needed insights on how these domains interact together within the AhR machinery, but can also offer detailed answers on their interactions with other AhR partners (
Most of the
In many AhR studies, the human hypoxia inducible factors (HIF-2α) crystal structures served as templates for AhR-PAS B domain because it has the highest sequence similarity towards the AhR-PAS B domain. Table 2 provides a list of the reported
PDB ID | Structure method | Year of study | Reference |
---|---|---|---|
3H82 | X-ray diffraction | 2014 | [41] |
4GHI | X-ray diffraction | 2014 | [43] |
3H3W | Electron microscopy | 2016 | [44] |
3F1O, 3H7W, 3H82 | X-ray diffraction | 2018, 2018 | [45, 46] |
4XT2 | X-ray diffraction | 2019 | [47] |
3F1N, 3F1O, 3F1P, 3H7W, 3H82, 4GHI, 4GS9, 4XT2, 4ZP4, 4ZQD | X-ray diffraction | 2019 | [12] |
3H82, 3H7W, 4ZQD | X-ray diffraction | 2020 | [48] |
Report studies that used different crystal structures of human hypoxia inducible factors (HIF-2α).
For example, Bisson and his group established an agonist-optimized model of the human AhR-PAS B domain, followed by docking around five thousand chemical structures, including AhR agonists and antagonists, within the PAS B domain. Docking results were then filtered and the top five systems were subjected to long MD simulations (~ 60 ns) to study the conformational and dynamical changes in these generated complexes. Findings from Bisson’s work revealed the importance of residues 307–329 in the PAS B domain, which were shown to be very flexible, acting as an access gate to the ligand-binding pocket. These residues can also adopt different conformations upon AhR ligands’ binding and play a primary function in controlling the structural changes and accessibility of the ligands to the AhR ligand binding pocket [41].
With the 3-dimensional structure of the PAS B domain in hand, many groups focused on studying its binding to different ligands (
Chemical structures of AhR ligands in this study obtained from pubchem database.
Mutations at outer residues (e.g., Arg282, Thr311, Glu339, and Lys350) into alanine did not impact TCDD binding to AhR [57]. In the human AHR-LBD a mutation at Ala375 to Val and Leu decreases the binding affinity of TCDD and makes indirubin a less potent endogenous AhR ligand [45, 58]. Additional site-directed mutagenesis within AhR-LBD residues has been used to identify key residues promoting for ligand selectivity in AhR. These developed models provided a clear basis towards understanding the mechanism of ligand-dependent activation of AHR via its PAS B domain. In particular, the above mentioned molecular docking and mutagenesis analyses helped in identifying and confirming the binding pocket of TCDD and other AhR modulators [52, 57, 59, 60].
Examples of these models include those developed by Kim and her team, who constructed 3D models from several avian species including, chicken, albatross, and cormorant, and studied the sensitivity of dioxin derivatives against multiple AhR isoforms. All models were subjected to docking simulations with TCDD followed by MD simulations. Kim’s results used the mean square displacement (MSD) of the MD trajectories as a stability indicator for the bound ligands. These findings revealed Ile324 and Ser380 from chicken AhR1 exhibited the least MSD values compared to all AhR-LBD residues in other avian species. The size of binding pocket was also shown to be variable among the different species. Moreover, stabilization of TCDD in the binding pocket of chicken AhR relied on the features of Ile324 and Ser380, which explained why chicken AhR is more sensitive to TCDD binding compared to other AhR isoforms [54, 61, 62, 63].
Further mutational and functional analysis studies were expanded to include additional AhR modulators other than TCCD. For example, the work of Faber and her team studied induribin binding to AhR in both mouse and human. This study revealed that a mutation in His326Tyr and Ala349Thr in mouse AhR, and Tyr332 and Thr355 in human AhR can increase the potency of indole compounds, particularly, indirubin. Also, although indirubin and vemurafenib can fit within the same binding pocket in AhR, the two compounds showed two different modes of binding [45, 47]. For example, flutamide efficiently binds to residues inside the AHR-LBD with a high affinity in both mouse and human AHR to activate the AhR pathway [64]. It is important to note that, the biological response of AhR is dependant on the type of the bound ligand and has been shown to change based on the interaction of a given ligand with the residues forming the LBD in the PAS B domain [48, 65].
Over the last few decades, virtual screening has been used as a major tool to in hit identification campaigns against numerous biological targets [66]. In this regard, AhR is no exception and various
Pharmacophore modeling maps the ligand-target interactions into a set of steric and electronic features structured in a specific 3D arrangement [70]. These pharmacophore models can be then used to screen millions of available chemical structural libraries for compounds that satisfy these pharmacophore features, which can be used for scaffold hopping and fragment-based drug design. On the other hand, structure–based methods require the knowledge of target protein crystal structure, or its 3D developed homology models. Ligands from a given database can be fitted into the active site of the target protein and can be ranked based on the predicted binding affinities. In this context, molecular docking and molecular dynamics simulations are among the many valuable tools that can be used to predict the most probable mode of binding of a given ligand within the target. Furthermore, structure-based pharmacophore models can provide more detailed insights on the interaction of ligand with the binding site [69, 71, 72].
As discussed below, several AhR screening studies combined both methods to enhance the search for possible AhR candidates [67, 73]. The plethora of accumulated physicochemical, chemical and structural data on AhR modulators augmented this hit identification search with great tools to build reliable machine learning models, which require large datasets of chemical structures along with their interaction kinetics with AhR [74].
An example of AhR
In a similar approach, Rath and his team built two human PAS B domain; a wild type and mutant (Val381 Ala, Val381Asn) models. Around 60 natural compounds from
Compound name | Induction of AhR transcription | Binding free energy (kcal/mol) | Reference |
---|---|---|---|
Withanolide A | + | −7.5 | [77] |
Pinocembrin (5,7-Dihydroxyflavanone, R-form) | + | −2.9 | [60] |
5-hydroxy-7-methoxyflavone | + | −4.3 | [60] |
IMA-06201 (N-ethyl- | + | Not report | [46] |
IMA-06504 (N-(4-trifluoromethylphenyl)-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide) | + | Not report | [46] |
Activation of AhR transcription by chemical compounds that identified by in silico screening of different chemical libraries.
In another screening study, Mahiout, et al. identified IMA-06201 and IMA-06504 as two novel AhR agonists, with similar modes of binding to that of TCDD. Both compounds showed great stability in the central area of the AhR ligand-binding pocket. Furthermore, these AhR agonists were shown to be more efficient and more potent as selective AhR modulators than TCDD. To confirm that, Mahiout used CYP1A1 enzyme activity as a biomarker for AhR activation and compared the efficacy and potency of IMA-06201 and IMA-06504 (see Figure 5 and Table 3) to that of TCDD in the presence and absence of the AhR antagonist, CH-223191, at different concentrations in rat hepatoma cell lines. Their results showed that the new compounds, IMA-06201 and IMA-06504, were able to induce CYP1A1 activity in a similar efficacy to that of TCDD, where CH-223191 was shown to block their CYP1A1 induction. Also, in an Ames test to assess the genotoxicity of the new identified compounds, IMA-06201 and IMA-06504 did not show mutagenic effects at low concentrations [46].
Machine-learning algorithms combined with QSAR have been recently used to screen for new AhR ligands. For instance, Matsuzaka used deep learning (DL) to construct machine-learning models to predict AhR activators. These models showed advantages on enhanced input data based on the 3D chemical structures of the compounds into these models, and their performance was better than traditional machine learning models [78]. To enhance the screening process of AhR ligands, Zhu established a virtual screening protocol from combining ligand-based and structure-based screening with supervised machine learning to screen around eight thousand from the pesticide databases to identify an agonistic effect on AHR activity. Zhu’s results revealed sixteen compounds as AhR activators and these findings were validated in a zebrafish
Towards improving the prediction accuracy of his model, Yang, et al. used machine learning algorithms to construct two-dimensional quantitative structure–activity relationship (2D-QSAR) models from multiple linear regression (MLR) and artificial neural network (ANN) algorithms. He used the pEC50 values of 60 dioxins derivatives as AhR activators to build. These models predicted the toxicity of 162 new dioxin derivatives, showing a good correlation between compounds’ chemical structures and their IC50 and EC50 values.
Recently, Goya-Jorge employed various machine learning algorithms to build a set of QSAR models. These models adopted the adoboost (AdB), random forest (RF), gradient boosting (GB), support vector machine (SVM), and multilayer perceptron (MLP) as classifiers to examine around 1900 compounds from synthetic and natural sources on their AhR agonism. Around 40 compounds baring the benzothiazole scaffold were classified as AhR agonists. In vitro validation of these hits showed that indole derivatives can serve as AhR ligands, including the endogenous substances [80, 81]. Table 3 reports some of the top hits emerging from different
Identifying novel AhR modulators using in silico approaches require establishing more comprehensive computational models of this target. These models should describe the detailed organization of the different AhR domains as well is its interaction with other protein/DNA partners. While the available crystal structures provide a glimpse of these missing pieces of information, there are still more to be done in this regard. For example, all currently available AhR crystal structures deposited in the protein data bank are lacking two important AhR domains, namely the PAS B domain and the transactivation domain [39]. The transactivation domain is essential in AhR intercellular trafficking.
On the other hand, the PAS B domain interacts with an AhR ligand, which can modulate the AhR activity. While homology modeling has helped constructing acceptable models for this domain, the similarity of the templates used to build the PAS B domain is very low, leaving a lot of doubt about their accuracy. A crystal structure of the PAS B domain would be a great leap forward towards understanding the mode of action of AhR modulators and towards identifying better agonists/antagonists for this important target. Furthermore, there is a gap of knowledge on how AhR interact with other protein partners in the inactive state, including co-chaperone, AIP, and the protein kinase SRC. This builds an additional challenge to identify druggable pockets at their protein–protein interfaces [7, 82]. With the apparent advances in obtaining 3D experimental structures of protein (e.g. Cryo-electron microscopy (cryo-EM)) one expects several of these structural challenges can be solved in the near future, opening new gates for the computational science to identify new AhR modulators and to help understand its functional, structural and biological characterizes more clearly.
The AhR is a ligand-activated transcriptional factor. It regulates various genes’ expression and plays a pathophysiological function in numerous diseases. Crystallography has been employed to resolve three crystal structures containing bHLH and PAS A domains from human and mouse origin and to identify four protein–protein interfaces. However, all these structures lacked the PAS B domain, which plays a fundamental role in ligands’ binding domain to AhR. Computational and mutational studies revealed important residues that constitute the binding pockets within the PAS B domain. Towards identifying novel AhR modulators, several virtual screening and machine learning algorithms were constructed based on the available structural and pharmacological properties of known AhR ligands. Computational methods are extremely fast and intensely reduce the cost and time in screening millions of compounds to find compounds that could interact with the AhR. Recent studies employing these methods against AhR have been reviewed and discussed in this chapter. We hope the literature presented here can help advance the development of novel, selective and potent AhR modulators.
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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. 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He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. 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Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. 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He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). 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He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. 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