\r\n\tThe planning and technology of the tunnel and underground structures is an important issue for building of the structure. Depending on the particulars of each project location and the construction time available, the adopted construction methods have an important influence on the success of the project. Traditional and novel methods are underlined with the focus on reliable and cost effective technology. \r\n\tOnce built, the tunnel needs to guarantee comfort to the users and reduce the risks of accident. The equipment is important to obtain adequate visibility and reduced concentration of contaminants. For these purposes, an adequate lighting system and ventilation system are necessary. Ventilation is also crucial in the case of emergency conditions, as it used to control fire development and smoke propagation. Operational and safety systems are to be analysed to fulfill the all the operational and emergency needs. The book investigates the relevant topics in these regards as the crucial point of tunnel exploitation. \r\n\tThe aim of the book in focused also on the aspect of the optimised maintenance strategy of tunnels that bases on a systematic condition assessment through the investigations. Operation and maintenance works in tunnels have an adverse effect on the traffic, hence it is essential to plan operation and maintenance works rationally and effectively as the maintenance have to minimise the impact on the daily traffic and to ensure cost effectiveness at all times.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"f640f0187c5c2db846fc350f222cb6a0",bookSignature:"Prof. Peter Vidmar",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8538.jpg",keywords:"Planning of tunnels, Development of tunnel, Geomechanics, Investigation, Tunnel construction, Process monitoring, Tunnel installations, Technologies, Tunnel safety, Maintenance, Underground pipelines, Cables",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"August 30th 2019",dateEndSecondStepPublish:"September 20th 2019",dateEndThirdStepPublish:"November 19th 2019",dateEndFourthStepPublish:"February 7th 2020",dateEndFifthStepPublish:"April 7th 2020",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"3 years",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"69701",title:"Prof.",name:"Peter",middleName:null,surname:"Vidmar",slug:"peter-vidmar",fullName:"Peter Vidmar",profilePictureURL:"https://mts.intechopen.com/storage/users/69701/images/system/69701.jpeg",biography:"Peter Vidmar holds a PhD in Maritime and Transport science at Faculty of maritime studies and transportation, University of Ljubljana and a M. Sc. in Nuclear engineering at Faculty of Mathematics and Physics, University of Ljubljana. He is employed at the University of Ljubljana, Faculty of maritime studies and transport as an associate professor of marine science.\r\n\r\nHis activity is mainly directed in simulation and safety analyses of maritime and transportation system with emphases on road tunnel safety assessments and industrial systems (port facilities, LNG terminals). His background includes mechanical engineering and CFD modelling. 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\n
1. Introduction
\n
The core of cell proliferation is the division of cells and replication of chromosomes. Among other factors, it is also regulated by the length of telomeres since short telomeres will either recruit telomerase, or, in the absence of telomerase, induce senescence, apoptosis, or genome instability, or activate a DNA damage response (e.g., telomere recombination). The main function of telomeres is the protection of chromosomal integrity during DNA replication; moreover, they themselves are protected by a shelterin protein complex. Telomeres stabilize the ends of linear chromosomes and prevent the ends from being recognized as a double strand break. In human cells, telomeres contain hexameric tandem repeats, 5′TTAGGG 3′, of DNA sequence. To maintain the proliferative ability of cells, the elongation of telomeres is executed by adding telomeric DNA repeats to the 3′chromosomal ends by telomerase. In the absence of telomerase, the telomeres shorten in every cell division. Telomerase as an RNA-dependent DNA polymerase repairs the sequences of telomeres after each cell division; but in humans, this enzyme is active in stem cells, germ cells [1, 2, 3], and cancer cells only.
\n
During development of an individual, mature oocytes and cleavage stage embryos display low or absent telomerase activity, whereas in the blastocyst stage, its activity is high again. As in cells during early cleavage, the telomeres become remarkably longer, and an alternate lengthening of telomeres may play a role in their elongation. Processes of telomeric DNA recombination between homologous sister chromatids take place in the cleavage stage, and the length of telomeres is then maintained from the blastocyst stage onward by telomerase [4]. Telomeric DNA recombination between telomeres on separate chromosomes such as gene conversion and the elongation of telomeres by DNA polymerase activity by mechanisms like break-induced replication can lengthen telomeres independently of telomerase activity [5].
\n
The mechanism of DNA replication results in progressive shortening of the ends of linear DNA molecule. That shortening limits the life span of individual cells and it is referred to as replication senescence [6]. Recently, it is well known that telomere attrition is observed during normal cellular aging, but telomere dysfunction may also contribute to the onset and progression of age-related diseases like atherosclerosis and myocardial infarction [7]. Telomere attrition is regarded as one of the so-called hallmarks of aging as proposed in [8].
\n
Many tissues and organs contain cycling undifferentiated stem cells that provide cells for their renewal. The frequency of their mitotic division is different among tissues; examples of the most active are epidermal cells and cells of the bone marrow. Those cells are characterized by high levels of telomerase expression and disorders of telomere homeostasis cause, or at least take part in, the pathogenesis of serious inherited diseases, for example, dyskeratosis congenita [9], aplastic anemia, other bone marrow syndromes [10, 11, 12] and/or idiopathic pulmonary fibrosis [13]. Moreover, increased incidence of diabetes mellitus was identified in patients suffering from those pathologies [14]. Inherited bone marrow failure syndromes threaten also the prenatal development due to fetal malformations and intrauterine growth retardation accompanied with an abnormally small placenta [15].
\n
The correct function of telomerase-telomere complex depends on both genetic predispositions and external factors (age, reactive oxygen species, and exogenous genotoxic factors). Mutations in the telomerase holoenzyme in either of the two genes, TERT encoding the reverse transcriptase, or TERC encoding the RNA template for the synthesis of telomeres by telomerase, can cause remarkable telomere attrition even in hemizygous individuals [16] and may take part in hereditary conditioned telomere disorders [17, 18, 19, 20].
\n
\n
\n
2. Placenta in pregnancy
\n
The prenatal development of an individual is conditioned by placenta, the transient organ that functions exclusively for the time of pregnancy. In order to meet fetal requirements, the placenta holds the functions of still undeveloped fetal organs, for example, lung and kidney. It is the site of transport of oxygen, ions, nutrients, and maternal immunoglobulins from mother to fetus, and carbon dioxide and wastes from fetus to mother. The placenta also maintains pregnancy by production of steroid and protein hormones and other factors. Due to its position between maternal and fetal bloodstreams, the placenta acts as a barrier against infectious agents and regulates the maternal immune tolerance, gas exchange, and fetal nutrition. On the other hand, its structure and function are negatively impacted by maternal and fetal metabolic disturbances in pathological pregnancies.
\n
Placental tissues originate in extraembryonic structures, that is in trophoblast, the outer layer of the blastocyst, which invades maternal tissues and gives rise to the cytotrophoblast and syncytiotrophoblast, and in extraembryonic mesoderm that is requisite for the formation of placental vasculature and supporting connective tissue.
\n
The progress of fetal growth and maturation of fetal organs is essentially accompanied by the growth of placental size. It is performed by continuous cell proliferation till the term of gestation [21] and balanced with differentiation and apoptosis in all tissue compartments. The weight of term placenta is 500–600 g, the estimated surface area of syncytiotrophoblast available for maternofetal transport is 11–13 m2, and the inner fetal capillary surface area is about 12 m2 [22].
\n
Human placenta is formed by chorionic plate and its repeatedly branched projections, chorionic villi, that are immersed in maternal blood circulating in the intervillous space. The growth of villi goes hand in hand with fetal growth. They develop into various types during pregnancy, and their classification depends on size and structural features. Basically, each villus is covered by the layer of trophoblast consisting of continuous cytoplasmic mass with numerous nuclei, that is, syncytiotrophoblast, and cuboidal cells of cytotrophoblast appearing as a continuous layer underneath syncytiotrophoblast in early gestation, but sparsely spread in term placenta. As nuclei in syncytiotrophoblast do not divide, cytotrophoblast cells play the role of stem cells of trophoblast. They undergo mitotic division, and their fusion with syncytiotrophoblast enlarges its mass. As shown by detection of cell cycle markers (e.g., Ki67, PCNA), they display proliferative potential over the duration of pregnancy [23, 24, 25].
\n
The other source of placental tissues is extraembryonic mesoderm. For the placental development, this cell population gives rise to the mesenchyme adjoining villous trophoblast. Mesenchymal derivatives, that is, cells of connective tissue, endothelial cells, pericytes, and smooth muscle cells then form villous stroma and vascular bed. It is obvious that they follow the growth of trophoblast, and their proliferation and subsequent differentiation contribute to the formation of new functionally efficient villi, and thus to the enlargement of the organ and its functional capacity. It is significant particularly in the third trimester when the rapid development of terminal villi accompanies the rapid enlargement of fetal size [22]. Previous studies have demonstrated the proliferative potential of cells in villous vascular bed and stroma in early pregnancy as well as at term [24, 25]. The proliferative potential of cells in terminal villi of normal human term placenta is also demonstrated in Figure 1\n.\n
\n
Figure 1.
Proliferative activity of cytotrophoblast (arrows), stromal cell (arrowhead), and capillary endothelium (asterisk) in terminal villi of normal term placenta demonstrated by Ki-67 immunohistochemistry. Bar = 50 μm.
\n
In order to provide nutrition for the increasing metabolic requirements of growing fetus, the placenta displays continuous cell proliferation during its entire existence. Despite the fact that fetal demands attain their maximal level at term, it is expected that cells in placenta at term decrease their proliferative capacity due to telomere shortening and undergo senescence similar to somatic cells in other organs. It is also supposed that those changes in telomere length might take part in the initiation of parturition [26]. Telomere shortening during pregnancy was found also in the placenta of mice [27]. As shown in another study in mouse, the proportion of representative short telomeres, that is, 3- and 5-kb telomere fragments, significantly increases toward the end of pregnancy. The authors conclude that the quantity of representative short telomeres increases prior to parturition and takes part in the mediation of cellular aging in the placenta, finally leading to parturition [26]. Those findings are consistent with other studies regarding the impact of short telomere rather than average telomere length [28].
\n
Due to its location in maternal uterus, the placenta is influenced by any abnormal metabolic conditions in both mother and fetus. The negative influence demonstrates itself in pathological structural features as well as in impaired function. In such organ displaying mitotic activity, altered telomere homeostasis may take part in those adverse changes. Here, we summarize data on telomere length and telomerase activity in placentas from normal pregnancies and pregnancies complicated by metabolic disturbances threatening pregnancy outcome, as are maternal diabetes mellitus, preeclampsia, and intrauterine growth restriction.
\n
\n
\n
3. Analysis of telomere homeostasis—methodological approaches
\n
In view of the facts mentioned above, telomere length emerged as a promising marker generally in medicine, but the utility of such measurements highly depends on valid methodologies [7]. The average telomere length is highly variable among different cell types and among different individuals. There are also gender differences, which could be detected at birth. Additionally, the average telomere length declines with age [16].
\n
Telomeres may be repaired either by the enzyme telomerase using its RNA template or by recombination. The methodologies examining telomere homeostasis in different tissues are therefore based not only on the determination of the length of telomeric DNA sequences, but they examine also the status and expression of the reverse transcriptase (hTERT) and the RNA template (hTERC) genes and recombination events on selected telomeres. In the following paragraphs and in Table 1, we summarize the main features and limitations of methodologies employed in placenta research, alternatively the methods applicable on human samples.
\nTerminal restriction fragment (TRF) analysis was originally developed to determine the lengths of telomeres in 1988 by Moyzis et al. [54]. Genomic DNA is isolated and then digested with a mixture of restriction enzymes that are selected to avoid the cutting of telomeric and subtelomeric sequences. The DNA fragments obtained after such a digestion are separated in agarose gel and hybridized with the probe containing telomeric sequences [55]. The need for high amounts of highly integral DNA samples represents one of the main limitations of this methodology [7].
\n
\nPolymerase chain reaction (PCR)-based methodologies were elaborated to overcome limits of the previous method. Cawthon [56] reported the technique based on quantitative PCR (qPCR). The sequences of primer pairs proposed by Cawthon avoid the primer dimer formation which frequently occurs when repetitive sequences are amplified. Cawthon’s qPCR technique and its subsequent modifications [56, 57, 58] belong to the most frequently used methods. Telomere length is quantified relatively—the ratio T/S between the quantity of repetitive telomeric sequences (T) and the quantity of sequences representing a single copy gene (S) is calculated. These ratios correlated very well with the absolute telomere lengths measured by TRF method in Cawthon’s original study [56]. An attempt to standardize this methodology over large spectrum of laboratories was made [59].
\n
O’Callaghan and Fenech [60] described the modification of qPCR-based technique allowing the determination of an absolute telomere length due to the use of artificially synthesized DNA standard containing the defined number of telomeric repeats.
\n
PCR-based techniques are quite popular among researchers because they require lower DNA quantity and usual laboratory equipment. Due to their relatively low costs, they may be employed in high-throughput epidemiologic studies. One shortcoming of PCR-based methodologies is that the resulting values inform only about the average telomere length in the specimens.
\n
\nSingle telomere length analysis (STELA) targets telomeric DNA from a single chromosome using primers specific to subtelomeric sequences [61]. All individual chromosomal subtelomeric regions do not contain suitable specific sequences; therefore, the method is able to examine only a limited set of chromosomes [7]. Using this methodological approach, Garcia-Martin et al. [32] found considerable intra-sample variability in examined placentas.
\n
\nQuantitative fluorescence in situ hybridization (Q-FISH)-based techniques are focused more on the work with cells than with isolated DNA. A fluorescent probe, mostly peptide nucleic acid (PNA) probe, complementary to telomeric repetitive sequences is hybridized to denatured DNA of metaphase chromosomes or interphase nuclei. The cells may be fresh, frozen, or formaldehyde-fixed and paraffin-embedded. The application of metaphase Q-FISH, which was developed in 1996 by Lansdorp and colleagues [62], results in the estimation of the length of all 92 telomeres in human cells. It allows the detection of telomere free ends. The most serious limitation of this approach is the requirement of metaphases from mitotically active cells. The method is labor intensive [7, 62].
\n
\nInterphase Q-FISH, first described in 1998 by de Pauw and colleagues [63], is applicable on nondividing cells. It compares the fluorescent signals obtained after hybridization with a telomere-specific probe and with a probe targeting a single copy gene. Its results inform, similar to the results of qPCR methodologies, about the average length of the telomeres in examined cell, the method is not able to recognize each individual telomere as metaphase Q-FISH.
\n
A method for telomere capture evaluation based on interphase Q-FISH has been established by Amiel et al. [64]. When telomeres shorten to the critical length, repair pathways are activated. In the process of telomere capture, a critically short telomere obtains a new telomeric sequence from another chromosomal end. In the original method, the number of fluorescent signals for a single copy gene, SNRP, which is localized on chromosome 13, was compared with the number of signals for 15qter region of this chromosome [64] to follow not only random aneuploidy but also telomere capture or translocation of telomere. The methodology was also used in placenta research [39, 48].
\n
The pq-ratio assay described in 2001 by Perrem et al. [40] belongs to methods that directly examine telomere recombination. This assay measures the variation in telomere lengths at the p and q arms of a chromosome. The telomere ratio for most chromosomes is expected to be q/p~1, because the telomeres at both ends of a given chromosome shorten at a similar rate. If recombination is used to maintain the ends, then it could alter the length of at least one telomere by a random amount of telomeric repeats. This results in variable values for the pq-ratio. The pq-ratio assay is very sensitive, and the data may become biased as the telomeres shorten. Small changes on a short telomere may be overrepresented and telomeres with no signal will not be represented at all [40, 65, 66].
\n
\nChromosome orientation-FISH (CO-FISH) was first described in 1993 [67, 68] as a method for strand-specific FISH. The method is dependent on cultivation of analyzed cells because it requires incorporation of bromodeoxyuridine (BrdU) into newly synthesized strands. This step allows subsequent enzymatic removal of BrdU containing strands after their damage caused by UV light in the presence of the dye Hoechst 33258. The remaining strands then serve as single-stranded targets for FISH. This approach allows differentiation between the telomeres produced via leading- or via lagging-strand DNA synthesis, and it enables the study of sister chromatid exchanges (SCE) and inversions in telomeric regions [69, 70].
\n
The methodology of directional genomic hybridization (dGH) represents the cytogenomic extension of strand-specific hybridization. Telo-dGH recognizes terminal exchange events—terminal inversions and generally different forms of genetic recombination occurring near the telomeres, namely sister chromatid exchange (SCE) [71].
\n
\nFlow-FISH represents the modification of interphase Q-FISH, which was introduced in 1998 by Hultdin et al. [72]. The cells in suspension are hybridized with fluorescent probes and then examined using flow cytometry. This approach is technically very demanding because the unfixed cells are often fragile and clustering. The technique is very sensitive to preservation of cells. FISH probes may also have affinity to cytoplasmic structures [7]. Higher numbers of cells are needed (typically > 1 × 105), the assay determines mean telomere lengths and it does not account for aneuploidy or SFE (signal free ends) but the methodology was successfully used in numerous studies [73, 74, 75].
\n
\nTELI-FISH is a combined FISH/immunofluorescence method which was developed in 2002 to assess human telomere lengths from standard formalin-fixed paraffin-embedded tissues. Combination with immunostaining allows the simultaneous identification of specific cell types. The assay requires very few cells (10–15). Validation showed excellent agreement with the commonly used TRF method based on Southern blotting [76].
\n
Microdissection followed by qPCR allows selection of cells for analysis using classical histological technique and it is suitable for the studies based on archival material [35]. Microdissected cells may be examined by qPCR methodology, and therefore, its main disadvantage is that it provides information only about the relative average length of telomeres in analyzed samples. The methodology does not result in the determination of the lengths of the longest or the shortest telomeres contained in the sample. Comparison of T/S ratios related to a reference sample allows evaluation of differences between the groups of samples (for instance between healthy controls and patients).
\n
Whole genome sequencing (WGS) captures sequence information from the entire genome, including the telomeres, and is increasingly being applied in research and in the clinic. In 2014, Ding et al. [77] demonstrated a novel method, TelSeq, which allows measurement of average telomere length by using whole genome or exome sequencing data. It was the first study that evaluated in detail the relationship between the frequency of telomere repeats and telomere length. With the potential to be a relatively high-throughput method, this may overtake qPCR as the method of choice in future studies. Their study was the first computational method that had been validated against an established experimental method (Southern blot measurements of the mean length of terminal restriction fragments).
\n
\n
\n
3.2 Methods examining genes coding for telomerase and its RNA components, their expression, and telomerase activity
\n
The telomere length is closely associated with telomerase (human telomerase reverse transcriptase—hTERT) activity (TA) and the availability of its RNA component (hTERC or TERRA—telomeric repeat-containing RNA) in tissues.
\n
\nThe copy number of both genes hTERT and hTERC in nuclei in archive tissues or cultivated cells is examined by FISH methodology. This approach was applied also in placenta research [36, 41, 46, 48]. RNA-FISH is based on the use of fluorescently labeled probes and allows the cellular localization of TERC [78].
\n
The presence of telomerase itself may be detected in tissues by means of immunohistochemistry—a methodology which is generally well established in laboratories of pathologists [76]. This methodology was also widely used in placenta research—see reference in Table 1\n.\n
\n
In Table 1, the studies that examined the expression of hTERT using reverse transcription and subsequent qPCR to quantify the amount of hTERT transcripts are also summarized.
\n
The telomerase activity may be measured by a wide panel of methodologies based on addition of telomerase substrate and detection of amplified telomerase products by telomere repeat amplification protocols—TRAPs—developed by Kim et al. [79]. Recently existing numerous methodological modifications of this approach were reviewed by Mensa et al. [78].
\n
\nhTERC (TERRA) is a long noncoding RNA, which can be transcribed from nearly all telomeres in mammalian cells because its transcription starts from their subtelomeric regions. Therefore, the quantity of such transcripts can be measured by RT-qPCR starting from RNA isolated from analyzed cells or tissues followed by reverse transcription and PCR with chromosome-specific primers. Molecular mechanisms associated with the role of TERC in telomere reparation are intensively studied [80, 81].
\n
\nNorthern blotting or RNA dot blotting needs mostly radiolabeled probes and cannot detect the minor changes in quantity of TERC [78].
\n
\nDetection of G4 quadruplexes using antibodies is based on the fact that during hTERC transcription, the RNA:DNA hybrids at the chromosome ends are formed, and they can fold into G-quadruplexes [78]. The G-quadruplex structure formed by telomere DNA plays also an important role in the regulation of the telomerase reaction [82].
\n
\n
\n
3.3 Methods examining epigenetic changes and chromatin structure
\n
Not only the presence of DNA sequences of genes hTERT and hTERC but also their functional state determined epigenetically plays a crucial role in the regulation of their expression.
\n
Wilson et al. [37] used array technology (Illumina Infinium Human Methylation 450 BeadChip) to study methylation alterations in genes hTERT, DNMT1, and DNMT3A in human placentas. MALDI-TOF technology was employed to determine the level of DNA methylation of hTERC in placenta using Sequenom EpiTyper platform [29]. Lower levels of gene methylation were found in normal placentas compared with other somatic cells.
\n
\nQuantitative Telomeric Chromatin Isolation Protocol (QTIP) was introduced in 2013 by Grolimund et al. [83]. It allows the comprehensive determination of telomere protein composition and the quantitative comparison of telomere protein compositions between cells with different telomeric states. Chromatin is cross-linked, immunopurified, and analyzed by mass spectrometry. The methodology may be also adapted for examination of other chromatin regions within the genome [83].
\n
\n
\n
\n
4. Placenta in normal pregnancy
\n
The assessment of telomere length in normal pregnancy gives important data regarding dynamics of placental cellular proliferation. The study on third trimester placentas using the qPCR has shown decreased telomere length between gestational weeks 28 and 42 (13.98–10.56 kbp) [38]. The application of qPCR and Southern blot-based terminal restriction fragment (TRF) assay confirmed considerably longer telomeres in first trimester villi than in term placentas, telomeres of which were found to be longer than those in cord blood mononuclear cells [29, 84].
\n
Some authors took into consideration that the position of villous tissue in the placenta may influence the telomere length, and therefore collected and processed samples of the whole placenta from more locations [29, 37, 84]; nevertheless, no site-specific differences of telomere length were determined except [84] showing that the telomerase activity was detected in term placenta restricted to biopsy sites near umbilical cord only. Moreover, the Southern blot-based TRF assay discovered longer telomere length in placental samples than in cord blood cells [84]. The study by qPCR proved that telomeres in placentas of female fetuses are longer than in placentas of male fetuses at the same gestational week. This finding suggests an influence of hormonal milieu during intrauterine development [37]. On the other hand, the other study performed by single telomere length analysis (STELA) revealed neither influence of fetal sex nor influence of the mode of delivery [32].
\n
The above-mentioned findings in chorionic villi and normal placenta suggest that telomere length is maintained by active telomerase during pregnancy. Nevertheless, the papers dealing with this topic present equivocal results. Using TRAP assay, Wright et al. [33] found no detectable telomerase activity in placenta. To the contrary, telomerase activity studied by TRAP assay and in situ TRAP assay was found in both chorionic villi at 5–14 weeks of gestation and normal placentas at 23–42 weeks of gestation [49]. Expression of telomerase protein was detected by immunohistochemistry in cytotrophoblast of chorionic villi [47, 85]. Decreasing relative telomerase activity was shown in comparison of chorionic villi in first, second and third trimester. In normal villi from 6 to 40 gestational weeks, the presence of telomere RNA component (TERC) was demonstrated, whereas telomerase reverse transcriptase (TERT) was not found in samples from second and third trimesters [86]. Immunohistochemical reaction revealed telomerase expression in trophoblast and stroma of villi in 10th week, but not in term placenta [87]. Using RT-PCR method, the hTERT-RNA expression was found in normal chorionic villi from 6th to 10th gestational week as well as in normal placentas from 12th to 41st gestational week, whereas hTERT protein expression was found in chorionic villi, but only in the fourth part of placental samples [88].
\n
\n
\n
5. Placenta in pregnancy pathologies
\n
It is evident that normal placental growth and development carried out by cell proliferation is conditioned by appropriate telomere length ensured by homeostasis of telomerase system. For optimal course of those processes, normal metabolic milieu is necessary in mother, placenta, and fetus. The most critical condition of intrauterine development is adequate oxygen supply. The early pregnancy phase, that is, first 10 weeks, runs under low oxygen levels. This relative hypoxia before the constitution of the fetoplacental and uteroplacental blood circulation induces various factors, one being the hypoxia-inducible factor 1, that upregulates hTERT expression (and telomerase activity), and its decrease with gestational age is in correlation with decrease of telomerase activity logically followed by telomere shortening [88]. As the placenta consumes about 40% of the oxygen supplied to fetoplacental unit [89], the hypoxic conditions have negative impact on all processes running there. And hypoxia also represents a key factor in genesis of pregnancy pathologies discussed in the following parts of this chapter.
\n
\n
5.1 Maternal diabetes mellitus
\n
There are two main forms of maternal diabetes mellitus, the insulin-dependent form with onset before conception, and gestational diabetes diagnosed usually in second half of pregnancy that disappears after birth. In the insulin-dependent type diabetes, an autoimmune process destroys β-cells of the islets of Langerhans completely and the patient is then treated by insulin supplementation.
\n
As shown in experiments with mice, the type 2 diabetes, and similarly gestational diabetes, may involve telomere shortening during pathogenesis. Shorter telomeres are associated with impaired β-cell regeneration, impaired glucose-stimulated insulin secretion by disorders of insulin release leading to impaired glucose tolerance as well as to increased β-cell senescence [14, 90].
\n
Both forms of maternal diabetes are characterized by maternal hyperglycemia and thus higher amount of glucose transported to fetus. Metabolic complications derived from hyperglycemia threaten the mother; manifest themselves in placental structure and function; have negative influence on fetal well-being, perinatal morbidity and mortality; and long-lasting effect on the postnatal life of the individual. In pregnancies complicated by maternal diabetes mellitus, the alterations of placental structure and function as well as the pregnancy outcome depend on the quality of metabolic control. Placentas from poorly controlled diabetes are larger and heavier and microscopic picture shows disturbances of villous maturation [22]. The oxidative stress produced by imbalance of glucose and oxygen supply in fetoplacental unit is compensated by enhanced placental angiogenesis demonstrated by higher villous capillary branching [91]. It is possible to suppose that both, the higher placental weight and enhanced angiogenesis, are a consequence of escalated cell proliferation leading to exhaustion of telomeres available for mitotic division.
\n
Regarding the telomere length in placenta from pregnancies complicated by maternal diabetes, the available data are not quite consistent. In the qPCR-based study examining large cohort of placentas, maternal diabetes was found associated with longer telomere length [38]. In another study comparing telomere length in cytotrophoblast of placentas from poorly controlled maternal diabetes and normal pregnancies by FISH method, the result indicated shorter telomeres in the diabetic group [42]. In the same groups of patients, the immunohistochemically identified telomerase expression, the expression of mRNA for hTERT, and the expression of TERC gene copy number were lower in diabetic placentas [41]. On the other hand, no difference of mean telomere length was found in peripheral villi of normal placentas and placentas in well-controlled maternal diabetes examined by laser capture microdissection and qPCR [35], although the study on the same placental material discovered lower proliferative potential of cytotrophoblast and vascular endothelium of terminal villi in maternal diabetes [25]. Single telomere length analysis (STELA) was used for measurement of telomere length in normal placentas and placentas from gestational diabetes treated either by lifestyle intervention or by metformin or insulin therapy. The result showed that the therapy by metformin or insulin protected from telomere shortening in placentas of male fetuses [34].
\n
\n
\n
5.2 Preeclampsia
\n
Preeclampsia is a disease of pregnancy characterized by new-onset maternal hypertension and proteinuria. It may begin in 28–34 gestational weeks (early-onset preeclampsia) or after 34 weeks (late-onset preeclampsia). It is commonly accepted that the preeclampsia originates in deficient placentation, that is, decreased invasion of the maternal tissues by extravillous trophoblast. Under normal conditions, the endothelium and smooth muscle cells of uterine spiral arterioles are replaced with trophoblast and their diameter becomes wide allowing delivery of blood at low pressure to the intervillous space. The decreased trophoblastic invasion produces narrow uteroplacental arteries and the resulting malperfusion of the intervillous space causes oxidative stress of the fetoplacental unit manifested among others by reduced development of the villous tree and placental growth retardation. Increased placental proliferative activity found using detection of PCNA and Ki67 in preeclampsia may be a sign of increased cell turnover [92]. The associated systemic vascular inflammation in maternal organism may cause injury of multiple organs.
\n
In placentas in preeclampsia, the analysis of villous cytotrophoblast based on the quantitative FISH method showed shorter telomeres, more end-to-end telomere aggregates, and abnormal TERC gene copy number as well as decreased hTERT expression detected by immunohistochemistry [39, 43, 44]. Common expression of hTERT protein and HIF-1α in term preeclamptic placenta gives an evidence of response to hypoxia by telomerase upregulation [88]. Nevertheless, the measurement of average telomere length by qPCR did not show significant differences between control, early-onset preeclamptic, and later-onset preeclamptic placentas [37]. Another study has also shown no differences of telomere length between normal placentas and placentas in preeclampsia [30]. Enhanced levels of placental hTERT-mRNA in preeclampsia [50] if not associated with longer telomeres as a result of enhanced telomerase activity suggests that there is a conceivable disturbance in translation or post-translation processes of the enzyme protein.
\n
\n
\n
\n
6. Intrauterine growth restriction
\n
In intrauterine growth restriction (IUGR), the growth and development of fetus is delayed by 3–4 weeks regarding the gestational age and the birth weight is low, under 10th percentile for gestational age. Fetal growth restriction is associated with restricted placental size caused by arrest mechanisms reducing cell proliferation [45]. There are two types of IUGR, symmetric and asymmetric. The fetus displaying symmetric IUGR has normal body proportion, the fat and muscle tissue are reduced. It is usually associated with genetic factors causing, for example, already mentioned bone marrow syndromes [9, 10, 11, 12] or infections. The asymmetric IUGR is characterized by normal size of head and reduced chest and abdominal circumference due to reduced fat and muscle tissue. It is often associated with placental insufficiency arising, for example, in preeclampsia and may be related to oxidative stress.
\n
Studies performed by quantitative FISH method and RT-PCR on placental cytotrophoblast in IUGR gave an evidence of shorter telomeres, lower telomerase activity, decreased hTERT mRNA, and decreased TERC gene copy number [45, 46, 48]. The relative telomere length and hTERT expression were found lower in cytotrophoblast of placentas in IUGR as well as in IUGR combined with preeclampsia [43].
\n
Lower proliferative potential found in placenta in IUGR [52, 70, 76, 93] seems to be consistent with decreased telomerase activity in cytotrophoblast of IUGR placenta [52, 76]. In placenta associated with asymmetric IUGR, only weak, if any, telomerase activity, hTERT expression, and copy numbers of telomerase reverse transcriptase were found by qPCR and in situ TRAP assay [49, 51, 53]. Shorter telomeres associated with higher expression of cell senescence markers were found in placenta samples in IUGR [31] and shorter telomeres detected by quantitative FISH technique and reduced average telomere length detected by qPCR were shown in [36]. To the contrary, no difference was revealed in average telomere length assessed by qPCR between normal placenta and placenta in IUGR [37].
\n
\n
\n
7. Conclusions
\n
Appropriate fetal growth and development is conditioned by appropriate placental growth and development. It is accomplished by balanced cell proliferation, differentiation, and apoptosis. Cell proliferation is influenced by the length of telomeric sequences of chromosomes and their elongation due to telomerase activity. This review article summarizes available data on telomere length and telomerase activity of placenta in pregnancy-complicating situations, that is, maternal diabetes mellitus, preeclampsia, and intrauterine growth restriction (Table 2) as well as methods used for this research (Table 1).
\n
\n
\n
\n
\n\n
\n
Diagnosis
\n
Telomere length
\n
Telomerase activity
\n
\n\n\n
\n
Normal placenta
\n
Telomere length is reduced in the course of pregnancy; placental telomere length is not site-specific [32, 33, 37, 38, 84]
\n
hTERT expression and telomerase activity were found [47, 49, 84, 85]; telomerase activity decreases in the course of pregnancy [86, 87, 88]
\n
\n
\n
Placenta associated with maternal diabetes mellitus
\n
Maternal diabetes is associated with longer placental telomeres [38]; there is no difference in placental telomere length in well-controlled diabetes [34, 35]; telomeres are shorter in placentas from poorly controlled diabetes [42]
\n
Lower expression of hTERT, hTERT-mRNA, lower TERC copy number in placentas from poorly controlled diabetes [41]
\n
\n
\n
Placenta associated with preeclampsia
\n
No differences of telomere length between normal placentas and placentas in preeclampsia [37, 84]; shorter telomeres, more end-to-end telomere aggregates, higher telomere aggregates count [43, 44]
\n
Lower expression of hTERT [44], abnormal TERC copy gene number [39]; higher expression of hTERT mRNA [50]
\n
\n
\n
Placenta associated with IUGR
\n
Shorter telomeres [31, 36, 45]; no difference in telomere length [37]
\n
Lower expression of hTERT, hTERT-mRNA, lower TERC copy number [46, 48, 51, 52, 53]
\n
\n\n
Table 2.
Summarized data on telomere length and telomerase activity in normal placenta and placenta in case of maternal diabetes mellitus, preeclampsia, and IUGR.
\n
In normal placentas, longer telomeres and higher telomerase activity were found in early pregnancy, they gradually decreased till the term. Although the available studies on placentas from pregnancies complicated by maternal diabetes are not numerous, their results corroborated by experimental studies suggest that diabetic metabolic conditions contribute to telomere shortening and that the appropriate metabolic control achieved by adequate treatment may function as a prevention of this adverse process. The results of research on telomere length and telomerase activity in preeclampsia are still equivocal and rather suggest debatable comparability of methods applied in those studies. The telomere length in placenta associated with IUGR was found lower and accompanied with decreased expression and activity of components of telomerase apparatus.
\n
Maternal diabetes mellitus, preeclampsia as well as IUGR do not only complicate pregnancy but are also taken as causes of adverse outcomes for individuals later in postnatal period. Further investigation of the effect of factors influencing telomere length and telomerase activity may contribute to better understanding of those links. The placental DNA is identical to the DNA of fetal cells and the period of its existence equal to the prenatal period of the fetus spent in the same maternal environment. As telomeres are susceptible to external conditions of maternal milieu (i.e., oxidative stress, reactive oxygen species, exogenous genotoxic insults), those epigenetic influences may accelerate their shortening [94]. Prospective studies in experimental models and of course in long-time prospective studies in human should elucidate if there is a relation of final telomere length in placentas at term and newborn and if the measurement of placental telomere length could have a predictive potential for individual.
\n
Recently, the immunomodulatory role of telomeric sequences was recognized [78, 95]. Telomeric sequences originated from trophoblasts may circulate in the pool of cell-free DNA in maternal plasma and contribute to timing of parturition [26] by stimulation of maternal immune response against placenta. The role of telomeric sequences contained in cell-free DNA in plasma of healthy persons in the regulation of immune system performance was also described [95]. Additionally, the telomeric sequences were found also in cytoplasm where they regulate inflammatory response via their interaction with TLR9 receptor [78].
\n
In view of all these facts, the study of telomeres and their homeostasis in placenta seems to be crucial for the understanding of pathogenesis in the broad spectrum of pregnancy complications.
\n
\n
Acknowledgments
\n
This work was funded by the grant No. Progres Q25/LF1 of the Ministry of Education, Youth and Sport of the Czech Republic, and by the grant RVO-VFN 64165 of the Ministry of Health of the Czech Republic.
\n
Conflict of interest
There are no conflicts of interest.
Abbreviations
FISH
fluorescence in situ hybridization
IUGR
intrauterine growth restriction
HIF
hypoxia induced factor
hTERT
human telomere reverse transcriptase = catalytic component of telomerase activity
IUGR
intrauterine growth retardation
qPCR
quantitative polymerase chain reaction
RT-PCR
reverse transcriptase polymerase chain reaction
SFE
signal free ends
\nTERC\n
telomerase RNA component gene
\nTERT\n
telomerase catalytic component gene
TRAP
telomeric repeat amplification protocol
TRF
terminal restriction fragment
\n',keywords:"pathology, placenta, pregnancy, telomerase, telomere",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/67048.pdf",chapterXML:"https://mts.intechopen.com/source/xml/67048.xml",downloadPdfUrl:"/chapter/pdf-download/67048",previewPdfUrl:"/chapter/pdf-preview/67048",totalDownloads:682,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:35,impactScoreQuartile:2,hasAltmetrics:0,dateSubmitted:"December 17th 2018",dateReviewed:"April 12th 2019",datePrePublished:"October 22nd 2019",datePublished:"April 1st 2020",dateFinished:"May 10th 2019",readingETA:"0",abstract:"Placenta is a transient organ ensuring the intrauterine development of the individual. To meet fetal requirements, rapid and continuous cell proliferation enlarges the areas of tissues maintaining maternofetal transport. The cell division in placenta is accompanied with shortening of telomeres leading to cell senescence. Telomerase activity, on the other hand, ensures replication of telomeres and allows the organ to serve till the end of pregnancy. This balanced process may be negatively influenced by unfavorable circumstances. Here, we summarize available data on telomere length as well as telomerase activity in placentas from normal and complicated pregnancies; attention is also paid to the comparison of methods used in relevant studies.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/67048",risUrl:"/chapter/ris/67048",book:{id:"6986",slug:"telomerase-and-non-telomerase-mechanisms-of-telomere-maintenance"},signatures:"Marie Jirkovská, Marie Korabečná and Soňa Laššáková",authors:[{id:"90383",title:"Prof.",name:"Marie",middleName:null,surname:"Jirkovská",fullName:"Marie Jirkovská",slug:"marie-jirkovska",email:"mjirk@lf1.cuni.cz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Charles University",institutionURL:null,country:{name:"Czech Republic"}}},{id:"289686",title:"Prof.",name:"Marie",middleName:null,surname:"Korabečná",fullName:"Marie Korabečná",slug:"marie-korabecna",email:"marie.korabecna@lf1.cuni.cz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"295751",title:"MSc.",name:"Soňa",middleName:null,surname:"Laššáková",fullName:"Soňa Laššáková",slug:"sona-lassakova",email:"sonakucejova@yahoo.co.uk",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Placenta in pregnancy",level:"1"},{id:"sec_3",title:"3. Analysis of telomere homeostasis—methodological approaches",level:"1"},{id:"sec_3_2",title:"3.1 Methods examining telomeric DNA sequences",level:"2"},{id:"sec_4_2",title:"3.2 Methods examining genes coding for telomerase and its RNA components, their expression, and telomerase activity",level:"2"},{id:"sec_5_2",title:"3.3 Methods examining epigenetic changes and chromatin structure",level:"2"},{id:"sec_7",title:"4. Placenta in normal pregnancy",level:"1"},{id:"sec_8",title:"5. Placenta in pregnancy pathologies",level:"1"},{id:"sec_8_2",title:"5.1 Maternal diabetes mellitus",level:"2"},{id:"sec_9_2",title:"5.2 Preeclampsia",level:"2"},{id:"sec_11",title:"6. Intrauterine growth restriction",level:"1"},{id:"sec_12",title:"7. Conclusions",level:"1"},{id:"sec_13",title:"Acknowledgments",level:"1"},{id:"sec_16",title:"Conflict of interest",level:"1"},{id:"sec_15",title:"Abbreviations",level:"1"}],chapterReferences:[{id:"B1",body:'\nKeefe DL. Telomeres and genomic instability during early development. European Journal of Medical Genetics. 2019:S1769-7212(19)30058-8. DOI: 10.1016/j.ejmg.2019.03.002. [Epub ahead of print]\n'},{id:"B2",body:'\nOzturk S, Sozen B, Demir N. Telomere length and telomerase activity during oocyte maturation and early embryo development in mammalian species. Molecular Human Reproduction. 2014;20:15-30. DOI: 10.1093/molehr/gat055\n'},{id:"B3",body:'\nWright DL, Jones EL, Mazer JF, Oehninger S, Gibbons WE, Lanzendorf SE. Characterization of telomerase activity in the human oocyte and preimplantation embryo. Molecular Human Reproduction. 2017;10:947-955\n'},{id:"B4",body:'\nLiu L, Bailey SM, Okuka M, Muñoz P, Li C, You L, et al. Telomere lengthening early in development. 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Telomerase activity in human germline and embryonic tissues and cells. Developmental Genetics. 1996;18:173-179. DOI: 10.1002/(sici)1520-6408(1996)18:2<173::aid-dvg10>3.3.co;2-5\n'},{id:"B34",body:'\nGarcia-Martin I, Penketh RJA, Janssen AB, Jones RE, Grimstead J, Baird DM, et al. Metformin and insulin treatment prevent placental telomere attrition in boys exposed to maternal diabetes. PLoS One. 2018;13:e0208533. DOI: 10.1371/journal.pone.0208533\n'},{id:"B35",body:'\nZinková A, Marová D, Koperdáková J, Mirchi TP, Korabečná M, Jirkovská M. Relative amount of telomeric sequences in terminal villi does not differ between normal term placentas and placentas from patients with well-controlled type 1 diabetes mellitus. Placenta. 2017;55:1-4. DOI: 10.1016/j.placenta.2017.04.016\n'},{id:"B36",body:'\nToutain J, Prochazkova-Carlotti M, Cappellen D, Jarne A, Chevret E, Ferrer J, et al. Reduced placental telomere length during pregnancies complicated by intrauterine growth restriction. PLoS One;8(1):e54013. DOI: 10.1371/journal.pone.0054013\n'},{id:"B37",body:'\nWilson SL, Liu Y, Robinson WP. Placental telomere length decline with gestational age differs by sex and TERT, DNMT1, and DNMT3A DNA methylation. Placenta. 2016;48:26-33. DOI: 10.1016/j.placenta.2016.10.001\n'},{id:"B38",body:'\nGielen M, Hageman G, Pachen D, Derom C, Vlietinck R, Zeegers MP. Placental telomere length decreases with gestational age and is influenced by parity: A study of third trimester liveborn twins. Placenta. 2014;35:791-796. DOI: 10.1016/j.placenta.2014.05.010\n'},{id:"B39",body:'\nSukenik-Halevy R, Amiel A, Kidron D, Liberman M, Ganor-Paz Y, Biron-Shental T. Telomere homeostasis in trophoblast and in cord blood cells from pregnancies complicated with preeclampsia. American Journal of Obstetrics and Gynecology. 2016;214:283.e1-283.e7. DOI: 10.1016/j.ajog.2015.08.050\n'},{id:"B40",body:'\nPerrem K, Colgin LM, Neumann AA, Yeager TR, Reddel RR. Coexistence of alternative lengthening of telomeres and telomerase in hTERT-transfected GM847 cells. Molecular and Cellular Biology. 2001;21(12):3862-3875\n'},{id:"B41",body:'\nBiron-Shental T, Liberman M, Elbaz M, Laish I, Sharony R, Amiel A. Telomere homeostasis in placentas from pregnancies with uncontrolled diabetes. Placenta. 2016;44:13-18. DOI: 10.1016/j.placenta.2016.05.009\n'},{id:"B42",body:'\nBiron-Shental T, Sukenik-Halevy R, Naboani H, Liberman M, Kats R, Amiel A. Telomeres are shorter in placentas from pregnancies with uncontrolled diabetes. Placenta. 2015;36:199-203. DOI: 10.1016/j.placenta.2014.11.011\n'},{id:"B43",body:'\nBiron-Shental T, Sukenik-Halevy R, Sharon Y, Goldberg-Bittman L, Kidron D, Fejgin MD, et al. Short telomeres may play a role in placental dysfunction in preeclampsia and intrauterine growth restriction. American Journal of Obstetrics and Gynecology. 2010;202:381.e1-381.e7. DOI: 10.1016/j.ajog.2010.01.036\n'},{id:"B44",body:'\nSukenik-Halevy R, Fejgin M, Kidron D, Goldberg-Bittman L, Sharony R, Biron-Shental T, et al. Telomere aggregate formation in placenta specimens of pregnancies complicated with pre-eclampsia. Cancer Genetics and Cytogenetics. 2009;195:27-30. DOI: 10.1016/j.cancergencyto.2009.03.015\n'},{id:"B45",body:'\nBiron-Shental T, Sukenik-Halevy R, Goldberg-Bittman L, Kidron D, Fejgin MD, Amiel A. Telomeres are shorter in placental trophoblast of pregnancies complicated with intrauterine growth restriction (IUGR). Early Human Development. 2010;86:451-456. DOI: 10.1016/j.earlhumdev.2010.06.002\n'},{id:"B46",body:'\nBiron-Shental T, Kidron D, Sukenik-Halevy R, Goldberg-Bittman L, Sharony R, Fejgin MD, et al. TERC telomerase subunit gene copy number in placentas from pregnancies complicated with intrauterine growth restriction. Early Human Development. 2011;87:73-75. DOI: 10.1016/j.earlhumdev.2010.08.024\n'},{id:"B47",body:'\nLehner R, Bobak J, Kim NW, Shroyer KR. Localization of telomerase hTERT protein and survivin in placenta: Relation to placental development and hydatiform mole. Obstetrics and Gynecology. 2001;97:965-970\n'},{id:"B48",body:'\nBiron-Shental T, Sukenik-Halevy R, Sharon Y, Laish I, Fejgin MD, Amiel A. Telomere shortening in intrauterine growth restriction placentas. Early Human Development. 2014;90:465-469. DOI: 10.1016/j.earlhumdev.2014.06.003\n'},{id:"B49",body:'\nKudo T, Izutsu T, Sato T. Telomerase activity and apoptosis as indicators of ageing in placenta with and without intrauterine growth retardation. Placenta. 2000;21:493-500. DOI: 10.1053/plac.2000.0538\n'},{id:"B50",body:'\nGeifman-Holtzman O, Xiong Y, Holtzman EJ, Hoffman B, Gaughan J, Liebermann DA. Increased placental telomerase mRNA in hypertensive disorders of pregnancy. Hypertension in Pregnancy. 2010;29:434-445. DOI: 10.3109/10641950903214625\n'},{id:"B51",body:'\nIzutsu T, Izutsu N, Iwane A, Takada A, Nagasawa T, Kanasugi T, et al. Expression of human telomerase reverse transcriptase and correlation with telomerase activity in placentas with and without intrauterine growth retardation. Acta Obstetricia et Gynecologica Scandinavica. 2006;85:3-11\n'},{id:"B52",body:'\nIzutsu T, Kudo T, Sato T, Nishiya I, Ohyashiki K, Nakagawara K. Telomerase and proliferative activity in placenta from women with and without fetal growth restriction. Obstetrics and Gynecology. 1999;93:124-129\n'},{id:"B53",body:'\nIzutsu T, Kudo T, Sato T, Nishiya I, Ohyashiki K, Mori M, et al. Telomerase activity in human chorionic villi and placenta determined by TRAP and in situ TRAP assay. Placenta. 1998;19:613-618\n'},{id:"B54",body:'\nMoyzis RK, Buckingham JM, Crams LS, Dani M, Deaven LL, Jones M, et al. A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proceedings of the National Academy of Sciences. 1988;85:6622-6626\n'},{id:"B55",body:'\nKimura M, Stone RC, Hunt SC, Skurnick J, Lu X, Cao X, et al. Measurement of telomere length by the Southern blot analysis of terminal restriction fragment lengths. Nature Protocols. 2010;5:1596-1607. DOI: 10.1038/nprot.2010.124\n'},{id:"B56",body:'\nCawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Research. 2002;30:e47\n'},{id:"B57",body:'\nGil ME, Coetzer TL. Real-time quantitative PCR of telomere length. Molecular Biotechnology. 2004;27:169-172. DOI: 10.1385/MB:27:2:169\n'},{id:"B58",body:'\nCawthon RM. Telomere length measurement by a novel monochrome multiplex quantitative PCR method. Nucleic Acids Research. 2009;37:e21. DOI: 10.1093/nar/gkn1027\n'},{id:"B59",body:'\nMartin-Ruiz CM, Baird D, Roger L, Boukamp P, Krunic D, Cawthon R, et al. Reproducibility of telomere length assessment-an international collaborative study. International Journal of Epidemiology. 2015;44:1749-1754. DOI: 10.1093/ije/dyv171\n'},{id:"B60",body:'\nO\'Callaghan NJ, Fenech MA. Quantitative PCR method for measuring absolute telomere length. Biological Procedures Online. 2011;13:3. DOI: 10.1186/1480-9222-13-3\n'},{id:"B61",body:'\nBaird DM, Rowson J, Wynford-Thomas D, Kipling D. Extensive allelic variation and ultrashort telomeres in senescent human cells. Nature Genetics. 2003;33:203-207. DOI: 10.1038/ng1084\n'},{id:"B62",body:'\nLansdorp PM, Verwoerd NP, Rijke FM, Dragowska V, Little MT, Dirks RW, et al. Heterogeneity in telomere length of human chromosomes. Human Molecular Genetics. 1996;5(5):685-691\n'},{id:"B63",body:'\nde Pauw ES, Verwoerd NP, Duinkerken N, Willemze R, Raap AK, Fibbe WE, et al. Assessment of telomere length in hematopoietic interphase cells using in situ hybridization and digital fluorescence microscopy. Cytometry. 1998;32:163-169\n'},{id:"B64",body:'\nAmiel A, Goldzak G, Gaber E, Yosef G, Fejgin MD, Yukla M, et al. Random aneuploidy and telomere capture in chronic lymphocytic leukemia and chronic myeloid leukemia patients. Cancer Genetics and Cytogenetics. 2005;163(1):12-16\n'},{id:"B65",body:'\nMorrish TA, Bekbolysnov D, Velliquette D, Morgan M, Ross B, Wang Y, et al. Multiple mechanisms contribute to telomere maintenance. Journal of Cancer Biology and Research. 2013;1:1012-1036\n'},{id:"B66",body:'\nMorrish TA, Greider CW. Short telomeres initiate telomere recombination in primary and tumor cells. PLoS Genetics. 2009;5:e1000357. DOI: 10.1371/journal.pgen.1000357\n'},{id:"B67",body:'\nGoodwin E, Meyne J. Strand-specific FISH reveals orientation of chromosome 18 alphoid DNA. Cytogenetics and Cell Genetics. 1993;63:126-127\n'},{id:"B68",body:'\nGoodwin EH, Meyne J, Bailey SM. Strand-specific in-situ hybridization reveals long-range molecular order in repetitive DNA. Cytogenetics and Cell Genetics. 1993;63:253\n'},{id:"B69",body:'\nBailey SM, Goodwin EH, Cornforth MN. Strand-specific fluorescence in situ hybridization: The CO-FISH family. Cytogenetic and Genome Research. 2004;107(1-2):14-17. DOI: 10.1159/000079565\n'},{id:"B70",body:'\nBailey SM, Brenneman MA, Goodwin EH. Frequent recombination in telomeric DNA may extend the proliferative life of telomerase-negative cells. Nucleic Acids Research. 2004 Jul 16;32(12):3743-3751\n'},{id:"B71",body:'\nMcKenna MJ, Robinson E, Goodwin EH, Cornforth MN, Bailey SM. Telomeres and NextGen CO-FISH: Directional genomic hybridization (Telo-dGH™). Methods in Molecular Biology. 2017;1587:103-112. DOI: 10.1007/978-1-4939-6892-3_10\n'},{id:"B72",body:'\nHultdin M, Grönlund E, Norrback KF, Eriksson-Lindström E, Just T, Roos G. Telomere analysis by fluorescence in situ hybridization and flow cytometry. Nucleic Acids Research. 1998;26(16):3651-3656\n'},{id:"B73",body:'\nBaerlocher GM, Lansdorp PM. Telomere length measurements in leukocyte subsets by automated multicolor flow-FISH. Cytometry. Part A. 2003;55(1):1-6\n'},{id:"B74",body:'\nBaerlocher GM, Lansdorp PM. Telomere length measurements using fluorescence in situ hybridization and flow cytometry. Methods in Cell Biology. 2004;75:719-750\n'},{id:"B75",body:'\nBaerlocher GM, Vulto I, de Jong G, Lansdorp PM. Flow cytometry and FISH to measure the average length of telomeres (flow FISH). Nature Protocols. 2006;1:2365-2376\n'},{id:"B76",body:'\nMeeker AK, Gage WR, Hicks JL, Simon I, Coffman JR, Platz EA, et al. Telomere length assessment in human archival tissues: Combined telomere fluorescence in situ hybridization and immunostaining. The American Journal of Pathology. 2002;160(4):1259-1268\n'},{id:"B77",body:'\nDing Z, Mangino M, Aviv A, Spector T, Durbin R, UK10K Consortium. Estimating telomere length from whole genome sequence data. Nucleic Acids Research. 2014;42:9. DOI: 10.1093/nar/gku181\n'},{id:"B78",body:'\nMensa E, Latini S, Ramini D, Storci G, Bonafe M, Olivieri F. The telomere world and aging: Analytical challenges and future perspectives. Ageing Research Reviews. 2019;50:27-42. DOI: 10.1016/j.arr.2019.01.004\n'},{id:"B79",body:'\nKim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994;266(5193):2011-2015\n'},{id:"B80",body:'\nFeretzaki M, Lingner J. A practical qPCR approach to detect TERRA, the elusive telomeric repeat-containing RNA. Methods. 2017;114:39-45\n'},{id:"B81",body:'\nPorro A, Feuerhahn S, Delafontaine J, Riethman H, Rougemont J, Lingner J. Functional characterization of the TERRA transcriptome at damaged telomeres. Nature Communications. 2014;31(5):5379\n'},{id:"B82",body:'\nSun D, Lopez-Guajardo CC, Quada J, Hurley LH, Von Hoff DD. Regulation of catalytic activity and processivity of human telomerase. Biochemistry. 1999;38(13):4037-4044\n'},{id:"B83",body:'\nGrolimund L, Aeby E, Hamelin R, Armand F, Chiappe D, Moniatte M, et al. A quantitative telomeric chromatin isolation protocol identifies different telomeric states. Nature Communications. 2013;4:2848\n'},{id:"B84",body:'\nAllsop R, Shimoda J, Easa D, Ward K. Long telomeres in the mature human placenta. Placenta. 2007;28:324-327. DOI: 10.1016/j.placenta.2006.04.003\n'},{id:"B85",body:'\nRama S, Suresh Y, Rao AJ. Regulation of telomerase during human placental differentiation. A role of TGFbeta1. Molecular and Cellular Endocrinology. 2001;182:233-248\n'},{id:"B86",body:'\nNishi H, Yahata N, Ohyashiki K, Isaka K, Shiraishi K, Ohyashiki JH, et al. Comparison of telomerase activity in normal chorionic villi to trophoblastic diseases. International Journal of Oncology. 1998;12:81-85\n'},{id:"B87",body:'\nNishi H, Ohyashiki K, Fujito A, Yahata N, Ohyashiki JH, Isaka K, et al. Expression of telomerase subunits and localization of telomerase activation in hydatiform mole. Placenta. 1999;20:317-323. DOI: 10.1053/plac.1998.0386\n'},{id:"B88",body:'\nNishi H, Nakada T, Kyo S, Inoue M, Shay JW, Isaka K. Hypoxia-inducible factor 1 mediates upregulation of telomerase (hTERT). Molecular and Cellular Biology. 2004;24:6076-6083. DOI: 10.1128/MCB.24.13.6076-6083.2004\n'},{id:"B89",body:'\nCarter AM. Placental oxygen consumption. Part I: In vivo studies-a review. Placenta. 2000;21(Suppl. A):S31-S37. DOI: 10.1053/plac.1999.0513\n'},{id:"B90",body:'\nKuhlow D, Florian S, von Figura G, Weimer S, Schulz N, Petzke KJ, et al. Telomerase deficiency impairs glucose metabolis and insulin secretion. Aging. 2010;2:650-658\n'},{id:"B91",body:'\nJirkovská M, Kučera T, Kaláb J, Jadrníček M, Niedobová V, Janáček J, et al. The branching pattern of villous capillaries and structural changes of placental terminal villi in type 1 diabetes mellitus. Placenta. 2012;33:343-351. DOI: 10.1016/j.placenta.2012.01.014\n'},{id:"B92",body:'\nUnek G, Ozmen A, Mendilcioglu I, Simsek M, Korgun ET. The expression of cell cycle related proteins PCNA, Ki67, p27 and p57 in normal and preeclamptic human placentas. Tissue & Cell. 2014;46:198-205. DOI: 10.1016/j.tice.2014.04.003\n'},{id:"B93",body:'\nUnek G, Ozmen A, Ozekinci M, Sakinci M, Korgun ET. Immunolocalization of cell cycle proteins (p57, p27, cyclin D3, PCNA and Ki67) in intrauterine growth retardation (IUGR) and normal human term placentas. Acta Histochemica. 2014;116:493-502. DOI: 10.1016/j.acthis.2013.10.007\n'},{id:"B94",body:'\nAhmed W, Lingner J. Impact of oxidative stress on telomere biology. Differentiation. 2018;99:21-27. DOI: 10.1016/j.diff.2017.12.002\n'},{id:"B95",body:'\nZinková A, Brynychová I, Svačina A, Jirkovská M, Korabečná M. Cell-free DNA from human plasma and serum differs in content of telomeric sequences and its ability to promote immune response. Scientific Reports. 2017;7:2591. DOI: 10.1038/s41598-017-02905-8\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Marie Jirkovská",address:"mjirk@lf1.cuni.cz",affiliation:'
First Faculty of Medicine, Charles University, and General University Hospital in Prague, Prague, Czech Republic
First Faculty of Medicine, Charles University, and General University Hospital in Prague, Prague, Czech Republic
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The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.
",metaTitle:"Our story",metaDescription:"The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.",metaKeywords:null,canonicalURL:"/page/our-story",contentRaw:'[{"type":"htmlEditorComponent","content":"
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\\n\\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\\n\\n
The IntechOpen timeline
\\n\\n
2004
\\n\\n
\\n\\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\\n\\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\\n
\\n\\n
2005
\\n\\n
\\n\\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\\n
\\n\\n
2006
\\n\\n
\\n\\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\\n
\\n\\n
2008
\\n\\n
\\n\\t
Downloads milestone: 200,000 downloads reached
\\n
\\n\\n
2009
\\n\\n
\\n\\t
Publishing milestone: the first 100 Open Access STM books are published
\\n
\\n\\n
2010
\\n\\n
\\n\\t
Downloads milestone: one million downloads reached
\\n\\t
IntechOpen expands its book publishing into a new field: medicine.
\\n
\\n\\n
2011
\\n\\n
\\n\\t
Publishing milestone: More than five million downloads reached
\\n\\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\\n\\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\\n\\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\\n
\\n\\n
2012
\\n\\n
\\n\\t
Publishing milestone: 10 million downloads reached
\\n\\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\\n
\\n\\n
2013
\\n\\n
\\n\\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\\n
\\n\\n
2014
\\n\\n
\\n\\t
IntechOpen turns 10, with more than 30 million downloads to date.
\\n\\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\\n
\\n\\n
2015
\\n\\n
\\n\\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\\n\\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\\n\\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\\n\\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\\n
\\n\\n
2016
\\n\\n
\\n\\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\\n
\\n\\n
2017
\\n\\n
\\n\\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\\n\\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\n\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\n\n
The IntechOpen timeline
\n\n
2004
\n\n
\n\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\n\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\n
\n\n
2005
\n\n
\n\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\n
\n\n
2006
\n\n
\n\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\n
\n\n
2008
\n\n
\n\t
Downloads milestone: 200,000 downloads reached
\n
\n\n
2009
\n\n
\n\t
Publishing milestone: the first 100 Open Access STM books are published
\n
\n\n
2010
\n\n
\n\t
Downloads milestone: one million downloads reached
\n\t
IntechOpen expands its book publishing into a new field: medicine.
\n
\n\n
2011
\n\n
\n\t
Publishing milestone: More than five million downloads reached
\n\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\n\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\n\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\n
\n\n
2012
\n\n
\n\t
Publishing milestone: 10 million downloads reached
\n\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\n
\n\n
2013
\n\n
\n\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\n
\n\n
2014
\n\n
\n\t
IntechOpen turns 10, with more than 30 million downloads to date.
\n\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\n
\n\n
2015
\n\n
\n\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\n\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\n\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\n\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\n
\n\n
2016
\n\n
\n\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\n
\n\n
2017
\n\n
\n\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\n\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
\n
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Cyanide is formed following the hydrolysis of cyanogenic glycosides that occur during crushing of the edible plant material either during consumption or during processing of the food crop. Exposure to cyanide from unintentional or intentional consumption of cyanogenic glycosides may lead to acute intoxications, characterized by growth retardation and neurological symptoms resulting from tissue damage in the central nervous system (CNS). Processing methods can detoxify cyanogenic glycosides and reduce the risk of cyanide poisoning. The efficiency of cyanide removal, however, depends on the processing technique employed and the extent of processing. Processing operations such as fermentation, boiling/cooking, and drying, applied to process food‐containing cyanogenic glycosides have been reported to reduce cyanide content to acceptably safe levels. 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It deals with the assessment of the toxicological properties of nanoparticles (NPs) with the intention of determining whether (and to what extent) they pose an environmental or societal threat. Inherent properties of NPs (including size, shape, surface area, surface charge, crystal structure, coating, and solubility/dissolution) as well as environmental factors (such as temperature, pH, ionic strength, salinity, and organic matter) collectively influence NP behavior, fate and transport, and ultimately toxicity. The mechanisms underlying the toxicity of nanomaterials (NMs) have recently been studied extensively. Reactive oxygen species (ROS) toxicity represents one such mechanism. An overproduction of ROS induces oxidative stress, resulting in inability of the cells to maintain normal physiological redox-regulated functions. In the context of this book, this chapter includes topics pertaining to chemical and physical properties of NMs and characterization for proper toxicological evaluation, exposure, and environmental fate and transport, and ecological and genotoxic effects. This chapter reviews the available research pertaining specifically to NMs in the aquatic environment (in plants, aquatic invertebrates, and fish) and their use in biomarker studies.",book:{id:"5362",slug:"toxicology-new-aspects-to-this-scientific-conundrum",title:"Toxicology",fullTitle:"Toxicology - New Aspects to This Scientific Conundrum"},signatures:"Chavon Walters, Edmund Pool and Vernon Somerset",authors:[{id:"176939",title:"Dr.",name:"Chavon",middleName:null,surname:"Walters",slug:"chavon-walters",fullName:"Chavon Walters"}]},{id:"52341",doi:"10.5772/65266",title:"Environmental Fate of Zinc Oxide Nanoparticles: Risks and Benefits",slug:"environmental-fate-of-zinc-oxide-nanoparticles-risks-and-benefits",totalDownloads:3592,totalCrossrefCites:12,totalDimensionsCites:25,abstract:"Zinc oxide nanoparticles (ZnO-NPs) are among nanoscale materials displaying exponentially growing production due to their applications in the field of cosmetology, medicine, as antibacterial agent and catalyst. The ZnO nanomaterials release into the aquatic ecosystems through domestic and industrial wastewaters has the potential to induce pernicious effects on fish and other organisms. Increasing concerns on the environmental hazard to aquatic biota have been highlighted by the toxic potential of some metal-based nanomaterials. Several characteristics of ZnO-NPs (e.g. size, shape, surface charge and agglomeration state) play a central role in biological effects such as genotoxic, mutagenic or cytotoxic effects. Overall, Zn bioaccumulation, histopathological, and hematological changes with oxidative and cellular stress have been reported in ZnO-NPs exposed animals.",book:{id:"5362",slug:"toxicology-new-aspects-to-this-scientific-conundrum",title:"Toxicology",fullTitle:"Toxicology - New Aspects to This Scientific Conundrum"},signatures:"Asfina Beegam, Parvathy Prasad, Jiya Jose, Miguel Oliveira,\nFernando G. Costa, Amadeu M.V.M. Soares, Paula P. Gonçalves, Tito\nTrindade, Nandakumar Kalarikkal, Sabu Thomas and Maria de\nLourdes Pereira",authors:[{id:"30304",title:"Prof.",name:"Tito",middleName:null,surname:"Trindade",slug:"tito-trindade",fullName:"Tito Trindade"},{id:"79715",title:"Prof.",name:"Maria De Lourdes",middleName:null,surname:"Pereira",slug:"maria-de-lourdes-pereira",fullName:"Maria De Lourdes Pereira"},{id:"146943",title:"Prof.",name:"Sabu",middleName:null,surname:"Thomas",slug:"sabu-thomas",fullName:"Sabu Thomas"},{id:"174419",title:"Prof.",name:"Fernando",middleName:null,surname:"Garcia E Costa",slug:"fernando-garcia-e-costa",fullName:"Fernando Garcia E Costa"},{id:"194616",title:"BSc.",name:"Asfeena",middleName:null,surname:"Began",slug:"asfeena-began",fullName:"Asfeena Began"},{id:"194617",title:"BSc.",name:"Parvathy",middleName:null,surname:"Prasad",slug:"parvathy-prasad",fullName:"Parvathy Prasad"},{id:"194618",title:"Dr.",name:"Jhose",middleName:null,surname:"Jyia",slug:"jhose-jyia",fullName:"Jhose Jyia"},{id:"194619",title:"Prof.",name:"Miguel",middleName:null,surname:"Oliveira",slug:"miguel-oliveira",fullName:"Miguel Oliveira"},{id:"194620",title:"Prof.",name:"Amadeu",middleName:null,surname:"M.V.M. Soares",slug:"amadeu-m.v.m.-soares",fullName:"Amadeu M.V.M. Soares"},{id:"194621",title:"Prof.",name:"Paula",middleName:null,surname:"Gonçalves",slug:"paula-goncalves",fullName:"Paula Gonçalves"},{id:"194622",title:"Dr.",name:"Nandakumar",middleName:null,surname:"Kalarikkal",slug:"nandakumar-kalarikkal",fullName:"Nandakumar Kalarikkal"}]},{id:"52031",doi:"10.5772/64815",title:"Microplastics in Aquatic Environments and Their Toxicological Implications for Fish",slug:"microplastics-in-aquatic-environments-and-their-toxicological-implications-for-fish",totalDownloads:3167,totalCrossrefCites:10,totalDimensionsCites:24,abstract:"The intensive use of plastics and derivatives during the last century has increased the contamination of animal habitats. The breakdown of these primary plastics in the environment results in microplastics (MP), small fragments of plastic typically <1–5 mm in size. Apart from the potential negative effects of the MPs per se, it is generally assumed that microplastics may increase the exposure of marine aquatic organisms to chemicals associated with the plastics. In addition, to enhance the performance of plastics, additives are added during manufacture. Furthermore, they are active in absorbing other contaminants and be used as vectors of highly and well‐documented persistent contaminants. Finally, these small MPs are easily ingested by animals and affect their physiology and behaviour. Thus, aquatic living organisms are continuously exposed to these MPs, and associated contaminants, and could suffer from its contamination but also introduce them into the food chain.",book:{id:"5362",slug:"toxicology-new-aspects-to-this-scientific-conundrum",title:"Toxicology",fullTitle:"Toxicology - New Aspects to This Scientific Conundrum"},signatures:"Cristóbal Espinosa, M. Ángeles Esteban and Alberto Cuesta",authors:[{id:"28342",title:"Dr.",name:"M. Ángeles",middleName:null,surname:"Ăngeles Esteban",slug:"m.-angeles-angeles-esteban",fullName:"M. Ángeles Ăngeles Esteban"},{id:"72817",title:"Dr.",name:"Alberto",middleName:null,surname:"Cuesta",slug:"alberto-cuesta",fullName:"Alberto Cuesta"},{id:"194251",title:"Dr.",name:"Cristobal",middleName:null,surname:"Espinosa",slug:"cristobal-espinosa",fullName:"Cristobal Espinosa"}]},{id:"51762",doi:"10.5772/64468",title:"Toxic Effects as a Result of Herbal Medicine Intake",slug:"toxic-effects-as-a-result-of-herbal-medicine-intake",totalDownloads:4437,totalCrossrefCites:12,totalDimensionsCites:23,abstract:"Concurrent use of herbs with therapeutic drugs increases the potential of herb-drug interactions. The clinical importance of herb-drug interactions is associated with the particular herb, drug, and patient profile. Herbs are potentially potent as they affect body functions. The use herbal medicine and supplements can be risky as they are not subject to review by the FDA. In this chapter, we make an attempt to discuss the possible reasons for toxic effects, types of toxicities, some reported cases of toxicities involving the use of herbal medicine alone, and some herb-drug interactions. In addition to this, possible ways to reduce toxic effects of herbal medicines have also been discussed.",book:{id:"5362",slug:"toxicology-new-aspects-to-this-scientific-conundrum",title:"Toxicology",fullTitle:"Toxicology - New Aspects to This Scientific Conundrum"},signatures:"Nudrat Fatima and Naira Nayeem",authors:[{id:"186023",title:"Dr.",name:"Nudrat",middleName:null,surname:"Fatima",slug:"nudrat-fatima",fullName:"Nudrat Fatima"},{id:"186802",title:"Dr.",name:"Naira",middleName:null,surname:"Nayeem",slug:"naira-nayeem",fullName:"Naira Nayeem"}]}],mostDownloadedChaptersLast30Days:[{id:"52207",title:"A Review of Cyanogenic Glycosides in Edible Plants",slug:"a-review-of-cyanogenic-glycosides-in-edible-plants",totalDownloads:7494,totalCrossrefCites:18,totalDimensionsCites:50,abstract:"Cyanogenic glycosides are natural plant toxins that are present in several plants, most of which are consumed by humans. Cyanide is formed following the hydrolysis of cyanogenic glycosides that occur during crushing of the edible plant material either during consumption or during processing of the food crop. Exposure to cyanide from unintentional or intentional consumption of cyanogenic glycosides may lead to acute intoxications, characterized by growth retardation and neurological symptoms resulting from tissue damage in the central nervous system (CNS). Processing methods can detoxify cyanogenic glycosides and reduce the risk of cyanide poisoning. The efficiency of cyanide removal, however, depends on the processing technique employed and the extent of processing. Processing operations such as fermentation, boiling/cooking, and drying, applied to process food‐containing cyanogenic glycosides have been reported to reduce cyanide content to acceptably safe levels. The present review discusses the level of cyanogenic glycosides in specific plant foods, health implications of consuming cyanogenic plants and effect of various processing method on cyanogenic glycosides with updated information gathered from the published reports on cyanogenic glycosides.",book:{id:"5362",slug:"toxicology-new-aspects-to-this-scientific-conundrum",title:"Toxicology",fullTitle:"Toxicology - New Aspects to This Scientific Conundrum"},signatures:"Islamiyat Folashade Bolarinwa, Moruf Olanrewaju Oke, Sulaiman\nAdebisi Olaniyan and Adeladun Stephen Ajala",authors:[{id:"190129",title:"Dr.",name:"Islamiyat Folashade",middleName:null,surname:"Bolarinwa",slug:"islamiyat-folashade-bolarinwa",fullName:"Islamiyat Folashade Bolarinwa"},{id:"194068",title:"Dr.",name:"Sulaiman Adebisi",middleName:null,surname:"Olaniyan",slug:"sulaiman-adebisi-olaniyan",fullName:"Sulaiman Adebisi Olaniyan"},{id:"194071",title:"Dr.",name:"Adeladun Steven",middleName:null,surname:"Ajala",slug:"adeladun-steven-ajala",fullName:"Adeladun Steven Ajala"},{id:"194073",title:"Dr.",name:"Moruf Olanrewaju",middleName:null,surname:"Oke",slug:"moruf-olanrewaju-oke",fullName:"Moruf Olanrewaju Oke"}]},{id:"52341",title:"Environmental Fate of Zinc Oxide Nanoparticles: Risks and Benefits",slug:"environmental-fate-of-zinc-oxide-nanoparticles-risks-and-benefits",totalDownloads:3592,totalCrossrefCites:12,totalDimensionsCites:25,abstract:"Zinc oxide nanoparticles (ZnO-NPs) are among nanoscale materials displaying exponentially growing production due to their applications in the field of cosmetology, medicine, as antibacterial agent and catalyst. The ZnO nanomaterials release into the aquatic ecosystems through domestic and industrial wastewaters has the potential to induce pernicious effects on fish and other organisms. Increasing concerns on the environmental hazard to aquatic biota have been highlighted by the toxic potential of some metal-based nanomaterials. Several characteristics of ZnO-NPs (e.g. size, shape, surface charge and agglomeration state) play a central role in biological effects such as genotoxic, mutagenic or cytotoxic effects. Overall, Zn bioaccumulation, histopathological, and hematological changes with oxidative and cellular stress have been reported in ZnO-NPs exposed animals.",book:{id:"5362",slug:"toxicology-new-aspects-to-this-scientific-conundrum",title:"Toxicology",fullTitle:"Toxicology - New Aspects to This Scientific Conundrum"},signatures:"Asfina Beegam, Parvathy Prasad, Jiya Jose, Miguel Oliveira,\nFernando G. Costa, Amadeu M.V.M. Soares, Paula P. Gonçalves, Tito\nTrindade, Nandakumar Kalarikkal, Sabu Thomas and Maria de\nLourdes Pereira",authors:[{id:"30304",title:"Prof.",name:"Tito",middleName:null,surname:"Trindade",slug:"tito-trindade",fullName:"Tito Trindade"},{id:"79715",title:"Prof.",name:"Maria De Lourdes",middleName:null,surname:"Pereira",slug:"maria-de-lourdes-pereira",fullName:"Maria De Lourdes Pereira"},{id:"146943",title:"Prof.",name:"Sabu",middleName:null,surname:"Thomas",slug:"sabu-thomas",fullName:"Sabu Thomas"},{id:"174419",title:"Prof.",name:"Fernando",middleName:null,surname:"Garcia E Costa",slug:"fernando-garcia-e-costa",fullName:"Fernando Garcia E Costa"},{id:"194616",title:"BSc.",name:"Asfeena",middleName:null,surname:"Began",slug:"asfeena-began",fullName:"Asfeena Began"},{id:"194617",title:"BSc.",name:"Parvathy",middleName:null,surname:"Prasad",slug:"parvathy-prasad",fullName:"Parvathy Prasad"},{id:"194618",title:"Dr.",name:"Jhose",middleName:null,surname:"Jyia",slug:"jhose-jyia",fullName:"Jhose Jyia"},{id:"194619",title:"Prof.",name:"Miguel",middleName:null,surname:"Oliveira",slug:"miguel-oliveira",fullName:"Miguel Oliveira"},{id:"194620",title:"Prof.",name:"Amadeu",middleName:null,surname:"M.V.M. Soares",slug:"amadeu-m.v.m.-soares",fullName:"Amadeu M.V.M. Soares"},{id:"194621",title:"Prof.",name:"Paula",middleName:null,surname:"Gonçalves",slug:"paula-goncalves",fullName:"Paula Gonçalves"},{id:"194622",title:"Dr.",name:"Nandakumar",middleName:null,surname:"Kalarikkal",slug:"nandakumar-kalarikkal",fullName:"Nandakumar Kalarikkal"}]},{id:"52031",title:"Microplastics in Aquatic Environments and Their Toxicological Implications for Fish",slug:"microplastics-in-aquatic-environments-and-their-toxicological-implications-for-fish",totalDownloads:3167,totalCrossrefCites:10,totalDimensionsCites:24,abstract:"The intensive use of plastics and derivatives during the last century has increased the contamination of animal habitats. The breakdown of these primary plastics in the environment results in microplastics (MP), small fragments of plastic typically <1–5 mm in size. Apart from the potential negative effects of the MPs per se, it is generally assumed that microplastics may increase the exposure of marine aquatic organisms to chemicals associated with the plastics. In addition, to enhance the performance of plastics, additives are added during manufacture. Furthermore, they are active in absorbing other contaminants and be used as vectors of highly and well‐documented persistent contaminants. Finally, these small MPs are easily ingested by animals and affect their physiology and behaviour. Thus, aquatic living organisms are continuously exposed to these MPs, and associated contaminants, and could suffer from its contamination but also introduce them into the food chain.",book:{id:"5362",slug:"toxicology-new-aspects-to-this-scientific-conundrum",title:"Toxicology",fullTitle:"Toxicology - New Aspects to This Scientific Conundrum"},signatures:"Cristóbal Espinosa, M. Ángeles Esteban and Alberto Cuesta",authors:[{id:"28342",title:"Dr.",name:"M. Ángeles",middleName:null,surname:"Ăngeles Esteban",slug:"m.-angeles-angeles-esteban",fullName:"M. Ángeles Ăngeles Esteban"},{id:"72817",title:"Dr.",name:"Alberto",middleName:null,surname:"Cuesta",slug:"alberto-cuesta",fullName:"Alberto Cuesta"},{id:"194251",title:"Dr.",name:"Cristobal",middleName:null,surname:"Espinosa",slug:"cristobal-espinosa",fullName:"Cristobal Espinosa"}]},{id:"51626",title:"Drug-Induced Cutaneous Toxicity",slug:"drug-induced-cutaneous-toxicity",totalDownloads:2537,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"The skin is the largest organ in the body and is continually exposed to external stimuli, such as chemical and environmental substances. Cutaneous toxicity can be broadly classified according to the mechanism of onset, namely: contact dermatitis, i.e., damage resulting from contact with a substance (irritant dermatitis, allergic contact dermatitis, chemical burns); photosensitivity, i.e., caused by combined effects of a substance and ultraviolet light (phototoxic dermatitis, photoallergic contact dermatitis); contact urticaria; chemical-induced acne; pigmentary disturbance; drug rash; hair disturbance; nail disturbance; or tumor-induced. This review outlines the function and structure of the skin, outlining characteristics of these types of cutaneous toxicity. In recent years, advances have been made in the development of pharmaceutical products targeting specific molecules or genes and nanotechnology-based pharmaceutical products, raising concerns about the onset of toxicity by novel mechanisms involving new pharmaceutical products. Therefore, it is important to understand the basic toxicity-related changes described herein.",book:{id:"5362",slug:"toxicology-new-aspects-to-this-scientific-conundrum",title:"Toxicology",fullTitle:"Toxicology - New Aspects to This Scientific Conundrum"},signatures:"Katsuhiko Yoshizawa, Michiko Yuki and Airo Tsubura",authors:[{id:"186317",title:"Associate Prof.",name:"Katsuhiko",middleName:null,surname:"Yoshizawa",slug:"katsuhiko-yoshizawa",fullName:"Katsuhiko Yoshizawa"},{id:"186355",title:"Prof.",name:"Airo",middleName:null,surname:"Tsubura",slug:"airo-tsubura",fullName:"Airo Tsubura"},{id:"186356",title:"Dr.",name:"Michiko",middleName:null,surname:"Yuki",slug:"michiko-yuki",fullName:"Michiko Yuki"}]},{id:"51762",title:"Toxic Effects as a Result of Herbal Medicine Intake",slug:"toxic-effects-as-a-result-of-herbal-medicine-intake",totalDownloads:4437,totalCrossrefCites:12,totalDimensionsCites:23,abstract:"Concurrent use of herbs with therapeutic drugs increases the potential of herb-drug interactions. The clinical importance of herb-drug interactions is associated with the particular herb, drug, and patient profile. Herbs are potentially potent as they affect body functions. The use herbal medicine and supplements can be risky as they are not subject to review by the FDA. In this chapter, we make an attempt to discuss the possible reasons for toxic effects, types of toxicities, some reported cases of toxicities involving the use of herbal medicine alone, and some herb-drug interactions. In addition to this, possible ways to reduce toxic effects of herbal medicines have also been discussed.",book:{id:"5362",slug:"toxicology-new-aspects-to-this-scientific-conundrum",title:"Toxicology",fullTitle:"Toxicology - New Aspects to This Scientific Conundrum"},signatures:"Nudrat Fatima and Naira Nayeem",authors:[{id:"186023",title:"Dr.",name:"Nudrat",middleName:null,surname:"Fatima",slug:"nudrat-fatima",fullName:"Nudrat Fatima"},{id:"186802",title:"Dr.",name:"Naira",middleName:null,surname:"Nayeem",slug:"naira-nayeem",fullName:"Naira Nayeem"}]}],onlineFirstChaptersFilter:{topicId:"1205",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[],lsSeriesList:[],hsSeriesList:[],sshSeriesList:[],testimonialsList:[]},series:{item:{id:"25",title:"Environmental Sciences",doi:"10.5772/intechopen.100362",issn:"2754-6713",scope:"
\r\n\tScientists have long researched to understand the environment and man’s place in it. The search for this knowledge grows in importance as rapid increases in population and economic development intensify humans’ stresses on ecosystems. Fortunately, rapid increases in multiple scientific areas are advancing our understanding of environmental sciences. Breakthroughs in computing, molecular biology, ecology, and sustainability science are enhancing our ability to utilize environmental sciences to address real-world problems. \r\n\tThe four topics of this book series - Pollution; Environmental Resilience and Management; Ecosystems and Biodiversity; and Water Science - will address important areas of advancement in the environmental sciences. They will represent an excellent initial grouping of published works on these critical topics.
",coverUrl:"https://cdn.intechopen.com/series/covers/25.jpg",latestPublicationDate:"April 13th, 2022",hasOnlineFirst:!1,numberOfPublishedBooks:1,editor:{id:"197485",title:"Dr.",name:"J. Kevin",middleName:null,surname:"Summers",slug:"j.-kevin-summers",fullName:"J. Kevin Summers",profilePictureURL:"https://mts.intechopen.com/storage/users/197485/images/system/197485.jpg",biography:"J. Kevin Summers is a Senior Research Ecologist at the Environmental Protection Agency’s (EPA) Gulf Ecosystem Measurement and Modeling Division. He is currently working with colleagues in the Sustainable and Healthy Communities Program to develop an index of community resilience to natural hazards, an index of human well-being that can be linked to changes in the ecosystem, social and economic services, and a community sustainability tool for communities with populations under 40,000. He leads research efforts for indicator and indices development. Dr. Summers is a systems ecologist and began his career at the EPA in 1989 and has worked in various programs and capacities. This includes leading the National Coastal Assessment in collaboration with the Office of Water which culminated in the award-winning National Coastal Condition Report series (four volumes between 2001 and 2012), and which integrates water quality, sediment quality, habitat, and biological data to assess the ecosystem condition of the United States estuaries. He was acting National Program Director for Ecology for the EPA between 2004 and 2006. He has authored approximately 150 peer-reviewed journal articles, book chapters, and reports and has received many awards for technical accomplishments from the EPA and from outside of the agency. Dr. Summers holds a BA in Zoology and Psychology, an MA in Ecology, and Ph.D. in Systems Ecology/Biology.",institutionString:null,institution:{name:"Environmental Protection Agency",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:0,paginationItems:[]},overviewPageOFChapters:{paginationCount:0,paginationItems:[]},overviewPagePublishedBooks:{paginationCount:0,paginationItems:[]},openForSubmissionBooks:{},onlineFirstChapters:{paginationCount:0,paginationItems:[]},subseriesFiltersForOFChapters:[],publishedBooks:{},subseriesFiltersForPublishedBooks:[],publicationYearFilters:[],authors:{}},subseries:{item:{id:"25",type:"subseries",title:"Evolutionary Computation",keywords:"Genetic Algorithms, Genetic Programming, Evolutionary Programming, Evolution Strategies, Hybrid Algorithms, Bioinspired Metaheuristics, Ant Colony Optimization, Evolutionary Learning, Hyperparameter Optimization",scope:"Evolutionary computing is a paradigm that has grown dramatically in recent years. This group of bio-inspired metaheuristics solves multiple optimization problems by applying the metaphor of natural selection. It so far has solved problems such as resource allocation, routing, schedule planning, and engineering design. Moreover, in the field of machine learning, evolutionary computation has carved out a significant niche both in the generation of learning models and in the automatic design and optimization of hyperparameters in deep learning models. This collection aims to include quality volumes on various topics related to evolutionary algorithms and, alternatively, other metaheuristics of interest inspired by nature. For example, some of the issues of interest could be the following: Advances in evolutionary computation (Genetic algorithms, Genetic programming, Bio-inspired metaheuristics, Hybrid metaheuristics, Parallel ECs); Applications of evolutionary algorithms (Machine learning and Data Mining with EAs, Search-Based Software Engineering, Scheduling, and Planning Applications, Smart Transport Applications, Applications to Games, Image Analysis, Signal Processing and Pattern Recognition, Applications to Sustainability).",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11421,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,series:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403"},editorialBoard:[{id:"111683",title:"Prof.",name:"Elmer P.",middleName:"P.",surname:"Dadios",slug:"elmer-p.-dadios",fullName:"Elmer P. 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