\r\n\t
",isbn:"978-1-83969-347-2",printIsbn:"978-1-83969-346-5",pdfIsbn:"978-1-83969-348-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"4fc73beb0e4416a20cc70c8163fe436f",bookSignature:"Dr. Pinar Erkekoglu",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9836.jpg",keywords:"KRAS Gene, Oncogene, Tumor Suppressor Gene, Mutation, Cancer, Microtubule-Associated Protein (MAP), GTPase, Pathological Conditions, Epidermal Nevus, Noonan Syndrome, Costello Syndrome, Environmental Chemicals",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 17th 2020",dateEndSecondStepPublish:"December 15th 2020",dateEndThirdStepPublish:"February 13th 2021",dateEndFourthStepPublish:"May 4th 2021",dateEndFifthStepPublish:"July 3rd 2021",remainingDaysToSecondStep:"a month",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher in toxicology, vaccinology, cosmetics, and Board Member of Turkish Pharmacists Association Pharmacy Academia and Board Member of Hacettepe Vaccine Institute. Published more than 150 scientific papers in international/national journals. Associate editor of the Turkish Journal of Pharmaceutical Sciences.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"109978",title:"Prof.",name:"Pinar",middleName:null,surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pinar Erkekoglu",profilePictureURL:"https://mts.intechopen.com/storage/users/109978/images/system/109978.JPG",biography:"Pınar Erkekoglu was born in Ankara, Turkey. She graduated with a BS from Hacettepe University Faculty of Pharmacy. Later, she received an MSci and Ph.D. in Toxicology. She completed a part of her Ph.D. studies in Grenoble, France, at Universite Joseph Fourier and CEA/INAC/LAN after receiving a full scholarship from both the Erasmus Scholarship Program and CEA. She worked as a post-doc and a visiting associate in the Biological Engineering Department at Massachusetts Institute of Technology. She is currently working as a full professor at Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Toxicology. Her main study interests are clinical and medical aspects of toxicology, endocrine-disrupting chemicals, and oxidative stress. She has published more than 150 papers in national and international journals. Dr. Erkekoglu has been a European Registered Toxicologist (ERT) since 2014.",institutionString:"Hacettepe University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"4",institution:{name:"Hacettepe University",institutionURL:null,country:{name:"Turkey"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"6",title:"Biochemistry, Genetics and Molecular Biology",slug:"biochemistry-genetics-and-molecular-biology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"301331",firstName:"Mia",lastName:"Vulovic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/301331/images/8498_n.jpg",email:"mia.v@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:"5176",title:"Nutritional Deficiency",subtitle:null,isOpenForSubmission:!1,hash:"a2e20dabc8ed6fbaef3686be8c6fce99",slug:"nutritional-deficiency",bookSignature:"Pınar Erkekoglu and Belma Kocer-Gumusel",coverURL:"https://cdn.intechopen.com/books/images_new/5176.jpg",editedByType:"Edited by",editors:[{id:"109978",title:"Prof.",name:"Pinar",surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pinar Erkekoglu"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5836",title:"Bisphenol A",subtitle:"Exposure and Health Risks",isOpenForSubmission:!1,hash:"446599b9e5cf929537d445edc546c449",slug:"bisphenol-a-exposure-and-health-risks",bookSignature:"Pinar Erkekoglu and Belma Kocer-Gumusel",coverURL:"https://cdn.intechopen.com/books/images_new/5836.jpg",editedByType:"Edited by",editors:[{id:"109978",title:"Prof.",name:"Pinar",surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pinar Erkekoglu"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7281",title:"Oncogenes and Carcinogenesis",subtitle:null,isOpenForSubmission:!1,hash:"728df4ace35f652725e5b94da45d0c4d",slug:"oncogenes-and-carcinogenesis",bookSignature:"Pinar Erkekoglu",coverURL:"https://cdn.intechopen.com/books/images_new/7281.jpg",editedByType:"Edited by",editors:[{id:"109978",title:"Prof.",name:"Pinar",surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pinar Erkekoglu"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6486",title:"Glutathione in Health and Disease",subtitle:null,isOpenForSubmission:!1,hash:"23fb1f2e0cea5cf004d57bc8c0d46ce4",slug:"glutathione-in-health-and-disease",bookSignature:"Pinar Erkekoglu and Belma Kocer-Gumusel",coverURL:"https://cdn.intechopen.com/books/images_new/6486.jpg",editedByType:"Edited by",editors:[{id:"109978",title:"Prof.",name:"Pinar",surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pinar Erkekoglu"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6694",title:"New Trends in Ion Exchange Studies",subtitle:null,isOpenForSubmission:!1,hash:"3de8c8b090fd8faa7c11ec5b387c486a",slug:"new-trends-in-ion-exchange-studies",bookSignature:"Selcan Karakuş",coverURL:"https://cdn.intechopen.com/books/images_new/6694.jpg",editedByType:"Edited by",editors:[{id:"206110",title:"Dr.",name:"Selcan",surname:"Karakuş",slug:"selcan-karakus",fullName:"Selcan Karakuş"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"67647",title:"Programmed Cell Death in Seeds: An Adaptive Mechanism Required for Life",doi:"10.5772/intechopen.86833",slug:"programmed-cell-death-in-seeds-an-adaptive-mechanism-required-for-life",body:'\nThe life cycle of organisms requires targeted cell types to be removed in a predictable and genetically organized way. This process of cellular suicide, named programmed cell death (PCD), occurs from embryogenesis to senescence and is an essential part of development and cell homeostasis of any multicellular organism [1, 2, 3]. Thus, PCD has been observed from the onset of zygotic embryogenesis until the germinative process ends [4, 5, 6]. The mechanism through which specific cells are targeted for PCD without affecting neighboring cells has not yet been resolved. Notable cellular compartments (i.e., mitochondria, chloroplasts, Golgi complex, endoplasmic reticulum (ER), and vacuoles) have been shown to be involved in PCD [7]. Plant PCD exhibits several hallmarks: (i) DNA laddering and strong chromatin condensation [8]; (ii) sometimes, release of cytochrome-c from the mitochondria to the cytosol, and its subsequent degradation, which is dependent on reactive oxygen species (ROS) and caspase-like activity [9]; (iii) generation of autophagic vacuoles due to the absence of an active phagocytosis system [10, 11]; (iv) degradation of organelles such as the plastidome, mitochondria, and peroxisomes [11]; (v) extensive vacuolation (i.e., appearance of a large vacuole) [12]; (vi) sometimes, development of ricinosomes concomitantly with the progression of nuclear DNA fragmentation [13, 14]; and (vii) contribution of nucleases and ROS [15, 16]. At the end of PCD, the cell is completely digested, and the remaining protoplast is surrounded by the cell wall (CW), which finally becomes disorganized and disintegrates in a coordinated and regulated way [17]. Because plants have CWs, they have developed their own PCD process, thus not requiring the apoptotic regulators and phagocytic processes present in animal cells.At the cellular level, plant PCD can be non-autolytic or autolytic (i.e., formation of large lytic vacuoles and rapid clearance of cytoplasm due to tonoplast rupture and the release of active hydrolases) [18]. Thus, developmental PCD (dPCD) is autolytic and is critical for many vegetative and reproductive processes [2, 19, 20]. However, environmental PCD (ePCD) is non-autolytic and is involved in responses to biotic and abiotic stresses. In this latter form of PCD is involved the hypersensitive response (HR), which prevents the growth and spread of pathogens into healthy tissues [21, 22, 23]. Recently, it has been suggested that dPCD and ePCD are characterized by separate regulatory pathways. In fact, a conserved core of transcriptionally controlled dPCD-associated genes has been defined [24]. Because plants and animals have different molecular mechanisms for PCD, an evolutionary parallelism of PCD pathways in plants and animals has been postulated [25].
\nThe involvement of PCD has been described in various plant life processes, including the emptying of xylem tracheary elements [26], aerenchyma formation [25, 27], and dynamic turnover of the root cap [28]. In addition, PCD is an integral part of the seed development and germination (i.e., dPCD), during which cells of the integuments, nucellus, suspensor, and endosperm face death [5, 6]. The following text presents an update on the substantial progress that has been made to our understanding of PCD through the life of the seed, an entity that represents the dispersal unit of the spermatophytes securing their survival and perpetuation. The role of papain-type KDEL-Cys-endoproteases (PLCPs), vacuolar processing enzymes (VPEs) and nucleases, is carefully reviewed.
\nCys-endopeptidases (Cys-EPs) are the most abundant group of proteases responsible for degradation and the mobilization of storage proteins (SPs), being the SPs of seeds the most affected [29]. Cys-EP is a member of a unique group of papain-type Cys-EPs found specifically during senescence. The ER-derived vesicles (e.g., protein bodies, glyoxysomes, and ricinosomes) accumulate in seeds, among other compounds, specific SPs, (e.g., prolamin and zein) and KDEL-tailed and papain-type proteases [30, 31]. The SPs’ accumulation process is mediated by ER chaperones such as the luminal binding protein (BiP) and protein disulfide isomerase (PDI). Interestingly, BiP can function either as a negative or a positive modulator of PCD events and also participate in innate immunity. Besides, in the seeds of castor bean, the immature 11S globulin was aggregated and then packaged in vesicles from ER [32]. That is, the ER-derived vesicles are thought to function as repositories of specific proteins until they are required for the cellular metabolism.
\nThe ricinosomes (Figure 1) are spherical plant-specific organelles that have been firstly documented in senescing germinating endosperms of castor bean [30, 33, 34, 35]. They are present prior to the appearance of other subcellular changes related to PCD and appear at the beginning of PCD and deliver large amounts of papain-type Cys-EPs in the final stages of cellular disintegration [13]. The ricinosomes contain large quantities of a 45-kDa pro-Cys-EP with a C-terminal KDEL (ER retention signal), and they are specifically for plant PCD [30, 36]. The ricinosomes are surrounded by a single ribosome-studded membrane and are directly sorted toward vacuoles through a Golgi-independent pathway to get involved in the PCD. These vesicles bud off from the ER in senescing tissues concomitantly with the progress of nuclear DNA fragmentation and have Cys-EPs as marker enzymes [37, 38]. KDEL-Cys-EPs are synthesized as inactive or weakly active pre-proenzyme which usually include a KDEL and an auto-inhibitory pro-domain that is cotranslationally transferred into the ER and then stored in ricinosomes because the pro-domain prevents premature activation of the protease [39]. Upon cytosolic acidification due to the LV collapse, the KDEL-Cys-EPs autocatalytic activation occurs [40]. This activation has been confirmed by in vitro acidification experiments of isolated ricinosomes and implies the cleavage of the N-terminal pro-peptide and the C-terminal KDEL motif. The presence of mature Cys-EP is consistent with the loss of tonoplast integrity. The mature and enzymatically active KDEL-Cys-EPs exhibit unusual broad substrate specificity (Figure 2A). This characteristic is due to the fact that the active site accepts a wide variety of amino acids, including proline and glycosylated hydroxyproline (e.g., extensions) from the glycoproteins of the CW [41]. When ricinosomes disintegrate and release their content into the cytoplasm, the cells that contain them are going to die [13, 14, 42]. More specifically, these ER vesicles are present prior to the appearance of other subcellular changes related to vacuolar cell death, one of the two classes of PCD previously defined [13, 35, 42, 43]. Interestingly, the ricinosomes, but not the enzymes within them, have also been implicated in the PCD of Solanum lycopersicum [35]. Likewise, anther dehiscence in tomato has also been linked to dPCD, and accumulation of ricinosome-like vesicles and the dPCD-associated SlCys-EP has been observed in the dehiscence zones of tomato anthers along with nuclear condensation and cytoplasmic retraction [13]. In year 2014, the first evidence for the existence of ricinosomes in Arabidopsis has been documented [44].
\nUltrastructure of ricinosomes purified from 5-day-old castor bean endosperm and immunolocalization of their marker enzyme Cys-EP. Electron micrographs (a, ×4400; b, ×12,000) and immunocytochemistry by using α-CysEP (c, ×12,000). Scale bar: a = 1.0 μm; b and c = 0.5 μm. From Schmid et al. [30] with permission of PNAS (USA).
Maturation, activation, and involvement of papain-type KDEL-Cys-EPs (A) and γVPE (B) in plant PCD. Endoplasmic reticulum (ER), N-terminal pro-peptide (NTPP), self-inhibitory C-terminal pro-peptide (CTPP), signal peptide (SiP), and storage protein (SP) (see text for more details).
Papain-like Cys-EPs (PLCPs; often called cathepsins in animals) are essential and central hubs of plant immunity, germination, development, and senescence [45, 46]. Thus, when activated, PLCPs induce a broad spectrum of defense responses, including PCD [46]. On the other hand, PLCPs constitute one of the most abundant groups of the proteases responsible for the degradation and mobilization of SPs in seeds [47]. Their role during germination has been reported in a wide range of both monocot and dicot plants [48]. PLCPs in plants are divided into nine subfamilies. Thus, 32, 41, and 45 PLCPs’ members have been identified in Arabidopsis, barley, and rice, respectively [49]. PLCPs have no structural relationship to the caspases, and its natural competitive and reversible inhibitors are the phytocystatins which are evolutionarily well conserved [50]. Recent results support the bifunctional ability of carboxy-extended phytocystatins in regulating legumain proteases via its carboxy-extended domain and PLCPs by its amino-terminal domain [51]. The activities of phytocystatins and PLCPs need to maintain a relatively balanced level to ensure the normal seed germination [29].
\nKDEL-tailed Cys-protease SH-EP is the first Cys-EP found to have a KDEL tail in spite of the fact that the protease localizes in the protein storage vacuoles [52]. KDEL-tailed protease-accumulating vesicles in germinating mung bean (Vigna mungo) cotyledons are similar to ricinosomes in that they accumulate the KDEL-tailed cysteine protease SH-EP [53, 54]. During the seeds’ life, the ricinosomes accumulate PLCPs for the degradation of seed storage materials in both cotyledons and endosperm [30, 53]. Upon cell death, the content of ricinosomes (i.e., PLCPs) is released into the cell corpse where the proteinases are activated and proceed to degrade any remaining protein for the growing seedling in the case of nutritive seed tissues. Alternatively, PLCPs can also digest CW extensions in the final stage of PCD when the cell collapses and tissue breaks down [55]. Thus, the absence of ricinosomes during seed development (e.g., perisperm, integuments, chalaza, and pericarp) may be due to the fact that the CWs remain intact until germination, at which time these tissues are finally dismantled [56]. Interestingly, area micropylar of Chenopodium quinoa seeds does not have ricinosomes [6, 56]. KDEL-Cys-EPs are unique in digesting the extensions that form the basic scaffold for CW formation [55] (Figure 2A). So, KDEL-CPs like AtCEP1 are considered as late-acting proteases that digest CW proteins during the final stages of PCD and tissue remodeling after cellular disintegration [55, 57].
\nDuring seed germination, SPs are degraded to nourish the growing seedlings. This process is mainly triggered by PLCPs [29]. As a example, during both Zea mays and Triticum aestivum germination, the activity of Cys-EPs increases up to 90% of the total proteolytic activity. During barley seed germination, PLCPs were secreted from the scutellar and the aleurone layers to the endosperm to degrade the endosperm Sps [58]. Recently, the results of overexpression and silencing of HvPap-1, a gibberellin (GAs)-induced PLCP gen, indicated that PLCPs are important factors in mobilizing SPs to promote seed germination, and their expression and/or activity are regulated by GAs, ABA, and cystatins [49]. Ricinosomes and nuclear DNA are fragmented during PCD. In Arabidopsis, three KDEL-Cys-EPs called AtCEP1, AtCEP2, and AtCEP3 have been expressed in tissues undergoing PCD. Thus, the first gen is expressed in senescing ovules, the second in the vascular vessels, and the third in maturing siliques [55, 57, 58, 59]. Recently, AtCEP2 storing ricinosomes in Arabidopsis seedlings seems to be—like ER bodies—exclusively localized in epidermal cells [44]. The accumulation of KDEL-Cys-EPs and the appearance of ricinosomes may predict the occurrence of PCD during late seed development [37]. The ricinosomes containing pro-Cys-EP have been observed in anther tissues prior to PCD [13] and in the endosperm cells of imbibed tomato seeds (Solanum lycopersicum) where the reserve mobilization, Cys-EP accumulation and processing, is GA-induced [60]. Cereal aleurone PCD is controlled by phytohormones: the PCD promoting GAs and the antagonistically acting ABA [61]. The presence of ABA- and GA-responsive genes encoding proteases confirms their notable role in regulating the growth of cereal seeds [5, 62]. The endosperm in cereal seeds undergoes PCD during development, and, with the exception of the aleurone layer, is a dead tissue at maturity. In Ricinus communis the KDEL-Cys-EPs and ricinosomes were detected for the first time not only in the senescing endosperm of germinating seeds [30] but also in the nucellus of seeds during maturation [36, 63]. Ricinosomes with the pro-form of KDEL-Cys-EPs are also present in imbibed tomato seeds [60]. The presence of KDEL-Cys-EPs has been also demonstrated in (i) the hypogeous cotyledons of Vicia sativa [64]; (ii) the seed coat of Phalaenopsis [65]; (iii) the megagametophyte cells after germination of Picea glauca seeds [66]; (iv) the epigeous cotyledons of Vigna mungo [52]; (v) the senescing endosperm of germinating castor bean seeds [30, 67]; (vi) the nucellus in maturing castor bean seeds, where the endosperm expands at the expense of the nucellus cells [36]; (vii) the endosperm cells of imbibed tomato seeds [60]; and (viii) the germinating mung bean (Vigna mungo) cotyledons in that they accumulate the KDEL-tailed cysteine protease SH-EP [53]. Recently, an attractive PLCP protein called NbCP14 was characterized in Nicotiana benthamiana. This autocatalytically activated enzyme seems to be a Cath-H-like protease with great importance for the execution of PCD during plant development [68]. Previous to the NbCP14 identification, NtCP14 was also described in Nicotiana tabacum as a key component in triggering of PCD during the early stages of embryogenesis [69]. In the tobacco suspensor, PCD is antagonistically regulated by NtCP14 and its cystatin inhibitor NtCYS. Both silencing of NtCP14 and overexpression of NtCYS delay PCD [69].
\nThe cellular vacuoles execute essential functions for plant growth, development, and adaptation to biotic and abiotic stresses. In the absence of macrophages, the unwanted material for plant PCD is only degraded through vacuole-released hydrolytic enzymes, located in LVs (acidic pH) [70]. The formation of LVs involves the coalescence of protein storage vacuoles (PSVs, with a pH near neutrality), vacuolar lumen acidification, and intracellular material mobilization (i.e., cytoplasm engulfing). Only cells with high vacuolation resulted in PCD [12]. In brief, PSVs contain large amounts of defensive and SPs to be used during seed germination, while LVs contain hydrolytic enzymes [50]. Therefore, the degree of vacuolation can reflect the intensity of the PCD process. A clear example of vacuolization takes place in the aleurone cells during cereal seed germination [5, 12]. Mature cereal seeds consist mainly of dead cells, and only the embryo and aleurone layer are still alive. The PCD of aleurone cells is an essential process for the successful completion of post-germination storage mobilization, which is associated with the vacuole destruction [70]. Vacuolation and PCD of aleurone cells are initiated near the embryo and then gradually reach the distal area of the embryo [5, 12]. Similarly to the micro- or macroautophagy processes, the disruption of LVs and the concurrent release of various hydrolytic enzymes indicate that the PCD has been triggered [12]. The bursting of the tonoplast leads to a rapid cytoplasmic acidification and hydrolysis of the remaining cellular contents [71]. So much so, this vacuolar collapse needs to be rigorously organized to achieve PCD at a suitable timing [72]. Because the vacuolar collapse releases hydrolytic enzymes, the vacuole rupture is used as an indicator of PCD initiation [73]. Therefore, the tonoplast breakage is considered a point of no return during plant PCD [2]. In brief, the tonoplast rupture and vacuolar collapse are two important features of plant PCD. Finally, the plasmalemma integrity is maintained until the vacuole collapses [12, 74, 75, 76].
\nPlant PCD is accompanied by the upregulation of a heterogeneous group of vacuolar hydrolytic enzymes, being the vacuolar processing enzymes (VPEs), also called legumains, closely involved in its activation. VPEs originate from prokaryote pro-legumains. The VPEs have properties similar to animal caspases and fulfill relevant vacuolar functions in seeds [77]. Nevertheless, VPEs are directly involved in plant development and environmental stress responses [50]. Earlier studies in pumpkin seeds have demonstrated the identification of VPE as a vacuolar Cys-EP protein probably responsible for degradation of vacuolar SPs during germination [78]. Thus, the VPEs in monocots (i) are required for processing of glutelins that are the dominant seed SPs in rice [79], and (ii) they also process other seed SPs such as albumins, globulins, and ricins in storage vacuoles in seeds of pumpkin and castor bean [80]. However, VPE deficiency does not affect storage protein degradation in germinating seeds [81]. VPE was the first identified enzyme in plants with both caspase-like activity and activity against caspase-1-substrate [82]. Recent review contains the contributions of VPEs to plant PCD and its role in vacuole-mediated cell death [83]. Thus, the VPE4 expression pattern in the developing pericarp of Nicotiana benthamiana coincides with the profile of the caspase-1-like activity [84, 85]. Once vacuolar hydrolytic enzymes are activated, the proteolytic cascade leading PCD begins [70, 71]. However, although it is beyond question that VPE is an initiator of the vacuolar processing system, the mechanism by which VPE controls the vacuolar breakage and the execution of a variety of plant PCD is still unclear. In this regard, it was suggested that the disruption of the vacuole may be mediated by VPE in conjunction with protein kinases [86]. It has been also proposed that VPE and cathepsin-B (Cath-B), which have, respectively, caspase-1-like and caspase-3-like activity, may promote coalescence, accelerating the process of vacuolation and thus triggering vacuolar collapse during the PCD [87, 88]. However, no research yet has integrated the action of both VPE and Cath-B in the PCD pathway. VPE of N. benthamiana has been reported to mediate virus-induced HR by regulating tonoplast collapse [87, 89]. The PCD triggered by vacuolar collapse is unique to plants and has not been seen in animals (Figure 2B). As a result of this collapse and the liberation of active vacuolar hydrolases, the chromatin structure crumbled, the DNA is fragmented, and the plasma membrane disabled. Finally, the disintegration of the nuclear envelope starts [90], and the protoplast rapidly collapses and dies [5, 91].
\nAutophagy is a process known to mediate the degradation of residual proteins and aggregates of insoluble proteins and lipids and to remove damaged organelles. Likewise, autophagy is essential for vacuolation of cells undergoing developmental PCD and is activated by type-II metacaspases (McIIPa) [92]. Thus, during spruce embryogenesis McIIPa is transported from cytosol to the nucleus, where its presence is correlated to DNA fragmentation. These data reinforce that McIIPa is directly involved in a pathway which generates nuclear degradation, an event present in most programs of eukaryotic PCD. This McIIPa metacaspase can play a role on the cleavage of nuclear proteins [71, 93]. Besides metacaspases, VPE has been also described as another class of Cys-EPs involved besides in different types of PCD and also in development and immunity [70, 87, 94, 95]. The VPE contains a His-Cys catalytic dyad and cleaves a peptide bond at the C-terminal side involving an Asn residue, hence the name of asparaginyl endopeptidases [96]. VPEs are evolutionarily related to caspases and preferably localized in vacuoles (i.e., maximal activity at acidic pH) and are specific for plants [38, 70, 97]. Therefore, the plants might have evolved a VPE-mediated vacuolar system as a cellular suicide strategy. Plants encode at least four functional isoforms of VPEs, which are located in the vacuole ([77] and refs. therein). Plant VPEs are classified into vegetative, embryogenic, and seed-expressed types [98, 99, 100] (Figure 3). The genome of tomato has 14 VPE genes [95]. However, the genome of Arabidopsis has four VPE genes: α-VPE and β-VPE play a key role in the processing of SPs during seed maturation [80, 94], while γ-VPE and δ-VPE are expressed at early stage of seed development being involved in the formation of the inner integuments of the seed coat [101, 102, 103]. Interestingly, in spite of delayed vacuolation, Arabidopsis γ-VPE mutants have a normal germination phenotype. This suggests that vacuolation does not trigger, but rather is a consequence of germination [104].
\nDendrogram of VPEs of several plant species. VPEs (access numbers are within parentheses) were separated into three groups: βVPE (seed type), α/γVPE (vegetative type), and δVPE (embryogenesis type). Signal peptides were excluded from the sequences. Adapted mainly from Nakaune et al. [103] and other recent publications.
The δ-VPE was originated early during dicotyledonous diversification [103]. Regarding the maturation of γ-VPE in A. thaliana (Figure 2B), it is to know that the N-terminal signal peptide of VPE pre-protein precursor is cotranslationally removed in the ER to produce VPE pro-protein. The transfer of pro-protein precursor to the acidic vacuole causes the self-catalytic conversion into an intermediate isoform by removal of the C-terminal inhibitory pro-peptide. The subsequent removal of the N-terminal pro-peptide produces the mature γ-VPE [96]. In the case of the seed SPs, the VPEs’ vacuolar maturation is of major importance, as it conditions the establishment of vigorous seedlings [105]. A quadruple-KO mutant with no detectable VPE activity strongly suggests that there are no other proteases with a similar activity in Arabidopsis [106]. When the VPE genes were knocked out, no characteristics belonging to cell death were observed [12]. VPE orthologs are widely distributed in land plants including mosses (e.g., Physcomitrella patens) and ferns (e.g., Ceratopteris richardii) [83]. In rice, five VPE (OsVPE) genes are found [83, 107]. Phylogenetic analyses and gene expression studies have demonstrated that OsVPE2 (OsaLeg2) and OsVPE3 (OsaLeg3) are involved in H2O2-induced PCD and in salt-stressed seeds, whereas OsaLeg1, OsaLeg4, and OsaLeg5 would act as vegetative-related legumains [83]. The barley (Hordeum vulgare) genome contains eight VPE genes (HvVPEs) which are differentially expressed during vegetative and reproductive development [98].
\nThe first increase in a cascade of caspase-1-, caspase-3-, caspase-4-, caspase-6-, and caspase-8-like activities in the endosperm of Hordeum vulgare seeds may be related to PCD in the nucellus [84, 85, 108]. The importance of pericarp PCD for proper development of the endosperm has been recently described [84]. The increase in caspase-1-like activity may be acquired by HvVPE2a (called nucellain), HvVPE2b, and HvVPE2d proteases which is exclusively expressed in nucellus and nucellar projection. The expression patterns of the HvPhS2 and HvPhS3, which are exclusively active in the nucellar projection, coincide with the caspase-6-like activity profile in the early endosperm fraction indicating that HvPhS1 and HvPhS2 may be responsible for the caspase-6-like activity [84, 85]. Caspase-1-, caspase-3-, and caspase-6-like activities are also localized in the degenerating nucellus of Sechium edule [109]. In the degenerating nucellar tissue of castor bean, proteomic analyses identified multiple proteases and protease inhibitors [108]. The MADS-box transcription factor called MADS29 has been suggested to promote nucellar degeneration through the regulation of Cys-EP expression in rice and maize [61]. The α, β, γ, and δ-VPEs of Arabidopsis appear to share no direct one-to-one relationships of orthology with VPEs from gymnosperms. The VPE protein and its transcripts increase at the beginning of the HR reaction in the tobacco leaf, in which the cells showed typical PCD characteristics, and both the VPE inhibitor ESEN-CHO and the caspase-1-like activity inhibitor Ac-YVAD-CHO inhibit the appearance of PCD [98, 99]. These and other recent results [100] reaffirm that VPE is a protease with caspase-1-like activity in plants. VPE activation was started once the leaves of tobacco were infected with the TMV, leading to vacuole disruption and activation of PCD to prevent the proliferation of virus [70, 87]. Likewise, PCD during HR is critical for the removal of biotrophic pathogens, whose growth depends on the living host tissues [87, 99]. Together, VPE deficiency suppresses vacuolar collapse, leading to mycotoxin-induced cell death [83]. Interestingly, the results of Zhan’s group using the NbVPE silencing suggest that VPE plays an important role in elicitor signaling in plants of Nicotiana benthamiana [89]. Finally, and based on the results to date, (i) transcriptome sequence information has permitted the identification of new VPE genes than having a cyclization function rather a protease function ([77] and refs. therein), and (ii) VPEs and other vacuolar enzymes once released from LV to cytosol through a barely known route promote a VPE-mediated vacuolar disruption and constitute a fundamental piece in the plant PCD puzzle whose organization is far from unravelling.
\nAs shown throughout this review, the PCD process involves the selective removal of unwanted cells and the mobilization of cellular debris, including the products of DNA fragmentation, which is a known hallmark of PCD [6, 17, 93, 110, 111]. In plants, genomic DNA is actively degraded during dPCD (e.g., during seed coat formation [103] and barley pericarp development [112]). Although the enzymes directly involved in nuclear dismantling are unknown, there is increasing evidence linking proteases and nucleases to plant PCD [20]. What is known is that during PCD, different nucleases are induced, including a set of S1-type (Zn+2 dependent) endonucleases that are synthesized regardless of tissue type [113, 114]. While these nucleases are cytoplasmic and lack a canonical nuclear localization signal, upon induction of cell death, they become nuclear [115]. Thus, nucleases are tightly associated with different plant PCD processes, including HR [116], endosperm development aleurone cell death [4, 117], and xylogenesis [118]. It has been hypothesized that PCD-associated nucleases help to recycle DNA from dead cells by degrading it into smaller fragments so that it can be taken up to be reused by neighboring cells. In cereal seeds, the progression of endosperm PCD is accompanied by an increase in nuclease activity and the degradation of nuclear DNA at internucleosomal sites [4, 115]. PCD in the endosperm precedes PCD in the suspensor, suggesting that the endosperm and suspensor either receive different chemical signals or interpret them differently [119]. A nuclear-localized GA-induced nuclease was found to be active just prior to the appearance of DNA laddering in wheat aleurone cells undergoing PCD. Interestingly, this GA-induced nuclease is not detected in GA-insensitive mutants or when GA synthesis is inhibited [120]. Furthermore, aleurone layers that have not been treated with GAs do not complete PCD.
\nFoundational biochemical experiments revealed that plant nucleases are localized to a variety of different cellular spaces [5, 116, 120, 121]; for example, in barley aleurone, nuclease activity was found in the ER, Golgi, protein body, and vacuole [122]. A nuclease that is a promising candidate for involvement in PCD is the bifunctional nuclease-1 (BFN1). In Arabidopsis, the BFN1 gene is induced during senescence, abscission, and dPCD [123]. Recent studies revealed that the BFN1 protein, which possesses RNase and DNase activity, is responsible for rapid cell-autonomous corpse clearance and DNA fragmentation during root cap cell death [118, 124]. TUNEL assays showed a delay in nucleic acid degradation in both the nuclei and the cytoplasms of BFN1 mutants [123]. ORE1, a NAC (ANAC092) transcription factor that positively regulates leaf senescence, has been demonstrated to control the BFN1 expression [125]. ORE1 is located downstream of the ethylene signaling cascade. Considering this data, it is not surprising that BFN1 is an accepted marker of both plant senescence and PCD. Another nuclease, known as Zinnia endonuclease-1 (ZEN1), which shares a number of similarities with BFN1, has been directly implicated to function in PCD. ZEN1 is localized to vacuoles, which collapse before DNA is degraded. ZEN1 was demonstrated to be responsible for nuclear DNA fragmentation during PCD associated with xylem development [126]. Furthermore, silencing ZEN1 prevented the degradation of nuclear DNA, but did not affect vacuole collapse in a Zinnia elegans cell suspension culture. While these findings support the notion that ZEN1 may play a central role in plant DNA fragmentation [126], evidence exists that suggests that multiple nucleases are involved in plant PCD [15].
\nGiven the limited number of nucleases known to be involved in PCD, it has proven to be a challenge to identify these PCD-associated endonucleases. Once identified, other hurdles remain. Based on a study of the role of the nucleases in the process of leaf senescence [127], future studies must explore whether the nuclease is involved in cell death in different tissues in a same plant or in different processes (e.g., fertilization, zygotic embryogenesis, and seed dormancy and germination), is subcellularly localized to the nucleus, or possesses a PCD phenotype—an activity that involves creation of a mutant for the nuclease followed by experiments to observe the impact on genomic DNA during PCD. Additionally, these studies must consider how different nucleases work together to degrade nuclear and organelle DNA.
\nAlthough the biochemical and molecular understanding of plant PCD has increased over the last decade, the mechanisms of action are still very limited and restricted to determine species and some organs and cell compartments. Given its importance, the origin and evolution of genes involved in PCD still need to be resolved. For example, all through seed evolution, PCD has played a fundamental role. In my opinion, eight important goals are key for the best knowledge of plant PCD: (i) the molecular components used in its execution, (ii) the components that have been conserved during evolution, (iii) specific components of PCD, (iv) temporal and spatial expression of Cys-EPs involved in PCD, (v) subcellular Cys-EPs localization and interaction with other proteins, (vi) how the different proteases orchestrate PCD and if there is functional redundancy between the different gene families, (vii) activation of relevant Cys-EPs, and (viii) knowledge of the in vivo protein substrates. An example that justifies what has been said previously can be that VPEs are proposed to control indirectly tonoplast rupture during PCD. However, the detailed mechanism by which VPEs control tonoplast rupture is still diffuse. Together, the intense research carried out in the last decade on PCD in seeds is a strong scientific support to understand the coexistence between death and life.
\nWe wish to thank Drs. A. Gunawardena, C. Gietl, S. Maldonado, and M. Nowack for kindly sending their recent manuscripts. I apologize to all those scientists whose manuscripts and/or illustrations have not been directly mentioned.
\nThe authors declare no conflict of interest.
The portal hypertension is caused by an increased resistance to venous flow in portal vein. Which leads to an increase to pressure in the portal circulation. It is a result of chronic liver disease, obstruction of portal vein, or portosystemic shunt, which leads to hyperdynamic circulation.
The normal hepatic venous pressure gradient (HVPG) correlates with normal portal pressure which is 1–4 mm Hg. A pressure gradient of more than 10 mm Hg links to esophageal varices. The pressure 12 mm Hg predicts the risk of active bleeding. [1]
The most common complication of pediatric portal hypertension is acute variceal bleeding. The grading system of the Japanese Research Society for Portal Hypertension of esophageal varices is as follows: grade 1: flattened by insufflation, grade 2: not flattened by insufflation but is not circumferential, grade 3: not flattened and is circumferential. [2]
The three main venous embryo systems will be recognizable by the end of the 3rd week of gestation.
They include (1) the 2 cardinal veins which drain the embryo blood (intraembryonic system). To the sinus venosus (primitive atrium). The other two are extraembryonic systems, one of them transports the blood from the yolk sac to the heart (sinus venosus) which is called (2) the vitelline veins (two pairs). Finally, (3) the 2 umbilical veins transport the oxygenated blood from the placenta to the embryo’s heart. [3]
The hepatic bud starts branching off from the caudal end of the foregut, which expands into the transversum septum (Mesenchymal tissue in the pericardiac area). The cephalic part of the hepatic bud will eventually form the liver. And the caudal part will form the biliary tree and the gall bladder. During liver development, the primitive liver tissue in the transversum septum is in close contact with the two extraembryonic venous systems (Figure 1).
Schematic drawing represents the relation between the primitive hepatic bud and the major fetal venous systems. (Courtesy of Collardeau-Frachon and Scoazec et al. [4]. All the rights reserved).
The portal circulation of the liver develops between the 4th and 6th weeks, which is the result of a complex interaction between a primitive liver and a pair of vitelline veins and umbilical veins.
Initially, the vitelline veins form 4 sites of anastomoses between each other in their way to the sinus venosus, which are the caudal-ventral anastomosis, middle dorsal (they named according to their relation to the foregut), subhepatic, and finally the subdiaphragmatic anastomosis.
A net of smaller anastomoses between the right and the left vitelline veins extend in the area between the subdiaphragmatic and the subhepatic anastomoses in the same site where the hepatic bud will proliferate and develop to form the liver (the caudal part of the septum transversum). Synchronously, the umbilical veins in their way to the sinus venosus each vein are divided into 2 branches. One runs in parallel to the primitive liver and the other one ends in the liver parenchyma. The right umbilical vein and its branches atrophy in the 4th week. Also, the direct branch to the sinus venosus disappears in the same period. But the left branch of the umbilical vein to the liver parenchyma persists. It increases in size gradually inside liver parenchyma till communicates with the left end of the subhepatic anastomosis of the vitelline veins. That is known as a portal sinus. So, all the oxygenated blood is conveyed to the liver via the left umbilical vein. Due to massive blood influx to the liver, one of the anastomosing veins between the subhepatic and subdiaphragmatic anastomoses increases in size tremendously (Ductus venosus) to accommodate the oxygenated blood from the portal sinus to sinus venosus via a subdiaphragmatic anastomosis. [4]
The future portal vein is formed of the inferior section of the left vitelline vein, middle dorsal anastomosis, and the superior section of the right vitelline vein. By end of this process in the 6th week, the S-shape portal vein starts to appear. By this, the definitive fetal portal circulation is formed. [4]
The next major event happens at birth when the umbilical blood flow ceases. Subsequently, intravascular pressure in the umbilical vein and the ductus venosus drop and obliterating of these veins start within minutes after birth, which usually takes 15–20 days for complete closure. [3]
The portal vein is formed by the union of the superior mesenteric and the splenic veins behind the neck of the pancreas. It passes behind the first part of the duodenum, then it runs in the free edge of the lesser momentum posterior to the common bile duct (on the right side) and hepatic artery proper (on the left side) up to the porta hepatis where it divides into right and the left portal veins. Both main branches continue breaking down up to the sinusoids.
There is a specific pattern of the breakdown of the portal vein, the biliary duct, and hepatic arteries within the liver parenchyma, which does not correlate with the liver surface anatomy.
The Cantlie’s line extends from the inferior vena cava to the fundus of the gall bladder, which divides the liver into right and left lobes. Cantlie’s line represents the true surgical division of the liver into right and left lobes. [5]
The description of further portal triad breakdowns and its correlation with hepatic veins is delineated by a French surgeon and anatomist “Claude Couinaud”, depending on his framework that every half further divides into sectors, and a hepatic sector according to Couinaud system (Figure 2) is a region bounded by 2 hepatic veins or a hepatic vein and the hepatic edge. And the segment in the region of the liver that has an independent portal triad (separate branches from the portal vein, the hepatic artery, and the biliary duct) supplies it. These anatomical facts guide the hepatobiliary surgeons to execute the hepatectomy (right or left) and segmentectomy precisely. [7]
Drawing represents the Couinaud system and the relation of left portal vein to ligamentous teres in the umbilical fissure. (Courtesy of John E. Skandalakis et al. [6], All rights reserved).
The location of the Rex recess has an important surgical application in pediatric portal hypertension. That is where a branch from the left portal branch lies in the porto-umbilical fissure between the left lateral sector (segments II, III) and the left medial sector (segment IV). In intrauterine life, the left portal branch in the recess of Rex was communicating with the left umbilical vein. The fibrous remnant of the left umbilical postnatally known as ligamentous teres can be used as a reliable anatomical landmark for the recess of the Rex, which is surgically accessible and connecting it to the mesenteric vessel (superior mesenteric vein) via graft to bypass the portal occlusion and avoid the cavernoma, which is a net of collaterals formed after the portal obstruction in the area of porta hepatis. A portal vein occlusion is the commonest cause of portal hypertension in the pediatric age group.
Another important anatomical aspect of portal hypertension is the collateral anastomoses [8] between the portal and systemic circulations. Under normal circumstances, the mesenteric vein returns to the liver via the portal vein, then to the inferior vena cava (systemic circulation) via the hepatic veins to reach finally, the right atrium of the heart. This normal pathway would be interrupted in portal hypertension where the resistance to blood flow in the portal circulation is increased. This forces the blood to use the porto-systemic anastomoses as alternative pathways to reach the systemic circulation, which are negligible in normal situations. But in portal hypertension, these anastomoses increase in size with the increased potentiality of hemorrhage (ex: esophageal varices).
These anastomoses are as follows:
The esophageal branches of the left gastric vein (a tributary of the portal circulation) anastomose with esophageal branches of hemiazygos vein (systemic circulation).
The anastomosis between the superior rectal vein (portal circulation) with the middle and inferior rectal veins (systemic circulation) in the anal canal.
Paraumbilical anastomoses (caput medusa) are the communication between tributaries of portal vein which run in the falciform with the superficial veins of the anterior abdominal wall.
The communications between veins of ascending colon, descending colon, and duodenum (portal circulation) with the left renal vein (systemic circulation).
The veins of Retzius connect retroperitoneally between tributaries of inferior vena cava and tributaries of the superior and inferior mesenteric veins.
The accessory portal system of sappey is a set of diaphragmatic veins connecting the portal system to the systemic system.
The spectrum of causes is arranged in the pre-hepatic, the hepatic, and the post-hepatic lesions.
Pre-hepatic lesions: Extra-hepatic portal vein obstruction is the commonest cause of portal hypertension. The underlying cause of portal thrombosis is unidentifiable in most cases. [9] But it links to the predisposing factors. They are an injury to the portal vein in the cannulation of the umbilical vein, dehydration, abdominal sepsis, omphalitis, and hypercoagulable state. Another factor is the extra-mural compression like enlarged lymph node due to inflammation or malignancy. [10]
The portosystemic shunt is another cause of portal hypertension which can be surgical or iatrogenic cause or congenital shunts. Lautz et al. proposed a classification for congenital portosystemic shunts which divide them into 2 types. Type I with no intrahepatic portal venous flow. Type II with some intrahepatic portal venous flow. [11]
Hepatic lesions: Hepatic cellular injury of any cause (e.g. Biliary atresia, Schistosomiasis) stimulates collagen deposition via activated stellate cells, which leads to an increase resistance to venous outflow. [12]
Post-hepatic lesions: They include the hepatic veno-occlusive disease. [13] Busulfan containing regimes use for a bone marrow ablation in the bone marrow transplant considered are risk factors for hepatic veno-occlusive disease, because of hepatic and endothelial cellular injuries, which cause hepatic venules obstruction leading to venous congestion and eventually, to portal hypertension. Budd-Chiari syndrome is another cause of post-hepatic obstruction. Although it is uncommon in the pediatric age group, Budd-Chiari syndrome does occur in children. The level of obstruction can be at any level from the hepatic veins up to the level of the aortocaval junction. The most underlying cause of Budd-Chiari syndrome in children is the hypercoagulable state (Protein C, S deficiency, antithrombin III deficiency). [14]
How the pediatric patient with portal hypertension is presented depends on 2 essential factors: (1) the site of the obstruction (2) whether the patient has liver cirrhosis or not.
Upper GI bleeding: It is a frightening and common presenting symptom of portal hypertension in the pediatric age group. About 70% of the extra-hepatic portal hypertension cases present with upper GI bleeding, which is the common cause of pediatric portal hypertension presented. [10] But since the liver parenchyma and functions are preserved for decades in the extra-hepatic portal hypertension at the time of the presentation almost all the patients have a normal liver function. For this reason, most of these patients recovered without serious complications with a low mortality rate. This is true for all patients with compensated liver function presented with upper GI bleeding. Unfortunately, this is not the case for patients with decompensated liver disease (cirrhosis). Mathieu Duche et al. in their study reported that 1/5 of patients with cirrhosis developed life-threatening complications after upper GI bleeds. [15]
Portal hypertensive gastropathy: It is gastric lesions related to portal hypertensive disease. It ranges from erythema to diffuse gastritis. It is an occasional cause of upper GI bleeding. But it most commonly causes iron deficiency anemia due to chronic blood loss, which also may manifest as melena. [16]
Splenomegaly and hypersplenism: Splenomegaly alone could be the presenting symptom in the extra-hepatic portal hypertension, in this scenario usually there are no other hepatic signs and symptoms, which necessitates excluding hematologic causes. If the patient has cirrhosis, the signs, and symptoms of liver disease (e.g. spider naevi, jaundice, ascites) will be presented with splenomegaly. Splenomegaly imposes a significant risk in adolescent patients due to the type of sports and activities involved in this age group. It may lead to a spleen rupture and catastrophic bleeding. Splenectomy may be the only option in these patients, who do not complaint about avoiding contact sports. Also, these patients may develop hypersplenism (splenomegaly, with thrombocytopenia and leukopenia). [17] Although the hepatomegaly is not common in pediatric portal hypertension. But it could be associated with Budd-Chiari syndrome and congenital hepatic fibrosis. [14, 18]
Encephalopathy: It is a known complication of liver cirrhosis. But it can be associated with normal liver function in the extra-hepatic portal hypertension patients caused by port-systemic shunts, whether it is congenital or systemic shunts. It could be manifested as learning difficulties and behavior abnormalities. [19]
Pulmonary related disorders: Pulmonary hypertension is associated with portal hypertension with or without liver disease. [20] It is caused by increased vascular resistance due to pulmonary vasoconstriction as a result of shunting vasoactive substance to the systemic circulation whether is due to prehepatic shunting or inability of the liver to process the proteins (liver cirrhosis). And the hepatopulmonary syndrome is the contrast to pulmonary hypertension, which present with dyspnea and hypoxia resulting from pulmonary arteriovenous shunting and partial oxygenation of the blood due to massive capillary dilation as a response to vasodilators proteins bypassed to the systemic circulation. [21]
Patients with portal hypertension may present with signs of liver disease if the underlying cause of portal hypertension is the damage of liver parenchyma. For example, Ascites develops due to 2 important factors: (1) protein synthesis failure in the liver which impairs the intravascular oncotic pressure (2) dilated abdominal vascular capillaries and lymphatic microcirculation as a result of the increased portal hydrostatic pressure. [22] Jaundice is another sign of decompensated liver function. It happens due to the inability of the liver to process the bilirubin as one product of hemoglobin breakdown. [23]
Blood investigation:
Complete blood count (CBC): It is useful to identify the presence of and type of anemia. Also, it is essential in the management of acute variceal bleeding. The presence of thrombocytopenia and leukopenia in portal hypertension investigation usually indicate hypersplenism.
Liver function test: It assesses the functionality of the liver. That will help to point toward the underlying cause of portal hypertension with help of other investigation modalities (see later). Low protein level (albumin) and prolonged coagulation profile indicate the impaired synthetic ability of the liver. The increased bilirubin level and hepatic enzymes indicate hepatocellular damage.
Renal function test: It assesses dehydration especially in acute variceal bleeding, and impaired renal function test associated with liver diseases, like congenital hepatic fibrosis which linked to polycystic kidney disease.
Other investigations are requested according to the clinical status of the patients. Blood glucose will be low in decompensated liver cirrhosis and it is low in glycogen storage disease. Also, the ammonia level is indicated to confirm the diagnosis of encephalopathy. The coagulation screen in liver cirrhosis is prolonged. But in the extra-hepatic portal thrombosis, the coagulation profile shows secondary hypercoagulable abnormalities. [24] It will be reversed after the obstruction is overcomed.
Endoscopy: It is an essential tool in portal hypertension management. It confirms the presence of varices in the esophagus and the stomach and identifies the cause of the upper GI bleeding whether from varices or other origins like hemorrhagic gastritis or Mallory-Weiss syndrome. Also, in cases of acute upper GI bleeding are not responsive to medical management, endoscopy offers an important therapeutic option to control the variceal bleeding whether via variceal banding or sclerotherapy. [25]
Radiological modalities: The first radiological modality in use as part of the diagnosis armamentarium is an abdominal ultrasound with Doppler. It provides a lot of important and useful information, which include the size, echogenicity of the liver, and presence of the cysts or nodules. It also delineates the status of the intra and extra biliary tree, the patency of the portal vein, and the presence of the cavernoma in the porta hepatis. The size and echogenicity of the spleen are demonstrated in the abdominal ultrasound. And by assessing the vascularity of the abdomen it can provide valuable information for the surgical team such as the patency of the superior mesenteric, renal, and splenic veins. The neck Doppler ultrasound plays an important role in planning for surgical intervention, by confirming the patency of Jugular veins. This allows using one of them as an autologous graft provided both veins are patent. [26] Furthermore, the distance between the veins can assess the possibility of shunting between them like the distance between the renal and the spleen veins to assess the possibility of the splenorenal shunting. It may also pick up the portosystemic shunting. But the computed tomography angiography and magnetic resonance angiography are more accurate to pick up such anomalies. The later radiological modalities are usually the second step in the work up to delineate the anatomy more accurately. Invasive radiological investigations are required in specific cases. For example, the wedged hepatic venography is required in the congenital porto-systemic shunts [27] and to check the patency of the left portal vein tributary in the Rex recess to assess the possibility of Rex shunt.
The upper GI bleeding can be the first presenting symptom of pediatric portal hypertension, especially when the extra-hepatic portal vein thrombosis is the underlying cause of portal hypertension. The mortality risk from the first variceal bleeding is less than 1% in pediatric portal hypertension. [28] This is due to 2 facts. First, portal hypertension in children develops early in course of the pathology, which leads subsequently to early variceal formation in children who have well-compensated liver function. Thus, the ability of the children’s recover is better comparing with adults (adult mortality rate ranging from 7 to 15%). Secondly, improved medical management reduce the mortality rate in all age groups. [12]
The management of acute variceal bleeding should start with securing the airway. Insertion 2 large cannulas withdraw the blood simultaneously for urgent investigations, which should include complete blood count, blood crossmatch, urea and electrolytes, liver function test, and blood clotting profile. The other blood tests as the medical situation are mandatory. [12]
The volume replacement should start as soon as possible with crystalloids and packed red blood cells aiming to maintain the hemoglobin at or above 7 g/dL. [25] This strategy prevents tissue hypoxia which reduces lactic acid accumulation in the tissues and blood. Therefore, blood acidosis becomes less likely. Eventually, the impairment of clotting factors (proteins) function also becomes less likely. This strategy hinders the slipping towards deleterious complications of disseminated intravascular coagulopathy. The insertion of the nasogastric tube is also beneficial in observing the continuity of the bleeding and evacuating the blood of the stomach. Evacuation of the blood from the stomach has significant importance in cirrhotic patients to prevent encephalopathy. The octreotide is a synthetic analogue of somatostatin, which reduces the portal venous inflow by constriction of the splanchnic arterioles via a direct effect on the arteriole smooth muscles. It is started as a bolus dose (1 mcg/kg) followed by infusion (1 mcg/kg/H) usually for 4–5 days, which is often followed endoscopy after controlling the bleeding. [29] The only accepted situations to use endoscopic sclerotherapy in children should be acute bleeding not responding to the medical management with technical difficulty to apply band and infant’s cases where there is no banding device available for them. There is a randomized trial showing the administration of erythromycin intravenously by 30 minutes before the endoscopy improves visibility and reduces the time of the procedure. [30] In a situation where medical management (including the endoscopy) fails to stop the bleeding, urgent shunt surgery or trans-jugular intrahepatic portosystemic shunt (TIPS) should be performed. The optimal environment for the management of these patients is the intensive care unit, where all the vital signs are monitored closely.
The primary prophylaxis aims to prevent the first variceal bleeding. The efficiency of the primary prophylaxis is well established in adult by screening the portal hypertension patients and identify the high-risk elements for variceal bleeding like the large size of varices (Grade 2,3), presence of the red wale on varices’ surface, and the severity of the liver disease. [31] Using the endoscopic banding and/or non-selective beta-blockers which act by decreasing the portal pressure via un-opposed action of alfa-receptor on the splanchnic arterioles and decreasing the cardiac output. Sclerotherapy is not recommended for primary prophylaxis because of increased mortality in one randomized study which is forced the discontinuity of this study. [32] Regarding the children, there is no consensus about the primary prophylaxis in the pediatric age group because there is no substantial data to decide which patients need screening and what are the predictive factors for variceal presence. [28] Some studies indicate that the presence of varices in children should be related to low albumin levels, increased size of the spleen, and thrombocytopenia. But there is a need for larger, well designed randomized studies to standardize these predictive factors for children. Also, the necessity for general anesthesia for endoscopic sessions in children is another worrying point. The deleterious effect of general anesthesia on the neurodevelopment of children is well documented. [33] And the recurrence of esophageal varices after eradication is common if the underlying cause of portal hypertension is not treated. There is increased incidence of gastric varices and portal hypertensive gastropathy after eradication of esophageal varices. The same is true regarding the non-selective beta-blocker. There is no properly designed randomized study to assess the therapeutic doses and the safety of the drug in children [34]. Taking into account the mortality rate due to the first variceal bleeding is exceedingly low (1%). All these points together came against standardizing the primary prophylaxis in children. But in special circumstances, the primary prophylaxis in children is justifiable like the child living away from the medical facilities which may necessitate primary prophylaxis.
The secondary prophylaxis is the prevention of recurrence of variceal bleeding after the first variceal bleeding. Secondary prophylaxis is recommended in children due to the high recurrence rate after the first bleeding and enough data supporting the efficiency and safety of endoscopic banding and superior to endoscopic sclerotherapy therapy. As in the primary prophylaxis, no enough data support the safety and efficiency of non-selective beat-blockers. [28, 35]
TIPS refers to an establishment of intrahepatic portosystemic by inserting a stent (a communication) between the portal and hepatic veins. [36] It can be used in acute variceal bleeding uncontrolled by other means. Also, it is considered a good option for bridging to liver transplant for patients who have cirrhosis to improve the severe symptoms (e.g. Massive ascites). In this scenario, TIPS is considered an ideal option by avoiding abdominal operation with subsequent adhesions and fibrosis, which makes the liver transplant operation much easier. [26]
This technique is considered as a non-selective shunt where most of the portal blood diverted to the systemic circulation which participates in encephalopathy. Also, TIPS has potential complications, which are shunt stenosis/thrombosis, bleeding, and dislodge of the stent to the right atrium. [26, 34]
The type of surgery depends on the level of obstruction (pre-hepatic, hepatic. Post-hepatic).
Pre-hepatic portal vein thrombosis with suitable anatomy means a patent left portal vein in the umbilical fissure and the patent superior mesenteric vein. They connect via graft whether synthetic or autologous, but as a rule in pediatric surgery, the use of autologous graft is always preferred whenever it is possible due to the fact the graft grows with the child. The most used autologous graft is one of the internal jugular veins after making sure the contralateral one patent pre-operatively by doppler ultrasound. After the anastomosis has been established, the porto-systemic circulation is re-established. Another important point that the liver parenchyma in the extrahepatic portal thrombosis is preserved for a long time. Based on this fact the functionality of the liver is expected to recover after re-establishing the porto-systemic circulation. Fortunately, the data of the surgical outcome confirms this concept. The secondary coagulation abnormalities, hepatopulmonary syndrome, liver adenomas, encephalopathy, and neurocognitive all will be reverted after successful Rex shunt. [37] And for the congenital portosystemic shunt the surgical ligation of the shunt when it is technically feasible. [27]
When the cause of portal hypertension is liver cirrhosis in the modern era the suitable option is a liver transplant. [38]
There are other surgical options for portal hypertension which are considered palliative rather than therapeutic: (1) Selective shunt: the technique is known as distal splenorenal shunt (Warren shunt). The principle of this technique is diverting part of the portal circulation to the systemic circulation by dividing the splenic vein and anastomosing the distal end to the left renal vein. It helps to reduce gastroesophageal variceal pressure subsequently reducing the bleeding potentials. Also, hypersplenism and encephalopathy are improved. But the issue with this shunt is that with time the selective shunt becomes non-selective due to the formation of collaterals. [26]
(2) Non-selective shunt: its principle is based on diverting the whole portal circulation to systemic circulation by mobilization of the superior mesenteric vein and creation of side to side anastomosis with inferior vena cava or by used graft to connect the 2 veins whether synthetic or autologous grafts. This technique is not preferred in children because of the high-risk encephalopathy and deleterious effect on the cognitive ability of the children. [38]
IntechOpen aims to guarantee that original material is published while at the same time giving significant freedom to our Authors. We uphold a flexible Copyright Policy, guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
',metaTitle:"Publication Agreement - Monograph",metaDescription:"IntechOpen aims to guarantee that original material is published while at the same time giving significant freedom to our authors. For that matter, we uphold a flexible copyright policy meaning that there is no transfer of copyright to the publisher and authors retain exclusive copyright to their work.",metaKeywords:null,canonicalURL:"/page/publication-agreement-monograph",contentRaw:'[{"type":"htmlEditorComponent","content":"When submitting a manuscript, the Author is required to accept the Terms and Conditions set out in our Publication Agreement – Monographs/Compacts as follows:
\\n\\nCORRESPONDING AUTHOR'S GRANT OF RIGHTS
\\n\\nSubject to the following Article, the Author grants to IntechOpen, during the full term of copyright, and any extensions or renewals of that term, the following:
\\n\\nThe foregoing licenses shall survive the expiry or termination of this Publication Agreement for any reason.
\\n\\nThe Author, on his or her own behalf and on behalf of any of the Co-Authors, reserves the following rights in the Work but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Work as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\\n\\nThe Author, and any Co-Author, confirms that they are, and will remain, a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\\n\\nSubject to the license granted above, copyright in the Work and all versions of it created during IntechOpen's editing process, including all published versions, is retained by the Author and any Co-Authors.
\\n\\nSubject to the license granted above, the Author and Co-Authors retain patent, trademark and other intellectual property rights to the Work.
\\n\\nAll rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the specific approval of the Author or Co-Authors.
\\n\\nThe Author, on his/her own behalf and on behalf of the Co-Authors, will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Work as a consequence of IntechOpen's changes to the Work arising from the translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits as determined by IntechOpen.
\\n\\nAUTHOR'S DUTIES
\\n\\nWhen distributing or re-publishing the Work, the Author agrees to credit the Monograph/Compacts as the source of first publication, as well as IntechOpen. The Author guarantees that Co-Authors will also credit the Monograph/Compacts as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Work.
\\n\\nThe Author agrees to:
\\n\\nThe Author will be held responsible for the payment of the agreed Open Access Publishing Fee before the completion of the project (Monograph/Compacts publication).
\\n\\nAll payments shall be due 30 days from the date of issue of the invoice. The Author or whoever is paying on behalf of the Author and Co-Authors will bear all banking and similar charges incurred.
\\n\\nThe Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Work worldwide for the full term of the above licenses, and shall provide to IntechOpen, at its request, the original copies of such consents for inspection or the photocopies of such consents.
\\n\\nThe Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example from case reports or photographs.
\\n\\nThe Author shall respect confidentiality during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Author and Co-Authors are confidential and are intended only for the recipients. The contents of any communication may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\nAUTHOR'S WARRANTY
\\n\\nThe Author and Co-Authors confirm and warrant that the Work does not and will not breach any applicable law or the rights of any third party and, specifically, that the Work contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy.
\\n\\nThe Author and Co-Authors confirm that: (i) the Work is their original work and is not copied wholly or substantially from any other work or material or any other source; (ii) the Work has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) Authors and any applicable Co-Authors are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) Authors and any applicable Co-Authors have not assigned, and will not during the term of this Publication Agreement purport to assign, any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licences in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author confirms that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) the Author has the authority to enter into this biding Publication Agreement on behalf of each Co-Author. The Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each Co-Author.
\\n\\nThe Author agrees to indemnify IntechOpen harmless against all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
\\n\\nNothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\nTERMINATION
\\n\\nIntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Author and/or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Author and/or any Co-Author (being a private individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any Co-Author (as a corporate entity) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for, or enters into, any compromise or arrangement with any of its creditors.
\\n\\nIn the event of termination, IntechOpen will notify the Author of the decision in writing.
\\n\\nIntechOpen’s DUTIES AND RIGHTS
\\n\\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
\\n\\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen agrees to provide publishing services which include: managing editing (editorial and publishing process coordination, Author assistance); publishing software technology; language copyediting; typesetting; online publishing; hosting and web management; and abstracting and indexing services.
\\n\\nIntechOpen agrees to offer free online access to readers and use reasonable efforts to promote the Publication to relevant audiences.
\\n\\nIntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors against third parties, for example in cases of plagiarism or copyright infringements. In respect of any such infringement or suspected infringement of the copyright in the Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\nIntechOpen has the right to include/use the Author and Co-Authors names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Work and has the right to contact the Author and Co-Authors until the Work is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\nMISCELLANEOUS
\\n\\nFurther Assurance: The Author shall ensure that any relevant third party, including any Co-Author, shall execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\nThird Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\nEntire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by, or on behalf of, the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (known as the "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of any fraudulent pre-contract misrepresentation or concealment.
\\n\\nWaiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\nVariation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or their duly authorized representatives.
\\n\\nSeverance: If any provision, or part-provision, of this Publication Agreement is, or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted. Any modification to, or deletion of, a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\nNo partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Author or any Co-Author, nor authorize any party to make or enter into any commitments for, or on behalf of, any other party.
\\n\\nGoverning law: This Publication Agreement and any dispute or claim, including non-contractual disputes or claims arising out of, or in connection with it, or its subject matter or formation, shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of, or in connection with, this Publication Agreement, including any non-contractual disputes or claims.
\\n\\nPolicy last updated: 2018-09-11
\\n"}]'},components:[{type:"htmlEditorComponent",content:'When submitting a manuscript, the Author is required to accept the Terms and Conditions set out in our Publication Agreement – Monographs/Compacts as follows:
\n\nCORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\nSubject to the following Article, the Author grants to IntechOpen, during the full term of copyright, and any extensions or renewals of that term, the following:
\n\nThe foregoing licenses shall survive the expiry or termination of this Publication Agreement for any reason.
\n\nThe Author, on his or her own behalf and on behalf of any of the Co-Authors, reserves the following rights in the Work but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Work as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Author, and any Co-Author, confirms that they are, and will remain, a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Work and all versions of it created during IntechOpen's editing process, including all published versions, is retained by the Author and any Co-Authors.
\n\nSubject to the license granted above, the Author and Co-Authors retain patent, trademark and other intellectual property rights to the Work.
\n\nAll rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the specific approval of the Author or Co-Authors.
\n\nThe Author, on his/her own behalf and on behalf of the Co-Authors, will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Work as a consequence of IntechOpen's changes to the Work arising from the translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits as determined by IntechOpen.
\n\nAUTHOR'S DUTIES
\n\nWhen distributing or re-publishing the Work, the Author agrees to credit the Monograph/Compacts as the source of first publication, as well as IntechOpen. The Author guarantees that Co-Authors will also credit the Monograph/Compacts as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Work.
\n\nThe Author agrees to:
\n\nThe Author will be held responsible for the payment of the agreed Open Access Publishing Fee before the completion of the project (Monograph/Compacts publication).
\n\nAll payments shall be due 30 days from the date of issue of the invoice. The Author or whoever is paying on behalf of the Author and Co-Authors will bear all banking and similar charges incurred.
\n\nThe Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Work worldwide for the full term of the above licenses, and shall provide to IntechOpen, at its request, the original copies of such consents for inspection or the photocopies of such consents.
\n\nThe Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example from case reports or photographs.
\n\nThe Author shall respect confidentiality during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Author and Co-Authors are confidential and are intended only for the recipients. The contents of any communication may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\nAUTHOR'S WARRANTY
\n\nThe Author and Co-Authors confirm and warrant that the Work does not and will not breach any applicable law or the rights of any third party and, specifically, that the Work contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy.
\n\nThe Author and Co-Authors confirm that: (i) the Work is their original work and is not copied wholly or substantially from any other work or material or any other source; (ii) the Work has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) Authors and any applicable Co-Authors are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) Authors and any applicable Co-Authors have not assigned, and will not during the term of this Publication Agreement purport to assign, any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licences in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author confirms that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) the Author has the authority to enter into this biding Publication Agreement on behalf of each Co-Author. The Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each Co-Author.
\n\nThe Author agrees to indemnify IntechOpen harmless against all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
\n\nNothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\nTERMINATION
\n\nIntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Author and/or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Author and/or any Co-Author (being a private individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any Co-Author (as a corporate entity) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for, or enters into, any compromise or arrangement with any of its creditors.
\n\nIn the event of termination, IntechOpen will notify the Author of the decision in writing.
\n\nIntechOpen’s DUTIES AND RIGHTS
\n\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
\n\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen agrees to provide publishing services which include: managing editing (editorial and publishing process coordination, Author assistance); publishing software technology; language copyediting; typesetting; online publishing; hosting and web management; and abstracting and indexing services.
\n\nIntechOpen agrees to offer free online access to readers and use reasonable efforts to promote the Publication to relevant audiences.
\n\nIntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors against third parties, for example in cases of plagiarism or copyright infringements. In respect of any such infringement or suspected infringement of the copyright in the Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\nIntechOpen has the right to include/use the Author and Co-Authors names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Work and has the right to contact the Author and Co-Authors until the Work is publicly available on any platform owned and/or operated by IntechOpen.
\n\nMISCELLANEOUS
\n\nFurther Assurance: The Author shall ensure that any relevant third party, including any Co-Author, shall execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\nThird Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\nEntire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by, or on behalf of, the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (known as the "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of any fraudulent pre-contract misrepresentation or concealment.
\n\nWaiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\nVariation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or their duly authorized representatives.
\n\nSeverance: If any provision, or part-provision, of this Publication Agreement is, or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted. Any modification to, or deletion of, a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\nNo partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Author or any Co-Author, nor authorize any party to make or enter into any commitments for, or on behalf of, any other party.
\n\nGoverning law: This Publication Agreement and any dispute or claim, including non-contractual disputes or claims arising out of, or in connection with it, or its subject matter or formation, shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of, or in connection with, this Publication Agreement, including any non-contractual disputes or claims.
\n\nPolicy last updated: 2018-09-11
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5681},{group:"region",caption:"Middle and South America",value:2,count:5161},{group:"region",caption:"Africa",value:3,count:1683},{group:"region",caption:"Asia",value:4,count:10200},{group:"region",caption:"Australia and Oceania",value:5,count:886},{group:"region",caption:"Europe",value:6,count:15610}],offset:12,limit:12,total:117095},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{topicId:"7"},books:[{type:"book",id:"9553",title:"Cryptocurrency Economy",subtitle:null,isOpenForSubmission:!0,hash:"2548b2dab88b36797382292832f86563",slug:null,bookSignature:"Dr. Sebahattin Demirkan",coverURL:"https://cdn.intechopen.com/books/images_new/9553.jpg",editedByType:null,editors:[{id:"336397",title:"Dr.",name:"Sebahattin",surname:"Demirkan",slug:"sebahattin-demirkan",fullName:"Sebahattin Demirkan"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10551",title:"Beyond Human Resources - Research Paths Towards a New Understanding of Workforce Management Within Organizations",subtitle:null,isOpenForSubmission:!0,hash:"4a34551c1324fb084e902ad7f56e584d",slug:null,bookSignature:"Dr. Gonzalo Sánchez-Gardey, Dr. Fernando Martín-Alcázar and Dr. Natalia García-Carbonell",coverURL:"https://cdn.intechopen.com/books/images_new/10551.jpg",editedByType:null,editors:[{id:"332101",title:"Prof.",name:"Gonzalo",surname:"Sánchez",slug:"gonzalo-sanchez",fullName:"Gonzalo Sánchez"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10753",title:"Taxes",subtitle:null,isOpenForSubmission:!0,hash:"9dc0293dca676c8e873312737c84b60c",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10753.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10755",title:"Corporate Governance",subtitle:null,isOpenForSubmission:!0,hash:"33697a6f655fc4d7f4a21a0a083a9096",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10755.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10757",title:"Agricultural Value Chain",subtitle:null,isOpenForSubmission:!0,hash:"732ee82bf579a4bc4c5c929ceba2db26",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10757.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10915",title:"Leadership",subtitle:null,isOpenForSubmission:!0,hash:"f8f21ec8134eff175fa49450269811d8",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10915.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10916",title:"Firm Value",subtitle:null,isOpenForSubmission:!0,hash:"0de75a8efe6a5f4c8d42858ca3016f08",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10916.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10917",title:"Entrepreneurship",subtitle:null,isOpenForSubmission:!0,hash:"904717638ed1e5538792e4d431fe59a5",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10917.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10918",title:"Digital Economy",subtitle:null,isOpenForSubmission:!0,hash:"dbdfd9caf5c4b0038ff4446c7bc6a681",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10918.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10919",title:"Consumer Behavior",subtitle:null,isOpenForSubmission:!0,hash:"51700695578f48743b0514ba6d8735b2",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10919.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:9},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:17},{group:"topic",caption:"Business, Management and Economics",value:7,count:2},{group:"topic",caption:"Chemistry",value:8,count:7},{group:"topic",caption:"Computer and Information Science",value:9,count:10},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:5},{group:"topic",caption:"Engineering",value:11,count:14},{group:"topic",caption:"Environmental Sciences",value:12,count:2},{group:"topic",caption:"Immunology and Microbiology",value:13,count:5},{group:"topic",caption:"Materials Science",value:14,count:4},{group:"topic",caption:"Mathematics",value:15,count:1},{group:"topic",caption:"Medicine",value:16,count:60},{group:"topic",caption:"Nanotechnology and Nanomaterials",value:17,count:1},{group:"topic",caption:"Neuroscience",value:18,count:1},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:6},{group:"topic",caption:"Physics",value:20,count:2},{group:"topic",caption:"Psychology",value:21,count:3},{group:"topic",caption:"Robotics",value:22,count:1},{group:"topic",caption:"Social Sciences",value:23,count:3},{group:"topic",caption:"Technology",value:24,count:1},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:2}],offset:12,limit:12,total:10},popularBooks:{featuredBooks:[{type:"book",id:"9208",title:"Welding",subtitle:"Modern Topics",isOpenForSubmission:!1,hash:"7d6be076ccf3a3f8bd2ca52d86d4506b",slug:"welding-modern-topics",bookSignature:"Sadek Crisóstomo Absi Alfaro, Wojciech Borek and Błażej Tomiczek",coverURL:"https://cdn.intechopen.com/books/images_new/9208.jpg",editors:[{id:"65292",title:"Prof.",name:"Sadek Crisostomo Absi",middleName:"C. Absi",surname:"Alfaro",slug:"sadek-crisostomo-absi-alfaro",fullName:"Sadek Crisostomo Absi Alfaro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9139",title:"Topics in Primary Care Medicine",subtitle:null,isOpenForSubmission:!1,hash:"ea774a4d4c1179da92a782e0ae9cde92",slug:"topics-in-primary-care-medicine",bookSignature:"Thomas F. Heston",coverURL:"https://cdn.intechopen.com/books/images_new/9139.jpg",editors:[{id:"217926",title:"Dr.",name:"Thomas F.",middleName:null,surname:"Heston",slug:"thomas-f.-heston",fullName:"Thomas F. Heston"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8697",title:"Virtual Reality and Its Application in Education",subtitle:null,isOpenForSubmission:!1,hash:"ee01b5e387ba0062c6b0d1e9227bda05",slug:"virtual-reality-and-its-application-in-education",bookSignature:"Dragan Cvetković",coverURL:"https://cdn.intechopen.com/books/images_new/8697.jpg",editors:[{id:"101330",title:"Dr.",name:"Dragan",middleName:"Mladen",surname:"Cvetković",slug:"dragan-cvetkovic",fullName:"Dragan Cvetković"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9785",title:"Endometriosis",subtitle:null,isOpenForSubmission:!1,hash:"f457ca61f29cf7e8bc191732c50bb0ce",slug:"endometriosis",bookSignature:"Courtney Marsh",coverURL:"https://cdn.intechopen.com/books/images_new/9785.jpg",editors:[{id:"255491",title:"Dr.",name:"Courtney",middleName:null,surname:"Marsh",slug:"courtney-marsh",fullName:"Courtney Marsh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9343",title:"Trace Metals in the Environment",subtitle:"New Approaches and Recent Advances",isOpenForSubmission:!1,hash:"ae07e345bc2ce1ebbda9f70c5cd12141",slug:"trace-metals-in-the-environment-new-approaches-and-recent-advances",bookSignature:"Mario Alfonso Murillo-Tovar, Hugo Saldarriaga-Noreña and Agnieszka Saeid",coverURL:"https://cdn.intechopen.com/books/images_new/9343.jpg",editors:[{id:"255959",title:"Dr.",name:"Mario Alfonso",middleName:null,surname:"Murillo-Tovar",slug:"mario-alfonso-murillo-tovar",fullName:"Mario Alfonso Murillo-Tovar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7831",title:"Sustainability in Urban Planning and Design",subtitle:null,isOpenForSubmission:!1,hash:"c924420492c8c2c9751e178d025f4066",slug:"sustainability-in-urban-planning-and-design",bookSignature:"Amjad Almusaed, Asaad Almssad and Linh Truong - Hong",coverURL:"https://cdn.intechopen.com/books/images_new/7831.jpg",editors:[{id:"110471",title:"Dr.",name:"Amjad",middleName:"Zaki",surname:"Almusaed",slug:"amjad-almusaed",fullName:"Amjad Almusaed"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8468",title:"Sheep Farming",subtitle:"An Approach to Feed, Growth and Sanity",isOpenForSubmission:!1,hash:"838f08594850bc04aa14ec873ed1b96f",slug:"sheep-farming-an-approach-to-feed-growth-and-sanity",bookSignature:"António Monteiro",coverURL:"https://cdn.intechopen.com/books/images_new/8468.jpg",editors:[{id:"190314",title:"Prof.",name:"António",middleName:"Cardoso",surname:"Monteiro",slug:"antonio-monteiro",fullName:"António Monteiro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8816",title:"Financial Crises",subtitle:"A Selection of Readings",isOpenForSubmission:!1,hash:"6f2f49fb903656e4e54280c79fabd10c",slug:"financial-crises-a-selection-of-readings",bookSignature:"Stelios Markoulis",coverURL:"https://cdn.intechopen.com/books/images_new/8816.jpg",editors:[{id:"237863",title:"Dr.",name:"Stelios",middleName:null,surname:"Markoulis",slug:"stelios-markoulis",fullName:"Stelios Markoulis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9376",title:"Contemporary Developments and Perspectives in International Health Security",subtitle:"Volume 1",isOpenForSubmission:!1,hash:"b9a00b84cd04aae458fb1d6c65795601",slug:"contemporary-developments-and-perspectives-in-international-health-security-volume-1",bookSignature:"Stanislaw P. Stawicki, Michael S. Firstenberg, Sagar C. Galwankar, Ricardo Izurieta and Thomas Papadimos",coverURL:"https://cdn.intechopen.com/books/images_new/9376.jpg",editors:[{id:"181694",title:"Dr.",name:"Stanislaw P.",middleName:null,surname:"Stawicki",slug:"stanislaw-p.-stawicki",fullName:"Stanislaw P. Stawicki"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7769",title:"Medical Isotopes",subtitle:null,isOpenForSubmission:!1,hash:"f8d3c5a6c9a42398e56b4e82264753f7",slug:"medical-isotopes",bookSignature:"Syed Ali Raza Naqvi and Muhammad Babar Imrani",coverURL:"https://cdn.intechopen.com/books/images_new/7769.jpg",editors:[{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9279",title:"Concepts, Applications and Emerging Opportunities in Industrial Engineering",subtitle:null,isOpenForSubmission:!1,hash:"9bfa87f9b627a5468b7c1e30b0eea07a",slug:"concepts-applications-and-emerging-opportunities-in-industrial-engineering",bookSignature:"Gary Moynihan",coverURL:"https://cdn.intechopen.com/books/images_new/9279.jpg",editors:[{id:"16974",title:"Dr.",name:"Gary",middleName:null,surname:"Moynihan",slug:"gary-moynihan",fullName:"Gary Moynihan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7807",title:"A Closer Look at Organizational Culture in Action",subtitle:null,isOpenForSubmission:!1,hash:"05c608b9271cc2bc711f4b28748b247b",slug:"a-closer-look-at-organizational-culture-in-action",bookSignature:"Süleyman Davut Göker",coverURL:"https://cdn.intechopen.com/books/images_new/7807.jpg",editors:[{id:"190035",title:"Associate Prof.",name:"Süleyman Davut",middleName:null,surname:"Göker",slug:"suleyman-davut-goker",fullName:"Süleyman Davut Göker"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5126},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"9208",title:"Welding",subtitle:"Modern Topics",isOpenForSubmission:!1,hash:"7d6be076ccf3a3f8bd2ca52d86d4506b",slug:"welding-modern-topics",bookSignature:"Sadek Crisóstomo Absi Alfaro, Wojciech Borek and Błażej Tomiczek",coverURL:"https://cdn.intechopen.com/books/images_new/9208.jpg",editors:[{id:"65292",title:"Prof.",name:"Sadek Crisostomo Absi",middleName:"C. Absi",surname:"Alfaro",slug:"sadek-crisostomo-absi-alfaro",fullName:"Sadek Crisostomo Absi Alfaro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9139",title:"Topics in Primary Care Medicine",subtitle:null,isOpenForSubmission:!1,hash:"ea774a4d4c1179da92a782e0ae9cde92",slug:"topics-in-primary-care-medicine",bookSignature:"Thomas F. Heston",coverURL:"https://cdn.intechopen.com/books/images_new/9139.jpg",editors:[{id:"217926",title:"Dr.",name:"Thomas F.",middleName:null,surname:"Heston",slug:"thomas-f.-heston",fullName:"Thomas F. Heston"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8697",title:"Virtual Reality and Its Application in Education",subtitle:null,isOpenForSubmission:!1,hash:"ee01b5e387ba0062c6b0d1e9227bda05",slug:"virtual-reality-and-its-application-in-education",bookSignature:"Dragan Cvetković",coverURL:"https://cdn.intechopen.com/books/images_new/8697.jpg",editors:[{id:"101330",title:"Dr.",name:"Dragan",middleName:"Mladen",surname:"Cvetković",slug:"dragan-cvetkovic",fullName:"Dragan Cvetković"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9785",title:"Endometriosis",subtitle:null,isOpenForSubmission:!1,hash:"f457ca61f29cf7e8bc191732c50bb0ce",slug:"endometriosis",bookSignature:"Courtney Marsh",coverURL:"https://cdn.intechopen.com/books/images_new/9785.jpg",editors:[{id:"255491",title:"Dr.",name:"Courtney",middleName:null,surname:"Marsh",slug:"courtney-marsh",fullName:"Courtney Marsh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9343",title:"Trace Metals in the Environment",subtitle:"New Approaches and Recent Advances",isOpenForSubmission:!1,hash:"ae07e345bc2ce1ebbda9f70c5cd12141",slug:"trace-metals-in-the-environment-new-approaches-and-recent-advances",bookSignature:"Mario Alfonso Murillo-Tovar, Hugo Saldarriaga-Noreña and Agnieszka Saeid",coverURL:"https://cdn.intechopen.com/books/images_new/9343.jpg",editors:[{id:"255959",title:"Dr.",name:"Mario Alfonso",middleName:null,surname:"Murillo-Tovar",slug:"mario-alfonso-murillo-tovar",fullName:"Mario Alfonso Murillo-Tovar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8468",title:"Sheep Farming",subtitle:"An Approach to Feed, Growth and Sanity",isOpenForSubmission:!1,hash:"838f08594850bc04aa14ec873ed1b96f",slug:"sheep-farming-an-approach-to-feed-growth-and-sanity",bookSignature:"António Monteiro",coverURL:"https://cdn.intechopen.com/books/images_new/8468.jpg",editors:[{id:"190314",title:"Prof.",name:"António",middleName:"Cardoso",surname:"Monteiro",slug:"antonio-monteiro",fullName:"António Monteiro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8816",title:"Financial Crises",subtitle:"A Selection of Readings",isOpenForSubmission:!1,hash:"6f2f49fb903656e4e54280c79fabd10c",slug:"financial-crises-a-selection-of-readings",bookSignature:"Stelios Markoulis",coverURL:"https://cdn.intechopen.com/books/images_new/8816.jpg",editors:[{id:"237863",title:"Dr.",name:"Stelios",middleName:null,surname:"Markoulis",slug:"stelios-markoulis",fullName:"Stelios Markoulis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7831",title:"Sustainability in Urban Planning and Design",subtitle:null,isOpenForSubmission:!1,hash:"c924420492c8c2c9751e178d025f4066",slug:"sustainability-in-urban-planning-and-design",bookSignature:"Amjad Almusaed, Asaad Almssad and Linh Truong - Hong",coverURL:"https://cdn.intechopen.com/books/images_new/7831.jpg",editors:[{id:"110471",title:"Dr.",name:"Amjad",middleName:"Zaki",surname:"Almusaed",slug:"amjad-almusaed",fullName:"Amjad Almusaed"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9376",title:"Contemporary Developments and Perspectives in International Health Security",subtitle:"Volume 1",isOpenForSubmission:!1,hash:"b9a00b84cd04aae458fb1d6c65795601",slug:"contemporary-developments-and-perspectives-in-international-health-security-volume-1",bookSignature:"Stanislaw P. Stawicki, Michael S. Firstenberg, Sagar C. Galwankar, Ricardo Izurieta and Thomas Papadimos",coverURL:"https://cdn.intechopen.com/books/images_new/9376.jpg",editors:[{id:"181694",title:"Dr.",name:"Stanislaw P.",middleName:null,surname:"Stawicki",slug:"stanislaw-p.-stawicki",fullName:"Stanislaw P. Stawicki"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7769",title:"Medical Isotopes",subtitle:null,isOpenForSubmission:!1,hash:"f8d3c5a6c9a42398e56b4e82264753f7",slug:"medical-isotopes",bookSignature:"Syed Ali Raza Naqvi and Muhammad Babar Imrani",coverURL:"https://cdn.intechopen.com/books/images_new/7769.jpg",editors:[{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"8468",title:"Sheep Farming",subtitle:"An Approach to Feed, Growth and Sanity",isOpenForSubmission:!1,hash:"838f08594850bc04aa14ec873ed1b96f",slug:"sheep-farming-an-approach-to-feed-growth-and-sanity",bookSignature:"António Monteiro",coverURL:"https://cdn.intechopen.com/books/images_new/8468.jpg",editedByType:"Edited by",editors:[{id:"190314",title:"Prof.",name:"António",middleName:"Cardoso",surname:"Monteiro",slug:"antonio-monteiro",fullName:"António Monteiro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9523",title:"Oral and Maxillofacial Surgery",subtitle:null,isOpenForSubmission:!1,hash:"5eb6ec2db961a6c8965d11180a58d5c1",slug:"oral-and-maxillofacial-surgery",bookSignature:"Gokul Sridharan",coverURL:"https://cdn.intechopen.com/books/images_new/9523.jpg",editedByType:"Edited by",editors:[{id:"82453",title:"Dr.",name:"Gokul",middleName:null,surname:"Sridharan",slug:"gokul-sridharan",fullName:"Gokul Sridharan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9785",title:"Endometriosis",subtitle:null,isOpenForSubmission:!1,hash:"f457ca61f29cf7e8bc191732c50bb0ce",slug:"endometriosis",bookSignature:"Courtney Marsh",coverURL:"https://cdn.intechopen.com/books/images_new/9785.jpg",editedByType:"Edited by",editors:[{id:"255491",title:"Dr.",name:"Courtney",middleName:null,surname:"Marsh",slug:"courtney-marsh",fullName:"Courtney Marsh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9018",title:"Some RNA Viruses",subtitle:null,isOpenForSubmission:!1,hash:"a5cae846dbe3692495fc4add2f60fd84",slug:"some-rna-viruses",bookSignature:"Yogendra Shah and Eltayb Abuelzein",coverURL:"https://cdn.intechopen.com/books/images_new/9018.jpg",editedByType:"Edited by",editors:[{id:"278914",title:"Ph.D.",name:"Yogendra",middleName:null,surname:"Shah",slug:"yogendra-shah",fullName:"Yogendra Shah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8816",title:"Financial Crises",subtitle:"A Selection of Readings",isOpenForSubmission:!1,hash:"6f2f49fb903656e4e54280c79fabd10c",slug:"financial-crises-a-selection-of-readings",bookSignature:"Stelios Markoulis",coverURL:"https://cdn.intechopen.com/books/images_new/8816.jpg",editedByType:"Edited by",editors:[{id:"237863",title:"Dr.",name:"Stelios",middleName:null,surname:"Markoulis",slug:"stelios-markoulis",fullName:"Stelios Markoulis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9585",title:"Advances in Complex Valvular Disease",subtitle:null,isOpenForSubmission:!1,hash:"ef64f11e211621ecfe69c46e60e7ca3d",slug:"advances-in-complex-valvular-disease",bookSignature:"Michael S. Firstenberg and Imran Khan",coverURL:"https://cdn.intechopen.com/books/images_new/9585.jpg",editedByType:"Edited by",editors:[{id:"64343",title:null,name:"Michael S.",middleName:"S",surname:"Firstenberg",slug:"michael-s.-firstenberg",fullName:"Michael S. Firstenberg"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10150",title:"Smart Manufacturing",subtitle:"When Artificial Intelligence Meets the Internet of Things",isOpenForSubmission:!1,hash:"87004a19de13702d042f8ff96d454698",slug:"smart-manufacturing-when-artificial-intelligence-meets-the-internet-of-things",bookSignature:"Tan Yen Kheng",coverURL:"https://cdn.intechopen.com/books/images_new/10150.jpg",editedByType:"Edited by",editors:[{id:"78857",title:"Dr.",name:"Tan Yen",middleName:null,surname:"Kheng",slug:"tan-yen-kheng",fullName:"Tan Yen Kheng"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9386",title:"Direct Numerical Simulations",subtitle:"An Introduction and Applications",isOpenForSubmission:!1,hash:"158a3a0fdba295d21ff23326f5a072d5",slug:"direct-numerical-simulations-an-introduction-and-applications",bookSignature:"Srinivasa Rao",coverURL:"https://cdn.intechopen.com/books/images_new/9386.jpg",editedByType:"Edited by",editors:[{id:"6897",title:"Dr.",name:"Srinivasa",middleName:"P",surname:"Rao",slug:"srinivasa-rao",fullName:"Srinivasa Rao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9139",title:"Topics in Primary Care Medicine",subtitle:null,isOpenForSubmission:!1,hash:"ea774a4d4c1179da92a782e0ae9cde92",slug:"topics-in-primary-care-medicine",bookSignature:"Thomas F. Heston",coverURL:"https://cdn.intechopen.com/books/images_new/9139.jpg",editedByType:"Edited by",editors:[{id:"217926",title:"Dr.",name:"Thomas F.",middleName:null,surname:"Heston",slug:"thomas-f.-heston",fullName:"Thomas F. Heston"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9208",title:"Welding",subtitle:"Modern Topics",isOpenForSubmission:!1,hash:"7d6be076ccf3a3f8bd2ca52d86d4506b",slug:"welding-modern-topics",bookSignature:"Sadek Crisóstomo Absi Alfaro, Wojciech Borek and Błażej Tomiczek",coverURL:"https://cdn.intechopen.com/books/images_new/9208.jpg",editedByType:"Edited by",editors:[{id:"65292",title:"Prof.",name:"Sadek Crisostomo Absi",middleName:"C. Absi",surname:"Alfaro",slug:"sadek-crisostomo-absi-alfaro",fullName:"Sadek Crisostomo Absi Alfaro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"22",title:"Robotics",slug:"physical-sciences-engineering-and-technology-robotics",parent:{title:"Physical Sciences, Engineering and Technology",slug:"physical-sciences-engineering-and-technology"},numberOfBooks:99,numberOfAuthorsAndEditors:1355,numberOfWosCitations:3495,numberOfCrossrefCitations:3030,numberOfDimensionsCitations:5998,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"physical-sciences-engineering-and-technology-robotics",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"9902",title:"Service Robotics",subtitle:null,isOpenForSubmission:!1,hash:"9b42f533ea14906bcd1e07df74b33ac2",slug:"service-robotics",bookSignature:"Volkan Sezer, Sinan Öncü and Pınar Boyraz Baykas",coverURL:"https://cdn.intechopen.com/books/images_new/9902.jpg",editedByType:"Edited by",editors:[{id:"268170",title:"Dr.",name:"Volkan",middleName:null,surname:"Sezer",slug:"volkan-sezer",fullName:"Volkan Sezer"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6864",title:"Autonomous Vehicles",subtitle:null,isOpenForSubmission:!1,hash:"c320902fc1cfc252c1db006b944996fb",slug:"autonomous-vehicles",bookSignature:"George Dekoulis",coverURL:"https://cdn.intechopen.com/books/images_new/6864.jpg",editedByType:"Edited by",editors:[{id:"9833",title:"Prof.",name:"George",middleName:null,surname:"Dekoulis",slug:"george-dekoulis",fullName:"George Dekoulis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8883",title:"Autonomous Vehicle and Smart Traffic",subtitle:null,isOpenForSubmission:!1,hash:"841c82c0bf27716a7c800bc1180ad5de",slug:"autonomous-vehicle-and-smart-traffic",bookSignature:"Sezgin Ersoy and Tayyab Waqar",coverURL:"https://cdn.intechopen.com/books/images_new/8883.jpg",editedByType:"Edited by",editors:[{id:"156004",title:"Associate Prof.",name:"Sezgin",middleName:null,surname:"Ersoy",slug:"sezgin-ersoy",fullName:"Sezgin Ersoy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8872",title:"Multi Agent Systems",subtitle:"Strategies and Applications",isOpenForSubmission:!1,hash:"6b0454f8f575d5d65603f329af59c80b",slug:"multi-agent-systems-strategies-and-applications",bookSignature:"Ricardo López - Ruiz",coverURL:"https://cdn.intechopen.com/books/images_new/8872.jpg",editedByType:"Edited by",editors:[{id:"9849",title:"Prof.",name:"Ricardo",middleName:null,surname:"Lopez-Ruiz",slug:"ricardo-lopez-ruiz",fullName:"Ricardo Lopez-Ruiz"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7792",title:"Unmanned Robotic Systems and Applications",subtitle:null,isOpenForSubmission:!1,hash:"53805f091c3107536edd2579c9987649",slug:"unmanned-robotic-systems-and-applications",bookSignature:"Mahmut Reyhanoglu and Geert De Cubber",coverURL:"https://cdn.intechopen.com/books/images_new/7792.jpg",editedByType:"Edited by",editors:[{id:"15068",title:"Dr.",name:"Mahmut",middleName:null,surname:"Reyhanoglu",slug:"mahmut-reyhanoglu",fullName:"Mahmut Reyhanoglu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6865",title:"Becoming Human with Humanoid",subtitle:"From Physical Interaction to Social Intelligence",isOpenForSubmission:!1,hash:"e208316a62e4ab5b042486aea682ee18",slug:"becoming-human-with-humanoid-from-physical-interaction-to-social-intelligence",bookSignature:"Ahmad Hoirul Basori, Ali Leylavi Shoushtari and Andon Venelinov Topalov",coverURL:"https://cdn.intechopen.com/books/images_new/6865.jpg",editedByType:"Edited by",editors:[{id:"13394",title:"Prof.",name:"Ahmad Hoirul",middleName:null,surname:"Basori",slug:"ahmad-hoirul-basori",fullName:"Ahmad Hoirul Basori"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7779",title:"Path Planning for Autonomous Vehicle",subtitle:"Ensuring Reliable Driverless Navigation and Control Maneuver",isOpenForSubmission:!1,hash:"91196f0aadb70bd5cecac290401d614f",slug:"path-planning-for-autonomous-vehicles-ensuring-reliable-driverless-navigation-and-control-maneuver",bookSignature:"Umar Zakir Abdul Hamid, Volkan Sezer, Bin Li, Yanjun Huang and Muhammad Aizzat Zakaria",coverURL:"https://cdn.intechopen.com/books/images_new/7779.jpg",editedByType:"Edited by",editors:[{id:"268173",title:"Dr.",name:"Umar Zakir Abdul",middleName:null,surname:"Hamid",slug:"umar-zakir-abdul-hamid",fullName:"Umar Zakir Abdul Hamid"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7386",title:"Advances in Human and Machine Navigation Systems",subtitle:null,isOpenForSubmission:!1,hash:"a60a4da048a8bee2e12c3fe40236afe9",slug:"advances-in-human-and-machine-navigation-systems",bookSignature:"Rastislav Róka",coverURL:"https://cdn.intechopen.com/books/images_new/7386.jpg",editedByType:"Edited by",editors:[{id:"112777",title:"Dr.",name:"Rastislav",middleName:null,surname:"Róka",slug:"rastislav-roka",fullName:"Rastislav Róka"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7227",title:"Applications of Mobile Robots",subtitle:null,isOpenForSubmission:!1,hash:"b4993517c29aed9abd474e362370e28a",slug:"applications-of-mobile-robots",bookSignature:"Efren Gorrostieta Hurtado",coverURL:"https://cdn.intechopen.com/books/images_new/7227.jpg",editedByType:"Edited by",editors:[{id:"38850",title:"Dr.",name:"Efren",middleName:null,surname:"Gorrostieta Hurtado",slug:"efren-gorrostieta-hurtado",fullName:"Efren Gorrostieta Hurtado"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7400",title:"Multi-Agent Systems",subtitle:"Control Spectrum",isOpenForSubmission:!1,hash:"ba8de13ac5162187fbc7f932a7fb0b34",slug:"multi-agent-systems-control-spectrum",bookSignature:"Vladimir Shikhin",coverURL:"https://cdn.intechopen.com/books/images_new/7400.jpg",editedByType:"Edited by",editors:[{id:"237011",title:"Dr.",name:"Vladimir",middleName:null,surname:"Shikhin",slug:"vladimir-shikhin",fullName:"Vladimir Shikhin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7270",title:"Agricultural Robots",subtitle:"Fundamentals and Applications",isOpenForSubmission:!1,hash:"404b9128ab371832f2b7f0b6f32b2951",slug:"agricultural-robots-fundamentals-and-applications",bookSignature:"Jun Zhou and Baohua Zhang",coverURL:"https://cdn.intechopen.com/books/images_new/7270.jpg",editedByType:"Edited by",editors:[{id:"242047",title:"Dr.",name:"Jun",middleName:null,surname:"Zhou",slug:"jun-zhou",fullName:"Jun Zhou"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6322",title:"Advanced Path Planning for Mobile Entities",subtitle:null,isOpenForSubmission:!1,hash:"438f519ccb7ac4196660ada6b648e15f",slug:"advanced-path-planning-for-mobile-entities",bookSignature:"Rastislav Róka",coverURL:"https://cdn.intechopen.com/books/images_new/6322.jpg",editedByType:"Edited by",editors:[{id:"112777",title:"Dr.",name:"Rastislav",middleName:null,surname:"Róka",slug:"rastislav-roka",fullName:"Rastislav Róka"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:99,mostCitedChapters:[{id:"10088",doi:"10.5772/8835",title:"Intention-Based Walking Support for Paraplegia Patients with Robot Suit HAL",slug:"intention-based-walking-support-for-paraplegia-patients-with-robot-suit-hal",totalDownloads:4593,totalCrossrefCites:15,totalDimensionsCites:166,book:{slug:"climbing-and-walking-robots",title:"Climbing and Walking Robots",fullTitle:"Climbing and Walking Robots"},signatures:"Kenta Suzuki, Gouji Mito, Hiroaki Kawamoto, Yasuhisa Hasegawa and Yoshiyuki Sankai",authors:null},{id:"240",doi:"10.5772/4876",title:"Geminoid: Teleoperated Android of an Existing Person",slug:"geminoid__teleoperated_android_of_an_existing_person",totalDownloads:3800,totalCrossrefCites:61,totalDimensionsCites:108,book:{slug:"humanoid_robots_new_developments",title:"Humanoid Robots",fullTitle:"Humanoid Robots: New Developments"},signatures:"Shuichi Nishio, Hiroshi Ishiguro and Norihiro Hagita",authors:[{id:"11981",title:"Prof.",name:"Hiroshi",middleName:null,surname:"Ishiguro",slug:"hiroshi-ishiguro",fullName:"Hiroshi Ishiguro"}]},{id:"172",doi:"10.5772/4808",title:"Limit Cycle Walking",slug:"limit_cycle_walking",totalDownloads:4521,totalCrossrefCites:9,totalDimensionsCites:91,book:{slug:"humanoid_robots_human_like_machines",title:"Humanoid Robots",fullTitle:"Humanoid Robots, Human-like Machines"},signatures:"Daan G.E. Hobbelen and Martijn Wisse",authors:null}],mostDownloadedChaptersLast30Days:[{id:"62563",title:"Online Mapping-Based Navigation System for Wheeled Mobile Robot in Road Following and Roundabout",slug:"online-mapping-based-navigation-system-for-wheeled-mobile-robot-in-road-following-and-roundabout",totalDownloads:759,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"applications-of-mobile-robots",title:"Applications of Mobile Robots",fullTitle:"Applications of Mobile Robots"},signatures:"Mohammed A. H. Ali and Musa Mailah",authors:[{id:"32016",title:"Prof.",name:"Musa",middleName:null,surname:"Mailah",slug:"musa-mailah",fullName:"Musa Mailah"},{id:"243606",title:"Dr.",name:"Mohammed A. H",middleName:null,surname:"Ali",slug:"mohammed-a.-h-ali",fullName:"Mohammed A. H Ali"}]},{id:"39430",title:"Novel Yinger Learning Variable Universe Fuzzy Controller",slug:"novel-yinger-learning-variable-universe-fuzzy-controller",totalDownloads:1662,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"fuzzy-controllers-recent-advances-in-theory-and-applications",title:"Fuzzy Controllers",fullTitle:"Fuzzy Controllers - Recent Advances in Theory and Applications"},signatures:"Ping Zhang and Guodong Gao",authors:[{id:"141337",title:"Dr.",name:"Ping",middleName:null,surname:"Zhang",slug:"ping-zhang",fullName:"Ping Zhang"},{id:"160791",title:"Dr.",name:"GuoDong",middleName:null,surname:"Gao",slug:"guodong-gao",fullName:"GuoDong Gao"}]},{id:"465",title:"Omnidirectional Mobile Robot - Design and Implementation",slug:"omnidirectional_mobile_robot_-__design_and_implementation",totalDownloads:40971,totalCrossrefCites:31,totalDimensionsCites:40,book:{slug:"bioinspiration_and_robotics_walking_and_climbing_robots",title:"Bioinspiration and Robotics",fullTitle:"Bioinspiration and Robotics Walking and Climbing Robots"},signatures:"Ioan Doroftei, Victor Grosu and Veaceslav Spinu",authors:null},{id:"70496",title:"Sky-Farmers: Applications of Unmanned Aerial Vehicles (UAV) in Agriculture",slug:"sky-farmers-applications-of-unmanned-aerial-vehicles-uav-in-agriculture",totalDownloads:710,totalCrossrefCites:2,totalDimensionsCites:3,book:{slug:"autonomous-vehicles",title:"Autonomous Vehicles",fullTitle:"Autonomous Vehicles"},signatures:"Chika Yinka-Banjo and Olasupo Ajayi",authors:null},{id:"73486",title:"Application of Artificial Intelligence (AI) in Prosthetic and Orthotic Rehabilitation",slug:"application-of-artificial-intelligence-ai-in-prosthetic-and-orthotic-rehabilitation",totalDownloads:292,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"service-robotics",title:"Service Robotics",fullTitle:"Service Robotics"},signatures:"Smita Nayak and Rajesh Kumar Das",authors:[{id:"204704",title:"Mrs.",name:"Smita",middleName:null,surname:"Nayak",slug:"smita-nayak",fullName:"Smita Nayak"},{id:"321308",title:"Dr.",name:"Rajesh",middleName:null,surname:"Das",slug:"rajesh-das",fullName:"Rajesh Das"}]},{id:"67705",title:"Advanced UAVs Nonlinear Control Systems and Applications",slug:"advanced-uavs-nonlinear-control-systems-and-applications",totalDownloads:909,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"unmanned-robotic-systems-and-applications",title:"Unmanned Robotic Systems and Applications",fullTitle:"Unmanned Robotic Systems and Applications"},signatures:"Abdulkader Joukhadar, Mohammad Alchehabi and Adnan Jejeh",authors:null},{id:"51224",title:"Series Elastic Actuator: Design, Analysis and Comparison",slug:"series-elastic-actuator-design-analysis-and-comparison",totalDownloads:2498,totalCrossrefCites:2,totalDimensionsCites:5,book:{slug:"recent-advances-in-robotic-systems",title:"Recent Advances in Robotic Systems",fullTitle:"Recent Advances in Robotic Systems"},signatures:"Arnaldo Gomes Leal Junior, Rafhael Milanezi de Andrade and\nAntônio Bento Filho",authors:[{id:"182082",title:"Dr.",name:"Rafhael",middleName:"Milanezi De",surname:"Andrade",slug:"rafhael-andrade",fullName:"Rafhael Andrade"},{id:"185372",title:"Dr.",name:"Antônio",middleName:null,surname:"Bento Filho",slug:"antonio-bento-filho",fullName:"Antônio Bento Filho"},{id:"185373",title:"MSc.",name:"Arnaldo",middleName:null,surname:"Gomes Leal Junior",slug:"arnaldo-gomes-leal-junior",fullName:"Arnaldo Gomes Leal Junior"}]},{id:"74572",title:"Visibility-Based Technologies and Methodologies for Autonomous Driving",slug:"visibility-based-technologies-and-methodologies-for-autonomous-driving",totalDownloads:62,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:null,title:"Self-driving Vehicles and Enabling Technologies",fullTitle:"Self-driving Vehicles and Enabling Technologies"},signatures:"Said Easa, Yang Ma, Ashraf Elshorbagy, Ahmed Shaker, Songnian Li and Shriniwas Arkatkar",authors:null},{id:"62978",title:"Intelligent Robotic Perception Systems",slug:"intelligent-robotic-perception-systems",totalDownloads:1219,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"applications-of-mobile-robots",title:"Applications of Mobile Robots",fullTitle:"Applications of Mobile Robots"},signatures:"Cristiano Premebida, Rares Ambrus and Zoltan-Csaba Marton",authors:[{id:"203409",title:"Ph.D.",name:"Cristiano",middleName:null,surname:"Premebida",slug:"cristiano-premebida",fullName:"Cristiano Premebida"},{id:"254880",title:"Dr.",name:"Rares",middleName:null,surname:"Ambrus",slug:"rares-ambrus",fullName:"Rares Ambrus"},{id:"254881",title:"Dr.",name:"Zoltan-Csaba",middleName:null,surname:"Marton",slug:"zoltan-csaba-marton",fullName:"Zoltan-Csaba Marton"}]},{id:"150",title:"Sensor-based Global Planning for Mobile Manipulators Navigation Using Voronoi Diagram and Fast Marching",slug:"sensor-based_global_planning_for_mobile_manipulators_navigation_using_voronoi_diagram_and_fast_march",totalDownloads:2690,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"mobile_robots_perception_navigation",title:"Mobile Robots",fullTitle:"Mobile Robots: Perception & Navigation"},signatures:"S. Garrido, D. Blanco, M.L. Munoz, L. Moreno and M. Abderrahim",authors:null}],onlineFirstChaptersFilter:{topicSlug:"physical-sciences-engineering-and-technology-robotics",limit:3,offset:0},onlineFirstChaptersCollection:[{id:"74572",title:"Visibility-Based Technologies and Methodologies for Autonomous Driving",slug:"visibility-based-technologies-and-methodologies-for-autonomous-driving",totalDownloads:63,totalDimensionsCites:0,doi:"10.5772/intechopen.95328",book:{title:"Self-driving Vehicles and Enabling Technologies"},signatures:"Said Easa, Yang Ma, Ashraf Elshorbagy, Ahmed Shaker, Songnian Li and Shriniwas Arkatkar"},{id:"74396",title:"Design Considerations for Autonomous Cargo Transportation Multirotor UAVs",slug:"design-considerations-for-autonomous-cargo-transportation-multirotor-uavs",totalDownloads:30,totalDimensionsCites:0,doi:"10.5772/intechopen.95060",book:{title:"Self-driving Vehicles and Enabling Technologies"},signatures:"Denis Kotarski, Petar Piljek and Josip Kasać"},{id:"74476",title:"Selected Issues and Constraints of Image Matching in Terrain-Aided Navigation: A Comparative Study",slug:"selected-issues-and-constraints-of-image-matching-in-terrain-aided-navigation-a-comparative-study",totalDownloads:58,totalDimensionsCites:0,doi:"10.5772/intechopen.95039",book:{title:"Self-driving Vehicles and Enabling Technologies"},signatures:"Piotr Turek, Stanisław Grzywiński and Witold Bużantowicz"}],onlineFirstChaptersTotal:19},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",middleName:null,surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:1},route:{name:"profile.detail",path:"/profiles/183243/robyn-gillespie",hash:"",query:{},params:{id:"183243",slug:"robyn-gillespie"},fullPath:"/profiles/183243/robyn-gillespie",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()