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1. Introduction
1.1. Rationale for comparison of MCM and RecQ helicase families
DNA helicases are currently organized into superfamilies based on their sequence structures and 3-D conformations. Within each superfamily, there are members that have further evolved for specialized functions [1]. There is conservation of RecQ proteins from bacteria to humans. Whereas bacteria have one RecQ helicase, humans have evolved at least five different proteins [2]. The RecQ members belong to the helicase Superfamily II, and as such have the characteristic Rec fold [1]. In this chapter, we will focus on RecQ family members WRN, BLM and RECQL4 (RecQ protein-like 4), which is also referred to in the literature as RECQ4. Eukaryotic and archaeal MCMs belong to the helicase Superfamily VI, and have the AAA+ (ATPases associated with diverse cellular activities) fold [1, 3, 4, 5]. Both Rec and AAA+ folds are based on the ancestral ASCE (additional strand conserved E) fold or an alpha-beta-alpha domain necessary for nucleoside triphosphate binding and catalysis [1, 6, 7]. A rationale for comparison of the RecQ and MCM family members relates to the importance of their activities for genomic integrity. The WRN and BLM proteins as well as other members of the RecQ family are characterized by this feature [8]. Both WRN and BLM are involved in DNA repair and a role for WRN in telomere homeostasis in humans is well established [2, 9]. MCM2-7 proteins, along with cofactors, are thought to function as the eukaryotic replicative helicase [10]. MCM8 [11, 12] and MCM9 [13, 14] are more recently discovered and their roles are less well defined. Although data point to a role for MCM8 in DNA replication, that role may be specialized in higher organisms. In human cells, MCM10 is recruited to chromosomal domains before they replicate and studies in yeast suggest a role in DNA replication, but not as a helicase [15-18]. Members of each family are essential for chromosome homeostasis. When replication forks stall, there may be involvement of members of each family. These proteins have interlocking functions since, for example, a stalled replication fork with attendant MCM proteins can lead to a DNA double-strand break (DSB), which requires RecQ proteins for repair [19].
2. RecQ and MCM family structures
Breaks in double-strand DNA can occur during DNA replication, at specific loci (e.g., at telomeres) and during meiosis. RecQ helicases are implicated in DNA repair based on their involvement in such processes as DNA end resection, branch migration, D-loop processing, Holliday Junction (HJ) and double Holliday junction (dHJ) resolution [2]. RecQ proteins function at multiple steps, both early and late, during repair of DSB [19]. RecQ helicases travel in a 3’ to 5’ direction on ssDNA [20]. The RecQ proteins have an ancient lineage based on an ancestral ASCE fold (αβα domain) of distant relation to P-loop NTPase folds. RecQ structural domains include a conserved core helicase domain for binding and hydrolysis of nucleoside triphosphate that is equivalent to the Walker A and Walker B boxes seen in MCM proteins [21]. They have a helicase and RNAase D C-terminal (HRDC) domain thought to mediate structure-specific nucleic acid binding, double HJ dissolution and protein-protein interactions. They also have a RecQ C-terminal (RQC) domain thought to mediate interactions with other proteins, structure-specific nucleic acid binding and metal cofactor binding [22]. Acidic regions present in many RecQ proteins aid in protein-protein interactions. There are also nuclear localization signals in some RecQ proteins (e.g., H. sapiens WRN and BLM). There are two RecQ members with an exonuclease domain, one of which is H. sapiens WRN. Two members have been functionally characterized as having an N-terminal strand exchange domain, one of which is H. sapiens BLM [2].
RECQL4 has been reported to have ssDNA binding and DNA strand-annealing activities. In this single study, RECQL4 did not display substrate unwinding or resolution of substrates resembling replication or recombination intermediates [23]. Recognizable HRDC and RQC domains that are important in BLM activity are missing in RECQL4 [22, 24]. As observed, the ssDNA annealing activity would allow RECQL4 to function during synthesis-dependent strand annealing (SDSA) along with another helicase. RECQL4 could help direct pathway choice during HR in DSB repair through aiding ssDNA annealing activity in non-homologous end joining (NHEJ) [19]. Thus, RECQL4 is similar to other RecQ helicases in its core helicase domain, but its function as a helicase is unclear [23, 25, 26].
AAA+ proteins, including MCMs, have a core molecular motor. Like the RecQ proteins, the AAA+ fold is also based on the ancestral ASCE fold. Acquisition of a catalytic glutamate (Fig. 1) to initiate efficient hydrolysis of ATP marked the emergence of the ASCE division from the ancestral P-loop fold [7]. For further discussion of the glutamate “switch” in AAA+ proteins, see reference [27]. Mechanisms of action are diverse, although members are typically oligomeric ring assemblies with inter-subunit communication. The central AAA+ motor has been adapted in evolution through structural changes to the core module and through domains added either N- or C-terminal to the AAA+ core. Activities are facilitated by recognition of protein partners functioning in these diverse events. Thus, AAA+ proteins display a variety of macromolecular remodelling events that are energy-driven by nucleotide hydrolysis thought to be occurring throughout what is typically a hexameric complex assembly [28, 29]. The conserved Walker A and Walker B motifs within the central module mediate ATP-binding and hydrolysis [7, 30-32]. MCM proteins have two active site motifs, the P-loop domain and the lid. Motifs in the P-loop include Walker A, Walker B and Sensor 1. The lid domain contains the arginine finger and Sensor 2. A catalytic site is created by a dimer interface that employs a cis P-loop from one subunit and a trans lid from the adjacent subunit [4, 33, 34]. A similar catalytic site created at the interfaces between adjacent monomers is also characteristic of the RecQ ATPase core [21].
Figure 1.
Comparison of conserved ATPase motifs in RecQ proteins WRN, BLM and RECQL4 to the Walker A and Walker B boxes of MCM8. MCM8 was chosen as the MCM for comparison because it has a canonical GKS Walker A [12] and the signature MCM IDEFDKM Walker B ATP-binding domains. In the Walker B motif, note the conserved structural features and the conserved DE motif (containing aspartate, D, and the catalytic glutamate, E).
3. RecQ and MCM helicases: association with disease and aging
3.1. BLM and Bloom syndrome, WRN and Werner syndrome, RECQL4 and Rothmund-Thomson syndrome
As a group, mutations in the RecQ helicases lead to adult segmental progeria with abnormalities in development, predisposition to cancer and acceleration of aging processes. Three of the RecQ family members are associated with rare autosomal recessive diseases [19]. These disorders Werner syndrome (WS) [35], Bloom syndrome (BS) [36] and Rothmund-Thomson syndrome (RTS) [37, 38] are caused by mutations in the genes coding for WRN, BLM and RECQL4, respectively. RTS is a heterogeneous disorder with about 60% of cases resulting from mutations in the RECQL4 gene [37]. Mutations in RECQL4 can also lead to two other disease phenotypes [39], but only RTS will be discussed here. The RecQ deficiency diseases are associated with cancer predisposition and several characteristics of aging [8, 20, 26, 40]. In BS cells, there is a 10-fold elevation in frequency of homologous recombination (HR), and reciprocal exchanges occur between homologous chromosomes and sister chromatids [41, 42]. WS cells, on the other hand, display large chromosome deletions and an increase in illegitimate recombination [43]. A higher frequency of chromosomal aberrations is reported for cells from RTS [44]. These deficiencies thus provide hints as to the cellular activities of these three helicases. Clinical features of these diseases, as referenced above, are as follows.
BS manifests in pleiotropic phenotypes such as growth retardation leading to proportional dwarfism, erythema with light sensitivity, skin lesions with hypo- and hyperpigmentation, immunodeficiency, susceptibility to type II diabetes, male infertility, female sub-fertility, reports of mental retardation, cancer predisposition (all types but at an earlier age of diagnosis than in the normal population).
WS leads to short stature and early onset age-related diseases, including greying hair, alopecia, bilateral cataracts, osteoporosis, arteriosclerosis, atherosclerosis, skin atrophy, hypogonadism, type II diabetes mellitus and susceptibility to tumors, especially those of mesenchymal origin (sarcomas).
RTS manifests as early growth deficiency, congenital bone defects, poikiloderma, cataracts, greying hair, alopecia, hypogonadism, and some increased susceptibility to cancer, especially osteogenic sarcomas.
3.2. MCMs and genomic stability
The MCM proteins 2-7 are necessary for DNA replication in yeast [45, 46], and this basic life function extends in evolution to a single MCM protein in archaea [47-49]. MCM2-7 are also essential for replication in Xenopus [50, 51] and have been proposed as a licensing factor for initiation of eukaryotic replication [52, 53]. The MCM proteins 2-8 have an identical Walker B-box motif of IDEFDKM. The MCM2-7 complex is enigmatic in that MCMs 4, 6 and 7 function alone as a heterohexameric helicase [54, 55]. For a discussion of individual MCM subunit arrangements and activities, see the references [33, 34]. MCM2-7 have now been shown to have helicase activity in vitro [56], and to be components of a holo-helicase Cdc45/MCM2-7/GINS (CMG) complex [57, 58]. The MCMs require a clamp-loading factor to assemble as a multimeric ring on DNA, and this function is fulfilled in known cases by the protein Cdc6 [59-64] although the regulation of this step in the formation of the CMG complex proceeds through multiple pathways [57, 58]. Various papers have dealt with the function of MCM proteins in DNA replication [10, 46, 65-68], and regarding their processive mechanism of DNA unwinding [27, 56, 58, 69, 70] and only certain lingering, disease-related questions will be considered here. A summary statement can be made regarding known relationships between MCM and RecQ helicases. Members of the MCM protein family are essential for the life-creating process of DNA replication, whereas members of the RecQ family are essential for the life-prolonging maintenance of the genome.
Due to their essential roles, it is not surprising that there are few diseases directly ascribed to defects in MCMs 2-7. This does, however, bring up an unresolved MCM enigma: there are more MCM proteins than are required to form initiation complexes at cellular origins active within a given round of DNA replication [71]. In addition, MCM proteins in human cells remain at peak levels in G2 phase of the cell cycle, after DNA replication is complete [59, 72, 73] This high copy number could be an aspect of securing sufficient protein quantities for basic function. A role for MCM proteins in transcription has also been proposed, and this remains to be defined [74]; for further discussion see reference [46]. Redundancy of functions among MCM members is also a factor to be considered. Intriguingly, knockdown of MCM8 [75], not even present in yeast [12], retards S-phase approximately 25% in human cells in culture [75], suggesting a specialized function in higher eukaryotes critical for basic replication. It has been suggested that the excess MCMs license dormant origins, which are used under conditions of stress upon normally functional origins [71]. An overview provides a discussion of recent work connecting dormant origins of replication and tumor suppression based on the role of dormant origins during fork restart after repair of DNA damage [76].
Mutations in MCM family members have been studied in yeast and mouse models, and they confirm an essential role for MCM2-7 in DNA replication [34, 45, 77, 78]. A human MCM4 mutation (destabilizing the MCM2-7 complex) was recently reported concurrently by two groups who studied consanguineous families, and the resulting phenotype was found to be associated with immune deficiency (NK cells), adrenal insufficiency and short stature [79, 80]. Patient fibroblasts showed chromosome fragility [79]. The susceptibility of these patients to cancer is not currently known [80]. An MCM8 disruption and alternative splice form have been noted in hepatic carcinoma [11] and choriocarcinoma [12], respectively. Although not necessarily a cause of disease, the MCM proteins may be useful tools in diagnoses [81-85]. Elevated levels of MCM proteins 2-7 have been observed in several cancers [81, 84, 85]. In contrast, reduced levels of MCM8 mRNA have been reported in colon carcinoma [12]. Nuclear MCM7 is a good marker for proliferating cells [86], and MCMs 2, 5 or 7 may be an alternative to the Ki-67 marker to distinguish certain hyperproliferative disorders [83].
3.2.1. A structural domain deleted from MCM8 and present in WRN and BLM
A brief discussion of MCM8 is included in this section because it contains a motif that may be structurally similar to one found in BLM and WRN and is linked to neoplasia. Human MCM8 has a splice variant that results in a 16 amino acid (aa) deletion in a location between the Zn finger of MCM8 and its Walker A box [12], Fig. 2. Thus far this deletion has been detected by various different groups only in cases of choriocarcinoma. MCM8 with this same sequence deleted (Fig. 2) has, however, been detected in several higher eukaryotes other than humans, suggesting that the variant does have, or perhaps lacks, a function. That function is as yet unknown, but clues to it may be gleaned from a comparison of the MCM8 deletion with sequences from WRN and BLM. These RecQ proteins have a counterpart 16 aa domain with partial sequence homology and notable structural homology, as denoted in Fig. 2. This sequence in the RecQ proteins is located in a different orientation to that of MCM8 with regard to the helicase Walker A and B boxes (Fig. 2). In each case the first 8 aa of this sequence are highly charged and, in WRN, BLM and MCM8, contain a polar S. The 9th aa in this deletion is a conserved C. The remaining 7 aa contain a preponderance of aromatic and hydrophobic residues. This configuration of charged and aromatic residues is characteristic of known single-stranded nucleic acid binding proteins [87]. Among MCMs, this 16 aa domain is identifiable in the single MCM of Sulfolobus solfataricus, in which it has been implicated as a single-stranded DNA-binding “finger” [88]. Mutations of the positively charged amino acids strongly reduce single-stranded DNA binding of this MCM. In contrast, in BLM the polar S residue is thought to be involved in ATP binding [89]. Because of the aromatic nature of a portion of this domain, binding to one or more DNA nucleotide bases may be involved as a common link between functions of these 16 aa in RECQ and MCM helicases.
Figure 2.
Comparison of placement of selected structural motifs in human RecQ and MCM8 helicases. MCM8 has a splice variant that results in a 16 aa deletion in choriocarcinoma [12]. The Walker A and B boxes and the MCM Zn finger (ZnF) domains are indicated by filled rectangles. The MCM8 variant 2 deletion (Var2 del) is indicated by an open rectangle, as is its partially-homologous counterpart (del hom) in WRN and BLM. This conservatively structured domain consists of an N-terminal highly charged sequence followed by a conserved C and an aromatic-hydrophobic sequence. The open box is located in a different orientation relative to Walker A and B boxes in WRN vs. MCM8. The positions of black and white boxes are approximately to scale.
4. Supportive roles for WRN, BLM helicases and RECQL4 during replication elongation
During normal metabolism, such as in mitochondrial respiration, endogenous reactive oxygen species (ROS) are produced that lead to oxidative DNA modifications. In addition to endogenous mutagens, there are also environmental mutagens that damage the DNA [90]. Furthermore, during replication and transcription, duplex DNA is transiently opened, and there is an opportunity for non-B DNA structures to form in the genomic DNA [40]. RecQ helicases act on recombination intermediates, on preferred substrates including those resembling G-quadruplex DNA [91, 92], D-loops [93], HJ [94] and double HJ [95]. RecQ helicases may play a regulatory role in both pro- and anti-HR events. They function at the interface of HR with the stressed replication fork and may affect repair pathway choice. There is little evidence for a specific clear cut role, but for a discussion of proposed mechanistic models of RecQ protein function, see the references [19, 20].
4.1. BLM and RECQL4
In BS cells, there are S-phase defects in DNA replication involving abnormal replication intermediates, and replication elongation is slower [96-98]. These cells don’t recover well from induced fork stalling and accumulate DSB [99, 100]. In human cells, RECQL4 interacts with the MCM2-7 complex, Cdc45 and GINS. The interaction is facilitated by MCM10 [25]. BLM and RECQL4 are at their highest levels during S phase. At stalled replication forks, BLM physically associates with Rad51 and p53, and BLM and p53 function synergistically in HR [101]. BLM colocalizes in foci with PCNA and with the BASC (BRCA1-associated genome surveillance complex) [102]. BLM is phosphorylated by ATR [103]. When replication forks are stalled by use of hydroxyurea (HU), BLM colocalizes with Chk1 and p53BP1 foci. Chk1 is required for BLM and 53BP1 foci formation. Thus Chk1 may recruit BLM to stalled forks [104]. This implicates RecQ proteins as DNA damage checkpoint mediators in response to stalled forks. In vitro studies with use of substrates similar to Okazaki fragments showed BLM stimulation of flap endonuclease [105] (a protein that functions in lagging strand synthesis [106]). BLM functions to prevent the association of homologous sequences in the displaced flap DNA of the Okazaki fragment and the sister chromatid [107-110]. D-loops are formed when a ssDNA tail invades a homologous duplex, and BLM has a preference for dissociating D-loops with a 5’ invaded end suggesting a selection of recombination intermediates that are not extended by polymerase [93, 111, 112]. BLM is able to disrupt the initial Rad51 filament formation step to destabilize recombinase-nucleoprotein filaments. D-loops are susceptible to BLM activity when Rad51 is in an inactive form (ADP-bound) [112, 113]. BLM physically associates with CAF-1 (chromatin assembly factor I) largest subunit, and the colocalization of these two proteins occurs at sites of DNA synthesis. BLM inhibits CAF-1 function in chromatin assembly during DNA repair in vitro, and inhibits its mobilization after damage induction in vivo [114]. Mammalian WRN and BLM interact [115], and they both interact with RPA [116-118] and p53 [119-121]. Based on coimmunoprecipitation there is limited BLM and WRN interaction, but they may function in the same pathway during HR [20]. BLM helicase activity is stimulated by its binding to the RPA70 kDa subunit [116]. In mouse spermatocytes during meiotic prophase, BLM and RPA are nuclear colocalized [122]. This suggests a potential role for these proteins in resolution of recombination intermediates during meiosis [8]. BLM has a preference for unwinding G-quadruplex structures versus HJ [92]. Both mammalian WRN and BLM bind to G-quadruplex structures, which are roadblocks to polymerases [123, 124].
Aberrant replication intermediates arise in cells lacking WRN and BLM [97, 125]. Such unresolved replication or recombination structures lead to incomplete chromosome segregation. BLM, topoisomerase 3 alpha (Topo3α) and BLAP75/RMI1 (for BLM-associated polypeptide/RecQ-mediated genome instability) or a BLM-Topo3α-BLAP75/RMI1 complex localizes to resulting anaphase bridges [126]. A helicase known as PICH arrives first, followed by the resolution activity of BLM [127]. As helicases unwind duplex DNA, torsional stress produced in the DNA may require relief through topoisomerase activity, and such activity finally decatenates interlocked DNA molecules [128, 129]. In vitro studies show that BLM can partner with Topo3α to resolve dHJ and prevent sequence exchange through resolution of this recombination intermediate [95]. The double-junction dissolution reaction requires the HRDC domain of BLM [24]. An additional protein, BLAP75/DMI1 mediates formation of the “dissolvasome” (BLM, Topo3α and BLAP75/RMI1) [130-132]. Mammalian BLAP18/RMI2 has also been found to be part of this complex [133].
4.2. WRN
Over 50 distinct WRN mutations have been reported, most of which lead to premature termination of translation [19]. Recent missense mutations in the exonuclease domain in one patient compromised protein stability [134]. Most mutations in WS patients occur in the WRN C-terminal domain, which could disrupt the WRN/p53 interaction [20, 134]. Such premature termination could also disrupt the Del hom sequence shown in Fig. 2. No WS mutations have been reported that eliminate only helicase or only exonuclease activity. Both activities are compromised in the development of WS [134]. WS fibroblasts undergo replicative senescence prematurely [135-139]. Telomere defects in WS cells suggest WRN activity in human telomere homeostasis [19]. Telomeres are needed to avoid loss of genetic material. They are important for chromosome end replication and for protection of the ends from enzymatic attack [140]. Human telomeres contain 5 to 20 kb of the repetitive sequence TTAGGG [141]. At the terminal there are 100-200 bp of 3’ ssDNA overhang. This overhang can anneal with telomere DNA to form a stable D-loop leading to a structure referred to as a ‘t-loop’ [142, 143]. Alternatively, this free unannealed end may form G-quadruplex DNA [144]. Human WRN functions in lagging-strand synthesis, and in the replication of telomeric G-rich DNA ends [145]. C. elegans WRN-1 can disrupt D-loops [146] and human WRN can prevent aberrant recombination [147]. WRN 3’ to 5’ exonuclease is stimulated by the interacting Ku70/Ku86 complex supporting a role for WRN in DNA repair [148]. Evidence suggests that in the absence of telomerase, WRN and BLM have a role in the ALT (Alternate Lengthening of Telomeres) pathway for telomere maintenance [149, 150]. In biochemical experiments, WRN releases a 3‘ invading tail from a telomeric type D-loop by coordinated WRN helicase and exonuclease activities [149].
WRN and BLM catalytic activities are comparable except for 3’ to 5’ exonuclease activity of WRN [151-153], which BLM lacks. On dsDNA and on RNA-DNA hybrids, the WRN exonuclease activity degrades a 3’ recessed end. This activity can remove only one mismatched NT at the end of the recessed 3’ DNA and can initiate exonuclease activity from a gap or nick [154, 155]. The exonuclease activity of WRN can degrade abnormal DNA structures suggesting that WRN helicase and exonuclease activities are involved in resolution of aberrant DNA structures at stalled forks [156]. Human WRN interacts with proteins involved in DNA replication. WRN coimmunoprecipitates with PCNA and topoisomerase 1 [157]. WRN functionally and physically interacts with RPA [117], and it functionally interacts with DNA polymerase delta [152]. WS cells accumulate recombination intermediates that impede cell growth [158]. In cells treated with HU, WRN colocalizes with RPA foci and is thought to dissociate recombination intermediates at the stalled forks [94, 147]. WRN stimulates polymerase delta activity in the absence of its processivity factor PCNA. This suggests a role for WRN in recruiting polymerase delta for replication restart at blocked or collapsed forks [152]. RPA can stimulate the processivity of WRN. The stimulation of WRN by RPA is due to protein-protein interactions as opposed to enhanced ATPase activity [117, 118].
5. Unification of BLM, WRN, RECQL4 and MCM2-7 activities in DNA replication and recombination/repair
5.1. BLM: Role in DNA damage response with a complex role in inhibiting or promoting HR
BLM is found mostly in fine granules throughout the nucleoplasm at highest levels during S and G2 phases of the cell cycle. Its focal localization is in PML nuclear bodies (PML-NB). The name PML derives from the promyelocytic leukemia protein, PML [159-162]. This protein forms the structural groundwork of the PML bodies, which store various nuclear proteins [163]. These PML-NB store repair proteins (e.g., Topo3α, MRN and p53) and may be involved in sensing DNA damage [163]. By regulating the availability of repair proteins, response can be directed to DNA damage sites. Trafficking of proteins to the PML-NB is regulated by sumoylation [164]. The sumoylation pathway involves E1, E2 and E3 enzymes, which regulate respectively, SUMO activation, SUMO conjugation and targeting of specific substrates for sumoylation through ligation [165]. BLM contains a motif for SUMO binding that would facilitate its integration into this repair protein storage network [166]. In addition, BLM is SUMO-1 and SUMO-2 modified [167]. When mutants are prepared in which the SUMO-binding sequences are deleted, BLM cannot localize to PML-NB [168]. When mutants are prepared that do not allow BLM localization to PML-NB, there is about a two-fold increase in sister chromatid exchange. These findings indicate that there is a need for BLM-SUMO interaction in order for BLM to localize to PML-NB, and that BLM activity, such as its accumulation at stalled replication forks, may be regulated by this specific localization [168].
At sites of DSB, repair foci form. A central player, H2AX, is phosphorylated when DSBs are induced, and this phosphorylation involves ATM, ATR and DNA-PK. Over one million bp are then marked by phosphorylated H2AX (γH2AX) on each side of the break [112, 168-171]. γH2AX recruits additional repair proteins to the damage site [172]. In studies where normal S-phase cells are treated with DNA damaging agents (HU, UV and cross-linking agents), BLM responds by leaving the PML-NBs to relocate to repair foci and colocalize with the marker γH2AX [101, 173]. BLM interacts physically and functionally with γH2AX as well as with ATM and ATR [103, 173-175]. In damage that is S-phase specific, BLM associates with the complex ATR/CHK1/53BP1, which gathers at repair foci as an early response to the damage. Based on kinetic studies, BLM may facilitate BRCA1 and MRN complex localization at repair foci in S phase [173], which may involve BLM regulation of p53 in these foci [101]. This early function of BLM at repair foci may allow for BML to influence the choice of repair pathways and facilitate a BLM function in anti-recombination at stalled forks that perhaps involves SUMO regulation [19].
As discussed in the previous section, BLM interacts with the recombinase, Rad51. Rad51 catalyzes the pairing of a ssDNA tail and a homologous stretch of dsDNA to promote strand exchange early in the HR pathway [111]. Following ionizing radiation, Rad51 foci contained BLM [159]. Rad51 functions in HR, and localizes to ssDNA when DSB are induced [176]. BML can displace the recombinase from the ssDNA filament [112], which can be viewed as an anti-recombinagenic function [19]. In Rad51-associated D-loops, BLM can interact with Rad51 and unwind DNA in front of the polymerase [177]. This could favor SDSA leading to pro-recombinagenic function [19, 177]. BLM, however, also functions in resolution of G-quadruplex DNA structure and has higher binding affinity for it compared to HJ. BLM helicase activity is required for resolution of this structure [92]. Whereas the BLM/Rad51 interaction would represent an early event in a DNA damage/repair process, the formation of HJ, on the other hand, is a late event in HR. As discussed in section 5.1, the BLM-Topo3α-BLAP75/RMI1 complex functions to “dissolve” dHJ by convergent fork migration to generate non-cross-over products [178]. This is facilitated by Topo3α relief of superhelicity and by its ability to cleave and rejoin one strand of a DNA duplex. In the absence of BLM, Topo3α activity would involve break and rejoining activities instead of dissolution, which could lead to crossover events and an increase in sister chromatid exchange in BS cells [19]. BLM that is mutated to be unable to interact with Topo3α can only partially rescue the frequency of sister chromatid exchange [168]. Thus, together in a complex, BLM and Topo3α achieve dissolution of a recombinogenic intermediate. BLM has been proposed to regulate ploidy based on a role along with other members of this complex in resolution of anaphase bridges [126]. BLM has been found in complexes with mismatch repair protein MLH1 [179, 180]. It has been found to be present in large complexes containing not only BLM-Topo3a-BLAF75, but also additional factors. These additional factors could include several BLAF factors, proteins from the FA (Fanconi anemia) pathway, RPA, and mismatch repair protein MLH1. [181, 182]. The interactive role of these pathway components remains to be determined.
5.2. WRN: Helicase and exonuclease activities in concert
When WRN biochemical activities were compared using nonhydrolyzable ATPγS to inhibit only WRN helicase activity or aa substitutions to eliminate only the WRN exonuclease activity, the exonuclease activity was shown to function in degradation of the leading strand on replication fork-type substrates and in degradation of the annealed telomere overhangs on substrates resembling D-loop structures. WRN binding proteins were inhibitory [149, 183]. In addition, WRN was found to degrade ssDNA substrates longer than 40 nt with dependence upon the helicase activity [183]. WRN activities were also explored using WS fibroblasts. In WS cells, WRN and the enzyme telomerase are able to reverse the phenotype of excess chromosome fusion. In these cells, the anaphase bridges were missing telomere DNA. Dominant negative telomerase was not able to rescue the phenotype indicating that a stable telomere length was needed for rescue [184]. Telomeres are stabilized by a complex of proteins that bind DNA, known as the shelterin complex [185]. This complex consists of TRF1, TRF2 (double-strand DNA binding proteins), and POT1 (single-strand DNA binding protein) as well as adaptor proteins. The coordinate action of these proteins in the presence of telomerase is needed to regulate telomere length. Without telomerase, telomeres shorten in length each cell division [185]. In S phase, WRN colocalizes with TRF2 [145, 186]. TRF1 and TRF2 limit WRN exonuclease activity on synthetic telomere D-loops [149]. WRN helicase is stimulated by single-stranded DNA binding proteins, RPA or POT1. These proteins modulate WRN exonuclease degradation of the 3’ overhang [149, 187]. The hypothesis is that WRN could unwind D-loops to facilitate leading strand synthesis through telomeric DNA, and there is also the possibility that WRN prevents interchromosomal interactions between telomeres [19].
5.2.1. WRN activities in response to G-quadruplex structures in the lagging strand
At the telomere, the G-rich strand is duplicated by lagging-strand synthesis. It may assume a G-quadruplex structure, which would interrupt the replication fork. Experimentally, when inhibiting WRN by use of overexpression of a dominant-negative WRN, the helicase deficiency leads to loss almost entirely affecting the sister telomere on the lagging strand [145]. WRN interaction with FEN-1 (the flap endonuclease involved in the processing of Okazaki fragments, [188]) could assist in the maturation of these fragments [105, 189]. Data suggest that WRN may function in concert with lagging strand synthesis perhaps in unwinding complex structure at the telomere. WRN interacts physically with DNA polymerase delta to stimulate its activity [190]. WRN can prevent stalling of polymerases delta at telomere sequence in vitro [191]. WRN stimulation of polymerase delta happens only in the absence of PCNA, which suggests that WRN has a role at stalled forks rather than in the regulation of processive DNA synthesis [19]. WRN, as opposed to BLM, is specific for G-quadruplex structure in the trinucleotide repeat of Fragile X syndrome [192].
5.2.2. WRN and Ku in suppression of aberrant recombination at telomeres
Proteins involved in the NHEJ path for repair of DSBs that are found at telomeres include Ku heterodimer, DNA-PK, MRN complex and ATM [193]. Through interaction with NBS1, WRN colocalizes with two of these components, Ku and the MRN complex [194]. Under unstable conditions, Ku can suppress sister chromatid exchange at telomeres [195]. Mouse knockout studies show that WRN normally suppresses aberrant recombination at telomeres [196].
5.2.3. WRN activities in base excision repair and interstrand cross link repair by HR
WS cells show increased sensitivity to alkylating agents and to agents that increase ROS. Human fibroblasts in which WRN has been knocked down respond to oxidative stress with an increase in DNA damage [197]. These observations support a role for WRN in repair of such damage [198]. DNA damage resulting from oxidation, alkylation, methylation and deamination is repaired by the base excision repair (BER) pathway. WRN interacts with proteins in this pathway. In addition, WRN helicase activity stimulates and is stimulated by polymerase beta activity [199]. There is evidence that WRN activity in BER is regulated by PARP-1, but the reader is referred to references [200, 201]. BRCA1 and BRCA2 play an important role in DSB repair in the HR subpathway [202, 203]. HR is a pathway for repairing interstrand crosslinks (ICL). Cells deficient in either WRN or BRCA1 are hypersensitive to induction of ICLs [204, 205]. A physical interaction of WRN with BRCA1 enhances the activities of WRN [206]. In addition, data from WRN and/or BRCA1 knockdown studies indicate that BRCA1 may act cooperatively with WRN in HR during ICL repair [206].
5.3. RECQL4
Data from Recql4-/- mice indicate a role for mouse RECQL4 in genomic stability and in the promoting cohesion between sister chromatids [207]. Depleting the X. laevis homologue of RTS, xRTS, in Xenopus egg extracts led to reduced DNA synthesis and an inhibition of RPA stabilization of ssDNA prior to polymerase loading at unwound origins. The addition of purified human RECQL4 could reverse this effect [208]. A nonhelical region in the N terminus of xRTS could be important in initiation of DNA replication based on its interaction with the Cut5 protein and the importance of xRTS in loading DNA polymerase alpha onto chromatin [209]. The N terminus of xRTS is not homologous to that of RECQL4 in mammals, however, and this role may not be conserved [19]. RECQL4, along with Ctf4 and MCM10, has been shown to be required for stable association of the CMG complex in human cells. In this study, Cut5/TopBP1 was not required for CMG stabilization [210]. In the Xenopus replication model, RECQL4 binds to chromatin that has been processed to resemble DSBs with a dependence on RPA and ATM activity [211]. Chromatin immunoprecipitation experiments show that RECQL4 functions on DNA in close association with Ku [212]. In HeLa cells human RECQL4 forms a complex with Rad51 and colocalizes with Rad51 foci formed after treatment with etoposide [212]. PML-NB contain a portion of RECQL4 [212]. It is also found in the nucleolus [213]. When using a T7 phage display screen, RECQL4 was found to interact with PARP-1, and the association influenced the nuclear localization of RECQL4. PARP-1 has a role in RECQL4 movement to the nucleolus from the nucleoplasm. When oxidative stress is induced, as opposed to other types of damage induction, RECQL4 increasingly localizes in the nucleolus. This trafficking is inhibited by inhibition of PARP [213]. RTS cells decrease proliferation and synthesis of DNA when exposed to hydrogen peroxide [214]. Lack of proper response to ROS could lead to premature aging as see in RTS. PARP is also involved in an end-joining pathway of DNA repair [215, 216]. The role of RECQL4 in its interaction with PARP-1 is not known (for further discussion see reference [19]).
5.4. MCM2-7
Replication fork stalling, can lead to DSB and chromosomal rearrangements. An S phase checkpoint is triggered by these events and there is a block to elongation. When this occurs, the proteins Mrc1, Tof1, and Csm3 (M/T/C complex) interact with the MCM2-7 complex to stabilize the replication fork. When the M/T/C complex is missing, the replisome continues, but synthesis stops. This may be partially due to loss of DNA polymerase epsilon from the fork [217-219]. Studies in yeast provide insight into these activities. The M/T/C complex associates with MCM2-7 [218, 220-222] and also with polymerase epsilon [221, 223]. These physical interactions permit communication between polymerase epsilon and the MCM complex [223]. The M/T/C complex may be part of the normal replication fork protein entourage [218, 220, 221, 224]. Mrc1 and Cdc45 coimmunoprecipitate, indicating an interaction of Mrc1 with the The Replication Progression Complex core, which includes Cdc45, the MCMs and GINS [223]. In each cell cycle Mrc loads onto replication origins along with the polymerases. This occurs after the Replication Progression Complex forms. Mrc migrates with the replication forks. [218, 219, 224-226]. Tof1, like Mrc, also coimmunoprecipitates with Cdc45 [227]. The exact mechanism of action of the M/T/C complex is not known. In a yeast study, the Tof1 homologue could switch regulation between pro- and anti-recombination activities in a site-specific manner [228]. Data indicate that a Mrc1 and MCM6-C terminal interaction senses alkylated DNA damage [221]. The other two subunits Tof1 and Csm3, may function to sense other types of damage. Although the helicase domains of MCM2-7 are conserved, the N and C terminals are divergent. Other negative regulators could differentially bind to these regions to regulate powering of elongation by the MCM2-7 helicase during times of stress [10]. A future question relates to the extent to which leading or lagging strand polymerase arrest is associated with formation of ssDNA, fork regression and formation of abnormal DNA structures [66]. These data indicate a functional connection between the MCM proteins, which act at stalled forks, and the RecQ proteins, which facilitate repair of the resulting damage.
6. Summary
BLM, WRN and RECQL4 act during events that stress the advancing replication fork providing relief through DNA damage repair and through resolution of aberrant replication/ recombination intermediates, including those present at the telomere. At checkpoint, the replication proteins at a stalled fork are held stable through communication that occurs due to proteins that bind and signal to both the MCM complex and polymerase(s). This would allow repair proteins such as WRN and BLM helicases and RECQL4 to resolve the stress and thus aid in fork restart. Advancing our knowledge of the RecQ and MCM family activities and the mechanisms and signalling behind these activities will increase our understanding of cancer and aging and perhaps enlighten us regarding how to accommodate these challenges to human health.
Acknowledgments
This. work was supported by NIH funding to EMJ and resources derived from grant funding from Virginia’s Commonwealth Health Research Board to DCD.
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Johnson",authors:[{id:"42103",title:"Prof.",name:"Dianne",middleName:"C.",surname:"Daniel",fullName:"Dianne Daniel",slug:"dianne-daniel",email:"danieldc@evms.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Eastern Virginia Medical School",institutionURL:null,country:{name:"United States of America"}}},{id:"85937",title:"Dr.",name:"Edward",middleName:null,surname:"Johnson",fullName:"Edward Johnson",slug:"edward-johnson",email:"johnsoem@evms.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Eastern Virginia Medical School",institutionURL:null,country:{name:"United States of America"}}},{id:"165849",title:"Dr.",name:"Ayuna",middleName:null,surname:"Dagdanova",fullName:"Ayuna Dagdanova",slug:"ayuna-dagdanova",email:"dagdanav@evms.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1. Rationale for comparison of MCM and RecQ helicase families",level:"2"},{id:"sec_3",title:"2. RecQ and MCM family structures ",level:"1"},{id:"sec_4",title:"3. RecQ and MCM helicases: association with disease and aging",level:"1"},{id:"sec_4_2",title:"3.1. BLM and Bloom syndrome, WRN and Werner syndrome, RECQL4 and Rothmund-Thomson syndrome ",level:"2"},{id:"sec_5_2",title:"3.2. MCMs and genomic stability",level:"2"},{id:"sec_5_3",title:"3.2.1. A structural domain deleted from MCM8 and present in WRN and BLM",level:"3"},{id:"sec_8",title:"4. Supportive roles for WRN, BLM helicases and RECQL4 during replication elongation",level:"1"},{id:"sec_8_2",title:"4.1. BLM and RECQL4",level:"2"},{id:"sec_9_2",title:"4.2. WRN",level:"2"},{id:"sec_11",title:"5. Unification of BLM, WRN, RECQL4 and MCM2-7 activities in DNA replication and recombination/repair ",level:"1"},{id:"sec_11_2",title:"5.1. BLM: Role in DNA damage response with a complex role in inhibiting or promoting HR",level:"2"},{id:"sec_12_2",title:"5.2. WRN: Helicase and exonuclease activities in concert ",level:"2"},{id:"sec_12_3",title:"5.2.1. WRN activities in response to G-quadruplex structures in the lagging strand",level:"3"},{id:"sec_13_3",title:"5.2.2. WRN and Ku in suppression of aberrant recombination at telomeres",level:"3"},{id:"sec_14_3",title:"5.2.3. WRN activities in base excision repair and interstrand cross link repair by HR ",level:"3"},{id:"sec_16_2",title:"5.3. RECQL4 ",level:"2"},{id:"sec_17_2",title:"5.4. MCM2-7",level:"2"},{id:"sec_19",title:"6. Summary",level:"1"},{id:"sec_20",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Berger JM. SnapShot: nucleic acid helicases and translocases. Cell. 2008 Sep 5;134(5):888- e1. 18775318'},{id:"B2",body:'Bernstein KA, Gangloff S, Rothstein R. The RecQ DNA helicases in DNA repair. 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Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4770-5. 19273851'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Dianne C. Daniel*",address:"danieldc@evms.edu",affiliation:'
Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia, USA
'},{corresp:null,contributorFullName:"Ayuna V. Dagdanova",address:null,affiliation:'
Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia, USA
'},{corresp:null,contributorFullName:"Edward M. Johnson",address:null,affiliation:'
Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia, USA
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1. Introduction
Water is essential for sustaining life, yet it is also the source of many diseases for living things [1]. With the increase in population and the development of industrial activities, surface water resources and groundwater have become increasingly polluted. Thus, humans are exposed to many chemicals found in drinking water.
Several chemicals (organic and inorganic) have been identified in drinking water, and the sources of pollution of the drinking water system are multiple [2]. Among these pollutants, the literature reports particularly chlorine disinfection by-products [3, 4, 5], fluorine [6, 7, 8], lead [9, 10] chromium [11, 12, 13], cadmium [14, 15], nitrates [16, 17], pesticides [18, 19], hardness [20, 21], arsenic [22, 23], etc. The presence of chemical substances in the municipal drinking water is a major health concern. Indeed, some substances detected in drinking water have been the subject of epidemiological studies [1]. The health effects reported in the literature are different cases of cancer, reproductive problems (malformations) cardiovascular and neurological diseases. Drinking water is therefore an important route of exposure to chemicals.
Pollutants, particularly heavy metals are released into the environment from a wide spectrum of natural and anthropogenic sources [24]. Heavy metals are omnipresent in the environment, occurring in varying concentrations in air, bedrock, soil, water, and all biological matter [25, 26]. The principal anthropogenic sources are industrial and urban effluents, runoff water, drinking water production and distribution equipment and drinking water treatment processes [1]. The presence of heavy metals in the environment constitutes a potential source of both soil and groundwater pollution.
In Haiti, the work carried out in the field of the physicochemical quality of water intended for pollutants such as: lead, chromium [27], fluorine [28]. Excessive concentrations of hardness have also been observed in water resources [29]. These concentrations of natural origin are added to those generated by anthropogenic actions, such as poor management of solid waste, the absence of urban sanitation networks and water treatment plants only increase the rate of human exposures to these pollutants. These exposures to chemical substances continue to put Haitians at risk, and several examples shed light on the realities of risk management with respect to toxic chemicals in developing Countries [30]. The fact that the hydrographic basin of Port-au-Prince consists mainly of karst aquifers [31], rainwater, polluted by atmospheric particles of substances originating from industrial activities, and urban wastewater feeds, through the dominant geology, groundwater, thus leading to suppose that the water resources of this region are subject to significant chemical pollution.
The impact on human health of natural materials such as water, rocks and minerals has been known for thousands of years, but there have been few systematic and multidisciplinary studies on the relationship between geologic materials and processes and human health (the field of study commonly referred to as medical geology) [32]. In order to achieve a better understanding in urban and rural areas of Haiti of the different routes of exposure and the causes of a number of environmental health problems generated by exposure to high concentrations of essential and non-essential chemicals for the organism that are detected in drinking water, it seems relevant that geoscientists, environmental and health science researchers; as well as public health specialists combine their skills to approach the problem of pollution of water intended for human consumption by taking into account the two main sources of the qualitative degradation of water: “geological contributions and anthropogenic actions”. The aim of this study is: (i) to analyze the contribution of geology and anthropogenic actions in the alteration of water quality, (ii) to review the toxicology of chemicals detected in water distributed in Port-au-Prince.
2. Medical geology and environmental health in the geographical context of Port-au-Prince
2.1 Environmental health and assessment of health risks associated with chemical mixtures in drinking water
During the 1950s, forms of anxiety gradually manifested themselves regarding the state of environmental degradation and its harmful consequences for the survival of ecosystems and for development [33]. Indeed, since the said decade, the environment-human health relationship has become a major concern in the field of public health. The questions of contaminated soil, emanations from landfills, destruction of the ozone layer, global warming, food contamination, radiation emitted by household appliances, new biological hazards … are among the subjects of intervention by government authorities [34].
Abenhaim [35] argues “Environmental health issues are among the most complex for scientists to study and the most difficult for policy makers to resolve. First, because it is rare that the exhibitions are pure, thus leaving room for many confounding factors. Then, because the contaminations are generally in relatively small quantity, at the limits of the observable effects. Finally, because the consequences of exposure often occur over the long term” [35]. Exposure to chemical mixtures is a reality that would seem to dictate the need to pay much attention to hazard identification, exposure assessment and risk characterization [36], of mixtures in water intended for human consumption. Contrary to this environmental reality, the toxicological reality is that until recently most of the research carried out in this field has been devoted to studies on the effects of substances acting independently, without considering the interactions or combined effects between pollutants at the inside the human organism [37].
In Haiti, all the work carried out on the health risk linked to the pollution of drinking water by chemical substances, the risk characterization was made based on the independent effects of the pollutants studied. This approach provides information on the level of exposure of the population to a substance but does not make it possible to assess the interactions of the various pollutants detected in the distributed water. It is now widely recognized that studying the combined effects of chemical mixtures in drinking water is an integral part of public health [37]. Characterizing the combined actions of chemical mixtures involves the challenge of how to define the antagonistic, additive, or synergistic effect. It is therefore important to understand the terminology that describes the combined effect of the agents in terms of the mechanism of action. Seventy years ago, three basic concepts of common action or the interaction of the combination of chemicals were defined by biomathematicians [38, 39, 40] and they are still valid today.
Indeed, Bliss [38] identified three modes of action of constituents within a mixture vis-à-vis living organisms:
“Independent joint action”: in this type of action, the constituents act on different sites of action and the biological response of one constituent is not influenced by another.
“Similar joint action”: the constituents act on the same sites of action and the biological response of one constituent is not influenced by another. This is the approach most used for the study of mixtures.
“Synergistic action”: where the response of a mixture cannot be known by the isolated responses of the constituents. The response of a mixture depends on the combined effects of its constituents.
All three basic principles of common action of pollutants are theoretical. However, these concepts will most likely need to be addressed at the same time, especially when the mixtures consist of more than two compounds and when the targets (individuals rather than cells) are more complex.
Fox et al. [41] considers the risk assessment of chemical mixtures or the cumulative risk assessment (CRA) as the most recent step in the evolution of assessment. USEPA [42, 43] defines this approach as an analysis, characterization, and possible quantification of the combined risks to human health or the environment due to multiple substances or stressors. This definition suggests that additivity is the initially accepted mode of action for the implementation of ERC.
U.S. EPA [44] developed for the implementation of cumulative risk assessment, the Hazard Index (HI) method. This approach first assesses the effects of a substance acting independently of the others. HI is calculated by dividing the measured or estimated exposure concentration by the reference concentration (RfC):
HI=Measured or estimated exposure concentration/RfC
For HI < 1, the exposure concentration is below the cutoff value, so no health effect can be expected. On the other hand, for HI ≥ 1, the exposure concentration exceeds the threshold value, further research on the health effects of the pollutant is recommended, by calculating the Hazard metric HM.
HM=Measured or estimated exposure concentration/NOAEL or adjusted LOAEL
Based on the additive action of pollutants, the application of the HI or HM model to assess the concentration of exposure due to chemical mixtures can be also expressed:
LCE=C1M1+C2M2+CnMn≤1E1
LCE: Limit of exposure concentration
C1, C2 and Cn: observed concentrations.
M: Maximum acceptable concentration (threshold value)
In the distribution units where chlorination is applied to raw water rich in organic matter, a quite common situation or process in Haiti, the populations served are exposed to a certain number of chemical substances (by example Disinfection by-products (DBPs)), very known for their adverse effects on human health, especially the occurrence of cancers [45, 46]. In the absence of national standards for the quality of drinking water, Haiti applies the guidelines of the World Health Organization. The application of the HI or HM model in the evaluation of the combined effects of by-products could be, in a simplified manner, carried out from:
TSWHO: WHO threshold value Different types of complex mixtures require different approaches, and the usefulness of a certain approach depends on the context in which one is confronted with a mixture, and on the amount, type and quality of the available data on the chemistry and the toxicity of the mixture [47]. Scientific literature reports the occurrence of several detected in drinking water in Haiti [26, 27, 28, 29]. Moreover, MSPP and WHO [48] note “the quality of water intended for human consumption is not subject to any control. In such a context, the study of the combined effects of several chemical substances in drinking water and the assessment of the risks generated for human health constitute an important topic of transdisciplinary public health research.
2.2 Medical geology and ONE HEALTH approach in health risks assessment of drinking water in Haiti
Located between 18° and 20°6’ Northern latitude and between 71°20′ and 74°30’ Western longitude, Haiti divides with Dominican Republic “the island of Hispaniola” which is the second biggest island of the Caribbean. Its capital, Port-au-Prince, is settled at the bottom of the Gulf of “La Gonâve”, in the south border of Plain of Cul-de-sac and in the north catchment area of the “Massif de la Selle” piedmont (Figure 1). The main municipalities which constitute urban community of Port-au-Prince are Port-au-Prince, Delmas, Pétion-ville, Croix-des-bouquets, Gressier and Carrefour.
Figure 1.
Map of the west department of Haiti and metropolitan area of Port-au-Prince [49].
Haiti is exposed to a considerable ecological imbalance, characterized by catastrophic flooding associated to torrential rains and hurricanes, devastating earthquakes, and deforestation [50]. Other problems, resulting from this imbalance include land use forming the immediate perimeter of headwaters and wells, wetlands draining, arable soils erosion, the decrease of the headwaters flow and groundwater, seawater intrusion, sewers obstruction and fecal pollution [51]. In addition, Haiti is one of the most vulnerable countries to climate change [52]. In general, Haiti’s geophysical environment is characterized by rugged relief. Most of the territory is occupied by mountains formed of limestone and karst aquifers [31, 53, 54, 55]. The existence of karst aquifers conditions in rainy weather the contamination of groundwater by surface pollution. Indeed, the main characteristics of karst aquifers are the existence of irregular networks of pores, cracks, fractures and pipes of various shapes and sizes. Such a structure, of significant physical and geometric heterogeneity, causes complex hydraulic conditions and the spatial and temporal variability of hydraulic parameters. After a downpour, rapid and turbulent groundwater recharge occurs through drainage in large conduits with high volume of unfiltered water [56].
Groundwater resources at Port-au-Prince are vulnerable to contamination related to polluted water infiltration such as leachates, cesspools and septic tanks, stormwater runoff, waste oil discharging, over-irrigation and industrial discharging [50]. These sources of groundwater recharge may contain organic and inorganic compounds which can be in dissolved and colloidal forms or associated to particles. Microbiological and physicochemical characterization of groundwater resources in the metropolitan area of Port-au-Prince, among other things, highlight the presence of heavy metals [57], fecal coliforms [27] and Cryptosporidium oocysts [58]. In addition to bacterial and metal contaminations, it was found that aquifers in Haiti are also exposed to seawater pollution [50]. According to Gonfiantini and Simonot [59], the salt water is slightly enriched with heavy isotopes with respect to fresh groundwater, not showing any deviation from the straight line of meteoric waters. In the area of Port-au-Prince, the salinity of the groundwater is the result of seawater intrusion because of intensive exploitation [59].
The geophysical environment of Port-au-Prince, the inefficiency of the sanitation system (collection and treatment of solid waste, drainage, and treatment of wastewater, etc.), which contribute to the microbiological and physicochemical quality of the water distributed by public networks to the population gives rise to a particular epidemiological environment where the water generates several dangers for the health of consumers. In such a context, the assessment and management of health risks associated with water intended for human consumption require a multidisciplinary approach and call on researchers, technicians, and specialists in several fields of life and earth sciences as well as the humanities and social sciences.
The 2030 Agenda for Sustainable Development of the United Nations (UN) establishes goals and targets in areas of critical importance for humanity [60, 61], Ramirez-Mendoza et al., 2020 [62]. Indeed, the SDGs are linked to one another, the success of one often depending on the resolution of problems generally associated with another objective [60]. They thus constitute a universal and transversal approach concerning all countries, in the North as in the South. Regarding the issue of water, objective 6 - access to safe water and sanitation - aims to meet the challenges of drinking water, sanitation, and hygiene for populations, as well as issues concerning aquatic ecosystems. In the absence of quality and sustainable water resources and sanitation, progress in several other areas of the Sustainable Development Goals, including health, education and reduce of poverty, will also be delayed [60]. This objective, taken in the prism of the situation of the urban and hydrological context, as well as the geophysical environment of Haiti, raises concerns. However, the launching by public authorities and funding agencies of large research programs with the objective of generating and applying knowledge, promoting innovations in the life and earth sciences, as well as in human and social sciences, in a context of transdisciplinary would be of great use, even essential for the development to achieve the various objectives [63]. Indeed, Medical geology, the science that deals with the relationship between natural geological factors and human and animal health problems [32], and the One Health approach, an approach that attempts to bringing together medical/public health researchers, veterinary researchers, and environmental scientists to tackle health problems, provides an adequate theoretical framework to address environmental health problems resulting from the degradation of natural environment in Port-au- Prince.
The interconnectedness of human, animal, and environmental health is at the heart of One Health, an increasingly important prism through which governments, NGOs (nongovernmental organizations), and practitioners view human health) [64]. Mazet et al., [65] note “An important implication of the One Health approach is that integrated policy interventions that simultaneously and holistically address multiple and interacting causes of poor human health—unsafe and scarce water, lack of sanitation, food insecurity, and proximity between animals and humans—will yield significantly larger health benefits than policies that target each of these factors individually and in isolation. By its very nature, the One Health approach is transdisciplinary, since it is predicated on agricultural scientists, anthropologists, economists, educators, engineers, entomologists, epidemiologists, hydrologists, microbiologists, nutritionists, physicians, public health professionals, sociologists, and veterinarians working collaboratively to improve and promote both human and animal health” [65].
3. Chemistry and toxicology of selected pollutants detected in water distributed in Port-au-Prince
3.1 Presence of fluoride in drinking water and risk for human health
Fluoride, the 13th most abundant element in the earth’s crust, is essential to human life [66]. Elemental fluorine almost never occurs in nature, but fluoride is widely distributed in the Earth’s crust, mainly as the mineral’s fluorspar, cryolite, apatite, mica, hornblende, and fluorite [67, 68]. Table 1 shows certain physical and chemical properties of fluoride.
Fluoride participates in the formation of bones and teeth and contributes to their solidification. It enters the body in the form of fluorides through drinking water, food, air, drugs, and cosmetics. It is known to have beneficial and harmful effects on humans [69]. Indeed, its deficiency has long been linked to the incidence of dental caries [70], while prolonged excessive intake has been associated with fluorosis [71]. Large populations throughout parts of the developing world suffer the effects of chronic endemic fluorosis [70].
The most important source of fluoride intake in the human body is drinking water [72]. According to WHO [73], the guideline value for fluoride in drinking-water is 1.5 mg/L, based on increasing risk of dental fluorosis at higher concentrations and that progressively higher levels lead to increasing risks of skeletal fluorosis. This value is higher than that recommended for artificial fluoridation of water supplies for prevention of dental caries, which is usually 0.5–1.0 mg/L. WHO [74] recommends that, in setting a standard, Member States should consider drinking-water consumption and the intake of fluoride from other sources. Nevertheless, a content of 1 mg/l of fluoride ions is approximately the desirable concentration in the water supplied to the population to ensure optimal dental health [75]. However, several factors, including temperature, can influence this optimum value, which varies from one climatic region to another. It is therefore important to determine this optimal dose for each region depending on whether it is in a temperate zone or in a tropical zone [76]. Dean [77] has shown that the optimum concentration of fluorine as a function of the ambient temperature is 1.0–1.2 mg/l.
The optimal dose of fluoride in drinking water is defined as the amount of fluoride which decreases the prevalence of dental caries with the absence of significant fluorosis [78, 79, 80]. Fluorosis is the demineralization of tooth enamel by excessive fluoride ingestion during the years of tooth calcification [81]. This phenomenon, observed in children, can range from mild fluorosis to a severe manifestation Indeed, Dean [78] observed that 10% of children consuming water containing 1.0 mg/l of fluoride could develop benign fluorosis. It is reported in the literature that children living in the southwestern United States develop severe fluorosis, much more so than those living in the midwestern, while both groups are exposed to the supply systems. Water containing the same concentration of fluorine [82]. Other studies have suggested that the extremely high temperature of the southwest is a major factor contributing to the increase in demand for drinking water and the increase in severe and endemic dental fluorosis [80, 81, 82].
In Haiti, studies carried out on the water resources of the Center-Sud hydrographic region of Haiti (Figure 2), revealed fluorine concentrations between 0 and 2 mg/l [28, 83]. The various localities of this region are exposed to an average daily temperature ranging from 17 to 36° C.
Figure 2.
Map of the “Centre-Sud” hydrographic region of Haiti.
These observations lead on the one hand to questioning the problems of dental caries and fluorosis from which the populations of the areas studied may suffer and, on the other hand, to determine the optimal dose of fluoride in water intended for human consumption. of the Center-South hydrographic region of the Republic of Haiti. Fluoride’s exposure is a major public health problem particularly for children. Indeed, intake of high-water fluoride concentration during child’s growth and development stages has been associated with mental and physical problems [84, 85, 86].
3.2 Water hardness and human health
Hardness is the traditional measure of the capacity of water to react with soap and describes the ability of water to bind soap to form lather, which is a chemical reaction detrimental to the washing process [87]. Water hardness results from the contact of groundwater with rock formations. It is the sum of the concentrations of dissolved polyvalent metal ions which Ca2+ and Mg2+ are predominant. The sources of the metallic ions are typically sedimentary rocks, and the most common are limestone (CaCO3) and dolomite (CaMg(CO3)2) [66].
Ca and Mg are present as simple ions Ca2+ and Mg2+ with the Ca levels varying from tens to hundreds of mg/L and the Mg concentrations varying from units of tens of mg/L [88]. Magnesium is significantly less abundant than calcium in rocks and in most natural waters. In addition, magnesium concentrations are much lower in the water than calcium. They are generally less than 50 mg/L, although values higher or equal to 100 mg/L are stored particularly in cold climates [87]. The physical and chemical properties of Ca2+ and Mg2+ are presented in Table 2.
Physical and chemical properties of Ca2+ and Mg2+.
Hardness (in mg equivalent CaCO3/L) can be determined by substituting the concentration of calcium and magnesium, expressed in mg/L, in the following equation [89]:
Total hardness=2.497Ca2+mg/L+4.118Mg2+mg/LE3
Each concentration is multiplied by the ratio of the formula weight of CaCO3 to the atomic weight of the ion; hence, the factors 2.497 and 4.118 are included in the hardness relation [89].
Hardness is most expressed as milligrams of calcium carbonate equivalent per liter [90]. Water containing calcium carbonate at concentrations below 60 mg/l is generally considered as soft; 60–120 mg/l, moderately hard; 120–180 mg/l, hard; and more than 180 mg/l, extremely hard [91]. Although hardness is caused by cations, it may also be discussed in terms of carbonate (temporary) and non-carbonate (permanent) hardness [90].
Calcium and magnesium are essential for the human body [90]. They contribute to the formation and solidification of bones and teeth and play a role in the decrease of neuromuscular excitability, myocardial system, heart, and muscle contractility, intracellular information, transmission, and blood contractility [87, 88, 92]. They also play a major role in the metabolism of almost all cells of the body and interacts with many nutrients [93]. However, inadequate, or excess intake of either nutrient can result in adverse health consequences [90].
According to WHO [90] “Inadequate intakes of calcium have been associated with increased risks of osteoporosis, nephrolithiasis (kidney stones), colorectal cancer, hypertension and stroke, coronary artery disease, insulin resistance and obesity. Most of these disorders have treatments, but not cures. Owing to a lack of compelling evidence for the role of calcium as a contributory element in relation to these diseases, estimates of calcium requirement have been made based on bone health outcomes, with the goal of optimizing bone mineral density.
To a great extent, individuals are protected from excess intakes of calcium by a tightly regulated intestinal absorption and elimination mechanism through the action of 1,25-dihydroxyvitamin D, the hormonally active form of vitamin D. When calcium is absorbed more than need, the excess is excreted by the kidney in healthy people who do not have renal impairment” [90].
Magnesium is the fourth most abundant cation in the body and the second most abundant cation in intracellular fluid [90]. In the cardiovascular system, magnesium is the candidate element. It plays an important role as a cofactor and activator of more than 300 enzymatic reactions including glycolysis, ATP metabolism, transport of elements such as Na, K and Ca through membranes, synthesis of proteins and nucleic acids, neuromuscular excitability and muscle contraction [94]. That can have hand in various mechanism where the main is the calcium antagonist effect which can be direct or indirect [95].
Low magnesium levels are associated with endothelial dysfunction, increased vascular reactions, elevated circulating levels of C-reactive protein (a proinflammatory marker that is a risk factor for coronary heart disease) and decreased insulin sensitivity. Low magnesium status has been implicated in hypertension, coronary heart disease, type 2 diabetes mellitus and metabolic syndrome. Magnesium deficiency has been implicated in the pathogenesis of hypertension, with some epidemiological and experimental studies demonstrating a negative correlation between blood pressure and serum magnesium levels. However, data from clinical studies have been less convincing [90].
Indeed, water hardness has become an important public excess health issue [96]. Kobayaski [97] showed a relationship between water hardness and the incidence of vascular diseases. The scientific literature reported the existence of a relationship between cardiovascular disease mortality and water hardness [98, 99, 100]. Miyake and Iki [101] observed a lack of association between water hardness and coronary heart diseases mortality in Japan. Nonetheless, many studies covering many countries suggest such a correlation and geochemically it is worthy of serious study [88]. Based on available information in the literature on the association of water hardness and the incidence of cardiovascular diseases (CVD), Eisenberg [102] considered that Mg seems to be the basic element. Indeed, extremely hard natural water with CaCO3 concentration higher than 200 mg/l with a magnesium concentration lower than 7 mg/l may affect various organs including the cardiovascular physiology [87].
In Haiti, studies on the spring waters used to supply a part of the population of the Metropolitan Area of Port-au-Prince (MAPP), the most important urban area of the country, showed a total hardness greater than 200 mg/l, with magnesium concentration less than 7 mg/l [29]. In addition, magnesium concentrations ranging from 5.58 to 6.9 mg/l have been measured in groundwater in the metropolitan area of Port-au-Prince [103]. Drinking water low in Mg significantly increases the likelihood of cardiovascular mortality [104]. Catling et al., [105] found significant evidence of an inverse association between magnesium levels in drinking water and cardiovascular mortality following a meta-analysis of case control studies. In Haiti, cardiovascular disease (CVD) is now the leading cause of adult mortality in Haiti [106, 107].
3.3 Groundwater pollution by heavy metals and human health
Metals are natural constituents of the Earth’s crust. The distribution and fate of metals in the environment is governed by their properties and the influence of environmental factors [108]. In environmental compartments, heavy metals constitute an ecological and human health concern since heavy metals are not degraded biologically like certain organic pollutants [109]. Metals exert biological effects that can be beneficial or harmful. Many metals such as Fe, Cu, Co, Mn, Zn, and Cr are essential for humans, and deficiency states with clinical abnormalities have been identified [27, 108, 110]. Other metals such as Hg, Pb, Cd, and As are not known to be essential for any animals [110]. Essential elements can also cause toxic effects at high doses.
In Haiti, heavy metals (lead, chromium, and nickel) have been measured in groundwater [27]. The physical and chemical properties of these heavy metals are presented in Table 3.
Physical and chemical properties of chromium, lead and nickel.
3.3.1 Effects of chromium on human health
Chromium is one of the heavy metals considered a major pollutant. It has been widely used in industrial processes for leather tanning, dyes and paint preparation, textile manufacturing, paper mills, wood preservation, stainless steel production, and photography [111]. Chromium exists in several oxidation states. The most stable and common forms are trivalent chromium, Cr(III), and hexavalent chromium, Cr(VI), which exhibit contrasting biochemical properties and toxicokinetics [112, 113]. Cr(III) compounds occur naturally in the form of oxides, hydroxides or sulfates, and they are nutritionally necessary to humans for glucose, fat and protein metabolism [114]. In contrast, Cr(VI) compounds are mainly anthropogenic and highly toxic; its mutagenic and carcinogenic nature and high oxidation state enhances its ability to move into living cells [114]. Cr(III) and Cr(VI) interchangeability depends on their concentration in solution, pH, the redox potential (Eh) of the medium, and the presence or absence of a strong oxidant or reductant [111, 115].
The toxicity of chromium is directly dependent on the valence state, with hexavalent chromate Cr(VI) and trivalent chromate Cr(III) being of the greatest interest [112]. Oral bioavailability varies with valence state, with Cr(VI) being more readily absorbed. Cr(VI) can be broken down into Cr(III) within the acidic environment of the stomach [111]. Acute exposure to chromium is indicated by immediate irritation of the eye, nose, throat, and respiratory tract, which results in burning, congestion, epistaxis, and cough. Ulceration, bleeding, and erosion of the nasal septum mark chronic exposure. Cough, chest pain, dyspnea, and chromium-induced asthma indicate exposure to soluble chromium products [113]. If chronic exposure is suspected, in conjunction with weight loss, cough, and hemoptysis, this suggests the development of bronchogenic carcinoma. Dermatological manifestations include painless, slow-healing ulceration of the fingers, knuckles, and forearms. Ingestion is marked by nausea, vomiting, abdominal pain, prostration, and death associated with uremia [114].
3.3.2 Effects of lead on human health
Drinking water is one of the major sources of human exposure to lead [115]. Lead particularly targets the nervous system, blood, and kidney [116]. Many studies found associations between low level environmental Pb exposure and chronic kidney disease, a general term for heterogeneous disorders affecting the structure and function of the kidney (CKD) [117, 118]. Long-term lead exposure may generate irreversible functional and morphological renal changes [119], distal motor neuropathy and possibly seizures and coma [120]. Infants and small children are more sensitive to the effects of lead, which moreover is transported through the placenta to the foetus [121]. Lead accumulation in fetuses and small children might cause developmental disruption in terms of neurological impairment characterized by a decrease of cognitive faculties, which can be reversible or not, evaluated by psychomotor tests such as the verbal IQ (Intellectual Quotient) test [27, 109]. The period when IQ is most affected is from birth to about 4 years of age [122].
Scientific literature on lead water pollution reports “Lead remains a problem in drinking water in many parts of the world, with millions of properties served by distribution systems containing lead components. Strong links have been established between human exposure to lead and health effects in both adults and children. As a result, the allowable levels of lead indrinking water have generally become lower. Implementation of these regulations is difficult with the controls available. Future recommendations for aspiring to zero lead in drinking water are: (i) improving sampling, monitoring and modeling; (ii) Wider application of short-term pointof- use devices; (iii) replacement of all lead pipes and plumbing through applicable regulations and increased awareness public” [123, 124, 125, 126].
3.3.3 Effects of nickel on human health
Nickel is insoluble in water. However, when it is in the form of exceptionally fine particles, it ionizes as Ni (II) in water and in body fluids such as blood. During oral exposure, the major effects observed are the death of a child after ingestion of 570 mg of nickel/kg [127] and intestinal disorders such as nausea, abdominal cramps, and diarrhea [128]. Immunological, hematological, hepatic, renal, genotoxic effects on embryonic development and reproduction have been reported depending on the route of entry into the body [129].
4. Conclusion
The aim of this study is: (i) to analyze the contribution of geological factors and anthropogenic actions in the alteration of water quality in Port-au-Prince. The toxicology of chemicals of three heavy metal (chromium, lead, and nickel) and fluoride, substances detected in groundwater and tap water, has been reviewed. The information available on the effects of the selected heavy metals highlights major chemical risks, particularly for children, relating to Pb (II), Cr (III), Cr (VI) and Ni (II) contained in the groundwater were also characterized [27]. The level of pollution of underground water resources in the metropolitan area of Port-au-Prince does not only require the application of an approach based on water treatment processes. It also reflects the need to approach the issue of the quality of water intended for human consumption in this urban space based on a transdisciplinary approach based on the theories of medical geology and the approach. One Health. Indeed, the level of organic and mineral pollution of these resources can compromise the rare efforts made to achieve the SDGs, more particularly the 3, 6, 11, 13. The results available in the literature and used in the context of this work clearly indicate the existence of chronic toxicities of trace heavy metals (Cr, Pb, Ni), fluoride and hardness of drinking water on the human organism and on kidney tissues. In the future, it will be necessary to initiate research work on the combined effects of these substances from observations on laboratory animals and then proceed to modeling to finally arrive at an understanding of certain interactions that may exist between these pollutants.
Acknowledgments
The authors are thankful to the “One Health” University Space of Quisqueya University, FOKAL-Open Society Foundation Haiti, the Agence universitaire de la Francophonie (AUF), the Representation of the Institute for Research for Development (IRD) in Mexico, Cuba, and Haiti, the SCAC (Service for Cooperation and Cultural Action) of the French Embassy in Haiti, and the AOG (Association communautaire paysanne des Originaires de Grande Plaine) for their support in carrying out this work.
\n',keywords:"chemical pollutions, drinking water, environmental health, medical geology, One Health, Haiti",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/76752.pdf",chapterXML:"https://mts.intechopen.com/source/xml/76752.xml",downloadPdfUrl:"/chapter/pdf-download/76752",previewPdfUrl:"/chapter/pdf-preview/76752",totalDownloads:237,totalViews:0,totalCrossrefCites:0,dateSubmitted:"April 8th 2021",dateReviewed:"April 16th 2021",datePrePublished:"June 8th 2021",datePublished:"December 15th 2021",dateFinished:"May 13th 2021",readingETA:"0",abstract:"The geophysical environment of the Republic of Haiti is characterized by hydrological and biogeographical climatic phenomena, and a relief marked by its rugged appearance. Most of the territory is occupied by mountains formed of limestone. The differences in level are very marked. Fragmentation is another feature of the relief. These environmental imperfections juxtaposed with difficult socioeconomic conditions and anthropogenic actions raise questions about possible chemical metal pollution of the country’s water resources. Indeed, the predominance of limestone in the Haitian geology generate water hardness, and in the case where the magnesium concentration is less than 7 mg/l, this water may be the source of cardiovascular diseases. Studies carried out on several water points show a total hardness greater than 200 mg/l. In Port-au-Prince, concentrations of lead ranging from 40 μg/L to 90 μg/L and high Cr (III) risks were measured and estimated in groundwater and drinking water. Concentration of fluorine ranging from 0 to 2 mg/l were obtained from water resources. Concentration above 1.5 mg/l have been found from alluvial aquifers. Chronic public health risks, such as cardiovascular diseases, deterioration of the psychological development of children, irreversible functional and morphological renal changes, and dental fluorosis, strain Haiti’s water resources. Chemicals’ exposures seem to pose a threat to public health in Haiti, which need to be studied. The aim of this study is: (i) to analyze the contribution of geology and anthropogenic actions in the alteration of water quality, (ii) to review the toxicology of chemicals detected in water distributed in Port-au-Prince.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/76752",risUrl:"/chapter/ris/76752",signatures:"Alexandra Emmanuel and Evens Emmanuel",book:{id:"10349",type:"book",title:"Environmental Health",subtitle:null,fullTitle:"Environmental Health",slug:"environmental-health",publishedDate:"December 15th 2021",bookSignature:"Takemi Otsuki",coverURL:"https://cdn.intechopen.com/books/images_new/10349.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83968-721-1",printIsbn:"978-1-83968-720-4",pdfIsbn:"978-1-83968-722-8",isAvailableForWebshopOrdering:!0,editors:[{id:"34101",title:"Prof.",name:"Takemi",middleName:null,surname:"Otsuki",slug:"takemi-otsuki",fullName:"Takemi Otsuki"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"293512",title:"Dr.",name:"Evens",middleName:null,surname:"Emmanuel",fullName:"Evens Emmanuel",slug:"evens-emmanuel",email:"evens.emmanuel@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"334364",title:"Ph.D.",name:"Alexandra",middleName:null,surname:"Emmanuel",fullName:"Alexandra Emmanuel",slug:"alexandra-emmanuel",email:"alex.emmanuel1603@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Medical geology and environmental health in the geographical context of Port-au-Prince",level:"1"},{id:"sec_2_2",title:"2.1 Environmental health and assessment of health risks associated with chemical mixtures in drinking water",level:"2"},{id:"sec_3_2",title:"2.2 Medical geology and ONE HEALTH approach in health risks assessment of drinking water in Haiti",level:"2"},{id:"sec_5",title:"3. Chemistry and toxicology of selected pollutants detected in water distributed in Port-au-Prince",level:"1"},{id:"sec_5_2",title:"3.1 Presence of fluoride in drinking water and risk for human health",level:"2"},{id:"sec_6_2",title:"3.2 Water hardness and human health",level:"2"},{id:"sec_7_2",title:"3.3 Groundwater pollution by heavy metals and human health",level:"2"},{id:"sec_7_3",title:"3.3.1 Effects of chromium on human health",level:"3"},{id:"sec_8_3",title:"3.3.2 Effects of lead on human health",level:"3"},{id:"sec_9_3",title:"3.3.3 Effects of nickel on human health",level:"3"},{id:"sec_12",title:"4. Conclusion",level:"1"},{id:"sec_13",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Kılıç, Z.(2020). The importance of water and conscious use of water. Int J Hydro. 4(5):239–241. DOI: 10.15406/ijh.2020.04.00250'},{id:"B2",body:'Calderon R. L. (2000). The epidemiology of chemical contaminants of drinking water. 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American Heart Journal. 124(2):544–549. doi: 10.1016/0002-8703(92)90633-7'},{id:"B103",body:'Emmanuel, E. (2004). Évaluation de risques sanitaire et écotoxicologiques liées aux effluents hospitaliers, thèse de l’Institut National des Sciences Appliquées de Lyon, Université de Lyon, France. p. 259'},{id:"B104",body:'Kozisek, F. (2020). Regulations for calcium, magnesium or hardness in drinking water in the European Union member states. Regulatory Toxicology and Pharmacology, 112, 104589. doi: 10.1016/j.yrtph.2020.104589'},{id:"B105",body:'Catling, L. A., Abubakar, I., Lake, I. R., Swift, L., & Hunter, P. R. (2008). A systematic review of analytical observational studies investigating the association between cardiovascular disease and drinking water hardness. Journal of water and health, 6(4), 433–442. doi:10.2166/wh.2008.054'},{id:"B106",body:'Roth, G. A., Johnson, C., Abajobir, A., Abd-Allah, F., Abera, S. F., Abyu, G., Ukwaja, K. N. (2017). 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FEMS microbiology reviews, 25(3), 335–347. doi: 10.1111/j.1574-6976.2001.tb00581.x'},{id:"B114",body:'Agency for Toxic Substance and Disease Registry [ATSDR]. (2000). Toxicological profile for chromium. Atlanta, Georgia, USA: U.S. Department of Health and Human Services. 461 p.'},{id:"B115",body:'Tadesse I, Isoaho SA, Green FB, Puhakka JA. 2006. Lime enhanced chromium removal in advanced integrated wastewater pond system. Bioresource Technology 97: 529–534.'},{id:"B116",body:'Académie des Sciences. (1998). Contamination des sols par les éléments traces: les risques et leur gestion. Rapport No 42. Paris: Lavoisier Tec&Doc. 440 p.'},{id:"B117",body:'Robson, M. (2003). Methodologies for assessing exposures to metals: human host factors. Ecotoxicology and Environmental Safety, 56(1), 104–109. doi:10.1016/S0147-6513(03)00054-X'},{id:"B118",body:'Lewis R. Metals. In: Ladou J, editor. Occupational and environmental medicine. New York: McGrawHill; 1997. p. 405–439. (Chapter 27).'},{id:"B119",body:'Fertmann, R., Hentschel, S., Dengler, D., Janßen, U., & Lommel, A. (2004). Lead exposure by drinking water: an epidemiologial study in Hamburg, Germany. International journal of hygiene and environmental health, 207(3):235–244. doi:10.1078/1438-4639-00285'},{id:"B120",body:'INERIS (Institut National de l’Environnement Industriel et des Risques). Plomb et ses dérivés, in Fiche de données toxicologiques et environnementales des substances chimiques. Paris: INERIS; ERIS-DRC-01-25590-ETSC-Api/SD-N 00df257, 90 p.'},{id:"B121",body:'Ab Latif Wani, A. A., & Usmani, J. A. (2015). Lead toxicity: a review. Interdisciplinary toxicology, 8(2):55. DOI: 10.1515/intox-2015-0009'},{id:"B122",body:'Needleman, H. (2004). Lead poisoning. Annu. Rev. Med., 55:209–222. doi:10.1146/annurev.med.55.091902.103653'},{id:"B123",body:'Christensen, J. M. (1995). Human exposure to toxic metals: factors influencing interpretation of biomonitoring results. Science of the total environment, 166(1–3):89–135. doi:10.1016/0048-9697(95)04478-J'},{id:"B124",body:'Cleymaet, R., Collys, K., Retief, D. H., Michotte, Y., Slop, D., Taghon, E., Coomans, D. (1991). Relation between lead in surface tooth enamel, blood, and saliva from children residing in the vicinity of a non-ferrous metal plant in Belgium. Occupational and Environmental Medicine, 48(10):702–709. doi:10.1136/oem.48.10.702'},{id:"B125",body:'Watt, G. C. M., Britton, A., Gilmour, H. G., Moore, M. R., Murray, G. D., & Robertson, S. J. (2000). Public health implications of new guidelines for lead in drinking water: a case study in an area with historically high water lead levels. Food and Chemical Toxicology, 38, S73-S79. doi:10.1016/S0278-6915(99)00137-4'},{id:"B126",body:'Jarvis, P., & Fawell, J. (2021). Lead in drinking water–an ongoing public health concern? Current Opinion in Environmental Science & Health, 100239. doi:10.1016/j.coesh.2021.100239'},{id:"B127",body:'Daldrup, T., Haarhoff, K., & Szathmary, S. C. (1983). Fatal nickel sulfate poisoning. Beitrage zur gerichtlichen Medizin, 41, 141–144.'},{id:"B128",body:'Sunderman Jr, F. W., Hopfer, S. M., Sweeney, K. R., Marcus, A. H., Most, B. M., & Creason, J. (1989). Nickel absorption and kinetics in human volunteers. Proceedings of the Society for Experimental Biology and Medicine, 191(1), 5–11. doi:10.3181/00379727-191-42881'},{id:"B129",body:'Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological Profile for Nickel. Altanta, GA: U.S. Department of Health and Human Services; 1993. http://www.atsdr.cdc.gov.'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Alexandra Emmanuel",address:null,affiliation:'
Groupe Haïtien d’Études et de Recherche en Environnement et Santé (GHERES), Pétion-Ville, Haiti
Association Haïtienne Femmes, Science et Technologie, Haiti
Groupe Haïtien d’Études et de Recherche en Environnement et Santé (GHERES), Pétion-Ville, Haiti
Université Quisqueya, Laboratoire Santé-Environnement (LS-E), Port-au-Prince, Haiti
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3.2 When submitting the Chapter, the Corresponding Author agrees to:
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Comply with all instructions and guidelines provided by IntechOpen;
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Produce the Chapter with all due skill, care and diligence, and in accordance with good scientific practice;
\\n\\t
Submit all the corrections in due time as defined during the publishing process schedule.
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The Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
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All payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\\n\\n
3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\\n\\n
The Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\\n\\n
3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\n
4. CORRESPONDING AUTHOR'S WARRANTY
\\n\\n
4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\n
The Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
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The Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
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4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n
5. TERMINATION
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5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\n
In case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n
6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n
6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\\n\\n
6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n
6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n
7. MISCELLANEOUS
\\n\\n
7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n
7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\n
7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n
7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n
7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\\n\\n
7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\\n\\n
Any modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\n
7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n
7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n
1. DEFINITIONS
\n\n
Corresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\n
Co-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\n
IntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\n
Book: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n
2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n
2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\n
\n\t
An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to publish, communicate to the public, reproduce, republish, transmit, sell, distribute and otherwise use and make available the Chapter in whole, partial or adapted from and/or incorporated in or in conjunction with other works, in electronic and print editions of the Publication and in derivative works and on any platform owned and/or operated by IntechOpen, throughout the world, in all languages, and in all media and formats now known or later developed.
\n\t
An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to create and store electronic archival copies of the Chapter, including the right to deposit the Chapter in open access digital repositories.
\n\t
An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to license others to reproduce, translate, republish, transmit and distribute the Chapter in whole, partial or adapted from and/or incorporated in or in conjunction with other works under the condition that the Corresponding Author and each Co-Author is attributed (currently this is carried out by publishing the Chapter under a Creative Commons Attribution 3.0 Unported License).
\n
\n\n
The aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n
2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\n
The Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\n
Subject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\n
Subject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n
2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n
2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n
3. CORRESPONDING AUTHOR'S DUTIES
\n\n
3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n
3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\n
\n\t
Comply with all instructions and guidelines provided by IntechOpen;
\n\t
Produce the Chapter with all due skill, care and diligence, and in accordance with good scientific practice;
\n\t
Submit all the corrections in due time as defined during the publishing process schedule.
\n
\n\n
The Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\n
All payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n
3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\n
The Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n
3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n
4. CORRESPONDING AUTHOR'S WARRANTY
\n\n
4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\n
The Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\n
The Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n
4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n
5. TERMINATION
\n\n
5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\n
In case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n
6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n
6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n
6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n
6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n
7. MISCELLANEOUS
\n\n
7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n
7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n
7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n
7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n
7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n
7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\n
Any modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n
7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n
7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\n
Last updated: 2020-11-27
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\n"}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"396",title:"Dr.",name:"Vedran",middleName:null,surname:"Kordic",slug:"vedran-kordic",fullName:"Vedran Kordic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/396/images/7281_n.png",biography:"After obtaining his Master's degree in Mechanical Engineering he continued his education at the Vienna University of Technology where he obtained his PhD degree in 2004. He worked as a researcher at the Automation and Control Institute, Faculty of Electrical Engineering, Vienna University of Technology until 2008. His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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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:"63215",title:"Smart Antenna Systems Model Simulation Design for 5G Wireless Network Systems",slug:"smart-antenna-systems-model-simulation-design-for-5g-wireless-network-systems",totalDownloads:2279,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"The most recent antenna array technologies such as smart antenna systems (SAS) and massive multiple input multiple output (MIMO) systems are giving a strong increasing impact relative to 5G wireless communication systems due to benefits that they could introduce in terms of performance improvements with respect to omnidirectional antennas. Although a considerable number of theoretical proposals already exist in this field, the most common used network simulators do not implement the latest wireless network standards and, consequently, they do not offer the possibility to emulate scenarios in which SAS or massive MIMO systems are employed. This aspect heavily affects the quality of the network performance analysis with regard to the next generation wireless communication systems. To overcome this issue, it is possible, for example, to extend the default features offered by one of the most used network simulators such as Omnet++ which provides a very complete suite of network protocols and patterns that can be adapted in order to support the latest antenna array systems. The main goal of the present chapter is to illustrate the improvements accomplished in this field allowing to enhance the basic functionalities of the Omnet++ simulator by implementing the most modern antenna array technologies.",book:{id:"6844",slug:"array-pattern-optimization",title:"Array Pattern Optimization",fullTitle:"Array Pattern Optimization"},signatures:"Vincenzo Inzillo, Floriano De Rango, Luigi Zampogna and Alfonso A. Quintana",authors:null},{id:"52919",title:"Waveform Design Considerations for 5G Wireless Networks",slug:"waveform-design-considerations-for-5g-wireless-networks",totalDownloads:3435,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"In this chapter, we first introduce new requirements of 5G wireless network and its differences from past generations. The question “Why do we need new waveforms?” is answered in these respects. In the following sections, time‐frequency (TF) lattice structure, pulse shaping, and multicarrier schemes are discussed in detail. TF lattice structures give information about TF localization of the pulse shape of employed filters. The structures are examined for multicarrier, single‐carrier, time‐division, and frequency‐division multiplexing schemes, comparatively. Dispersion on time and frequency response of these filters may cause interference among symbols and carriers. Thus, effects of different pulse shapes, their corresponding transceiver structures, and trade‐offs are given. Finally, performance evaluations of the selected waveform structures for 5G wireless communication systems are discussed.",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:"Evren Çatak and Lütfiye Durak‐Ata",authors:[{id:"19414",title:"Prof.",name:"Lutfiye",middleName:null,surname:"Durak-Ata",slug:"lutfiye-durak-ata",fullName:"Lutfiye Durak-Ata"},{id:"189749",title:"M.Sc.",name:"Evren",middleName:null,surname:"Çatak",slug:"evren-catak",fullName:"Evren Çatak"}]},{id:"54645",title:"Power‐Over‐Fiber Applications for Telecommunications and for Electric Utilities",slug:"power-over-fiber-applications-for-telecommunications-and-for-electric-utilities",totalDownloads:2602,totalCrossrefCites:12,totalDimensionsCites:0,abstract:"Beyond telecommunications, optical fibers can also transport optical energy to powering electric or electronic devices remotely. This technique is called power over fiber (PoF). Besides the advantages of optical fiber (immunity to electromagnetic interferences and electrical insulation), the employment of a PoF scheme can eliminate the energy supplied by metallic cable and batteries located at remote sites, improving the reliability and the security of the system. Smart grid is a green field where PoF can be applied. Experts see smart grid as the output to a new technological level seeks to incorporate extensively technologies for sensing, monitoring, information technology, and telecommunications for the best performance electrical network. On the other hand, in telecommunications, PoF can be used in applications, such as remote antennas and extenders for passive optical networks (PONs). PoF can make them virtually passives. We reviewed the PoF concept, its main elements, technologies, and applications focusing in access networks and in smart grid developments made by the author’s research group.",book:{id:"5914",slug:"optical-fiber-and-wireless-communications",title:"Optical Fiber and Wireless Communications",fullTitle:"Optical Fiber and Wireless Communications"},signatures:"Joao Batista Rosolem",authors:[{id:"202012",title:"Dr.",name:"Joao",middleName:"Batista",surname:"Batista Rosolem",slug:"joao-batista-rosolem",fullName:"Joao Batista Rosolem"}]},{id:"75267",title:"Wireless Power Charging in Electrical Vehicles",slug:"wireless-power-charging-in-electrical-vehicles",totalDownloads:657,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Wireless Power Transfer (WPT) technology can transfer electrical energy from a transmitter to a receiver wirelessly. Due to its many advantages, WPT technology is a more adequate and suitable solution for many industrial applications compared to the power transfer by wires. Using WPT technology will reduce the annoyance of wires, improve the power transfer mechanisms. Recently, the WPT gain enormous attention to charging the on-board batteries of the Electric Vehicle (EV). Several well-known car manufacturing companies start efforts to adopt WPT technology and enhance its features. Therefore, WPT can be achieved through the affordable inductive coupling between two coils named a transmitter and a receiver coil. In EV charging applications, transmitter coils are located underneath the road, and receiver coils are installed in the EV. The inductive WPT of resonant type is generally applied to medium-high power transfer applications like EV charging because it achieves better energy efficiency. In this chapter, various WPT technologies are discussed and tested in EV wireless charging applications. Furthermore, extensive information is given to developing an advanced WPT technology that can transfer maximum power by achieving maximum efficiency.",book:{id:"10514",slug:"wireless-power-transfer-recent-development-applications-and-new-perspectives",title:"Wireless Power Transfer",fullTitle:"Wireless Power Transfer – Recent Development, Applications and New Perspectives"},signatures:"Nassim Iqteit, Khalid Yahya and Sajjad Ahmad Khan",authors:[{id:"270815",title:"Dr.",name:"Khalid",middleName:"O. 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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"}}}},{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"}}}}]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null,scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
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\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
",coverUrl:"https://cdn.intechopen.com/series/covers/24.jpg",latestPublicationDate:"June 28th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:0,editor:{id:"262440",title:"Prof.",name:"Usha",middleName:null,surname:"Iyer-Raniga",slug:"usha-iyer-raniga",fullName:"Usha Iyer-Raniga",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRYSXQA4/Profile_Picture_2022-02-28T13:55:36.jpeg",biography:"Usha Iyer-Raniga is a professor in the School of Property and Construction Management at RMIT University. Usha co-leads the One Planet Network’s Sustainable Buildings and Construction Programme (SBC), a United Nations 10 Year Framework of Programmes on Sustainable Consumption and Production (UN 10FYP SCP) aligned with Sustainable Development Goal 12. The work also directly impacts SDG 11 on Sustainable Cities and Communities. She completed her undergraduate degree as an architect before obtaining her Masters degree from Canada and her Doctorate in Australia. Usha has been a keynote speaker as well as an invited speaker at national and international conferences, seminars and workshops. Her teaching experience includes teaching in Asian countries. She has advised Austrade, APEC, national, state and local governments. She serves as a reviewer and a member of the scientific committee for national and international refereed journals and refereed conferences. She is on the editorial board for refereed journals and has worked on Special Issues. Usha has served and continues to serve on the Boards of several not-for-profit organisations and she has also served as panel judge for a number of awards including the Premiers Sustainability Award in Victoria and the International Green Gown Awards. Usha has published over 100 publications, including research and consulting reports. 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Her focus is on quality, innovation, leadership, and personalised learning. She works primarily at the strategic and policy levels, both nationally and internationally, and with key international organisations. She is committed to promoting and improving OFDL in the context of SDG4 and the future of education. Ossiannilsson has more than 20 years of experience in her current field, but more than 40 years in the education sector. She works as a reviewer and expert for the European Commission and collaborates with the Joint Research Centre for Quality in Open Education. Ossiannilsson also collaborates with ITCILO and ICoBC (International Council on Badges and Credentials). She is a member of the ICDE Board of Directors and has previously served on the boards of EDEN and EUCEN. Ossiannilsson is a quality expert and reviewer for ICDE, EDEN and the EADTU. She chairs the ICDE OER Advocacy Committee and is a member of the ICDE Quality Network. She is regularly invited as a keynote speaker at conferences. She is a guest editor for several special issues and a member of the editorial board of several scientific journals. She has published more than 200 articles and is currently working on book projects in the field of OFDL. Ossiannilsson is a visiting professor at several international universities and was recently appointed Professor and Research Fellow at Victoria University of Wellington, NZ. Ossiannilsson has been awarded the following fellowships: EDEN Fellows, EDEN Council of Fellows, and Open Education Europe. She is a ICDE OER Ambassador, Open Education Europe Ambassador, GIZ Ambassador for Quality in Digital Learning, and part of the Globe-Community of Digital Learning and Champion of SPARC Europe. On a national level, she is a quality developer at the Swedish Institute for Standards (SIS) and for ISO. She is a member of the Digital Skills and Jobs Coalition Sweden and Vice President of the Swedish Association for Distance Education. She is currently working on a government initiative on quality in distance education at the National Council for Higher Education. 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He collaborates with the Environmental Resources Analysis Research Group (ARAM), University of Extremadura (UEx), Spain; VALORIZA - Research Center for the Enhancement of Endogenous Resources, Polytechnic Institute of Portalegre (IPP), Portugal; Centre for Tourism Research, Development and Innovation (CITUR), Madeira, Portugal; and AQUAGEO Research Group, University of Campinas (UNICAMP), Brazil.",institutionString:"University of Johannesburg, South Africa and WSB University, Poland",institution:{name:"University of Johannesburg",institutionURL:null,country:{name:"South Africa"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:54,paginationItems:[{id:"81595",title:"Prosthetic Concepts in Dental Implantology",doi:"10.5772/intechopen.104725",signatures:"Ivica Pelivan",slug:"prosthetic-concepts-in-dental-implantology",totalDownloads:25,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Current Concepts in Dental Implantology - From Science to Clinical Research",coverURL:"https://cdn.intechopen.com/books/images_new/10808.jpg",subseries:{id:"2",title:"Prosthodontics and Implant Dentistry"}}},{id:"80963",title:"Pain Perception in Patients Treated with Ligating/Self-Ligating Brackets versus Patients Treated with Aligners",doi:"10.5772/intechopen.102796",signatures:"Farid Bourzgui, Rania Fastani, Salwa Khairat, Samir Diouny, Mohamed El Had, Zineb Serhier and Mohamed Bennani Othmani",slug:"pain-perception-in-patients-treated-with-ligating-self-ligating-brackets-versus-patients-treated-wit",totalDownloads:22,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Current Trends in Orthodontics",coverURL:"https://cdn.intechopen.com/books/images_new/10780.jpg",subseries:{id:"2",title:"Prosthodontics and Implant Dentistry"}}},{id:"80964",title:"Upper Airway Expansion in Disabled Children",doi:"10.5772/intechopen.102830",signatures:"David Andrade, Joana Andrade, Maria-João Palha, Cristina Areias, Paula Macedo, Ana Norton, Miguel Palha, Lurdes Morais, Dóris Rocha Ruiz and Sônia Groisman",slug:"upper-airway-expansion-in-disabled-children",totalDownloads:35,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Oral Health Care - An Important Issue of the Modern Society",coverURL:"https://cdn.intechopen.com/books/images_new/10827.jpg",subseries:{id:"1",title:"Oral Health"}}},{id:"80839",title:"Herbs and Oral Health",doi:"10.5772/intechopen.103715",signatures:"Zuhair S. 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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. 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