\r\n\tIt is a relatively simple process and a standard tool in any industry. Because of the versatility of the titration techniques, nearly all aspects of society depend on various forms of titration to analyze key chemical compounds.
\r\n\tThe aims of this book is to provide the reader with an up-to-date coverage of experimental and theoretical aspects related to titration techniques used in environmental, pharmaceutical, biomedical and food sciences.
Cardiovascular diseases (CVDs) are the major causes of premature death and chronic disability worldwide [1]. Among CVD-related deaths, the occurrence of inherited lethal arrhythmias is the main reason for sudden cardiac death (SCD) in cardiac patients especially at young age [2]. Although many risk factors associated with SCD have been identified and understanding of pathogenesis of many cardiac diseases is progressing, the considerable number of cardiac patients still suffers SCD without warning, and we are still far from disease-specific treatment. Heterogeneous and multifactorial natures of genetic cardiac diseases are reasons for these complications. Furthermore, founder mutations causing cardiac disease have been reported in Finland [3], the Netherlands [4], and South Africa [5]. Not only disease phenotypes vary among different mutations, but also these vary among individuals carrying the same mutation. For example, long QT syndrome (LQTS) patients demonstrate a wide range of clinical phenotypes even among family members with the identical mutation [6]. Despite carrying the same gene variant resulting in cardiac disease, patients often demonstrate the wide spectrum of clinical outcomes ranging from the absence of distinct electrocardiogram (ECG) abnormalities and being lifelong asymptomatic to clear abnormalities in ECG (e.g., prolonged QT interval and arrhythmias) and premature SCD. In addition, SCD could also be the first manifestation of cardiac disease. These suggest that the type of genetic mutation cannot always be the sole factor that dictates the prognosis of disease and clinical phenotype in all individuals who carry it [7]. Thus, genetic cardiac diseases exhibit the incomplete penetrance and differ among genetic cardiac diseases. For example, Brugada syndrome (BrS) has a penetration range from 12.5 to 50%; mean penetrance of LQTS is ~40%, while overall penetrance of catecholaminergic polymorphic ventricular tachycardia (CPVT) is 78% [7]. Another convoluting factor that hinders the genotype-phenotype correlation is variable expressivity within one phenotype because some mutation carriers display all the phenotypic symptoms, whereas some only display part of mutation-specific phenotypes [8]. The clinical heterogeneity of genetic cardiac diseases suggests that ultimate disease severity (i.e., penetrance and expressivity) does not solely depend on one particular gene causing cardiac disease, but instead results from the combination of many modifying factors such as age, gender, and environmental and lifestyle factors, which either exacerbate or protect against disease [9]. In addition, patients carrying more than one disease-causing mutations (i.e., not polymorphisms) either in the same gene or different genes yield to more severe clinical disease including earlier onset of disease, early heart failure, and premature SCD [10]. Besides these, some of the cardiac diseases overlap their phenotypes with other cardiac diseases (Figure 1). For example, mutations in cardiac sodium (Na+) channel gene, SCN5A, are associated with type 3 long QT (LQT3), BrS, cardiac conduction diseases, and sinus node dysfunction [11]. These incomplete penetrance, variable expressivity, and phenotypic overlap impede the complete understanding of diseases’ mechanism as well as disease-specific treatment. Furthermore, the treatment therapies are mainly targeted for symptomatic patients to prevent and counteract the symptoms, but treatments in asymptomatic individuals are still of concern with variable opinions. Nevertheless, pharmacological therapies have been resulted in poor outcomes in the cardiac diseases [12]. So far, implantable cardioverter-defibrillator (ICD) is the only proven therapy for preventing detrimental consequences in cardiac patients with high risk of SCD [13]. However, ICD implantation is associated with its own complications and lower quality of life [14]. There are large groups of asymptomatic cardiac patients who do not have risk factors, which shift them into high-risk category as candidate for ICD implantation, but suffer SCD. Thus, the management for asymptomatic patients carrying pathogenic variant is the most challenging since SCD could be the first manifestation of disease [15, 16]. The clinical management of most cardiac diseases is suboptimal due to lack of comprehensive knowledge of mutations and possible mechanism involved. Thus, the mechanism of how mutation leads to modify the normal cardiac physiology and engender lethal arrhythmias should be deciphered so that the promising prevention and treatment could be established.
Heterogeneity of genetic cardiac diseases. (A) Overlapping genes causing channelopathies [27]. Brugada syndrome (BrS), long QT syndrome (LQTS), short QT syndrome (SQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT) (ref). (B) Overlapping genes causing cardiomyopathies [72]. Arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), left ventricular non-compaction cardiomyopathy (LVNC).
The prior cardiovascular research and drug screening have mostly been performed in animal models through knock-in/knock-out approaches. Although animal models have provided some fundamental information and led to many discoveries in genetic cardiac disease, physiological and pharmacological results cannot directly extrapolate from animals to humans because of some fundamental differences that exist between animal and human cardiac physiology [17]. For example, the resting heart rate of human is 75 bpm, while that of rat is 300 bpm, and the animal (mice and rats) can tolerate 6–400-fold higher concentration of some drugs compared to human [18]. The animal models become even worse when studying human cardiomyopathies due to mutations in contractile proteins, which are not highly expressed in mouse or rat. Therefore, it is more complicated to extrapolate physiological and pharmacological results from animal to human [17, 18]. Furthermore, most of cardiovascular drug screening and toxicology studies were performed in non-cardiac cell lines or animals, which do not accurately represent human CMs. Thus, considerable amount of cardiovascular drugs were withdrawn from market due to off-target effects [19]. Therefore, human tissues are required to study the human cardiac diseases and drug testing. However, the human sample exhibits some of the major challenges: there is limited supply of human cardiac biopsies, and it involves complex procedures and ethical issues. In addition, these cardiac biopsies are typically obtained from the end stage of cardiac diseases; hence it is not possible to understand the mechanism of cardiac diseases [20, 21]. These obstacles are mostly overcome by the groundbreaking discovery of reprogramming adult somatic cells into induced pluripotent stem cells (iPSCs) [22, 23] which can be differentiated into cardiomyocytes (CMs) (hiPSC-CMs) [24, 25, 26]. The main advantages of hiPSC-CMs are iPSCs can be generated at any period of a patient’s life, they have unlimited supply, and these retain the same genetic information as the donor, i.e., hiPSC-CMs are patient specific (Figure 2). These are superior features of hiPSC-CMs to the conventional in vitro modeling of cardiac diseases. In addition, hiPSC-CMs can be cultured for several months, which enable us to study acute and chronic effect of mutation and drugs on CMs. Thus, hiPSC-CMs not only provide the platform to investigate the mutation-specific mechanism but also assist to anticipate drug response on an individual basis and guide us to personalized medicine in future.
hiPSC-CM-based modeling of human genetic cardiac diseases. Human-induced pluripotent stem cells (hiPSCs) can be differentiated into hiPSC-derived cardiomyocytes (hiPSC-CMs). There are at least three subtypes of hiPSC-CMs, namely, ventricular-like, atrial-like, and nodal-like hiPSC-CMs. hiPSC-CMs derived from cardiac patients carrying genetic mutation recapitulate calcium and electrical abnormalities (early afterdepolarization (EAD) and delayed afterdepolarization (DAD)). Newly emerging gene editing techniques were able to mitigate these abnormalities in hiPSC-CMs.
Channelopathy cardiac diseases are caused by mutations in cardiac ion channels located in the cellular membrane or organelles. Mutations in ion channels result in misbalance of fine-tuning ion exchange during excitation-contraction coupling (ECC), which could lead to cardiac arrhythmias and SCD in the worst case. The main cardiac channelopathies are CPVT, LQTS, BrS, and short QT syndromes (SQTS) [27]. These cardiac channelopathies have been extensively studied using hiPSC-CMs and described below.
CPVT is an inherited cardiac disease with the prevalence of about 1:5000/10,000. This disease is characterized by premature ventricular contraction and/or polymorphic ventricular tachycardia (VT) induced by adrenergic stimulation in response to emotional stress or physical exercise in structurally normal heart. Over 150 mutations in ryanodine receptor type 2 (RYR2 gene) are responsible for ~ 55% of CPVT type 1 cases (CPVT1), and mutation in calsequestrin 2 (CASQ2 gene) CPVT accounts for 3–5% CPVT type 2 (CPVT2) cases [28, 29]. In addition, mutations in calmodulin (CALM1) genes and in triadin (TRDN) have been reported causing CPVT. RYR2, CASQ2, CALM1, and TRDN are involved in ECC, and mutation in any of these genes results in elevated intracellular Ca2+, which leads to abnormal Ca2+ handling and arrhythmias [28, 29]. In consistency with clinical phenotype, many hiPSC-CM model had demonstrated the exacerbation of electrophysiological and Ca2+ handling abnormalities upon adrenergic stimulation [26, 30, 31, 32]. Furthermore, Zhang and colleagues had modeled hiPSC-CMs harboring CPVT1-associated F2483I mutation in RYR2 gene and demonstrated that CPVT1 hiPSC-CMs had longer and wandering Ca2+ sparks and smaller sarcoplasmic reticulum Ca2+ content [32]. Later on, the same group corrected this mutation using clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9) gene editing technique and showed that this mutation is causative rather than associative to the disease [33]. hiPSC-CM model for CPVT has also been used in studying the efficacy of various drugs. Previously we had directly compared the clinical results from CPVT1 patients with dantrolene medication, and the clinical response of dantrolene was similar as in hiPSC-CMs from the same patients; dantrolene abolished or markedly reduced arrhythmias in patients and their hiPSC-CMs with certain mutation in RYR2, while it did not have any clinical effect with hiPSC-CMs or with other RYR2 mutations [31]. Furthermore, an antiarrhythmic drug, flecainide, used to treat CPVT1 patients [34] was able to reduce the Ca2+ irregularities under adrenergic stimulation in CPVT1 hiPSC-CMs [30, 35]. CPVT2 patients harboring homozygous CASQ2-G112 + 5X mutation in CASQ2 gene showed the rapid polymorphic VT under exercise stress test [36]. Adult rat ventricular myocytes were studied to understand the effect of CASQ2 mutation in ECC, demonstrating that mutated CMs exhibited spontaneous extrasystolic Ca2+ elevations and delayed afterdepolarization (DADs) upon adrenergic stimulation [36]. Later, hiPSC-CM model harboring CASQ2-G112 + 5X mutation emulated these phenotypic features of disease, and AAV9-based gene delivery effectively prevents the development of adrenergic-induced DADs and triggered arrhythmias in CPVT2 hiPSC-CMs [37].
LQT type 1 (LQT1) is caused by loss-of-function mutation in KCNQ1 gene encoding α subunit of potassium (K+) channel mediating slow delayed rectifier K+ current (IKs). LQT1 is responsible for 30–35% of all LQTS cases [38]. LQT1 is characterized by prolongation of QT interval in ECG, which could lead to SCD due to VT, typically torsades de pointes [39]. hiPSC-CMs derived from LQT1 patients faithfully recapitulated the clinical hallmark by showing prolonged action potential duration (APD) which is analogous to QT duration in ECG, and reduced IKs current densities are held responsible for abnormal repolarization [40, 41, 42]. ML277, an IKs activator, increased the IKs amplitude by enhancing the activation of IKs, thus resulting in shortening of APD in LQT1 hiPSC-CMs [40]. In addition, adrenergic stimulation in LQT1 hiPSC-CMs induced the early afterdepolarization (EAD) [42], which is similar to arrhythmias triggered in LQT1 patients by exercise or emotional stress [39]. Clinically, β-blockers were effective in minimizing the risk of cardiac events in LQT1 patients [43]. Similar antiarrhythmic effect of β-blockers has been observed in LQT1 hiPSC-CMs [42]. Furthermore, hypokalemia is the electrolyte disturbance caused by lower K+ level in blood serum, which aggravates the QT prolongation and facilitates the development of hypokalemia-induced torsades de pointes in LQT1 patients [39, 44]. We successfully developed and mimicked these disease phenotypes in LQT1 hiPSC-CMs carrying G589D or IVS7-2A > G mutation in KCNQ1 gene. Additionally, lowering the extracellular K+ concentration prolonged APDs and induced the formation of EADs in LQT1 hiPSC-CMs [45]. Both G589D- and IVS7-2A > G-specific LQT1 hiPSC-CMs displayed longer APD and higher Ca2+ abnormalities in baseline; G589D hiPSC-CMs demonstrated prolonged contraction, while IVS7-2A > G hiPSC-CMs showed impaired relaxation [46] observed in our video image-based software analysis [47].
LQT type 2 (LQT2) is an LQTS subtype, which is caused by loss-of-function mutations in KCNH2 gene also known as human ether-a-go-go-related gene (hERG) encoding K+ channel mediating rapid delayed rectifier K current (IKr). LQT2 is responsible for approximately 25–30% of all LQTS cases [38]. Similar to LQT1, LQT2 patients also exhibit the prolongation of QT interval and torsades de pointes. As in LQT1 hiPSC-CM model, LQT2 hiPSC-CMs also recapitulated clinical phenotypes by displaying longer APD resulted from reduced IKr current densities and enhanced EAD following the adrenergic stimulation [48, 49, 50]. Our early study of LQT2 hiPSC-CMs carrying R176W mutation in KCNH2 gene demonstrated the reduced IKr current densities, prolonged repolarization, and increased arrhythmogenicity although the donor is an asymptomatic carrier [50]. These results are in parallel with clinical findings that LQT2 patients usually display symptoms when heart rate is slow. In addition, this report illustrated that electrophysiological abnormalities can be detected in hiPSC-CMs, although iPSCs are derived from asymptomatic carriers of KCNH2 mutations. The application of IKr blockers (E4031 and sotalol) further prolonged the APD resulting in EADs, whereas Ca2+ channel blocker (nifedipine), IK,ATP channel opener (pinacidil and nicorandil), and IKr channel enhancer (PD-118057) reduced the APD and thus mitigated the formation of EAD in LQT2 hiPSC-CMs [48, 49]. Several novel pharmacological strategies including ICA-105574 (potent IKr activator) [51], chaperone modulator N-[N-(N-acetyl-L-leucyl)-L-leucyl]-L-norleucine (ALLN) [52], LUF7346 (hERG allosteric modulators) [53], as well as application of allele-specific RNA interference approach [54] have been attempts to rescue the LQT phenotype in LQT2 hiPSC-CMs. Correcting the mutation associated with LQT2 not only confirmed that mutation caused IKr reduction and APD prolongation but also suggested that trafficking defect as the pathological mechanism is responsible for the electrophysiological phenotype in LQT2 [51, 55].
LQT type 3 (LQT3) is caused by gain-of-function mutations in SCN5A encoding α subunit of cardiac Na+ channels [56]. The gain-of-function SCN5A mutation results in augmented late or persistent Na+ current (INaL), which leads to prolongation of QT interval in ECG and proarrhythmia. LQT3 is the third most common LQTS accounting for 5–10% of all LQTS cases [56]. LQT3 patients exhibit longer QT duration at slower heart rate, thus LQT3 patients are at higher risk for cardiac events during rest or sleep [57]. LQT3 patients harboring V1763 M mutation in SCN5A [58] R1644H mutation in SCN5A [59] or F1473C mutation in SCN5A and a polymorphism (K897 T) in KCNH2 [60] had prolonged QT interval, and in vitro models using hiPSC-CMs derived from all those LQT3 patients demonstrated prolonged APD resulting in the larger INa,L and altered biophysical properties of Na+ channels [58, 59, 60]. Mexiletine, a Na+ channel inhibitor commonly used in LQT3 therapy, lowered the INa,L and thereby rescued the APD prolongation phenotype [58, 59] and suppressed the occurrence of EAD [59] and also corrected the altered Na+ channel inactivation [60]. Incorporating the biophysics of Na+ channel and pharmacological analysis illustrated that the improper functioning of Na+ channel was responsible for LQT3 phenotypes rather than KCNH2 polymorphism [60]. In addition to LQT3, mutation in SCN5A gene can cause BrS, and mixed phenotypes are often seen, which is also known as the “overlap syndrome.” Loss in function of Na+ channel is often seen in BrS. Liang and co-workers had generated hiPSCs from two BrS patients, one with double missense mutation (R620H and R811H) in SCN5A gene (BrS(p1)) and another with one-base pair deletion mutation in the SCN5A gene (BrS(p2)), and showed that BrS hiPSC-CMs derived from both patients had reduced Na+ current and increased triggered activity and abnormal Ca2+ handling [61]. These phenotypes were alleviated by correcting the mutation by CRISPR/Cas9 in hiPSCs derived from BrS (p2) [61]. Importantly, only BrS hiPSC-CMs harboring BrS-associated SCN5A-1795insD mutation displayed reduced Na+ current and upstroke velocity, but not with three sets of hiPSC-CMs derived from BrS patients who tested negative for mutations in the known BrS-associated genes suggesting the Na+ channel dysfunction may not be prerequisite for BrS [62]. In another study, Na+ current and upstroke velocity were reduced, but not the voltage-dependent inactivation in BrS hiPSC-CMs carrying the mutations R1638X and W156X [63].
LQT type 7 (LQT7) or Andersen-Tawil syndrome (ATS) is a rare inherited cardiac disease associated with mutation in KCNJ2 gene (ATS type 1) encoding inward rectifying K+ channel (Kir2.1) and accounts for ~70% of all ATS cases. However, the genetic cause of the remaining 30% of ATS (ATS type 2) remains unknown. In ATS patients, QT interval prolongation is not common, but prominent U wave and QU interval in ECG could be hallmarks of ATS, and they experienced cardiac arrhythmias including non-sustained VT and torsade de pointes [64]. Kuroda and co-workers generated hiPSCs from ATS patients carrying R218W, R67W, and R218Q mutations in KCNJ2 gene and showed strong arrhythmic events and higher incidence of irregular Ca2+ handling in ATS hiPSC-CMs, but flecainide and KB-R7943 (a reverse-mode Na+/Ca2+ exchanger inhibitor) were able to suppress those events [65].
2.6 LQT type 8 (LQT8) or Timothy syndrome (TS) is a very rare genetic cardiac disease which results from mutation in CACNA1C gene encoding Ca2+ channel (CaV1.2). LQT8 is the most severe type of LQTS, which is characterized by markedly prolonged QT interval, severe ventricular arrhythmia, and multiorgan dysfunction [66]. hiPSC-CMs derived from TS patients recapitulated the disease phenotypes, but roscovitine rescued those abnormalities such as altered Ca2+ channel inactivation, prolonged APD, higher incidences of arrhythmias, and abnormal Ca2+ handling [67].
SQT is a rare inherited cardiac disease characterized by QT internal shortening, which is in contrast to QT prolongation observed in LQTS. SQT is associated with mutations in genes associated with K+ channel or Ca2+ channels [68]. The prevalence of SQT is between 0.02–0.1% and 0.05% in adults and children, respectively [69]. Recently El-Battrawy and co-workers had generated hiPSCs from SQT type 1 patients carrying a mutation (N588K) in KCNH2, and hiPSC-CMs mimicked the clinical phenotype of SQT by showing a shortened APD as a result of increased IKr current densities [70]. In addition, SQT hiPSC-CMs exhibited abnormal Ca2+ transients and rhythmic activities, which are enhanced by carbachol, but quinidine alleviated those carbachol-induced arrhythmias and prolonged the APD [70].
Cardiomyopathies are diseases of cardiac muscle and associated with structural and/or functional abnormalities. The most common genetic cardiomyopathies are hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). These genetic cardiomyopathies have been also extensively studied using hiPSC-CMs [71, 72].
HCM is one of the most common genetic cardiac diseases with an estimate prevalence of 1 in 500. HCM is characterized by unexplained symmetrical or asymmetrical left ventricular hypertrophy. Mutations in sarcomeric proteins account for ~60% of all HCM cases including mutation in β-myosin heavy chain (MYH7), cardiac myosin-binding protein C (MYBPC3), cardiac troponin I (cTnI), cardiac troponin T (cTnT), and tropomyosin (TPM1) [73]. Hypertrophy of myocytes and disarray of sarcomere are the histological hallmarks of HCM seen in cardiac biopsies from HCM patients [74], and these histological phenotypes are also observed in hiPSC-CM model of HCM [25, 75, 76, 77]. In addition, HCM hiPSC-CMs also demonstrated other hallmarks of HCM such as nuclear translocation of nuclear factor of activated T cells (NFAT) [75, 76, 77], elevation of β-myosin/α-myosin ratio, and calcineurin activation [75]. Furthermore, isolated CMs from HCM patients displayed the prolonged APDs, increased Ca2+ current densities, reduced transient outward K+ current densities, abnormal Ca2+ handling, and increased frequency of arrhythmias [21]. These electrophysiological and Ca2+ transient irregularity phenotypes have been faithfully recapitulated in HCM hiPSC-CMs [25, 75, 76, 78]. When HCM tissues carrying a mutation in MYBPC3 gene were compared with donor heart sample, no specific truncated MyBP-C peptides were detected, but the overall level of MyBP-C in myofibrils was significantly reduced [79]. Similar haploinsufficiency results were also shown in HCM hiPSC-CMs with mutation in MYBPC3 gene [25, 80], and gene replacement in HCM hiPSC-CMs partially improves the haploinsufficiency and reduces cellular hypertrophy [80]. Similar to higher myofilament Ca2+ sensitivity observed in isolated cardiac biopsies from HCM with E99K mutation in cardiac actin [81], in vitro model of HCM hiPSC-CMs carrying E99K mutation in cardiac actin demonstrated significantly stronger contraction and increased arrhythmogenic events [82] Furthermore, a study in HCM mice harboring I79N mutation in cTnT resulted in increased cardiac contractility, altered Ca2+ transients, and remodeling of action potential [83]. These phenotypes were faithfully recapitulated by HCM hiPSC-CMs carrying the same I79N mutation in cTnT [84]. These hypercontractility and increased arrhythmogenicity phenotypes were reversed in HCM hiPSC-CMs when the E99K mutation in cardiac actin [82] and I79N mutation in cTnT [84] were corrected using CRISPR/Cas9 gene editing technique. Recently, we have shown that HCM hiPSC-CMs carrying TPM1-Asp175Asn mutation exhibited VT type of arrhythmias [78], and this observation is in line with earlier clinical observation of HCM patients with TPM1-Asp175Asn mutation being at increased risk of fatal arrhythmias [85]. Currently, there is no specific pharmacological therapy for HCM patients, and drugs are prescribed mainly based on symptoms and personal history. However, drug therapy has also resulted in poor outcomes in HCM patients [12]. We reported the similar poor antiarrhythmic efficiency of β-blocker in preventing lethal arrhythmias in HCM hiPSC-CMs [78]. In another HCM report, several environmental factors were investigated with hiPSC-CMs to study their effect on disease progression [77]. They found that endothelin (ET)-1 was able to induce HCM phenotypes such as cellular hypertrophy and myofibrillar disarray in hiPSC-CMs, which are inhibited by ET receptor type A blocker [77]. HCM patients exhibited defects in mitochondrial functions and ultrastructure and abnormal energy metabolism [74]. These structural and functional phenotypes were recapitulated in hiPSC-CMs carrying m.2336 T > C mutation in mitochondrial genome causing HCM [86]. They reported that HCM hiPSC-CMs expressed reduced levels of mitochondrial proteins, ATP/ADP ratio, and mitochondrial membrane potential [86].
DCM is a myocardial disease characterized by ventricular chamber enlargement and systolic dysfunction and progressive heart failure without significant change in ventricular wall thickness. Mutations in >30 genes encoding proteins of cytoskeleton, sarcomere, and nuclear lamina are found in 30–35% of DCM patients [87]. DCM patients with mutations in RBM20, encoding RNA binding motif protein 20 (RBM20), have an early onset of disease phenotype [88]. Isolated CMs from DCM patients carrying mutation in RBM20 displayed elongated and thinner sarcomere structure [88], and such disorganized sarcomeric structure phenotypes were recapitulated in DCM hiPSC-CMs carrying mutation in RBM20 [89, 90]. RBM20 is the main regulator of the heart-specific titin splicing, and N2BA isoform is predominantly expressed in CMs from DCM patient carrying mutation in the RBM20 gene [91]. In vitro model of RBM20 hiPSC-CMs successfully mirrored the altered titin isoform expression (titin isoform switch) [89, 90]. Furthermore, RBM20 hiPSC-CMs showed delayed Ca2+ extrusion and reuptake and more Ca2+ being released during each ECC, which resulted into deficient muscle contraction, the hallmark of cardiac dysfunction of DCM patients [89, 90]. In addition, a three-dimensional engineered heart muscle generated from RBM20 hiPSC-CMs showed an impaired force of contraction, and passive stress was decreased in response to stepwise increase in strain, suggesting higher viscoelasticity caused by mutation in RBM20 [89]. Besides HCM, mutation in cTnT also caused DCM and resulted in shifts in Ca2+ sensitivity and force of contraction [92]. Sun and co-workers generated iPSCs from DCM patients carrying R173W mutation in cTnT and reported that DCM hiPSC-CMs exhibited altered Ca2+ handling, decreased contractility, and abnormal sarcomeric α–actinin distribution [93]. DCM patients with lamin A/C (LMNA) mutations show a highly variable phenotype. Cardiac biopsies from DCM patients harboring LMNA mutations exhibit reduced LMNA in nuclei with nuclear membrane damage such as focal disruption and nuclear pore clustering [94]. Nonsense mutation (R225X) in exon 4 of the LMNA gene causing DCM was associated with accelerated nuclear senescence and apoptosis of DCM hiPSC-CMs under electrical stimulation [95]. In another in vitro modeling of DCM, harboring A285V mutation in desmin (DES) using hiPSC-CMs displayed the pathogenic phenotypes of DCM such as diffuse abnormal DES aggregation, poor co-localization of DES with cTnT, and Z-disk streaming with accumulation of granulofilamentous materials or pleomorphic dense structures adjacent to the Z-disk or between the myofibrils [96]. DCM patients harboring R14del mutation in phospholamban (PLN) result in ventricular dilation, contractile dysfunction, and episodic ventricular arrhythmias [97]. Similarly, hiPSC-CMs carrying R14del mutation in PLN induced the Ca2+ handling abnormalities, irregular electrical activity, and abnormal intracellular distribution of PLN in DCM hiPSC-CMs [98]. These PLN R14del-associated disease phenotypes were mitigated upon correction of PLN R14del mutation by transcription activator-like effector nuclease (TALENs) gene editing technique [98]. Furthermore, genetic correction of PLN R14del mutation by TALENs improved the force development and restored the contractile function in three-dimensional human engineered cardiac tissue derived from R14del-iPSCs [99].
ARVC is rare genetic cardiac disease with the prevalence ranging from 1:000 to 1:5000 worldwide. The histopathological hallmark of ARVC is the substitution of the cardiac myocytes with fibro-fatty deposits, particularly within the free wall of the right ventricle. The consequent results from the disruption of normal myocardial architecture can lead to right ventricular dysfunction, life-threatening arrhythmias, and SCD [100]. ARVC is caused by mutations in genes encoding desmosomal proteins such as plakoglobin (JUP), desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSG2), and desmocollin-2 (DSC2) [100]. Similar to immunohistological results from the biopsy sample from ARVC patients [101], ARVC hiPSC-CMs harboring a plakophilin 2 (PKP2) gene mutation mimicked the reduced PKP2 immunosignal [102, 103]. In addition, clusters of lipid droplets accumulating within the cytoplasm were identified in ARVC-hiPSC-CMs associated with structural distortion of desmosomes [103]. Another study showed that induction of adult-like metabolic energetics from an embryonic/glycolytic state and abnormal peroxisome proliferator-activated receptor gamma (PPARγ) activation underlie the pathogenesis of ARVC [104]. It has been observed that male ARVC patients develop earlier and more severe phenotype than female ARVC patients [105]. To understand whether sex hormones in serum may contribute to the major arrhythmic cardiovascular events in ARVC, Akdis and co-workers combined a clinical study and in vitro hiPSC-CM model and showed that increased levels of testosterone accelerate ARVC pathologies, while premenopausal female estradiol levels slow down exaggerated apoptosis and lipid accumulation in ARVC hiPSC-CMs [106].
The reprogramming of somatic cells into pluripotent stems cells and subsequent differentiation into specific cell types is a newly emerging technique and is certainly not free from limitation.
One of the most questionable issues of hiPSC-CMs is their maturity. Despite expressing relevant ion channels [107] and structural genes [25, 26, 75, 76, 89, 108], hiPSC-CMs lack t-tubules and exhibit lower expression of Kir2.1 and weaker contractility; thus they do not fully resemble adult CMs. In order to improve the maturity of hiPSC-CMs and consequently upgrade the functionality of hiPSC-CMs, various techniques have been investigated in different groups. Three-dimensional construction of engineered heart tissue is a rapidly growing technique for structural and functional maturations of hiPSC-CMs [109], which resulted in higher Na+ current density and upstroke velocity [110], and enhances the metabolic maturation [111] comparable to adult CMs. Furthermore, Shadrin and co-workers introduced the “Cardiopatch” platform for three-dimensional culture and maturation of hiPSC-CMs; this platform produces robust electromechanical coupling, consistent H-zone and I bands, and evidence of t-tubules and M-bands [112].
Another issue of hiPSC-CMs is the purity of differentiated CMs. The CMs differentiated from hiPSCs yield in heterogeneous population of CMs. There are at least three subtypes of CMs such as ventricular, atrial, and nodal CMs; among them the majority (~70%) of CMs are ventricular-like, and only a minority of CMs are atrial-like (~20%) and nodal-like (~10%) [40, 58, 93, 107]. Although many molecular and functional characteristics are shared among these CMs subtypes, they also exhibit their own unique features. For example, ventricular CMs have prominent plateau phase (phase 2) in action potential profile, atrial CMs exclusively exhibit IKur channels, and nodal CMs lack strong upstroke velocity [113]. Most of the published methods of differentiation protocol yield in a lower amount of atrial-like and nodal-like CMs [40, 58, 93, 107], but sufficient numbers of subtype-specific CMs are needed to understand the subtype-related disease mechanism and development of specific therapeutic approaches. Atrial fibrillation (AF) is one of the most common cardiac arrhythmias; however, current antiarrhythmic drugs for treatment of AF are not atrial-specific and could cause unacceptable ventricular events [114]. Thus, sufficient supply of atrial CMs is crucial for investigating the AF cellular mechanism. hiPSCs have been differentiated into high-purity atrial-specific CMs by using retinoic acid signaling at the mesoderm stage of development [115]. These patient-specific atrial CMs allow us to investigate in detail mechanisms of AF and to develop atrial-specific therapeutic drugs. Furthermore, sinoatrial node (SAN) dysfunction can manifest bradycardia and asystolic pauses, but its pathophysiology is not completely understood [116]. SAN pacemaker cells from hiPSCs would facilitate the study of the disease mechanism and provide a cell source for developing a biological pacemaker. Protze and co-workers had reported the transgene-independent method for the generation of pacemaker cells (nodal-like CMs) from human pluripotent stem cells by stage-specific manipulation of developmental signaling pathways [117]. Besides CMs, the heart also consists of many other cell types such as fibroblast, endothelial and vascular smooth muscle cells, and also extracellular matrix. Importantly, the origin of cardiac diseases may not always exclusively originate from CMs, but might involve non-CMs. Thus, incorporating the fibroblasts [118], endothelial cells [119], and vascular smooth muscle cells [120] into CMs from the same hiPSCs could offer new insight of disease mechanism.
The establishment of appropriate control is another challenge in disease modeling using hiPSC-CMs. It is generally argued/suggested that when comparing the results between control and mutated hiPSC-CMs, both should have the same genetic background. This objective is achieved in somehow by using healthy family members as control [58, 93]. However, only ~50% of genome is shared between siblings, and phenotypic difference could result from DNA variants in the rest of genome besides disease-associated mutation [121]. Mutated genes can be corrected with the help of newly growing gene editing technology such as TALENs [98] and CRISPR/Cas9 [33, 51, 84], thus establishing the so-called isogenic lines. This isogenic line would be the most appropriate control for comparison as it differs only in the presence and absence of mutation. Therefore, advance genome engineering will not only provide more reliable control lines but also guide us to understand how mutation modifies the normal functioning of cells. However, for diseased CMs without known mutation, healthy family members or otherwise controls are still the best.
While animal models fail to recapitulate human cardiac disease phenotype properly, hiPSC-CMs have been successful in recapitulating crucial phenotypes of many genetic cardiac diseases in terms of morphology, contractility, Ca2+ handling, ion channel biophysics, cell signaling, and metabolism. Most strikingly, hiPSC-CMs provide the patient-specific platform to study the disease mechanism and drug response individually, which the traditional disease modeling technique would never offer. In addition, cardiac subtype-specific arrhythmias and drug screening could be performed with the help of unlimited supply of hiPSC-CMs; thus chamber-specific treatment modalities could be identified. Certainly, by improving the current weaknesses of hiPSC-CMs and incorporating with new gene editing techniques, complex cardiac disease mechanism could be deciphered, and novel effective treatment therapies could be identified to improve the life of cardiac patients.
We would like to thank funders for our research group: Tekes–Finnish Funding Agency for Innovation, Academy of Finland, and Finnish Cardiovascular Research Foundation.
No conflict of interest.
AF | atrial fibrillation |
ARVC/D | arrhythmogenic right ventricular cardiomyopathy/dysplasia |
APD | action potential duration |
ATS | Andersen-Tawil syndrome |
BrS | Brugada syndrome |
Ca2+ | calcium ion |
CPVT | catecholaminergic polymorphic ventricular tachycardia |
CRISPR | clustered regularly interspaced short palindromic repeats |
cTnT | cardiac troponin T |
CVDs | cardiovascular diseases |
DADs | delayed afterdepolarization |
DCM | dilated cardiomyopathy |
DSC2 | desmocollin-2 |
DSG2 | desmoglein-2 |
DSP | desmoplakin |
EAD | early afterdepolarization |
ECC | excitation-contraction coupling |
ECG | electrocardiogram |
ET | endothelin |
hiPSC-CMs | human-induced pluripotent stem cell-derived cardiomyocytes |
ICD | implantable cardioverter-defibrillator |
iPSCs | induced pluripotent stem cells |
K+ | potassium ion |
LMNA | lamin A/C |
LQTS | long QT syndromes |
MYBPC3 | cardiac myosin-binding protein C |
MYH7 | myosin heavy chain |
Na+ | sodium ion |
PKP2 | plakophilin-2 |
PLN | phospholamban |
SAN | sinoatrial node |
SCD | sudden cardiac death |
SQTS | short QT syndromes |
TALENs | transcription activator-like effector nucleases |
TS | Timothy syndrome |
VT | ventricular tachycardia |
IntechOpen aims to ensure that original material is published while at the same time giving significant freedom to our Authors. To that end we maintain a flexible Copyright Policy guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
',metaTitle:"Publication Agreement - Chapters",metaDescription:"IN TECH aims to guarantee that original material is published while at the same time giving significant freedom to our authors. For that matter, we uphold a flexible copyright policy meaning that there is no transfer of copyright to the publisher and authors retain exclusive copyright to their work.\n\nWhen submitting a manuscript the Corresponding Author is required to accept the terms and conditions set forth in our Publication Agreement as follows:",metaKeywords:null,canonicalURL:"/page/publication-agreement-chapters",contentRaw:'[{"type":"htmlEditorComponent","content":"The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\\n\\n1. DEFINITIONS
\\n\\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\\n\\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\\n\\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\\n\\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\\n\\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\\n\\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\\n\\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\\n\\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\\n\\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\\n\\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\\n\\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\\n\\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\\n\\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\\n\\n3. CORRESPONDING AUTHOR'S DUTIES
\\n\\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\\n\\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\\n\\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\\n\\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\\n\\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\\n\\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\\n\\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\n4. CORRESPONDING AUTHOR'S WARRANTY
\\n\\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\\n\\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\\n\\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n5. TERMINATION
\\n\\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\\n\\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\\n\\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\\n\\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n\\nLast updated: 2020-11-27
\\n\\n\\n\\n
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
\n\n\n\n
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. 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