Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
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This achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
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We are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
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Thank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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Coordinator for Post Graduate programs of the Faculty of Business (March 2006-April 2014), Chairperson of Center for Globalization and Sustainability Research (CGSR) (March2009-April2014), Multimedia University (MMU), Melaka Campus, Malaysia, member of Research and Development, research grants panel and the Institute of Postgraduate Studies (IPS) Coordination Committee (ICC) MMU. He is currently teaching Advanced Research Methodology, Entrepreneurship and Commercialization, and Economics for Managers at the postgraduate level and economic subjects at the undergraduate level.\nHis research interests include development economics, productivity analysis, knowledge-based economy, productivity and environment (green productivity), Bioeconomy, Islamic finance and microfinance, economic growth, (environment, tourism) and Entrepreneurship. He is the book\\'s author (Green Productivity: Applications in Malaysia’s Manufacturing) in 2012. 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\n
1. Overview
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Hox genes are responsible for the expression of a large family of transcriptional factors that play a key role in embryonic development, organogenesis, and anteroposterior body orientation [1, 2]. Even though the main function of these genes is well known during embryogenesis, their role in adults remains under investigation. Several studies have linked Hox genes with adult processes such as vascularization, hematopoiesis, tumor angiogenesis, and cell differentiation [3]. In this chapter, we will focus our attention on the origin and main role of Hox genes in adult tissues, especially on endothelial cell differentiation, neovasculogenesis, and angiogenesis.
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2. Origin of the Hox gene cluster
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The Hox genes were discovered in 1915 by Calvin Bridges in a mutant Drosophila melanogaster named Bithorax, which showed a partial duplication of the thorax [4]. Years later, another mutation in the Hox genes was identified resulting in a mutant fly exhibiting legs instead of antenna named Antennapedia [5]. The Hox genes were then grouped into these two complexes (Bithorax and Antennapedia), which are located on chromosome 3 and play a key role in conferring the identity along the anteroposterior axis of the body. The role of these genes in establishing the anteroposterior axis is highly conserved in vertebrates [5, 6]; however, the Hox gene cluster has changed during its evolution, evidenced by different numbers of clusters between species (Figure 1). For example, whereas invertebrates typically possess a single cluster, vertebrates such as mice and humans possess four gene clusters coding for the three different axes: cervical, thoracic, and lumbosacral [2, 6]. Despite these differences, Hox genes have been identified in all species, which reflects the important role of these genes in the regulation of body structure [1, 7]. In humans, the 39 mammalian Hox genes are grouped into four chromosomal clusters named HOXA, HOXB, HOXC, and HOXD, located on chromosomes 7p14, 17q21, 12q13, and 2q31, respectively [8]. This large family encodes homeodomain transcription factors that share highly conserved DNA sequence formed by 183 bp called “homeobox,” which encodes a polypeptide core of 61 amino acids formed by three alpha helices known as the homeodomain. Most homeodomains recognize highly conserved DNA elements that serve as a promoter for many genes (motif TAAT) being a T in the direction 5′ determinant for this coupling acknowledgment [9]. Hox transcription factors are well known for playing a key role during cell and tissue differentiation in developing embryos; however, other studies have shown that these homeotic genes also play a role in adult process such as hematopoiesis and embryo implantation by promoting neovasculogenesis and angiogenesis [10].
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Figure 1.
The composition and evolutionary differences of the HOX gene cluster between Drosophila melanogaster, mouse, and Homo sapiens. The HOX gene clusters and their chromosomal location were compared between Drosophila melanogaster, mouse, and Homo sapiens. Genes were grouped according to the distribution of the three axes corresponding to the anteroposterior part of the body (cervical, thoracic, lumbosacral).
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3. Hox genes in adult-related processes
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3.1. Endometrial tissue
\n
Hox genes are crucial during endometrium redevelopment and corpus luteum formation because they regulate cell growth and differentiation during each reproductive cycle [10]. Expression of HoxA10 in human epithelial and stromal endometrial cells has been significantly higher in the intermediate and late phase of the menstrual cycle, suggesting that it could favor the implantation of the embryo [11, 12, 13]. Mechanistically, the protein encoded by this gene regulates the expression of several proteins related to endometrial development such as Emx2/EMX2, integrin β3, insulin-like growth factor-binding protein-1 (IGFBP-1), cyclin inhibitors, Wnt family genes, and the prostaglandin receptors EP-3 and EP-4 [14, 15].
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Endometrium development is regulated by estrogen and progesterone; thus, any regulation of Hox genes by these hormones suggests that these genes play a role in the growth and development of the endometrium. For example, 17β-estradiol and progesterone significantly increased the expression of HoxA10 in endometrial cells [16] and primary culture of stromal endometrial cells, respectively, with a higher response induced by progesterone compared to 17β-estradiol [17] and even higher when both hormones were used in combination [17, 18].
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HOXA11 is another hox gene from the A cluster that has been closely associated with morphological alterations [19]. During the development of the female reproductive tract, HOXA11 is normally expressed in the cervix and lower uterine segment. When the expression of this gene is impaired, it promotes aberrant epithelial cell differentiation leading to epithelial ovarian neoplasia [20, 21]. In addition, HOXA11−/− mice exhibit reduced development of the stroma in the glandular tissue and decidua during pregnancy [18, 22], suggesting a role in myometrium preparation to implantation.
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More recently, Yim et al. suggested that HOXA11 promotes metastasis by regulating the expression of gene coding for metastasis-related proteins [23]. These findings indicate that HOXA11 plays a role in the aggressive nature of ovarian cancer cells through HOXA11-mediated expression of target genes such as matrix metalloproteinase (MMP) and VEGF.
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3.2. Implantation
\n
Implantation is a series of sequential biological events triggered after fertilization in which the blastocyst migrates from the fallopian tube into the uterus. The fertilized egg is then attached to the uterine wall and subsequently implanted in the endometrium. Implantation occurs only in a very specific time period and place during the mid-secretory phase of the uterine cycle [24]. During this period, the uterus becomes more receptive by promoting a series of cellular and molecular events favoring the implantation of the embryo. In this stage, the role of several intercellular mediators has been implicated, which include specific cytokines, growth factors, adhesion molecules, lipid mediators, steroid hormones, and Hox transcription factors [25]. Like in endometrial tissue, HOXA10 also plays a role during embryo implantation as it has been shown that despite the fact that HOXA10-deficient mice (HOXA10−/−) exhibited normal ovulation cycle, the implantation did not occur. Interestingly, implantation was restored when embryos from HOXA10−/− were transferred to wild-type mice; however, wild-type embryos were not implanted in HOXA10−/− female mice [18], suggesting that HOXA10 is required to have an adequate implantation environment. Moreover, HOXA10−/− and HOXA11−/− mice also exhibit poor implantation due to insufficient development of stromal glandular tissue and decidua during pregnancy [26]. In humans, the expression of both HOXA10 and HOXA11 genes rises gradually during the proliferative phase of the menstrual cycle, showing a peak of expression in mid-cycle, when implantation typically occurs [13, 27]. Interestingly, this peak of expression was not observed in women with endometriosis or in mice with induced endometriosis [13, 27], suggesting that HoxA10 and HoxA11 peaks require a healthy endometrium to support and continue with the implantation process. Several studies have shown that Hox10 not only promotes implantation directly but also inhibits detrimental factors such as empty spiracles homeobox 2 (EMX2), P300/CBP-associated factor (P/CAF), and gamma-aminobutyric acid (GABA). Studies by Taylor and colleagues demonstrated that HoxA10 repressed EMX2 expression, which in turn inhibited the proliferation of endometrial cells [28], suggesting that HoxA10 is a pro-proliferative and pro-implantation factor in these cells. Zhu and colleagues demonstrated that HoxA10 repressed the promoter activity of P/CAF, which impairs endometrial receptivity and embryo implantation by downregulating integrin β3 [29]. Recent studies have also shown that HoxA10 decreased mRNA levels and protein translocation of GABA receptor [30], which plays a role in the generation of uterine contractions and labor [31]. Thus, the quiescent uterus is required for adequate implantation and embryo development, along with reduced expression or activity of GABA receptor.
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3.3. Hematopoiesis
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Hox genes are highly expressed in hematopoietic stem cells (HSC) and immature progenitor cells [32]; however, this expression is gradually decreased upon cell differentiation. Moreover, overexpression of genes from the HOXA cluster impairs B and T lymphocyte differentiation, affects erythropoiesis, and reduces stem cell bone marrow homing, favoring the induction of myeloproliferative disorders and leukemias [33]. In fact, overexpression of HOXA1, HOXA4, and HOXA6 genes has been shown to favor the generation of permanent cell lines [34]. Studies by Wang et al. showed increased proliferation and higher self-growth and self-renewal of hematopoietic stem progenitor cells (HSC) (Line 9 and Line H1) when HoxA6 was overexpressed compared to normal conditions [34]. The authors observed that overexpression of this gene sustained HSC self-renewal and multipotency by promoting mature erythroid lineage cells and partial apoptosis of erythroid progenitors.
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Another gene involved in this process is HOXA5. Overexpression of HoxA5 in HSC isolated from umbilical cord blood, bone marrow [35], or mice [36] promotes a significant shift toward myeloid differentiation in relation to erythroid differentiation when compared to respective control cells [35, 36]. Then, the authors evaluated genes affected by HoxA5, and they observed downregulation of several genes involved in cell proliferation, differentiation, and metabolism [35, 36].
\n
HOXA9 has also been associated with the regulation of myeloid cell differentiation. The activation of HoxA9 complex favors the recruitment of CREB-binding protein (CBP/p300), histone acetylation, and activation of a number of transcription factors and proto-oncogenes, including Erg, FLT3, and SOX4 Myb, which regulate hematopoiesis [37].
\n
Another Hox gene family member linked to hematopoiesis is HOXA10. The expression of this gene is high in myeloid progenitor cells, and it decreases during cell maturation [38]. Bei et al. [39] studied the expression of HoxA10 in bone marrow from patients with human acute myeloid leukemia (AML), and they observed increased expression of this gene in patients with poor prognosis. Then, they developed a HoxA10-overexpresing mouse model identifying CDX4, a caudal gene that contain homeodomain and code for transcription factor that plays an important role in hematopoiesis, as a HOXA10 target gene [39]. Overall, their results demonstrated that HOXA10 was contributing to AML pathogenesis via CDX4-positive feedback. Other groups demonstrated that HoxA13 was associated with the development of monocytes and macrophages, and its expression was observed more often in monocytic leukemia cell lines in comparison with other types of leukemia [40]. Moreover, the expression of genes HOXB3 and HOXB4 has been found to be altered in patients with AML with poor prognosis [41].
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4. Hox genes in vascularity and angiogenesis
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The development of the vascular system involves two processes called vasculogenesis and angiogenesis [42]. During vasculogenesis, angioblasts derived from different sources, including mesodermal embryonic layer or bone marrow, differentiate into endothelial cells and subsequently form a primitive network of tubular structures called blood vessels [43]. Vasculogenesis occurs largely during embryonic development; however, the presence of a population of circulating endothelial progenitor cells (EPCs) derived from the bone marrow in adults strongly suggests that this process may occur in the postnatal period [44]. In contrast, angiogenesis refers to the formation of new blood vessels from preexisting vessels by cell migration and remodeling of the primitive vascular network [45]. Vasculogenesis and angiogenesis are involved in the development of the functional vascular system in the embryo and the formation of blood vessels in the postnatal period. Both vasculogenesis and angiogenesis are under the regulation of several growth factors, which include vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), platelet-derived growth factor (PDGF), and transforming growth factor β1 (TGF-β1), among others [45]. Interestingly, different research groups have found that Hox genes regulate the expression of these growth factors and, in turn, endothelial cell differentiation. In the next section, we will describe supporting evidence about the role of Hox genes in endothelial differentiation, vasculogenesis, and angiogenesis (Figure 2).
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Figure 2.
HOX genes modulate the expression of crucial target genes to promote the differentiation of mature endothelial cells. Hox genes promote the differentiation of endothelial progenitor cells, which exhibit an immature phenotype (CD70+CD34+Oct-4+), into mature endothelial cells that express endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor receptor 2 (VEGFR2 or KDR), CD31, von Willebrand factor (vWF), and the lectin-type oxidized LDL receptor 1 (LOX-1). To promote this phenotype, some Hox genes upregulate crucial genes such as fetal liver kinase 1 (Flk1), angiopoietin 2 (ANG2), ephrin type-B receptor 4 (EphB4), and FI3K receptor, whereas other Hox genes downregulate other factors such as hypoxia-induced factor type 1α (HIF1α), cyclooxygenase-2 (cox-2), ephrin type-a receptor 1 (EphwA1), and VEGFR2.
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4.1. HOXA3
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The HOXA3 gene is required for modeling the anterior body plan during embryogenesis, but they can also play a role in promoting angiogenesis [46, 47]. It has been shown that activation of HOXA3 favors the migration of endothelial cells and keratinocytes, associated with increased expression of urokinase-type plasminogen activator receptor (uPAR) in both in vitro and in vivo studies using mice [46, 47]. Similar results were demonstrated by Hansen et al. who confirmed that HOXA3 is a potent inducer of angiogenesis in vivo and also promotes direct keratinocyte migration [48]. These results suggest that HOXA3 potentiates two key processes involved in efficient wound repair: angiogenesis and reepithelialization [46, 48]. Gene transfer studies of HOXA3 suggest that this gene also functions as a potent inducer of wound repair in genetically modified diabetic animals. A single application of protein HoxA3 resulted in complete healing of wounds after 42 days, while wounds treated with the control plasmid without HOXA3 (β gal) required 77 days for complete tissue repair. In addition, it was demonstrated that secreted protein HoxA3 or HoxA5, coming from respective genes and derived from composite skin constructs, exhibits decreased expression of CCL-2 and CxCL-12 inflammatory mediators, which play a key role in the attraction of monocytes, macrophages, and other wound immune cells [48]. Thus, reduced recruitment of leukocytes mediated by HOXA3 may contribute to the prolonged integrity and viability of the composite skin constructs expressing HOXA3, by reducing inflammation during wound healing process. Taken together, the combined actions of HoxA3 on endothelial cells and keratinocytes lead to increased angiogenesis, normal epidermal differentiation, reduced expression of inflammatory mediators, and reduced graft contraction. These effects suggest that HoxA3 may have therapeutic benefits in wound repair by improving the integrity of composite skin grafts.
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4.2. HOXA9
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The HOXA9 gene code for two different proteins, HA-9A and HA-9B isoform A (HA-9A) and HoxA9 protein isoform B (HA-9B) [49] that share a common homeodomain [15]. The expression of HA-9A has been observed exclusively during fetal development, whereas the HA-9B has been found not only in fetal but also in adult organism and specifically in endothelial cells [49, 50].
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In 2004, Bruhl et al. showed that HOXA9 was able to regulate angiogenesis [51]. These authors using human umbilical vein endothelial cells (HUVECs) with sense/antisense oligonucleotides or siRNA for this gene observed that HOXA9 expression was essential for endothelial cell migration and tube formation. Also, they evaluated the regulation of ephrin type-B (Eph) receptor B4 (EphB4) by HOXA9, since previous reports [52, 53] showed that Eph receptors were homeobox protein potential targets. Then, they decided to study EphB4 since it was specifically associated with angiogenesis and cell migration processes [54, 55]. After elegant experimentation and analysis, they conclude that HoxA9 regulated endothelial cell migration and tube formation by promoting the expression of EphB4. Later in 2012, Zhang and colleagues established that HoxA9 was essential for postnatal neovascularization in vivo. In addition, they found that HoxA9 was able to regulate the expression of endothelial genes such as endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor receptor 2 (VEGFR2), and VE-cadherin in vitro in mature endothelial cells exposed to “shear stress” [56]. Furthermore, the HOXA9−/− mouse model showed a reduced number of circulating endothelial progenitor cells (EPCs) as well as reduced overall postnatal neovascularization after ischemia compared to wild-type mice. Altogether, these results demonstrated that HoxA9 is critical for postnatal neovascularization [57].
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4.3. HOXA13
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The central function of the placenta is to allow the formation of a vascular labyrinth, a juxtaposed series of finely branched blood vessels and trophoblast that regulate the exchange of nutrients and residues while maintaining the separation of maternal and fetal blood supplies. The study by Shaut et al. showed a morphological alteration in the labyrinth endothelial cells, branching of the vessels, and in the integrity of the vessels when HOXA13 was dysfunctional [58, 59]. These findings suggest that HOXA13 regulates a number of genes in the vascular endothelium required for vessel adhesion and branching, providing a functional explanation of the mean gestational lethality exhibited by HOXA13 mutant mice. The same authors identified that EphA6 and EphA7 were direct transcriptional targets of HOXA13 in the genital tubercle vascular endothelia [59]. Altogether, these findings provide a new genetic pathway to consider when placental pathologies or placental evolutionary ontogeny are characterized. Evidence for this coordination is observed in the labyrinth endothelium, where the genes required for cell adhesion and vascular branching are affected concomitantly by the loss of HOXA13 function, including Neuropilin-1, Enpp2, Lyve1, Caveolin-1, Foxf1, and Tie2, resulting in reduced levels of provascular factors required for the vascular development of the labyrinth [58].
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Besides HoxA genes, the HoxB and HoxD loci have also been involved in endothelial and angiogenesis regulation processes [60]. HUVECs, for example, express several genes from these loci [7], and it has been shown that some of these genes inhibit in vitro proliferation of HUVECs, whereas others have been associated with increased capillary morphogenesis and vasculogenesis [61].
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4.4. HOXB1
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Previous studies have revealed an overlap between HoxA1 and HoxB1 functions during the specification of the rhombomeres, a transiently divided segment of the developing neural tube, from which neural crest cells emerge. It has been demonstrated that both HoxA1 and HoxB1 functions are required for the heart development [62, 63]. HoxB1−/− embryos were previously described as embryos with normal pharyngeal arch arteries and cardiac neural crest-derived tissue remodeling [64]. However, more recently, Roux et al. observed one HoxB1 mutant embryo with an aortic arch artery defect, which is characteristic of a developmental failure of the left pharyngeal arch arteries (PAA) [65]. These data suggest that HOXB1 is important for PAA formation, and the authors provide a novel model to study the molecular origin of great artery defects, which are often observed in human patients.
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4.5. HOXB3
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The function of the HOXB3 gene was studied after finding the function of its paralogous gene, HOXD3. While HOXD3 is required for mediating the invasive and migratory behavior of endothelial cells during the early stages of neovascularization, HOXB3 is required for the morphogenesis of new capillary tubes, suggesting that these paralogous Hox genes may perform complementary functions [53]. The authors also found that the capillary morphogenesis induced by HOXB3 was mediated by ephrin A1 ligand (EFNA1) [53].
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4.6. HOXB5
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The HOXB5 gene, also known as Hox-2.1, codes for a potent transcriptional regulator present in several adult tissues. Similar to HOXA9, HOXB5 has been associated with vascular alterations. In this regard, studies have shown that HOXB5 homeobox protein regulates the expression of VEGFR2, the earliest marker of endothelial precursors, by direct binding to the HOXB5-binding element (HBE) in the VEGFR2 gene [66]. They also found that overexpression of HoxB5 increased the number of angioblasts during embryonic stem cell differentiation and the number of mature endothelial cells, which in turn have been associated with high expression of platelet endothelial cell adhesion molecule (PECAM) and the formation of primitive blood vessels [66]. Years later, the same research group investigated the in vivo role of HoxB5 in angiogenesis using the chick (Gallus gallus) chorioallantoic membrane assay. They concluded that HoxB5 exerted an activating effect on angiopoietin 2 (ANG2), which was essential for endothelial cell sprouting and vascular growth [60]. More recently, the same group investigated the role of HoxB5 overexpression during revascularization in ischemic disease using femoral artery ligation in C57BL/6 mice. They observed that HoxB5 enhanced perfusion restoration and increased capillary density in vivo via monocyte chemotactic protein-1 (MCP-1) and interleukin-6 (IL-6) upregulation and increased endothelial cell migration [67].
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Furthermore, other studies have shown that HoxB5 is a transactivator of the promoter of VEGFR2, an early marker of endothelial precursors [66], which might be involved in the differentiation of mesoderm-derived precursors toward an endothelial phenotype [66, 68]. In fact, it has been described that overexpression of HoxB5 leads to differentiation of mesoderm-derived precursors toward the endothelial phenotype, which in turn lead to high expression of angiopoietin 2 (ANG2) and therefore enhance vascularization in a model of fertilized white Leghorn chicken eggs [68].
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4.7. HOXB7
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HOXB7 has been associated with tumor progression and angiogenesis [61]. Care et al. in 2001 provided evidence that HoxB7 promotes tumor-associated angiogenesis by increasing the expression of VEGF, melanoma growth stimulatory activity/growth-related oncogene alpha, interleukin-8, and angiopoietin 2 (ANG2) in SkBr3 cells [69]. The authors concluded that HoxB7 acted as a key factor in a tumor-associated angiogenic switch [69]. In 2008, Murthi et al. identified differences in the expression of HoxB7 between micro- and macrovascular endothelial cells [70]. They observed higher expression of HoxB7 in macrovascular HUVECs and placenta compared to microvascular endothelial cells such as human placental endothelial cell (HPEC) line, human microvascular endothelial cells (HMVEC), and freshly isolated placental microvascular endothelial cells (PLEC). Storti et al. found that HoxB7 was expressed in 10 out of 22 multiple myeloma patients analyzed at the diagnosis related to high bone marrow angiogenesis [61]. They also found that HoxB7 was overexpressed in about 40% of myeloma cell lines compared with normal plasma cells [61]. Furthermore, they observed that HoxB7 overexpression in multiple myeloma cells significantly modified their transcriptional and angiogenic profile by upregulating VEGF, fibroblast growth factor 2 (FGF2), metalloproteinase-2 (MMP-2), platelet-derived growth factor A (PDGFA), and WNT5a, while HoxB7 also downregulates thrombospondin-2, an inhibitor of angiogenesis [61]. Finally, the homeobox gene HoxB7 is overexpressed across a range of cancers and promotes tumorigenesis by inducing cell proliferation, survival, invasion, and tumor angiogenesis in pancreatic adenocarcinoma [71], cervical cancer [72], glioblastoma tumors [73], and breast cancer [74].
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4.8. HOXD1
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HOXD1 is specifically expressed in mature endothelial cells compared to early-stage EPC [62, 75]. However, not only HoxD1 is expressed in these cells, but also microarray studies have revealed that several Hox genes from the cluster on chromosome 2 such as HOXD1, HOXD3, HOXD4, HOXD8, and HOXD9 were highly expressed in blood-derived endothelial cells [62]. In particular, HOXD1 regulates endothelial cell migration and cell adhesion on fibronectin by targeting integrin β1 (ITGβ1) in mature endothelial cells [75].
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4.9. HOXD3
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HOXD3 is a member of the HOXD cluster on chromosome 2, and it can be induced by extracellular matrix protein, Del-1, and integrin alphavbeta5 interaction on resting endothelium. Del-1 is a protein that accumulates around angiogenic blood vessels and promotes angiogenesis in the absence of exogenous growth factors [76]. Zhong et al. showed that Del-1 initiates angiogenesis by binding to integrin alphavbeta5 on the resting endothelium, resulting in expression of HoxD3 [76]. HoxD3 was then promoting angiogenesis by inducing the expression of the pro-angiogenic molecule integrin alphavbeta3 (integrin β3) [76]. These findings provide evidence for an angiogenic switch that can be initiated in the absence of exogenous growth factors indicating that the angiogenic matrix protein Del-1 may be a useful tool for the therapy of ischemic disease [76]. A year later, Chen and Ruley demonstrated the role of HoxD3 expression in human brain vessels [52]. They showed that HoxD3 expression significantly induced cerebral angiogenesis, increased focal cerebral blood flow, and reduced vascular leakage by inducing integrin β3. These data suggest that HoxD3 plays an important role in regulating angiogenesis. Other studies reported that HoxD3 mediates the basic fibroblast growth factor (bFGF)-induced expression of integrin β3 and urokinase plasminogen activator (uPA) in HUVECs [77] and promotes angiogenesis in in vivo models [78, 79]. Furthermore, HOXD3 has been shown to be involved in cerebral angiogenesis in mice [52].
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4.10. Hox genes with anti-angiogenic effects
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As previously described, several transcription factors encoded by Hox genes contribute to anti-angiogenic activity such as HOXA5, HOXC9, and HOXD10 [79].
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4.11. HOXA5
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It has been shown that the presence of HoxA5 was associated with the upregulation of thrombospondin-2 (TSP-2), a naturally occurring inhibitor of angiogenesis. In addition, HoxA5 expression was also associated with downregulation of pro-angiogenic genes such as Ephrin A1 (Efna1), VEGFR2, hypoxia-inducible 1α (HIF1α), and cyclooxygenase-2 (COX-2) [80].
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4.12. HOXC9
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HOXC9 is a transcription factor expressed in blood vessels in mice [81] and in the cardinal vein of zebrafish [82]. Kroll’s group investigated this transcription factor in human vascular endothelial cells and zebrafish, and they observed that this protein was a negative regulator of circulating endothelial cells. They found that HoxC9 was highly expressed in resting endothelial cells; however, its expression was downregulated under hypoxic conditions, and overexpression of this factor inhibited endothelial migration, tube formation, and endothelial cell proliferation by targeting IL-8 transcription [82]. Finally, using a zebrafish model, they observed in vivo that HoxC9 overexpression inhibited the development of their vascular structure; this defect was rescued with exogenous IL-8. This data suggests that HoxC9 plays a negative role in the induction of endothelial cell growth by inhibiting IL-8 production [81, 82].
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4.13. HOXD10
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HOXD10 is another negative regulator gene for angiogenesis as its overexpression inhibited dermal microvascular endothelial cell migration in vitro [53]. In addition, it has been shown that HoxD10 reduces the expression of GATA-binding protein transcription factor, a family of transcription factors that contain two zinc finger motifs and bind to the DNA sequence (A/T)GATA(A/G), from where it acquires its name. HoxD10 via those transcription factors is able to regulate expression of VEGFR1 and VEGFR2 in differentiated endothelial cells [83]. Therefore, these observations suggest that there is an overlapping and complementary role between Hox genes to maintain a balance between pro-angiogenic and anti-angiogenic states (Figure 3).
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Figure 3.
HOX genes regulate angiogenesis. Differential expression of Hox genes tightly regulates endothelial cell proliferation, migration, adhesion, and blood vessel formation (angiogenesis) by activating or silencing relevant target genes, such as fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), platelet factor 4 (PF4) or chemokine (C-X-C motif) ligand 4 (CXCL4), interleukin-8 (IL-8), integrin beta 1 (ITGβ1), and both vascular endothelial growth factor receptors 1 and 2 (VEGFR1/VEGFR2).
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5. Hox genes and adult stem cells
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Hox genes act as transcriptional regulators, which have been involved in the differentiation of stem cells into several lineages and different cell types. One of the main steps to initiate vasculogenesis and angiogenesis is the differentiation to endothelial lineage from pluripotent stem cells. Studies have suggested that Hox genes contribute to the differentiation of EPCs into mature endothelial cells (Table 1). In the next section, we will present the evidence for the role of Hox genes in the differentiation of adult stem cell.
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Cellular type
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Hox genes
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Period of expression
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Target gene
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Regulation
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Functions
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Reference
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Pro-angiogenic
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Endothelial cells of the human dermal microvasculature
Several members of the Hox family play an important role in the embryonic development of the cardiovascular system and regulate angiogenesis in adults [84]. In addition, some Hox transcription factors such as HoxD3, HoxC6, and HoxC8 modulate the expression of proteins in mature endothelial cells, whereas HoxB5 appears to be involved in the in vitro differentiation of embryonic precursor cells toward endothelial lineage [66, 81]. HoxA9 is important for myeloid, erythroid, and lymphoid hematopoiesis [88, 89] and stem cell expansion [90]. It is also essential for the migration and tube-forming capacity of mature endothelial cells [51] and could serve as a switch toward endothelial commitment during progenitor cell maturation. The HOXD3 gene is also involved in the differentiation of EPC to endothelial cell. The expression of HOXD3 retained endothelial cells in an invasive state and prevented vessel maturation leading to vascular malformations and vascular tumors. Therefore, HoxD3 regulates endothelial cell gene expression associated with the invasive stage of angiogenesis. The expression of HoxD genes has been shown to be temporally regulated as the expression of HoxD10 is maximal 3 days after stimulation with angiogenic factors, whereas the expression of HoxD3 increases after 3 days, indicating that the differentiation and maturation of endothelial cells work alongside with changes in the expression of Hox genes [90].
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6. Conclusions
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Hox genes have been traditionally recognized as genes involved in the embryonic development; however, further research showed that homeobox genes also play a role as master regulators of tissue and organ patterning in adults. These genes can regulate cell differentiation, proliferation, and migration to tissues exposed to constant turnover, such as vasculature, endometrium, and bone marrow. Thus, it has been shown that Hox genes can play a role in defining an endothelial phenotype and/or promoting neovascularization; however, other genes from the Hox family can also play an anti-angiogenic role by preventing angiogenesis. These genes regulate different processes by targeting key proteins related to angiogenesis such as VEGF, IL-8, Efna1, and TSP-2 among other gene targets.
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Since Hox genes play a role in the regulation of stem cell differentiation into endothelium, angiogenesis, and vasculogenesis, the manipulation of these genes could lead to a useful gene therapy in patients with vascular damage. A better understanding of the cellular and molecular mechanisms related to the biological effects of Hox genes is essential for designing new drugs and treatment to treat worldwide prevalent diseases such as cancer and cardiovascular disease.
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Acknowledgments
\n
We would like to thank the research staff of the Vascular Physiology Laboratory, the Group of Investigation in Tumor Angiogenesis (GIANT) from the University of Bio Bio, and the Group of Research and Innovation in Vascular Health (GRIVAS Health) for the outstanding discussion of the ideas presented in this manuscript.
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Source of funding
C.A. is funded by PCI N° PII20150053, and Dirección de Investigación, Universidad de Concepcion (DIUC 211.072.034-1.0), Chile, and Convenio de Desempeño, Universidad de Concepcion, UCO1201. C.E. is funded by Fondecyt Regular 1140586, Fondequip EQM140104, DIUBB 166709 3/R, and GI 171709/VC. E.N-L. is funded by CONICYT—Fondecyt de Iniciacion (Grant Number: 11170610) and Programa de Atracción e Inserción (Grant Number: 79170073).
\n',keywords:"Hox genes, endothelial cell differentiation, angiogenesis, vasculogenesis, embryonic development",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/61008.pdf",chapterXML:"https://mts.intechopen.com/source/xml/61008.xml",downloadPdfUrl:"/chapter/pdf-download/61008",previewPdfUrl:"/chapter/pdf-preview/61008",totalDownloads:1347,totalViews:294,totalCrossrefCites:3,totalDimensionsCites:6,totalAltmetricsMentions:0,impactScore:4,impactScorePercentile:92,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"May 12th 2017",dateReviewed:"March 23rd 2018",datePrePublished:"November 5th 2018",datePublished:"October 24th 2018",dateFinished:"April 25th 2018",readingETA:"0",abstract:"HOX genes belong to a family of transcription factors characterized by a 183 bp DNA sequence called homeobox, which code for a 61-amino-acid domain defined as the homeodomain. These genes play a central role during embryonic development by controlling body organization, organogenesis, and stem cell differentiation. They can also play a role in adult processes such as embryo implantation, hematopoiesis, and endothelial differentiation. Since endothelial cell differentiation is one of the main steps to initiate vasculogenesis and angiogenesis, we analyzed the role of several Hox genes in the regulation of these two processes. In this chapter, we summarized the evidence to support the function of Hox genes in adult tissues, specifically in endothelial cell differentiation, by studying their mechanism of action and how their target genes regulate vasculogenesis and angiogenesis. Understanding the cellular and molecular mechanisms triggered by Hox biological effects is pivotal for designing new drugs or therapies for high prevalent pathologies, such as cardiovascular diseases.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/61008",risUrl:"/chapter/ris/61008",book:{id:"6209",slug:"endothelial-dysfunction-old-concepts-and-new-challenges"},signatures:"Estefanía Nova-Lampeti, Valeria Aguilera, Katherine Oporto, Paula\nGuzmán, Valeska Ormazábal, Felipe Zúñiga, Carlos Escudero and\nClaudio Aguayo",authors:[{id:"166180",title:"Dr.",name:"Carlos",middleName:null,surname:"Escudero",fullName:"Carlos Escudero",slug:"carlos-escudero",email:"cescudero@ubiobio.cl",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Bío-Bío",institutionURL:null,country:{name:"Chile"}}},{id:"183934",title:"Dr.",name:"Claudio",middleName:null,surname:"Aguayo",fullName:"Claudio Aguayo",slug:"claudio-aguayo",email:"caguayo@udec.cl",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/183934/images/4883_n.jpg",institution:{name:"University of Concepción",institutionURL:null,country:{name:"Chile"}}},{id:"187834",title:"Dr.",name:"Estefania",middleName:null,surname:"Nova-Lamperti",fullName:"Estefania Nova-Lamperti",slug:"estefania-nova-lamperti",email:"enovalamperti@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"187835",title:"Dr.",name:"Felipe",middleName:null,surname:"Zuñiga",fullName:"Felipe Zuñiga",slug:"felipe-zuniga",email:"fzuniga@udec.cl",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"211035",title:"Dr.",name:"Valeska",middleName:null,surname:"Ormazabal",fullName:"Valeska Ormazabal",slug:"valeska-ormazabal",email:"vormazabal@udec.cl",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Overview",level:"1"},{id:"sec_2",title:"2. Origin of the Hox gene cluster",level:"1"},{id:"sec_3",title:"3. Hox genes in adult-related processes",level:"1"},{id:"sec_3_2",title:"3.1. Endometrial tissue",level:"2"},{id:"sec_4_2",title:"3.2. Implantation",level:"2"},{id:"sec_5_2",title:"3.3. Hematopoiesis",level:"2"},{id:"sec_7",title:"4. Hox genes in vascularity and angiogenesis",level:"1"},{id:"sec_7_2",title:"4.1. HOXA3",level:"2"},{id:"sec_8_2",title:"4.2. HOXA9",level:"2"},{id:"sec_9_2",title:"4.3. HOXA13",level:"2"},{id:"sec_10_2",title:"4.4. HOXB1",level:"2"},{id:"sec_11_2",title:"4.5. HOXB3",level:"2"},{id:"sec_12_2",title:"4.6. HOXB5",level:"2"},{id:"sec_13_2",title:"4.7. HOXB7",level:"2"},{id:"sec_14_2",title:"4.8. HOXD1",level:"2"},{id:"sec_15_2",title:"4.9. HOXD3",level:"2"},{id:"sec_16_2",title:"4.10. Hox genes with anti-angiogenic effects",level:"2"},{id:"sec_17_2",title:"4.11. HOXA5",level:"2"},{id:"sec_18_2",title:"4.12. HOXC9",level:"2"},{id:"sec_19_2",title:"4.13. HOXD10",level:"2"},{id:"sec_21",title:"5. Hox genes and adult stem cells",level:"1"},{id:"sec_21_2",title:"5.1. Endothelial progenitor cells",level:"2"},{id:"sec_23",title:"6. Conclusions",level:"1"},{id:"sec_24",title:"Acknowledgments",level:"1"},{id:"sec_27",title:"Source of funding",level:"1"}],chapterReferences:[{id:"B1",body:'Rux DR, Wellik DM. Hox genes in the adult skeleton: Novel functions beyond embryonic development. Developmental Dynamics: An Official Publication of the American Association of Anatomists. 2017;246(4):310-317\n'},{id:"B2",body:'Wagner GP, Amemiya C, Ruddle F. Hox cluster duplications and the opportunity for evolutionary novelties. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(25):14603-14606\n'},{id:"B3",body:'Hrycaj SM, Wellik DM. Hox genes and evolution. F1000Research. 2016;5:1-7\n'},{id:"B4",body:'Bender W, Akam M, Karch F, Beachy PA, Peifer M, Spierer P, Lewis EB, Hogness DS. 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Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepcion, Chile
Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepcion, Chile
Group of Research and Innovation in Vascular Health (GRIVAS Health), Chile
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1. Introduction
Self-limited epilepsy with centrotemporal spikes (SECTS), well-known as Rolandic epilepsy is the most frequent among the childhood focal epilepsies and may account for about 15–25% of all epileptic syndromes diagnosed between the ages of 5 to 15 years [1]. It is termed ‘rolandic’ epilepsy because the focal seizures are originated from the region around the lower part of the central gyrus of Rolando. The incidence range changes between 7.1–21 per 100000 in a population younger than 15 years with male predominance [2]. The age of onset in 90% of cases between 1 and 10 years with a peak around 6–7 years and recovery occurs before the age of 15–16 years [2, 3, 4].
Self-limited epilepsy with centrotemporal spikes is a syndrome of brief hemifacial motor seizures, frequently having associated somatosensory symptoms, usually without impairment of consciousness which tend to evolve into GTCS [3, 4, 5, 6]. Seizures are often related to sleep [7]. Genetic predisposition is frequent, and there is male predominance [3, 5, 8, 9]. An interictal EEG has normal background activity with biphasic high-voltage centrotemporal spikes, often followed by slow waves that are activated by sleep and tend to spread or shift from side to side [10]. Neurological and mental status before the debut of epilepsy is normal. There are no specific abnormalities on brain MRI or CT. Many studies reported that RE may cause transient or long-lasting cognitive and behavioral disturbances [4, 5, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40].
2. Terminology and classification
Panayiotopoulos described a concept of benign childhood susceptibility syndrome (BCSSS) to unify RE, Panayiotopoulos syndrome (PS) and childhood occipital epilepsy of Gastaut (ICOE-G) outlined the common features, course of diseases, prognosis, and the possible genetic predisposition in this group of associated syndromes [5].
1989 ILAE classification recognized three “age-related and localization-related epilepsies and syndromes”: (1) benign childhood epilepsy with centrotemporal spikes (BCECTS); (2) childhood epilepsy with occipital paroxysms; (3) primary reading epilepsy [10].
ILAE Commission on Classification and Terminology lists three childhood idiopathic focal epilepsy syndromes: (1) benign childhood epilepsy with centrotemporal spikes (BCECTS); (2) Panayiotopoulos syndrome, and (3) late-onset childhood occipital epilepsy (Gastaut type) [13].
Rolandic epilepsy had undergone significant terminological and classification changes. RE had been previously considered as benign childhood epilepsy. Frequently reported cognitive and language impairments and behavioral disturbances in children with RE led to the replacement of the terms “benign” and “idiopathic” by the “self-limited” in the new classification proposed by Sheffer I. and colleagues [41].
3. Etiology
The role of genetic factors in RE has been presumed since the first high incidence of centrotemporal spikes in family members of patients with RE was reported in 1964 [42]. RE and related syndromes with atypical features do not follow a Mendelian inheritance mode [43]. The clinical and genetic studies have shown complex inheritance [43, 44, 45, 46, 47, 48, 49, 50, 51].
The genetics of CTS is not the same as the clinical genetics of RE [52]. Although CTS is the primary EEG characteristics of RE or ARE, they are also observed in healthy children [53] or the children with autistic spectrum disorders without seizures [54]. Only 10% of EEG trait carriers had seizures [55, 56]. An autosomal dominant mode of inheritance of CTS on EEG has been reported by several authors [42, 55, 56] but it is still debated [52]. The linkage of CTS to ELP4-PAX6 region on 11p13 and chromosome 15q13 [57], 16p12–11.2 [58], and 15q14 [59] have been identified.
Doose et al. investigated the broad spectrum clinical and EEG manifestation of 147 children with RE and their 1266 family members revealed a high incidence of febrile convulsion and afebrile GTCS in patients and their relatives suggested multifactorial inheritance. EEG recordings of probands and their siblings showed a high rate of generalized EEG traits [43].
A multicentral twin study of eighteen twin pairs (10 MZ, 8 DZ) based on a twin database done by Vadlamudi and colleagues demonstrated that the etiology of RE and its inheritance mode is much more complicated than considered before [44].No twin pairs were concordant for RE. Only one monozygotic twin pair has shown centrotemporal spikes on EEG without seizures. Another intriguing finding from this twin data was that all twin pairs with atypical features RE, had a co-twin with seizures although discordant for RE, which emphasized that genetic factors may be more important in atypical cases of RE.
The genetic basis of RE/ARE is polygenic and complex, the interaction of environmental factors or other genes should be considered in etiology of RE spectrum epilepsy syndromes [60, 61]. A number of genes were found to follow the Mendelian inheritance and be associated with RE/ARE (Table 1).
Genetic mutations associated with RE/ARE spectrum.
Lemke et al., have identified GRIN2A mutations in 20% of patients with ARE associated with neurocognitive disturbances [66].
Although mutations in PRRT2, KCNQ2, KCNQ3, RBFOX1, and DEPDC5 genes with an autosomal dominant transmission reported in patients with RE spectrum epilepsy syndromes, they have not been confirmed by the studies based on large case series [70].
With the exception of GRIN2A and ELP4, many genes currently associated with RE/ARE, including KCNQ2, KCNQ3, CHRNA4, DEPDC5, RBFOX1/3, BDNF, and GABAA-R, were initially linked to other neurogenetic conditions, and later their phenotypes were expanded to RE/ARE.
4. Clinical features
The main seizure type in RE according to the ILAE 2017 seizure classification is focal aware seizure consisting of motor-hemifacial tonic or clonic contractions, oro-pharyngo-laryngeal symptoms, sensory symptoms represented by unilateral numbness or paresthesia of tongue, lips, gum, and inner part of the check, and associated with speech arrest, hypersalivation, and focal to bilateral seizures [2, 3, 4, 41, 71]. Hemiconvulsions and bilateral tonic–clonic seizures are less frequently observed ictal features, mainly seen in younger children due to rapid distribution of focal onset seizures [2, 3, 4, 6]. Hemiconvulsions may be followed by post-ictal Todd’s hemiparesis in 10% of cases [8, 72].
Seizures are brief, usually last from 30 sec to 2–3 minutes or longer if turn into bilateral tonic–clonic seizures [6, 18, 72]. Seizures mainly occur during night sleep or drowsiness, whereas the probability of awake seizures is less than 10% [73, 74]. Seizure frequency is low, most patients have less than 10 seizures, 10%–20% of patients have a single seizure [75]. Consciousness is completely preserved in around 60% of patients with RE [5].
Focal motor seizures in approximately one-third of cases manifest as unilateral oral-facial tonic or clonic contractions. These are brief (few seconds −1 min), a sudden burst of clonic contractions of the face, which may be entirely localized in the lower lip or spread to the ipsilateral upper and very rare to the lower extremities [1, 2, 3, 4, 5, 71, 76].
Tonic deviation of the mouth is frequently observed ictal motor manifestation [5].
Oro-pharyngo-laryngeal symptoms are mostly motor ictal phenomena with the involvement of the (epi-) glottis and pharynx (> 50%) produce guttural bizarre sounds, resembling gargling, grunting, wheezing [72]. These may be accompanied by contractions of the respiratory and abdominal muscles (vomiting like contractions) which appear in more than half of seizures [77]. They consist of unilateral sensory and motor manifestations inside the mouth, tongue, inner cheek, gums, teeth, and pharyngolaryngeal regions [3].
Speech arrest occurs in >40% of seizures with dys - or anarthria [3, 72]. The child usually is aware, with preserved receptive language, attempts to communicate with gestures, but unable to produce a single intelligible word [3, 5]. Speech arrest is considered more as a motor ictal manifestation associated with the loss of the power and coordination for the articulation of words [3]. There is no impairment of the cortical language mechanisms [4, 5].
Focal non-motor seizures commonly observed in RE.
Sensory symptoms may manifest as unilateral numbness or paraesthesias like tingling, prickling, freezing and their variations in the parts (rarely involve the whole area) of oral-facial-pharyngeal area, usually tongue, inner cheek, gum, teeth, lips [3, 4, 6]. Sensory seizures often occur in combination with motor seizures and hypersalivation [3, 5, 72].
Hypersalivation is one of the most characteristic autonomic ictal symptoms of RE, occurs in one-third of cases [2, 3, 4, 5, 71]. It is frequently associated with hemifacial motor symptoms. As well as the awareness is not disturbed in most of the cases, children usually are able to describe their sensations as sudden filling of the mouth with saliva and air, difficulty in pronouncing words, a lot of saliva flowing from the mouth [5].
Other autonomic ictal manifestations as ictal emesis and ictal syncope may observe rarely in RE. Although autonomic seizures are the cardinal symptom of Panayiotopoulos syndrome, they are reported in RE [74, 78, 79, 80, 81, 82]. The overlap of the clinical and EEG features of PS and RE has been widely investigated by several authors [5, 74, 79, 80]. The cases where two different types of childhood focal seizures presented at the same time or one form of epilepsy progressed to another have been thoroughly reported by different investigators [74, 79, 80, 81, 82, 83, 84, 85].
Focal to bilateral tonic–clonic seizures are a frequent seizure type present in one to two-thirds of children with RE. FBTCSs mostly appear during night sleep [86].
Status epilepticus is seen rarely and usually associated with an atypical course of the disease [87].
Focal motor SE occurs more often than generalized convulsive SE [3]. This state consists of unilateral or bilateral hemifacial contraction, subtle perioral myoclonus, speech arrest, dysarthria, excessive drooling, swallowing difficulties [88, 89, 90, 91, 92, 93].
5. EEG patterns
5.1 Interictal EEG
The EEG picture is distinctive in Rolandic epilepsy. The background activity is almost always preserved in an awake state and during sleep [91]. The characteristic interictal EEG pattern- centrotemporal spikes (CTS) or rolandic spikes are regarded as the neurobiological markers of RE. CTS is high-amplitude (usually > than 150 mkV) biphasic spikes or sharp waves of ∼ 70–80 milliseconds duration frequently followed by a slow activity on the central-mid temporal region (C3/C4, T3/T4) [2, 3, 4]. More posterior localization of CTS is often observed in the youngest patients [94]. The spikes may occur isolated or in clusters, in one or both hemispheres [95, 96] (Figure 1A and B). A focal rhythmic slow activity over the centrotemporal region is occasionally observed [2]. The most typical finding of the rolandic spikes is their significant increase in frequency during NREM sleep [74] (Figure 1C–E). The spikes appear only in sleep in about a third of children [97].
Figure 1.
7y.old boy with rolandic epilepsy. (A) Interictal awake EEG. Left centrotemporal spikes with rapid spreading to the right frontal-anterior temporal region. with maximum negativity over the C3T3,F7 and maximum positivity on the right-midline frontal-parietal region F4Fp2FzPzCz(AV montage, sensitivity 20Mkv/mm, paper speed 30mm/sec, LFF 70 Hz, HFF 0.5 Hz, Rejector 50 Hz). (B) Increased paper speed clearly demonstrates propagation of left centrotemporal spikes to the right frontal-anterior temporal region (AV montage, sensitivity 20 Mkv/mm, paper speed 120 mm/sec, LFF 70 Hz, HFF 0.5 Hz, Rejector 50 Hz). (C and D) Interictal 1NREM sleep EEG. The frequency of CTS of the same distribution is increased. (E) The same EEG sample in bipolar longitudinal montage demonstrates phase reversal on both right and left centrotemporal region (C3C4T3T4).
EEG and magnetoencephalography (MEG) studies show a stable horizontal dipole coming from the lower rolandic region with maximal electronegativity in the centrotemporal region and electropositivity in the frontal region, usually seen unilateral or bilateral [98, 99, 100]. Spikes may often appear in the central, parietal, midline, or even occipital regions which do not exclude a diagnosis of RE [98].
Somatosensory stimulation by the tapping of hands or feet or electrical stimulation of fingers at 1 Hz may activate CTS and somatosensory evoked potentials (SEPs) on the contralateral hemisphere [101].
Brief interictal generalized bursts of 3–5 Hz slow waves with intermixed small spikes distinctive than a pattern 3 Hz spike–wave seen in CAE may observe in about 4% of patients with RE [85, 102].
Many studies have tried to identify the source of rolandic discharges using topographic analysis, source modeling techniques, dipole tracing method, magnetoencephalography (MEG), and functional MRI (fMRI) investigations [99, 100, 101, 103, 104, 105, 106]. The functional MRI (fMRI) triggered by EEG of the rolandic spikes as well as MEG showed activation of the sensorimotor area [104], mainly in the orofacial division of the primary sensorimotor cortex [105]. However, it is challenging to distinguish the precentral or postcentral origin of CTS [103]. Ishitobi et al., suggested the precentral origin of rolandic spikes explained this theory by the continuity of cortical surface polarity from negative gyral cortex to the surface positive interhemispheric fissure based on the combination of scalp EEG and MEG [103]. Gregory and Wong analyzed 12 independent foci in 10 patients with RE assumed that the generator of a dipole discharge was located halfway between the maximum negative and positive poles, and was most likely situated at the depth of the lower rolandic fissure or Sylvian fissure [107]. The propagation pattern of rolandic spikes first studied by Jung et al., suggests that spike propagation was caused by intracortical spreading a single dipole across the central sulcus [108].
CTS are diagnostic markers of RE only in a suggestive clinical presentation [74]. It has been widely reported that 1.2 to 3.5% of normal healthy children population between 5 and 12 years old [109, 110], 6–34% of siblings and relatives of patients affected by RE [9, 111, 112], children with migraine, behavior disturbances, ADHD, variety of organic brain diseases with or without seizures, such as cerebral tumors, Rett syndrome, fragile X syndrome and focal cortical dysplasia [84, 113] also show CTS in routine EEG recording.
5.2 Ictal EEG
The first described ictal patterns are characterized by a quite monomorphic sequence of rhythmic sharp waves or spikes without significant post-ictal slowing [91, 114]. In 1990, Gutierrez et al. described an ictal event with speech arrest only characterized by a short train of ictal alpha activity, and then two multiple spikes and wave complexes originated from the left centrotemporal region followed by marked attenuation of the left hemispheric background [115]. Subclinical rhythmic discharges of spike and wave in the centrotemporal region have been documented by several authors in RE [116, 117]. Saint-Martin et al. in 2001 described a series of patients presenting with typical and also atypical ictal manifestations such as falls, negative myoclonus and observed that positive motor phenomenon correlated to the spike component preceding a negative motor phenomenon, correlated with the slow-wave component of the spike and wave complex [118].
Capovilla et al. recorded 34 seizures in 30 patients with RE and described four electrographic seizure patterns thus emphasizing that ictal pattern for RE is not unique [116]:
low-voltage activity of fast rhythmic spikes, increasing in amplitude and decreasing in frequency observed in the majority of patients,
a discharge of spikes intermixed with sharp waves increasing in frequency and amplitude,
monomorphic theta which progressively formed a discharge increasing in amplitude and decreasing in frequency,
initial focal depression of the electrical activity, followed by one of the three above described patterns.
Ictal EEG source analysis of 3 patients with RE demonstrated the activation of the opercula-insular area, time-locked to the contralateral focal myoclonic jerks [119].
6. Prognosis
In most cases, children with RE have a good prognosis regarding both seizures and neurodevelopment [120, 121]. The remission of seizures usually occurs before the age of 18 years [11, 98]. The cognitive and behavior problem may happen in an active period of disease which is reversible in most patients [11, 12].
Rolandic seizures occur in a period of significant brain maturation. The dysfunction of neuronal network activities such as focal discharges may be associated with neuropsychological problems, including, linguistic, cognitive, and behavioral impairment [28, 29, 30, 122]. The frequent spike discharges in sleep may boost language and attention processing problems [120, 123, 124, 125].
Mood and behavioral disorders were present in nearly a third of children (30.9%) with RE [126, 127, 128]. Retrospective studies have proposed that early age at onset pretends a more aggressive seizure course [18, 129, 130, 131].
Functional MRI study revealed CTS density caused hemodynamic changes even during wakefulness can interfere with the normal brain-language network and the bilateral insular cortex [132].
The neuropsychological tests such as Wechsler Intelligence Scale for Children-III (WISC-3rd), verbal fluency test, Wisconsin card sorting test, attention deficit diagnostic scale, and child behavior checklist scale are usually administered to measure a wide range of skills and cognitive functions of RE patients [35, 36, 37, 38, 133].
Many researchers showed a variety of neuropsychological deficits, behavioral and emotional difficulties in a limited cohort of patients with RE range from 19 to 67% [22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 134, 135]. The series of reported children with uncomplicated RE were described lower average results on neuropsychological tests involving visuomotor coordination, some executive functions, sustained attention, and language issues like spelling, reading aloud, reading comprehension, memory, and learning of auditory–verbal material, delayed recall, and verbal fluency, compared with controls. However, the Full-Scale Intelligence Quotient (FSIQ) was not significantly low in most of them.
D’Alessandro et al. investigated the neuropsychological data of 44 children with RE who did not have a seizure for more than 6 months without treatment. Attention, language, and visuomotor coordination tasks problems were more severe in children with a bilateral epileptiform discharge. However, in a follow-up assessment for 4 years, a re-examination of 11 children had revealed the normalization of cognitive functions in all [21].
Several studies reported that cognitive abnormalities and behavioral impairments are associated with a high interictal spike frequency [24, 25, 35, 120], the number of interictal abnormalities in wake or sleep [136], activation of interictal spikes during sleep [118, 137], and the presence of non-tangential dipole spikes [73].
Piccinelli et al. [138], investigated the frequency of specific learning disabilities such as reading, writing, and calculation in patients with typical RE and possible related electroclinical findings. They reported children with RE who developed seizures before age 8 years and had epileptiform discharges more than 50% of the sleep EEG recording in several tracings over more than a year were at risk of developing academic difficulties [138].
EEG may predict educational and behavioral impairments in children with RE. The presence of an intermittent slow-wave focus during wakefulness, a high number of spikes in the first hour of sleep (and during whole night sleep), and multiple asynchronous bilateral spike–wave foci in the first hour of sleep are associated with learning problems in children with RE [16, 139].
7. Atypical rolandic epilepsy
RE can present or evolve to an atypical form, characterized by atypical ictal semiology, different EEG findings, and poor neuropsychological outcomes [19, 140, 141].
Massa et al. described 5 interictal EEG patterns that significantly correlated with atypical evolutions of RE: [41] intermittent slow-wave focus; [2] multiple asynchronous spike–wave foci; [3] long spike–wave clusters; [4] generalized 3-c/s “absence-like” spike–wave discharges; [1] conjunction of interictal paroxysms with negative or positive myoclonia, and abundance of interictal abnormalities during wakefulness and sleep [136].
Several studies have shown an association between atypical rolandic epilepsy and known genes (Table 1). The identification of de novo or inherited mutations of N-methyl-D-aspartate (NMDA) receptor subunit-encoding genes (GRIN2A and GRIN2B) linked to speech and language, cognitive impairment, and behavioral difficulties have been a significant breakthrough in the understanding of the nature of atypical RE [142, 143, 144, 145]. Another relevant gene is elongation factor protein 4 (ELP4), which is associated with language impairment, autism spectrum disorder, mental retardation, and epilepsy with centrotemporal spikes on EEG [146].
Atypical rolandic epilepsy (ARE) is a severe epileptic condition especially with regards to cognitive consequences. The first description of atypical features of RE was published by Aicardi & Chevrie in 1982 showed rolandic epilepsy presenting periods with new types of seizures, mainly atonic and myoclonic, associated with continuous spike-and-waves in slow-sleep EEG (CSWS/ESES), and transitory learning difficulties [147]. Doose and Baier described similar patients with atonic fits leading to daily falls which is the hallmark seizure type for Lennox–Gastaut syndrome and termed the condition “pseudo-Lennox syndrome” to differentiate this two distinct conditions [148]. Patients with ARE have significantly lower full-scale and verbal IQ than the patients with typical RE [149]. Neuropsychological impairment, which may sometimes be present before the onset of the disease, is constantly present during the clinical course, but in contrast to ESES and LKS, the cognitive outcome is always favorable [92, 150]. Clinical semiology consists of typical for RE focal seizures, generalized tonic–clonic seizures, atypical absences, myoclonic seizures, and atonic seizures. The atonic attacks may involve the whole axial musculature or be localized, causing repeated brief (0.5–2.0 s) atonic episodes in the head or a limb (epileptic negative myoclonus) that usually occur for periods lasting one to several weeks, separated by seizure-free intervals of weeks or months [6, 90, 92]. Such atonic attacks are associated with the slow-wave component of spike and wave complexes, and the location of the EEG discharges corresponds to that of the atonic episodes [151, 152]. Interictal awake EEG shows bilateral sharp and sharp-slow wave complexes with higher amplitude in the rolandic area, which increases during sleep with bilateral synchronization [90, 92, 116, 153].
Using carbamazepine may promote the diffusion of spike–wave activity from the rolandic focus to induce atonic seizures, atypical absences in patients with RE [154].
Rolandic status epilepticus refers to status epilepticus that can be convulsive or non-convulsive, and either generalized or focal lasting days or weeks including motor facial seizures, oromotor dyspraxia, anarthria with persistent drooling and swallowing problems [155]. The interictal EEG usually shows focally or bilaterally synchronous sharp waves or sharp and slow wave complexes predominant in the rolandic area with a tendency to become continuous during sleep [146, 155]. The condition can be resolved with a good neurocognitive outcome with appropriate treatment [146]. These seizures can persist for more than 1 month without treatment [156, 157].
8. Treatment
The decision whether to treat children with RE or not requires a particularly careful risk–benefit analysis [2, 158, 159, 160, 161, 162, 163]. Many authors suggest that drug treatment is not necessary for typical RE because of its good prognosis, and usually infrequent nocturnal seizures [114, 154]. Moreover, in 40–50% of cases, the seizures are difficult to control with drugs [148]. Besides, the treatment with AED usually does not influence the duration of active epilepsy [163].
However, treatment may be indicated in patients with frequently recurring daytime seizures, generalized tonic–clonic seizures, young age at onset [164], or when the ictal events are disruptive to the patient or family [161, 163]. Furthermore, the presence of cognitive and behavioral disturbances, either transitory or persistent has to be considered [2, 5, 91, 92]. There is no single solution supported by definitive evidence which AED is more effective in the treatment of RE.
Internationally, carbamazepine (CBZ 20-40 mg/kg/d [165]) and valproate (VPA 20-30 mg/kg/d [166]) are the most often prescribed AED for children newly diagnosed RE [167]. However, the possible worsening of EEG in rolandic epilepsy by some drugs and particularly by CBZ, increasing epileptiform abnormalities during sleep, and inducing epileptic negative myoclonus have been reported [154].
Sulthiame, levetiracetam, and gabapentin were studied in a randomized controlled trial [158, 159, 167, 168, 169]. Sulthiame administered varied between 3.1 and 5.7 mg/kg/day was effective in controlling seizures in children with RE [159].
A prospective, open-label, pilot trial evaluating the efficacy and tolerability of levetiracetam (LVT 20-30 mg/kg/d) or oxcarbazepine (OXC 20-35 mg/kg/d) as monotherapy in two parallel groups of newly diagnosed RE patients demonstrated effectiveness in controlling seizures a follow-up period up to 2 years [162].
A randomized controlled multicenter trial comparing the effects of either Levetiracetam or Sulthiame on EEG in RE showed a reduction of epileptiform discharges after 12 weeks of treatment [158]. Persistent epileptiform discharges after 12 weeks of treatment are associated with recurrent seizures [158].
When the presence of ESES associated or not with negative myoclonus, clinical status, or acquired aphasia is detected in children with RE, a change of antiepileptic drugs should be considered. Class IV studies suggest that sulthiame, benzodiazepines, ethosuximide, and, in most severe cases, corticosteroids might be useful [91, 92].
Duration of treatment in RE should not exceed 1 year following the last seizure, regardless of EEG changes [2].
Acknowledgments
We are grateful to Dr. Sándor Beniczky for his valuable comments on EEG figures.
Disclosure
None of the authors has any conflict of interest to disclose.
\n',keywords:"rolandic epilepsy, EEG, BECTS, epilepsy, atypical rolandic epilepsy, centrotemporal spikes, seizures, cognitive outcome",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75338.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75338.xml",downloadPdfUrl:"/chapter/pdf-download/75338",previewPdfUrl:"/chapter/pdf-preview/75338",totalDownloads:469,totalViews:0,totalCrossrefCites:1,dateSubmitted:"June 15th 2020",dateReviewed:"January 22nd 2021",datePrePublished:"February 19th 2021",datePublished:"April 28th 2021",dateFinished:"February 19th 2021",readingETA:"0",abstract:"Childhood epilepsy with centrotemporal spikes, had been previously considered as benign childhood epilepsy. According to the new classification proposed by Sheffer I. and colleagues the term “benign” has been changed to “self-limited”. Many studies reported that BECTS may cause transient or long lasting cognitive and behavioral disturbances. Rolandic epilepsy is the most frequent among the childhood focal epilepsy and may account for about 15–25% of all epileptic syndromes diagnosed between the ages of 5 to 15 years. The incidence range changes between 7.1–21 per 100000 in population younger than 15 years with male predominance. The age of onset in 90% of cases between 1 and 10 years with peak around 6–7 years. Seizures mainly occur during a night sleep, whereas the probability of awake seizures are less than 10%. The characteristic clinical features are: (1) focal motor seizure with unilateral orofacial tonic or clonic contractions; (2) speech arrest; (3) hypersalivation; (4) sensory symptoms represented by unilateral numbness or paresthesia of tongue, lips, gum and inner part of the check; (5) unilateral clonic jerk in leg and arm with postictal paresis; (6) generalized seizures. The EEG picture is distinctive in Rolandic epilepsy. The background activity is almost always preserved in awake state and during a sleep. The typical interictal EEG pattern is high voltage, diphasic spikes or sharp waves frequently with slow activity on central-midtemporal region. The centrotemporal spikes or rolandic spikes come from the lower rolandic region created a horizontal dipole with maximal electronegativity in the centrotemporal region and electropositivity in the frontal region usually seen unilateral or bilateral. In most cases children with RE have a good prognosis regarding both seizures and neurodevelopment. The remission of seizures usually occurs before the age of 18 years. The cognitive and behavior problem may happen in active period of disease which are reversable in most of patients.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75338",risUrl:"/chapter/ris/75338",signatures:"Ulviyya Guliyeva, Nana Nino Tatishvili and Rauan Kaiyrzhanov",book:{id:"9519",type:"book",title:"Epilepsy",subtitle:"Update on Classification, Etiologies, Instrumental Diagnosis and Treatment",fullTitle:"Epilepsy - Update on Classification, Etiologies, Instrumental Diagnosis and Treatment",slug:"epilepsy-update-on-classification-etiologies-instrumental-diagnosis-and-treatment",publishedDate:"April 28th 2021",bookSignature:"Sandro Misciagna",coverURL:"https://cdn.intechopen.com/books/images_new/9519.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83962-289-2",printIsbn:"978-1-83962-288-5",pdfIsbn:"978-1-83962-290-8",isAvailableForWebshopOrdering:!0,editors:[{id:"103586",title:null,name:"Sandro",middleName:null,surname:"Misciagna",slug:"sandro-misciagna",fullName:"Sandro Misciagna"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"324284",title:"Dr.",name:"Ulviyya",middleName:null,surname:"Guliyeva",fullName:"Ulviyya Guliyeva",slug:"ulviyya-guliyeva",email:"doctor.ulya@gmail.com",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/324284/images/15548_n.jpg",institution:null},{id:"345949",title:"Prof.",name:"Nana",middleName:null,surname:"Tatishvili",fullName:"Nana Tatishvili",slug:"nana-tatishvili",email:"n_tatishvili@hotmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"346211",title:"Dr.",name:"Rauan",middleName:null,surname:"Kaiyrzhanov",fullName:"Rauan Kaiyrzhanov",slug:"rauan-kaiyrzhanov",email:"rauan.kaiyrzhanov.14@ucl.ac.uk",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Terminology and classification",level:"1"},{id:"sec_3",title:"3. Etiology",level:"1"},{id:"sec_4",title:"4. Clinical features",level:"1"},{id:"sec_5",title:"5. EEG patterns",level:"1"},{id:"sec_5_2",title:"5.1 Interictal EEG",level:"2"},{id:"sec_6_2",title:"5.2 Ictal EEG",level:"2"},{id:"sec_8",title:"6. Prognosis",level:"1"},{id:"sec_9",title:"7. Atypical rolandic epilepsy",level:"1"},{id:"sec_10",title:"8. Treatment",level:"1"},{id:"sec_11",title:"Acknowledgments",level:"1"},{id:"sec_11",title:"Disclosure",level:"1"}],chapterReferences:[{id:"B1",body:'Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984. Epilepsia. 1993 May-Jun;34(3):453-468. doi: 10.1111/j.1528-1157.1993.tb02586.x. PMID: 8504780'},{id:"B2",body:'Federico Vigevano, Nicola Specchio, Natalio Fejerman, Chapter 61 - Idiopathic focal epilepsies, Editor(s): Olivier Dulac, Maryse Lassonde, Harvey B. 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London: Cambridge University Press; 2002:251-268'},{id:"B158",body:'Tacke, M., Borggraefe, I., Gerstl, L., Heinen, F., Vill, K., Bonfert, M., … Baethmann, M. (2018).Effects of Levetiracetam and Sulthiame on EEG in benign epilepsy with centrotemporal spikes: A randomized controlled trial. Seizure, 56, 115-120. doi:10.1016/j.seizure.2018.01.015'},{id:"B159",body:'Dietz Rating, Christian Wolf, and Thomas Bast. Sulthiame as monotherapy in children with benign childhood epilepsy with centrotemporal spikes: A 6-month randomized, double-blind, placebo-controlled study. Epilepsia, 41(10):1284-1288, 2000'},{id:"B160",body:'Bruria Ben-Zeev, Nathan Watemberg, Pinchas Lerman, Itshak Barash, Nathan Brand, and Tally Lerman-Sagie. Sulthiame in childhood epilepsy. Pediatr. int., 46(5):521-524, 2004'},{id:"B161",body:'A Verrotti, G Coppola, R Manco, G Ciambra, P Iannetti, S Grosso, P Balestri, E Franzoni, and F Chiarelli. Levetiracetam monotherapy for children and adolescents with benign rolandic seizures. Seizure, 16(3):271-275, 2007'},{id:"B162",body:'Coppola G, Franzoni E, Verrotti A, Garone C, Sarajlija J, Operto FF, Pascotto A. Levetiracetam or oxcarbazepine as monotherapy in newly diagnosed benign epilepsy of childhood with centrotemporal spikes (BECTS): an open-label, parallel group trial. Brain Dev. 2007 Jun;29(5):281-284. doi: 10.1016/j.braindev.2006.09.008. Epub 2006 Oct 20. PMID: 17055681'},{id:"B163",body:'Hamada Y, Okuno T, Hattori H, Mikawa H. Indication for antiepileptic drug treatment of benign childhood epilepsy with centro-temporal spikes. Brain Dev 1994;16:159—161'},{id:"B164",body:'Bourgeois BF. Drug treatment of benign focal epilepsies of childhood. Epilepsia 2000;41:1057-1058'},{id:"B165",body:'Reed, M. D., & Gilman, J. T. (1991). Carbamazepine Dosing for Pediatric Seizure Disorders: The Highs and Lows. DICP, 25(10), 1109-1112. doi:10.1177/106002809102501017'},{id:"B166",body:'Guerrini, R. (2006). Valproate as a Mainstay of Therapy for Pediatric Epilepsy. Pediatric Drugs, 8(2), 113-129. doi:10.2165/00148581-200608020-00004'},{id:"B167",body:'Glauser TA, Ayala R, Elterman RD et al. (2000). Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology 66: 1654-1660'},{id:"B168",body:'George L. Morris, Gabapentin, Epilepsia, 40 (Suppl 5),1999'},{id:"B169",body:'Bourgeois B, Brown LW, Pellock JM, et al. Gabapentin monotherapy in children with benign childhood epilepsy with centro-temporal spikes (BECTS): a 36-week, double-blind. placebo-controlled study. Am Proc Epilepsy Soc Meef 1998'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Ulviyya Guliyeva",address:"doctor.ulya@gmail.com",affiliation:'
Department of Neurogenetics, Institute of Neurology, UCL, England
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Our business values are based on those any scientist applies to their research. The values of our business are based on the same ones that all good scientists apply to their research. We have created a culture of respect and collaboration within a relaxed, friendly, and progressive atmosphere, while maintaining academic rigour.
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Please check out our job board for open positions.
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Integrity - We are consistent and dependable, always striving for precision and accuracy in the true spirit of science.
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IntechOpen is a dynamic, vibrant company, where exceptional people are achieving great things. We offer a creative, dedicated, committed, and passionate environment but never lose sight of the fact that science and discovery is exciting and rewarding. We constantly strive to ensure that members of our community can work, travel, meet world-renowned researchers and grow their own career and develop their own experiences.
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If this sounds like a place that you would like to work, whether you are at the beginning of your career or are an experienced professional, we invite you to drop us a line and tell us why you could be the right person for IntechOpen.
Integrity - We are consistent and dependable, always striving for precision and accuracy in the true spirit of science.
\n\n
Openness - We communicate honestly and transparently. We are open to constructive criticism and committed to learning from it.
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Disruptiveness - We are eager for discovery, for new ideas and for progression. We approach our work with creativity and determination, with a clear vision that drives us forward. We look beyond today and strive for a better tomorrow.
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What makes IntechOpen a great place to work?
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IntechOpen is a dynamic, vibrant company, where exceptional people are achieving great things. We offer a creative, dedicated, committed, and passionate environment but never lose sight of the fact that science and discovery is exciting and rewarding. We constantly strive to ensure that members of our community can work, travel, meet world-renowned researchers and grow their own career and develop their own experiences.
\n\n
If this sounds like a place that you would like to work, whether you are at the beginning of your career or are an experienced professional, we invite you to drop us a line and tell us why you could be the right person for IntechOpen.
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Viana",authors:[{id:"15565",title:"Prof.",name:"Julio",middleName:null,surname:"Viana",slug:"julio-viana",fullName:"Julio Viana"},{id:"238389",title:"Ph.D.",name:"Sílvia",middleName:null,surname:"Cruz",slug:"silvia-cruz",fullName:"Sílvia Cruz"},{id:"247716",title:"Prof.",name:"Luís",middleName:null,surname:"Rocha",slug:"luis-rocha",fullName:"Luís Rocha"}]}],mostDownloadedChaptersLast30Days:[{id:"70315",title:"Some Basic and Key Issues of Switched-Reluctance Machine Systems",slug:"some-basic-and-key-issues-of-switched-reluctance-machine-systems",totalDownloads:1238,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Although switched-reluctance machine (SRM) possesses many structural advantages and application potential, it is rather difficult to successfully control with high performance being comparable to other machines. Many critical affairs must be properly treated to obtain the improved operating characteristics. This chapter presents the basic and key technologies of switched-reluctance machine in motor and generator operations. The contents in this chapter include: (1) structures and governing equations of SRM; (2) some commonly used SRM converters; (3) estimation of key parameters and performance evaluation of SRM drive; (4) commutation scheme, current control scheme, and speed control scheme of SRM drive; (5) some commonly used front-end converters and their operation controls for SRM drive; (6) reversible and regenerative braking operation controls for SRM drive; (7) some tuning issues for SRM drive; (8) operation control and some tuning issues of switched-reluctance generators; and (9) experimental application exploration for SRM systems—(a) wind generator and microgrid and (b) EV SRM drive.",book:{id:"8899",slug:"modelling-and-control-of-switched-reluctance-machines",title:"Modelling and Control of Switched Reluctance Machines",fullTitle:"Modelling and Control of Switched Reluctance Machines"},signatures:"Chang-Ming Liaw, Min-Ze Lu, Ping-Hong Jhou and Kuan-Yu Chou",authors:[{id:"37616",title:"Prof.",name:"Chang-Ming",middleName:null,surname:"Liaw",slug:"chang-ming-liaw",fullName:"Chang-Ming Liaw"},{id:"306461",title:"Mr.",name:"Min-Ze",middleName:null,surname:"Lu",slug:"min-ze-lu",fullName:"Min-Ze Lu"},{id:"306463",title:"Mr.",name:"Ping-Hong",middleName:null,surname:"Jhou",slug:"ping-hong-jhou",fullName:"Ping-Hong Jhou"},{id:"306464",title:"Mr.",name:"Kuan-Yu",middleName:null,surname:"Chou",slug:"kuan-yu-chou",fullName:"Kuan-Yu Chou"}]},{id:"52822",title:"Non-Orthogonal Multiple Access (NOMA) for 5G Networks",slug:"non-orthogonal-multiple-access-noma-for-5g-networks",totalDownloads:14819,totalCrossrefCites:27,totalDimensionsCites:37,abstract:"In this chapter, we explore the concept of non-orthogonal multiple access (NOMA) scheme for the future radio access for 5G. We first provide the fundamentals of the technique for both downlink and uplink channels and then discuss optimizing the network capacity under fairness constraints. We further discuss the impacts of imperfect receivers on the performance of NOMA networks. Finally, we discuss the spectral efficiency (SE) of the networks that employ NOMA with its relations with energy efficiency (EE). We demonstrate that the networks with NOMA outperform other multiple access schemes in terms of sum capacity, EE and SE.",book:{id:"5480",slug:"towards-5g-wireless-networks-a-physical-layer-perspective",title:"Towards 5G Wireless Networks",fullTitle:"Towards 5G Wireless Networks - A Physical Layer Perspective"},signatures:"Refik Caglar Kizilirmak",authors:[{id:"188668",title:"Dr.",name:"Refik Caglar",middleName:null,surname:"Kizilirmak",slug:"refik-caglar-kizilirmak",fullName:"Refik Caglar Kizilirmak"}]},{id:"77871",title:"Protection of Microgrids",slug:"protection-of-microgrids",totalDownloads:279,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The concept of microgrids goes back to the early years of the electricity industry although the systems then were not formally called microgrids. Today, two types of microgrids can be seen: independent and grid connected. The protection requirement of these two types differs as the protection needs of an independent microgrid are intended for protecting components and systems within the microgrid, whereas a grid connected microgrid demands both internal and external protection. The first part of this chapter is dedicated to independent microgrids. How protection devices such as residual current circuit breakers, miniature and moulded case circuit breakers, and surge protective devices should be selected for an example microgrid is discussed while referring to the relevant standards. In the next section, the protection of a grid connected microgrid is discussed. Particularly, micro-source protection, microgrid protection, loss of mains protection and fault ride-through requirements are discussed while referring to two commonly used distributed generator connection codes. An example with simulations carried out in the IPSA simulation platform was used to explain different protection requirements and calculation procedures. Finally, grounding requirements are discussed while referring to different interfacing transformer connections and voltage source inverter connections.",book:{id:"10176",slug:"microgrids-and-local-energy-systems",title:"Microgrids and Local Energy Systems",fullTitle:"Microgrids and Local Energy Systems"},signatures:"Janaka Ekanayake",authors:[{id:"328170",title:"Prof.",name:"Janake",middleName:null,surname:"Ekanayake",slug:"janake-ekanayake",fullName:"Janake Ekanayake"}]},{id:"47585",title:"Free Space Optical Communications — Theory and Practices",slug:"free-space-optical-communications-theory-and-practices",totalDownloads:9023,totalCrossrefCites:43,totalDimensionsCites:57,abstract:null,book:{id:"4473",slug:"contemporary-issues-in-wireless-communications",title:"Contemporary Issues in Wireless Communications",fullTitle:"Contemporary Issues in Wireless Communications"},signatures:"Abdulsalam Ghalib Alkholidi and Khaleel Saeed Altowij",authors:[{id:"100466",title:"Dr.",name:"Abdulsalam",middleName:null,surname:"Alkholidi",slug:"abdulsalam-alkholidi",fullName:"Abdulsalam Alkholidi"},{id:"131091",title:"MSc.",name:"Khalil",middleName:null,surname:"Altowij",slug:"khalil-altowij",fullName:"Khalil Altowij"}]},{id:"41657",title:"Algorithms for Efficient Computation of Convolution",slug:"algorithms-for-efficient-computation-of-convolution",totalDownloads:10069,totalCrossrefCites:15,totalDimensionsCites:20,abstract:null,book:{id:"3158",slug:"design-and-architectures-for-digital-signal-processing",title:"Design and Architectures for Digital Signal Processing",fullTitle:"Design and Architectures for Digital Signal Processing"},signatures:"Karas Pavel and Svoboda David",authors:[{id:"154795",title:"Ph.D. Student",name:"Pavel",middleName:null,surname:"Karas",slug:"pavel-karas",fullName:"Pavel Karas"},{id:"155141",title:"Dr.",name:"David",middleName:null,surname:"Svoboda",slug:"david-svoboda",fullName:"David Svoboda"}]}],onlineFirstChaptersFilter:{topicId:"116",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82123",title:"Microwave-Assisted Pyrolysis Process: From a Laboratory Scale to an Industrial Plant",slug:"microwave-assisted-pyrolysis-process-from-a-laboratory-scale-to-an-industrial-plant",totalDownloads:4,totalDimensionsCites:0,doi:"10.5772/intechopen.104925",abstract:"One of the great challenges for the European Union (EU) is the “Circular Economy Package,” and to achieve this goal, materials at the end of their life cycle must be recycled using a sustainable process. In this way, as a thermochemical treatment, pyrolysis represents a significant opportunity so long it leads to the recovery of both energy and chemical content of mixed, contaminated, or deteriorated plastics. An excellent history of an academic-industrial adventure started in 2008 at the Department of Chemistry of the University of Florence demonstrates the possibility of employing microwaves to recycle plastics to preserve their energy and chemical content. After that, Techwave started industrialization of the process in 2019, realizing a small-scale prototype followed by a full-scale pilot plant using different plastic materials (e.g., polystyrene, acrylonitrile-butadiene-styrene (ABS), and polypropylene). Nowadays, the plant may process 90 kg/h of plastics with a low formation of char and gas and an interesting amount of liquid useful as a source of chemicals or fuel because it has an LHV of 35–43 kJ/kg. The Microwave-Assisted Pyrolysis (MAP) is an industrial novelty in plastic recycling, and it looks very promising for a much more modern and innovative plastic waste recovery system.",book:{id:"11145",title:"Recent Microwave Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11145.jpg"},signatures:"Marco Frediani, Piero Frediani, Gianni Innocenti, Irene Mellone, Roberto Simoni and Gianpaolo Oteri"},{id:"82420",title:"Applications of Microwaves in Medicine and Biology",slug:"applications-of-microwaves-in-medicine-and-biology",totalDownloads:7,totalDimensionsCites:0,doi:"10.5772/intechopen.105492",abstract:"This chapter deals with the description of recent research activities oriented on the perspective of microwave technologies in medicine and biology. It brings new ideas about the possibilities of using microwaves in thermotherapy—above all toward hyperthermia in cancer treatment. Development of new types of hyperthermia applicators (based, e.g., on technologies such as metamaterials, evanescent modes in waveguides, and other types of transmission structures) will be discussed here. Furthermore, we would like to underline in this chapter perspectives of microwaves in medical diagnostics. It is possible to expect that, e.g., microwave differential tomography, UWB radar, and microwave radiometers (all three can be used both for medical diagnostic and for noninvasive temperature measurement) will soon play an important role in it. Finally, experimental equipment necessary for research on the biological effects of EM fields is presented.",book:{id:"11145",title:"Recent Microwave Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11145.jpg"},signatures:"David Vrba, Jan Vrba, Ondrej Fiser, Jesus Cumana, Milan Babak and Jan Vrba Senior"},{id:"81917",title:"Fluidics for Reconfigurable Microwave Components",slug:"fluidics-for-reconfigurable-microwave-components",totalDownloads:11,totalDimensionsCites:0,doi:"10.5772/intechopen.104857",abstract:"Dielectric and conducting liquids with varying electromagnetic properties can offer novel alternatives for building tunable microwave passive components as well as antennas. Injecting these fluidics in or around microwave substrates alters their overall electrical characteristics, enabling circuit reconfigurability. Alternatively, changing the shapes and dimensions of conductors by using liquid metals can achieve similar reconfigurability. An overview of different liquids and their electromagnetic properties is first given. The principles behind the reconfigurability of the electrical characteristics of typical guiding structures based on mode shape variation in the presence of fluids are discussed. The realization of an N-bit programmable impedance tuner in 3D LTCC technology based on these principles is presented.",book:{id:"11145",title:"Recent Microwave Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11145.jpg"},signatures:"Dorra Bahloul, Ines Amor and Ammar Kouki"},{id:"82046",title:"One Model of Microwave Heating of Water Drop",slug:"one-model-of-microwave-heating-of-water-drop",totalDownloads:7,totalDimensionsCites:0,doi:"10.5772/intechopen.104949",abstract:"This work deals with the modeling of microwave heating of a water drop. A drop model is reduced to its electric dipoles, masses, and charges are constructed using the associating of COMSOL Multiphysics and Matlab software. The considered model proposes a microscopic point of view on microwave heating, which transforms electrical energy into heat.",book:{id:"11145",title:"Recent Microwave Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11145.jpg"},signatures:"Serge Lefeuvre and Olga Gomonova"},{id:"82076",title:"Power Divider/Combiner",slug:"power-divider-combiner",totalDownloads:13,totalDimensionsCites:0,doi:"10.5772/intechopen.104911",abstract:"With the remarkable progress in the use of Internet of Things (IoT) and 5G, there is a demand for higher performance such as miniaturization, broadband/multiband, low loss, and high integration for several microwave circuits. This chapter treats microwave power dividers/combiners used in amplifiers, mixers, phase shifters, antenna feeding networks, and so on. Here, the treated circuits are composed of LC-ladder circuits and an absorption resistor. It shows that multiband (dual-band and tri-band) and broadband can be achieved by changing the number of stages of the LC-ladder circuit. In addition, the effectiveness of this design method is demonstrated by electromagnetic simulations and prototype experiments.",book:{id:"11145",title:"Recent Microwave Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11145.jpg"},signatures:"Tadashi Kawai, Ayumu Tsuchiya and Akira Enokihara"},{id:"82035",title:"Orbital Angular Momentum Wave and Propagation",slug:"orbital-angular-momentum-wave-and-propagation",totalDownloads:33,totalDimensionsCites:0,doi:"10.5772/intechopen.104477",abstract:"Orbital angular momentum (OAM) techniques are exploited for a wide range of potential radiofrequency (RF) and electromagnetic applications, including megahertz-through-terahertz wireless systems, fiber-based and free-space optical communications and sensing, just like acoustic and any other wave-based counterparts. In those RF and electromagnetic applications, OAM wave is set to enable the development of high-speed and high-capacity communications, radar imaging, and sensing systems, among many others. In this chapter, a comprehensive comparison between plane wave and OAM wave propagation using a patch antenna as a radiator at 2.45 GHz is presented and discussed. This comparison allows the appreciation of the fundamental properties of the OAM wave when compared against its plane wave counterpart. For simplified comparison and discussion, we will use two abbreviated terms: PWPA for plane-wave patch antenna and OWPA for OAM wave patch antenna. PWPA refers to as planar patch antenna that produces plane waves in far-field, whereas patch antenna that delivers OAM waves in far-field is termed as OWPA. In this context, all physical quantities for wave propagation such as electric field, magnetic field, wave impedance, wave vector, velocity, pitch, and propagation constant are theoretically studied for OAM waves and compared with plane waves. First, OAM wave generation is studied through widely used uniform circular antenna array (UCAA) in literature. Then, plane wave patch antenna (PWPA) and OAM wave patch antenna (OWPA) are designed and verified through simulation and measurement. OWPA is designed with characteristic mode analysis (CMA) based on a lossy substrate to excite a twisting wave at a determined patch location. With this in mind, a comparative investigation of PWPA and OWPA is conducted for different physical parameters. Cylindrical near-field scan clearly shows a helical wave motion for OWPA, whereas a normal plane wave motion for PWPA. Furthermore, the comparison of plane wave and OAM wave propagation is demonstrated using the combination of a Tx–Rx antenna pair. It is observed that the overall signal from OWPA can be received with two PWPAs at an angle as OWPA has a dispersive beam. Moreover, the receiving antenna with a large aperture and plane wave horn antenna (PWHA) in the line of sight (LOS) range can also be used to receive the overall signal from OWPA. The received signal in PWPA–PWPA, OWPA–OWPA, OWPA–PWPA–PWPA, OWPA–PWHA Tx–Rx pairs is thoroughly compared and studied. Measured and simulated results for transmission are −30 dB for 0 dB input signal in OWPA–PWPA–PWPA and OWPA–PWHA cases, which are reasonably justified within the sensitivity/dynamic range of short-distance communication and radar sensing receivers.",book:{id:"11145",title:"Recent Microwave Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11145.jpg"},signatures:"Pankaj Jha and Ke Wu"}],onlineFirstChaptersTotal:14},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"25",title:"Environmental Sciences",doi:"10.5772/intechopen.100362",issn:"2754-6713",scope:"
\r\n\tScientists have long researched to understand the environment and man’s place in it. The search for this knowledge grows in importance as rapid increases in population and economic development intensify humans’ stresses on ecosystems. Fortunately, rapid increases in multiple scientific areas are advancing our understanding of environmental sciences. Breakthroughs in computing, molecular biology, ecology, and sustainability science are enhancing our ability to utilize environmental sciences to address real-world problems. \r\n\tThe four topics of this book series - Pollution; Environmental Resilience and Management; Ecosystems and Biodiversity; and Water Science - will address important areas of advancement in the environmental sciences. They will represent an excellent initial grouping of published works on these critical topics.
",coverUrl:"https://cdn.intechopen.com/series/covers/25.jpg",latestPublicationDate:"June 28th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:1,editor:{id:"197485",title:"Dr.",name:"J. Kevin",middleName:null,surname:"Summers",slug:"j.-kevin-summers",fullName:"J. Kevin Summers",profilePictureURL:"https://mts.intechopen.com/storage/users/197485/images/system/197485.jpg",biography:"J. Kevin Summers is a Senior Research Ecologist at the Environmental Protection Agency’s (EPA) Gulf Ecosystem Measurement and Modeling Division. He is currently working with colleagues in the Sustainable and Healthy Communities Program to develop an index of community resilience to natural hazards, an index of human well-being that can be linked to changes in the ecosystem, social and economic services, and a community sustainability tool for communities with populations under 40,000. He leads research efforts for indicator and indices development. Dr. Summers is a systems ecologist and began his career at the EPA in 1989 and has worked in various programs and capacities. This includes leading the National Coastal Assessment in collaboration with the Office of Water which culminated in the award-winning National Coastal Condition Report series (four volumes between 2001 and 2012), and which integrates water quality, sediment quality, habitat, and biological data to assess the ecosystem condition of the United States estuaries. He was acting National Program Director for Ecology for the EPA between 2004 and 2006. He has authored approximately 150 peer-reviewed journal articles, book chapters, and reports and has received many awards for technical accomplishments from the EPA and from outside of the agency. Dr. Summers holds a BA in Zoology and Psychology, an MA in Ecology, and Ph.D. in Systems Ecology/Biology.",institutionString:null,institution:{name:"Environmental Protection Agency",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"38",title:"Pollution",coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",isOpenForSubmission:!0,annualVolume:11966,editor:{id:"110740",title:"Dr.",name:"Ismail M.M.",middleName:null,surname:"Rahman",slug:"ismail-m.m.-rahman",fullName:"Ismail M.M. Rahman",profilePictureURL:"https://mts.intechopen.com/storage/users/110740/images/2319_n.jpg",biography:"Ismail Md. Mofizur Rahman (Ismail M. M. Rahman) assumed his current responsibilities as an Associate Professor at the Institute of Environmental Radioactivity, Fukushima University, Japan, in Oct 2015. He also has an honorary appointment to serve as a Collaborative Professor at Kanazawa University, Japan, from Mar 2015 to the present. \nFormerly, Dr. Rahman was a faculty member of the University of Chittagong, Bangladesh, affiliated with the Department of Chemistry (Oct 2002 to Mar 2012) and the Department of Applied Chemistry and Chemical Engineering (Mar 2012 to Sep 2015). Dr. Rahman was also adjunctly attached with Kanazawa University, Japan (Visiting Research Professor, Dec 2014 to Mar 2015; JSPS Postdoctoral Research Fellow, Apr 2012 to Mar 2014), and Tokyo Institute of Technology, Japan (TokyoTech-UNESCO Research Fellow, Oct 2004–Sep 2005). \nHe received his Ph.D. degree in Environmental Analytical Chemistry from Kanazawa University, Japan (2011). He also achieved a Diploma in Environment from the Tokyo Institute of Technology, Japan (2005). Besides, he has an M.Sc. degree in Applied Chemistry and a B.Sc. degree in Chemistry, all from the University of Chittagong, Bangladesh. \nDr. Rahman’s research interest includes the study of the fate and behavior of environmental pollutants in the biosphere; design of low energy and low burden environmental improvement (remediation) technology; implementation of sustainable waste management practices for treatment, handling, reuse, and ultimate residual disposition of solid wastes; nature and type of interactions in organic liquid mixtures for process engineering design applications.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"201020",title:"Dr.",name:"Zinnat Ara",middleName:null,surname:"Begum",slug:"zinnat-ara-begum",fullName:"Zinnat Ara Begum",profilePictureURL:"https://mts.intechopen.com/storage/users/201020/images/system/201020.jpeg",biography:"Zinnat A. Begum received her Ph.D. in Environmental Analytical Chemistry from Kanazawa University in 2012. She achieved her Master of Science (M.Sc.) degree with a major in Applied Chemistry and a Bachelor of Science (B.Sc.) in Chemistry, all from the University of Chittagong, Bangladesh. Her work affiliations include Fukushima University, Japan (Visiting Research Fellow, Institute of Environmental Radioactivity: Mar 2016 to present), Southern University Bangladesh (Assistant Professor, Department of Civil Engineering: Jan 2015 to present), and Kanazawa University, Japan (Postdoctoral Fellow, Institute of Science and Engineering: Oct 2012 to Mar 2014; Research fellow, Venture Business Laboratory, Advanced Science and Social Co-Creation Promotion Organization: Apr 2018 to Mar 2021). The research focus of Dr. Zinnat includes the effect of the relative stability of metal-chelator complexes in the environmental remediation process designs and the development of eco-friendly soil washing techniques using biodegradable chelators.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorThree:null},{id:"39",title:"Environmental Resilience and Management",coverUrl:"https://cdn.intechopen.com/series_topics/covers/39.jpg",isOpenForSubmission:!0,annualVolume:11967,editor:{id:"137040",title:"Prof.",name:"Jose",middleName:null,surname:"Navarro-Pedreño",slug:"jose-navarro-pedreno",fullName:"Jose Navarro-Pedreño",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRAXrQAO/Profile_Picture_2022-03-09T15:50:19.jpg",biography:"Full professor at University Miguel Hernández of Elche, Spain, previously working at the University of Alicante, Autonomous University of Madrid and Polytechnic University of Valencia. Graduate in Sciences (Chemist), graduate in Geography and History (Geography), master in Water Management, Treatment, master in Fertilizers and Environment and master in Environmental Management; Ph.D. in Environmental Sciences. His research is focused on soil-water and waste-environment relations, mainly on soil-water and soil-waste interactions under different management and waste reuse. His work is reflected in more than 230 communications presented in national and international conferences and congresses, 29 invited lectures from universities, associations and government agencies. Prof. Navarro-Pedreño is also a director of the Ph.D. Program Environment and Sustainability (2012-present) and a member of several societies among which are the Spanish Society of Soil Science, International Union of Soil Sciences, European Society for Soil Conservation, DessertNet and the Spanish Royal Society of Chemistry.",institutionString:"Miguel Hernández University of Elche, Spain",institution:null},editorTwo:null,editorThree:null},{id:"40",title:"Ecosystems and Biodiversity",coverUrl:"https://cdn.intechopen.com/series_topics/covers/40.jpg",isOpenForSubmission:!0,annualVolume:11968,editor:{id:"209149",title:"Prof.",name:"Salustiano",middleName:null,surname:"Mato",slug:"salustiano-mato",fullName:"Salustiano Mato",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLREQA4/Profile_Picture_2022-03-31T10:23:50.png",biography:"Salustiano Mato de la Iglesia (Santiago de Compostela, 1960) is a doctor in biology from the University of Santiago and a Professor of zoology at the Department of Ecology and Animal Biology at the University of Vigo. He has developed his research activity in the fields of fauna and soil ecology, and in the treatment of organic waste, having been the founder and principal investigator of the Environmental Biotechnology Group of the University of Vigo.\r\nHis research activity in the field of Environmental Biotechnology has been focused on the development of novel organic waste treatment systems through composting. The result of this line of work are three invention patents and various scientific and technical publications in prestigious international journals.",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorTwo:{id:"60498",title:"Prof.",name:"Josefina",middleName:null,surname:"Garrido",slug:"josefina-garrido",fullName:"Josefina Garrido",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRj1VQAS/Profile_Picture_2022-03-31T10:06:51.jpg",biography:"Josefina Garrido González (Paradela de Abeleda, Ourense 1959), is a doctor in biology from the University of León and a Professor of Zoology at the Department of Ecology and Animal Biology at the University of Vigo. 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Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,series:{id:"11",title:"Biochemistry"}}},seriesLanding:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 29th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:4,numberOfPublishedChapters:318,numberOfPublishedBooks:32,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},subseries:[{id:"14",title:"Cell and Molecular Biology",keywords:"Omics (Transcriptomics; Proteomics; Metabolomics), Molecular Biology, Cell Biology, Signal Transduction and Regulation, Cell Growth and Differentiation, Apoptosis, Necroptosis, Ferroptosis, Autophagy, Cell Cycle, Macromolecules and Complexes, Gene Expression",scope:"The Cell and Molecular Biology topic within the IntechOpen Biochemistry Series aims to rapidly publish contributions on all aspects of cell and molecular biology, including aspects related to biochemical and genetic research (not only in humans but all living beings). We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics include, but are not limited to: Advanced techniques of cellular and molecular biology (Molecular methodologies, imaging techniques, and bioinformatics); Biological activities at the molecular level; Biological processes of cell functions, cell division, senescence, maintenance, and cell death; Biomolecules interactions; Cancer; Cell biology; Chemical biology; Computational biology; Cytochemistry; Developmental biology; Disease mechanisms and therapeutics; DNA, and RNA metabolism; Gene functions, genetics, and genomics; Genetics; Immunology; Medical microbiology; Molecular biology; Molecular genetics; Molecular processes of cell and organelle dynamics; Neuroscience; Protein biosynthesis, degradation, and functions; Regulation of molecular interactions in a cell; Signalling networks and system biology; Structural biology; Virology and microbiology.",annualVolume:11410,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"79367",title:"Dr.",name:"Ana Isabel",middleName:null,surname:"Flores",fullName:"Ana Isabel Flores",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRpIOQA0/Profile_Picture_1632418099564",institutionString:null,institution:{name:"Hospital Universitario 12 De Octubre",institutionURL:null,country:{name:"Spain"}}},{id:"328234",title:"Ph.D.",name:"Christian",middleName:null,surname:"Palavecino",fullName:"Christian Palavecino",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000030DhEhQAK/Profile_Picture_1628835318625",institutionString:null,institution:{name:"Central University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",fullName:"Francisco Javier Martin-Romero",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",institutionString:null,institution:{name:"University of Extremadura",institutionURL:null,country:{name:"Spain"}}}]},{id:"15",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",annualVolume:11411,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null,editorialBoard:[{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",fullName:"Abdulsamed Kükürt",profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",institutionString:null,institution:{name:"Kafkas University",institutionURL:null,country:{name:"Turkey"}}},{id:"241413",title:"Dr.",name:"Azhar",middleName:null,surname:"Rasul",fullName:"Azhar Rasul",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRT1oQAG/Profile_Picture_1635251978933",institutionString:null,institution:{name:"Government College University, Faisalabad",institutionURL:null,country:{name:"Pakistan"}}},{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",fullName:"Sergey Sedykh",profilePictureURL:"https://mts.intechopen.com/storage/users/178316/images/system/178316.jfif",institutionString:null,institution:{name:"Novosibirsk State University",institutionURL:null,country:{name:"Russia"}}}]},{id:"17",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",annualVolume:11413,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",fullName:"Anca Pantea Stoian",profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"203824",title:"Dr.",name:"Attilio",middleName:null,surname:"Rigotti",fullName:"Attilio Rigotti",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Pontifical Catholic University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"300470",title:"Dr.",name:"Yanfei (Jacob)",middleName:null,surname:"Qi",fullName:"Yanfei (Jacob) Qi",profilePictureURL:"https://mts.intechopen.com/storage/users/300470/images/system/300470.jpg",institutionString:null,institution:{name:"Centenary Institute of Cancer Medicine and Cell Biology",institutionURL:null,country:{name:"Australia"}}}]},{id:"18",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",annualVolume:11414,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,editorialBoard:[{id:"72288",title:"Dr.",name:"Arli Aditya",middleName:null,surname:"Parikesit",fullName:"Arli Aditya Parikesit",profilePictureURL:"https://mts.intechopen.com/storage/users/72288/images/system/72288.jpg",institutionString:null,institution:{name:"Indonesia International Institute for Life Sciences",institutionURL:null,country:{name:"Indonesia"}}},{id:"40928",title:"Dr.",name:"Cesar",middleName:null,surname:"Lopez-Camarillo",fullName:"Cesar Lopez-Camarillo",profilePictureURL:"https://mts.intechopen.com/storage/users/40928/images/3884_n.png",institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",institutionURL:null,country:{name:"Mexico"}}},{id:"81926",title:"Dr.",name:"Shymaa",middleName:null,surname:"Enany",fullName:"Shymaa Enany",profilePictureURL:"https://mts.intechopen.com/storage/users/81926/images/system/81926.png",institutionString:"Suez Canal University",institution:{name:"Suez Canal University",institutionURL:null,country:{name:"Egypt"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/102204",hash:"",query:{},params:{id:"102204"},fullPath:"/profiles/102204",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)}()