\r\n\tThis book intends to provide the reader with a comprehensive overview of the current state-of-the-art on Theileriosis, Babesiosis, and Anaplasmosis, both in humans and domestic animals. Particularly this book aims to permit the researchers to enter into a critical focus on the biology of the parasites, eco-epidemiology of the diseases, clinical manifestations, risk factors, immunology, surveillance, diagnosis, identification, and management of risks as well as the potential economic impact on animal production.
",isbn:"978-1-80356-384-8",printIsbn:"978-1-80356-383-1",pdfIsbn:"978-1-80356-385-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"3d72ae651ee2a04b2368bf798a3183ca",bookSignature:"Prof. Elisa Pieragostini",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11577.jpg",keywords:"Zoonosis, Global Climate Change, Epidemiology, Risk Factors, Haemoparasites, Prevention & Control, Piroplasmosis, Anaplasmosis, Babesiosis, Theileriosis, Tick-Borne Diseases, Ticks",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 23rd 2022",dateEndSecondStepPublish:"April 29th 2022",dateEndThirdStepPublish:"June 28th 2022",dateEndFourthStepPublish:"September 16th 2022",dateEndFifthStepPublish:"November 15th 2022",remainingDaysToSecondStep:"21 days",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Professor of Animal genetics and breeding at Bari University, a researcher in animal genetics related to the resilience of Apulian livestock to enzootic tick-borne haemoparasites and to the involved functional effect of hemoglobin variants. She is a member of national and international scientific associations.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"51521",title:"Prof.",name:"Elisa",middleName:null,surname:"Pieragostini",slug:"elisa-pieragostini",fullName:"Elisa Pieragostini",profilePictureURL:"https://mts.intechopen.com/storage/users/51521/images/system/51521.jpg",biography:"Dr. Pieragostini has a Degree in Biological Sciences, DPhil in Biochemistry received from Bologna University, Italy.\r\nShe was an Assistant professor of “Genetics” at the Faculty of Science of Bologna University, a Full professor of “Animal genetics and breeding” Bari University, Italy, and Elected President of course on “Agricultural Science and Technology” (2001-2010) Bari University.\r\nShe retired in 2015.\r\nFrom 1977 to 1984 she carried out intensive work on Drosophila investigating quantitative characters associated with biochemical markers. From the1985 onwards, she had been studying Apulian farm animals focusing on blood-based markers as well as on the structure-function relationship of the different hemoglobin variants come across and their relationship with the Apulian livestock resilience to the enzootic tick-borne diseases. \r\nShe was Project Director\r\nShe is a member of national and international scientific associations.",institutionString:"Independent Researcher",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Bari Aldo Moro",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"280415",firstName:"Josip",lastName:"Knapic",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/280415/images/8050_n.jpg",email:"josip@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copy-editing and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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The
The physiological process of
This figure illustrates the composition of the CFTR chloride channels (at rest and when activated) in the apical epithelial membranes. It is composed of different domains including the MSD, NBD, and the R domains.
The CFTR transport mechanism depends on two membrane-spanning domains (MSD) and two nucleotide-binding domains (NBD). The cycle of the transport of the chloride ions starts with the phosphorylation of the R domain that activates the channel. This step will start the ATP ligation to the NBD and the subsequent conformational changes and dimerization. This step will provide the energy for the release of the chloride ions across the cellular membrane. Once ATP is hydrolyzed, the NBD is destabilized, releasing ADP and phosphates; this results in the protein regaining its basal state. This cycle is called the ATP switch model of CFTR [3].
The
This figure describes the different classes of CF according to the production of the encoded CFTR protein.
Finally,
Although there are some approved drugs for specific patients who harbor certain mutations, genetic medicine is important as it offers the ultimate treatment for all CF mutations and can benefit every CF patient [8]. There are multiple genetic strategies that are currently under investigation for the treatment of CF. They can be summarized as follows (Figure 4).
This figure illustrates the different genetic medicine strategies for gene treatment of the CF mutations. It includes gene therapy, gene editing, mRNA repair, and mRNA therapy.
Gene therapy is currently the most advanced and promising field of CF genetic medicine. For a long time, the main obstacle of this approach has been the absence of an efficient delivery system for the lung. The barriers (intracellular or extracellular) that are there to protect us from viruses and bacteria also prevent the uptake of different gene treatments via inhalation. The barriers also include the nuclear membrane which prevents the passage of the genetic materials from the cytoplasm to the nucleus. Other obstacles include airway mucus, mucociliary clearance, CF mucopurulent sputum, and the humoral and cellular immune responses. All these hinder the efficiency and the effectiveness of gene therapy as a treatment for CF [8].
Vectors can be classified broadly into two categories: viral and nonviral [9]. Viral vectors include adenoviruses and adeno-associated viruses (AAV). Both viruses can infect the lung cells efficiently and carry specific proteins in their cell surface to overcome the lung’s natural defense systems [10]. However, any preexisting immunity toward the viruses will render them useless. Even if there is no previous immunity, the repeated administration of the virus will eventually lead to the development of immunity toward it and limit its success. However, recent preclinical studies in animals showed that multiple administrations of lentiviral vectors in immunocompetent lungs are effective [10]. Although some adenoviral clinical trials showed partial correction of the chloride transport in CF nasal epithelium by measuring the potential difference between the outer and inner cell membranes, this correction was only recorded after the nasal epithelium was damaged and removed during delivery [10].
Due to the simple structure of the nonviral vectors, they do not usually induce immune reactions inside the body [8]. The UK CF Gene Therapy Consortium (GTC) was formed from three groups in Edinburgh, London, and Oxford. Their aim was to share expertise to assess gene therapy and its ability to stop the progression of CF lung disease. After extensive research, they concluded that the nonviral cationic lipid formulation GL67A combined with the modified pGM169 plasmid (which encodes a CpG-free and codon-optimized CFTR) can produce some improvements in spirometry assessments in animals and even longer duration of response of up to 1 month [8]. In a randomized double-blind phase IIb trial, conducted on 120 patients with different mutations in the UK, it was found that pGM169/GL67A was associated with a small but statistically significant stabilization of lung function in the patients [11]. In addition, the safety of this nonviral system was validated following 12 monthly administrations.
Another promising viral vector that has been investigated is the lentivirus. However, because this virus lacks the lung tropism, it must be combined with another virus in order to transduce the lung cells. The VSV-G protein is commonly used for this purpose, but others like the HA protein from the influenza virus and the F and HN proteins from the Sendai virus (Figure 5) have also been used [12].
This figure shows the F/HN pseudotyped lentiviral vector. The virus loses its gp120 protein which originally enables it to enter the T-cells but it gains the HN envelope proteins from the Sendai virus to facilitate its transduction inside the lung epithelial cells.
It has been reported in murines that one dose of lentivirus leads to life-long stable expression of luciferase (almost for 2 years). In addition, repeated administrations of the vector (10 daily doses, or three administrations at monthly intervals) did not cause a significant immune response. In a comparison between the GL67A/ pGM169 and the lentivirus, it was found that the lentivirus is a much more effective form of gene therapy [8, 10].
At the end of 2017, the preparation for a clinical trial of a F/HN-pseudotyped lentivirus was announced [8]. This clinical trial will be a single-dose, double-blinded, dose-escalating phase I/IIa safety, and efficacy study. In a preliminary study, for the preparation of this clinical trial, it was predicted that only between 5 and 25% of the lung epithelial cells will need to be corrected in order to provide a clinical level of correction [13].
The human bocavirus virus-1 (HBoV1) is a parvovirus which efficiently infects the human airway epithelium. It was successfully recombined with an adenovirus to give a chimeric rAAV2/HBoV1 virus that was able to deliver a full-length
Marked progress in the development of vectors for airway gene delivery, along with a better understanding of CF pathophysiology and the presence of new animal models, has increased the possibility and the hope of gene therapy for CF. However, some obstacles to overcome include the percentage of the lung epithelial cells that need to be corrected to restore physiological function, as well as the limited life span of the ciliated epithelium of the lung. In addition, repeated dosing will require a better understanding of the immune system and the use of immune modulators. Regardless of the strategy, the benefit of a gene therapy approach will ultimately be realized in well-designed CF clinical trials [11].
Gene editing is an advanced form of genetic engineering which enables the insertion, deletion, or change of the nucleotide sequence of any living organism. It certainly gives the promise of providing therapy for diseases that were previously considered untreatable or difficult to treat. The field of genome-editing technologies is rapidly evolving and progressing, and the newer techniques seem to be more promising [15]. Gene editing was originally developed in the 1980s by Capecchi, Evans, and Smithies (awarded the 2007 Nobel Prize in Physiology or Medicine) but was mainly used in mice and pigs. The outstanding discovery that editing efficiency is increased at the site of double-stranded breaks (DSBs) made it possible to use the technique in larger studies of animal models and human cells. However, a method to create specific breaks at a certain genomic location with minimal off-target effects, insertions, and deletions in the DNA sequence had yet to be discovered [15].
In 2005, the development of fully programmable zinc finger nucleases (ZFNs) and their ability to perform this exact task led to its use in research extensively, but the limitation was the inefficiency and high cost of the ZFNs technology [16]. In 2009, the emergence of TAL-effector nucleases (TALENs) increased the gene editing specificity and the ease of design and production [16]. However, in 2013, the development of the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system has revolutionized gene editing as a research method that can be used by many groups worldwide [16].
CRISPR is an adaptive immunity function in bacteria like
Generally, the CRISPR/Cas9 system is composed of (Figure 6) the following:
The cas9 endonuclease that is capable of binding and unwinding the DNA helix and cleave any sequence complimentary to the guide RNA attached to it.
The guide RNA molecule (gRNA) that is designed to bind to the desired sequence and direct the Cas9 endonuclease. Usually, it is a short segment about 20 nucleotides long.
A template DNA, to achieve the repair of the DSB with homology directed repair (HDR) rather than nonhomologous end joining repair (NHEJ).
This figure illustrates the composition of the CRISPR/Cas 9 system [
The ribonucleoprotein complex of Cas9 and sgRNA first scans the DNA, anneals to the complementary DNA sequence and then makes a double strand cut before the sequence of the protospacer-associated motif (PAM) (it is a part of the DNA sequence ~2–6 base pair long immediately downstream of the sequence targeted by the Cas9 nuclease and it is essential for the Cas9 endonuclease function) [18].
The application of this system for the editing of the genomes is quite simple, efficient, multiplexed, applicable in many species, and relatively affordable compared to other forms of gene editing. In addition, this system can be modified to perform activation or repression of certain genes, and the Cas enzymes can be fused to epigenetic modifiers to create programmable epigenome-engineering tools [20].
A more advanced approach of genome editing is the base editing technique (BE), a newer approach to gene editing that achieves the direct and programmable conversion of one DNA base pair to another DNA base pair chemically, using specific enzymes, without inducing a DSB [21]. It was proposed that different base editors were needed to make more efficient and specific conversion of nucleotides with minimal off-target effects, e.g., the conversion of G: C to A: T by using the third-generation base editor (BE3) [21].
Typically, BE3 contains (Figure 7):
A catalytically inactive dCas9 that binds only to DNA but is not able to cut the strand. It is only capable of creating a DNA bubble at a guide RNA-specified region.
A cytidine deaminase enzyme that changes cytidine to uracil within a 3–5 nucleotide window of the single-stranded DNA bubble, e.g. APOBEC1 (Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 1 enzyme).
A uracil glycosylase inhibitor (UGI) that inhibits the automatic cellular repair mechanisms by inhibiting the base excision, therefore improving the efficiency of the BE technique.
Nickase activity: to make a cut only in one strand of the DNA in order to achieve manipulation of the cellular mismatch repair innate mechanisms of the cells to replace the G-containing DNA strand.
This figure describes the different components and the mechanism of action of base editing converting G: C to A: T [
These components combine to achieve a permanent C to T (or G to A) conversion in the cells with minimal or lack of in-del formation [21].
Moreover, additional modifications have been made to BEs to limit off-target effects (e.g., Hypa-BE3), decrease bystander effects (e.g., YE1-BE3, YE2-BE3), increase the editing window (BE-PLUS), and improve intracellular expression (BE4max) [23].
A recent technique (late 2017) is the use of Adenine base editor (ABE) which is able to convert A: T to G: C by using an adenine deaminase enzyme such as E. coli TAD-A, human ADAR2, mouse ADA, and human ADAT2 [22]. The adenine base is converted to inosine by deamination. Inosine is then treated as guanine by cell polymerases, therefore pairing it with cytidine in the opposite strand and ultimately converting A: T to G: C. The ABE also consists of a guide RNA, a catalytically impaired Cas9 and an adenine deaminase enzyme such as E. coli TAD-A (Figure 8).
This figure illustrates the composition and the mechanism of action of adenine base editing converting A: T to G: C [
Therefore, these base editors (both ABEs and BEs) revolutionize the field of genome editing and can position all the transitional DNA bases at specific loci in different cells with a minimum of harmful by-products [24].
In CF, CRISPR/Cas9 was used to correct the F508del mutation, which resulted in recovery of the functions of CFTR in human gastrointestinal tract stem cells in an intestinal organoid model [20]. CRISPR/Cas9 has also been used to edit
Added advantages of gene editing over gene therapy are the use of the endogenous cell machinery and the fact that the modifications are permanent for the cell’s life time. In addition, the reagents used for one mutation can also be used for any other CF mutation [8].
One of the main concerns when using the CRISPR/Cas9 system is the possibility of off-target effects; therefore, multiple modifications have been made to Cas9 to reduce such effects, e.g., the use of the nickase Cas9-D10A [27] in yeast achieved precise editing with completely undetectable off-target events. Moreover, both the meticulous choice of the target regions and the use of donor DNA templates with asymmetric homology arms have improved the on-target editing [28].
Other obstacles needed to be overcome in order to increase the gene editing efficiency in vivo are similar to those that affect gene transfer vectors such as the delivery mechanism to the stem basal cells of the lungs through the mucus-obstructed CF lung epithelium. Ideally, the target for the gene editing should be the basal airway progenitor cells, but unfortunately, these are “buried” beneath the surface epithelium and it is difficult to reach with the vectors available currently [29]. On the other hand, there is some optimism using different approaches to deliver CRISPR components: either as mRNA or directly as a protein or ribonucleoprotein complexes with modified lentiviral vectors [30].
Another dilemma, unique to CF, is which cells need to be corrected in the airway epithelium to achieve normal lung function and whether the lung stem cells should be targeted. Furthermore, unrestrained high CFTR expression across all the cells of the lung epithelium might have adverse effects, since normally the expression of the CFTR is controlled with tight activation and repression mechanisms [31, 32].
For CF, the repair of mRNA is a valuable therapeutic technique that was first investigated by Zamecnik et al. [33]. The mRNA repair could be done by either direct repair, exclusion of the defective exon, or a splice site change. The repair of the RNA is done using short double-stranded RNA oligonucleotides, targeting an mRNA sequence between 15 and 40 nucleotides. These oligonucleotides are designed to be specific for every mutation; hence, they might repair or remove the defective RNA [8]. In other studies, the oligonucleotide was designed to target the CFTR splicing mutation 3849 10 kb C-to-T, and it was shown that the defective splicing can be changed to include a cryptic exon and regain the CFTR function [34].
Moreover, ProQR Therapeutics developed QR-010 which targets the F508del mutation. It does not need to cross the nuclear membrane, since it acts in the cytoplasm. QR-010 showed that it can increase the CFTR Cl− channel activity in homozygous F508del HBE cells. Also, when administered intranasally to mice, it restored the normal potential difference of the lung epithelium [34, 35, 36, 37]. QR-010 is currently in a Phase Ib clinical study given as an inhalational drug to treat the homozygous F508del mutation in adults to evaluate its tolerability and its pharmacokinetics [37].
Small interfering RNA (siRNA) is one of the mRNA therapies that is used to silence the epithelial sodium channel, ENaC. It has been shown that upregulation of ENaC in CF leads to dehydration of the airway and formation of thickened mucus [38]. Due to the lack of a proper delivery system, the use of siRNA to transfect epithelial lung CF cells is difficult. However, ENAC silencing by siRNA when formulated with lipid-peptide nanocomplexes was recently reported both in vitro and in vivo [38].
Messenger RNA as a gene therapy approach has several advantages over DNA (as it does not require nuclear localization or transcription) and viruses, since it does not integrate in the genome once inside the cell. For years, scientists have been investigating the possibility of injecting the wild form of the CFTR mRNA to the cytoplasm to act as a template to produce wild-type CFTR protein [9]. Nevertheless, the unstable nature of RNA and its capacity to elicit innate immune responses pose limitations for in vivo applications. However, recent advances in synthetic biology helped alleviate these limitations by modifying the exogenously synthesized mRNAs to mimic their endogenous counterparts. These modifications have led in both an increase in mRNA transfection efficiency, as well as longer protein expression [39].
The immune system has evolved to recognize exogenous RNA, as it can also be found in viruses and other pathogens. Viral single- and double-stranded RNA can induce immune stimulation by interacting with pattern recognition receptors (PRR) tasked with identifying pathogen-associated molecular patterns. Endogenous RNAs evade immune response since they contain modified nucleotides that affect PRR engagement. For example, the incorporation of nucleotide analogs in the RNA sequence, such as 2-thiouridine (2-SU), 5-methylcytidine (5-meC), and 1-methylpseudouridine (m1Ψ), enables them to prevent recognition [40].
Furthermore, to optimize their translational efficiency and stability, the in vitro synthesized mRNAs incorporate a 5′-end modified cap (anti-reverse analogue [modified ARCA]) and a 3′-end poly(A) tail, eventually resembling fully-processed endogenous mRNA molecules [40]. In conclusion, as a result of extensive research, a variety of different chemical modifications of the mRNA in conjunction with its encapsulation into nanoparticles are currently under investigation [41, 42]. A recent study in bronchial epithelial cells has even demonstrated the restoration of chloride secretion using lipid nanoparticles (LNPs) to package and deliver chemically modified CFTR mRNA [43].
There are several drugs that were investigated for the treatment of CF mutations. According to the class of the mutation, different drugs with different mechanisms of action are used. CFTR modulators are small molecule drugs that improve CFTR protein function by a variety of mechanisms [44]. However, those molecules do not treat the main mutation defect of the
The potentiators that increase the gating function and the opening probability of the CFTR Cl− gates, e.g., Ivacaftor.
The correctors that promote protein folding, assisting the transition of the CFTR protein through the cytoplasm to the cell surface, and the rescue of the CFTR protein, e.g., Lumacaftor.
The read-through drugs that enable the overriding of the premature termination codons and subsequently lead to complete translation and production of the full length protein, e.g., ataluren.
The amplifiers that increase the amount of the CFTR inside the cells and are usually given with other modulators (mentioned above) to increase their efficiency.
Different mechanisms of action of drugs that are used to treat the different classes of CF mutations [
F508del accounts for ~69% of CF-causing alleles [46]. To address this mutation defect, two different forms of drugs are used: CFTR correctors to increase the amount of correctly-folded CFTR protein and CFTR potentiators that improve the gating mechanism of the apical CFTR protein [47]. When combined together, they restore the Cl− transport and improve the airway mucociliary clearance [48]. The commercially available formulations of these two drugs are the corrector Lumacaftor (VX-809) and the potentiator Ivacaftor (VX-770). When administered alone in patients homozygous for F508del, Lumacaftor lead to a modest, yet statistically significant reduction of ≥10 mmol/L in the sweat chloride concentration, but no other improvements in lung function (FEV1) and quality of life (CFQ-R) were observed [49]. On the other hand, in patients with the G551D mutation, Ivacaftor lead to an all-around improvement. In detail, after 48 weeks, the treated patients demonstrated an overall increase in BMI and quality of life markers, a 10.6% increase in FEV1, as well as a decrease of 48.1 mmol/L in sweat chloride levels, making Ivacaftor the first agent to achieve a reduction to values below the diagnostic threshold for CF (60 mmol/L). As a result, Ivacaftor was approved for the treatment of the Class III CF mutations in 2012 [50, 51]. The combination of both, which is called Orkambi, is currently available for CF patients as it proved beneficial for homozygous F508del mutation treatment. To elaborate, in addition to a significant general improvement in the clinical picture of the disease, such as increased BMI and CFQ-R, and a decreased rate of exacerbations, a 5% improvement of FEV1, when compared to the placebo, was observed [52, 53]. In 2019, a triple combination therapy consisting of the correctors Elexacaftor and Tezacaftor and the potentiator Ivacaftor (called Trikafta and developed by Vertex Pharmaceuticals) was tested in a double blind, randomized phase 3 clinical trial, demonstrating remarkable results. Among others, a significant increase in CFQ-R and a favorable safety profile. Moreover, there was a 10.4% increase in FEV1 and a considerable improvement in sweat chloride concentration, with a mean decrease of 43.4 mmol/L, achieving values below the diagnostic threshold for CF. Subsequently, Trikafta was approved by the FDA as a treatment among patients aged 12 years or older with the F508del mutation [53].
Furthermore, a number of proteins based on proteostasis modulation have been identified as useful drug targets for CF therapy [54, 55, 56]. Hsp90 and AHA1 are thought to have a role in CFTR folding and degradation. It was found that treatment with Hsp90-AHA1 inhibitors combined with Lumacaftor was more effective than Lumacaftor alone [56].
Ataluren is another drug that was used to facilitate the read-through of nonsense mutations in Duchene Muscular Dystrophy. However, a randomized clinical phase II trial showed no significant efficacy of Ataluren in the treatment of CF [57]. ELX-O2 is another drug that is recently developed by ELoxx Pharmaceuticals for its read-through effects. It is currently in a phase 2 clinical trial involving CF patients [58].
Another possible drug target is endoplasmic reticulum-associated degradation (ERAD), including chaperone proteins and ubiquitin complexes. RNF5 (also known as RMA1) was found to be important in the protein folding and NBD domain synthesis [59].
Interestingly, due to the presence of more than 2000 mutations in
For a long time, viral vectors dominated the fields of gene therapy and vector development, mainly due to their very high efficiency. However, over the last years, novel approaches in vector design and recent advances in microfluidics have turned nonviral vectors into a promising method of drug and gene delivery [60, 61]. There are multiple materials that can be used to create nonviral vectors, including liposomes, which allow the delivery of the nucleic acids inside the lung epithelial cells. Liposomes are spherical vesicles composed of two layers of phospholipids with a hydrophilic core. They are normally formulated with natural lipids and possess no immunogenicity [62].
Nonviral vectors have the advantages of simple large-scale production and a large capacity for nucleic acids as cargos. Furthermore, low host immunogenicity and the ability to maintain their efficiency even after repeated administration render them a popular alternative to their viral counterparts. In addition, recent advances in vector technology have yielded molecules and techniques with even higher transfection efficiencies [60, 61]. These new vectors can be used to deliver small molecules such as siRNAs, miRNAs, or even small therapeutic molecules and drugs, as well as bigger molecules like mRNA, minicircle, and plasmid DNA.
The cationic lipid-based vectors are an effective delivery approach for the CRISPR/Cas9 system but only after local administration [62]. However, the main problem about liposomes as drug delivery vectors for the treatment of CF or any chronic obstructive disease remains the development of inhalational formulations which can be delivered by nebulization. The nebulizer can alter the stability of the liposomes and cause their aggregation [63]. Therefore, several methods have been developed to stabilize the liposomal formulations such as lyophilisation [64] or use of dry powder inhaler (DPI) liposomal formulations which have shown promising results for drug administration in the lung, but those are still in an early development stage [65]. Targeted liposome-peptide nanocomplexes have been successfully nebulized, offering another alternative [66, 67].
Additionally, mucus-penetrating nanoparticles have emerged as a suitable vector to deliver various drugs and nucleic acids across the thick mucus barrier in cystic fibrosis. In CF, targeted mucus-penetrating nanocomplexes successfully delivered siRNA against ENAC in the airway epithelium and decreased the Na+ reabsorption, thus restoring the clearance of the mucus and regaining the function of cilia [38, 68]. Mucus-penetrating NPs have a small size which leads to a lower mucus surface tension and easy penetrance. Also, they are coated with polyethylene glycol (PEG) which is electrically neutral and lead to an enhancement of the penetrance of the thick mucus of CF [69]. PEGylated nanoparticles loaded with Ivacaftor were formulated to test the drug uptake capacity of CF artificial mucus (CF-AM) on human bronchial epithelial (16-HBE) cells [70]. It was found that there was a higher release and uptake of Ivacaftor by 12% compared to Ivacaftor alone. In light of these results, the PEGylated mucus-penetrating NPs are considered a good vehicle to deliver the CFTR modulators through pulmonary administration to treat CF patients [70]. However, in order to be effective, the size of mucus-penetrating NPs should be small enough to penetrate mucus and big enough to prevent rapid exhalation and expulsion from the lung. Moreover, in order to increase their efficacy, certain parameters must be considered such as the nanoparticle morphology and their surface properties [71].
In summary, both viral and nonviral vectors are used to introduce different nucleic acids into the cell. Though the design of viral vectors has improved in the last few years and they have become more efficient, the immunogenicity and safety concerns still remain a big issue. On the other hand, the nonviral vectors offer safe and low-cost therapies with increased transfection efficiencies. Further improvements and optimization of these therapies and delivery vehicles could lead to a great outcome for CF [72].
Having an animal model is a crucial step to understand the disease pathogenesis, progression, and to test new drugs. The CFTR-knockout pigs and ferrets were generated approximately 15 years ago [73]. These species have a similar lung biology to humans because their submucosal glands are in their cartilaginous parts of the lung. On the contrary, rats and mice have their submucosal glands in the trachea, and rabbits do not have glands at all [74].
Among other in vitro cell culture models, one that has particular value in CF is the use of organoids, which have become a very useful model for CF research [75]. Organoids are 3D cultures of the lung progenitor cells grown in the presence of appropriate medium. They grow also with supporting cells that organize in a very similar way as the in vivo organs. In CF research, organoids of the intestinal and respiratory systems are currently used to screen and test the newest drugs for CF [20]. Moreover, the intestinal organoids have been used as a model for the CRISPR/Cas9 technique [20].
These models could also be used potentially for testing gene editing-based therapeutics in CF [8, 76]. Another therapeutic option is to directly edit the progenitor cells in the lung epithelium in vivo, but a CRISPR editing system in CF lung in vivo has yet to be reported [8].
Human embryonic stem cells (ESCs) and iPSCs are newer models that can be used in CF. iPSCs are obtained by somatic cell reprogramming and differentiating these cells into specific human tissues [77]. The iPSCs can produce cell lines with the different rare CF mutations. The CRISPR/Cas9 technique was efficiently used to correct the CFTR F508del in patient-derived iPSCs that were differentiated to proximal airway cells [78].
Cystic fibrosis is a good example of how a deeper understanding of the genetics of disease can lead to personalized therapy for each patient. Continued efforts to develop better viral and nanoparticle-based nonviral vectors and produce novel gene editing with CRISPR/Cas9 are always investigated. Along with the advancement in the production of CF animal and in vitro human models and the presence of different electrophysiological methods such as transepithelial potential difference (TPD), all these give the promise and hope for the future of CF patients. Certainly, the recent use of organoids will be essential to personalized genetic medicine. This chapter has presented the past and current research that shows that the concept of genetic medicine can become a reality for CF patients in the near future.
The renin-angiotensin-aldosterone system (RAAS) is a powerful system that regulates fluid-electrolyte balance and systemic blood pressure. First, it has been stated that it is a hormonal and peptidergic endocrine system that regulates blood pressure and fluid-electrolyte balance [1, 2]. Until recently, RAAS was known only as an endocrine system that regulates blood pressure and fluid-electrolyte balance, but now it is noted that this system is not only found in circulation but also locally in organ systems, and also has autocrine-paracrine functions [3].
There are some components of RAAS responsible for these effects. One of these components, renin, is synthesised as prorenin from the juxtaglomerular apparatus, which is also found in kidney efferent arterioles. The protein is converted to active renin, stored in secretory granules and released into the circulation when necessary [4]. The release of renin, a proteolytic enzyme, is triggered by many physiological stimuli, including prostacyclins (PGI2), such as stimulation of macula densa in the distal tubule with low Na + concentration, reduction of arterial pressure, renal sympathetic nerve activation and stimulation of β1-receptors [5]. Circulating renin provides the formation of Angiotensin I (AngI) from angiotensinogen, most of which is synthesised from the liver [6]. AngI is converted to Angiotensin II (AngII) by Angiotensin-converting enzyme (ACE), a membrane-bound metalloproteinase found in high amounts on pulmonary vascular endothelial cell surfaces (Figure 1) [5, 7].
Renin-angiotensin-aldosterone system and effects.
ACE, a member of the zinc metallopeptidase class, had two main roles in metabolism. It takes part in the RAAS system and the kinin-kallikrein system (KKS). Another task is to inactivate substance P and neurokines [8, 9]. ACE has two forms in endothelial and epithelial cells and male spermatid. Its form in endothelial and epithelial cells is called “somatic form” (sACE), and the form found in spermatids is called “germinal form” (gACE) [10]. The primary structure of these two forms is different from each other. While sACE has two active sites with different catalytic properties, gACE has only one active [11]. ACE has another mammalian homologue named angiotensin-converting enzyme 2 (ACE2) [12]. Although ACE2 has carboxypeptidase activity like ACE, it cleaves an amino acid unlike ACE and its most important substrates are AngI and AngII [13].
In the body, AngII has many roles such as increasing blood pressure by direct contraction of vascular smooth muscles, increasing myocardial contractility, water and salt retention by stimulating aldosterone release from the adrenals, stimulation of catecholamine release from sympathetic nerve endings, cell growth and proliferation [14, 15]. It turns out that AngII can be generated locally in many tissues, including the brain, independent of circulating components [16]. AngII acts by binding to receptors in the protein structure on the plasma membranes of different tissues. These receptors are termed AngII type 1 (AT1R) and AngII type 2 (AT2R) receptors [17]. Changes in the balance of RAAS have been reported to have direct or indirect effects with cardiovascular system diseases, lung diseases, nervous system diseases and kidney diseases. Therefore, this section describes the mechanism of action of RAAS and the relationship of RAAS components with these diseases.
Ang II has a role in a variety of cardiac dysfunctions, including hypertrophy, arrhythmia, and ventricular dysfunction [18, 19]. Inability to pump enough blood to the body due to insufficient heart functions due to various reasons is known as heart failure. When looking at the role of RAAS in the case of heart failure, RAAS activation can occur when hypertrophy occurs in the heart muscle cells. This causes fluid retention in the body and peripheral vasoconstriction, resulting in cardiac overload and heart failure [20]. RAAS activation increases in heart rate and contractility, thus reducing coronary blood flow [21]. Experimental studies have shown that plasma renin activity increases in acute heart failure. Also, it was determined that plasma renin activity was normal in the compensated phase of chronic heart failure, and this shows that RAAS is associated with heart failure [22]. It has also been determined that when myocardial cells are exposed to excessive AngII and aldosterone, fibrosis is formed. This again shows that RAAS plays an important role in myocardial heart disease. It was determined that AT-1 receptor expression affected by AngII decreased in decompensated heart failure, while AT-2 receptors remained unchanged [23]. It has also been determined that ACE inhibitors play an important role in heart failure. It has been reported that ACE inhibitors are beneficial, especially in patients with left ventricular failure, and that death rates are reduced [24]. These findings are an important indicator that renin-angiotensin inhibition is crucial to improving cardiac dysfunction. When the relationship of RAAS with myocardial infarction is examined, it has been determined that ACE2 RNA expression increases in the case of myocardial infarction [25]. In another study, it was shown that ACE2 expression increased in the case of myocardial injury induced by ischemia–reperfusion in rats and this increase attenuated myocardial damage [26].
It has been determined that the plasma renin level changes in the case of hypertension. Plasma renin levels are not proportional to blood pressure, and it has been reported that plasma renin levels are low in some patients, normal in others and high in others. One of the reasons for the change in the renin level is that it is primarily caused by ischemia that develops in the nephrons. In this case, renin levels released from ischemic nephrons increase at different levels, resulting in normal or high plasma renin levels. The renin released from ischemic nephrons passes into the circulation leading to the formation of AngII [17, 27]. As a result, hypertension occurs with increased vasoconstriction and sodium retention in nephrons. The reason why plasma renin level is normal in some hypertensive patients is that aldosterone is not synthesised in response to sodium restriction. Also, it has been stated that resistance to renin and AngII is formed in the vessels and therefore they can increase blood pressure even at low levels. Besides, independent of RAAS in circulating blood, it has been determined that Ang II production by serine protein kinase activity is independent of ACE activity in the heart, brain, adrenal cortex and blood vessels [28]. Also, AngII contributes to hypertension [29]. When looking at the relationship between salt intake and RAAS, it is seen that high salt intake suppresses RAAS, while low salt intake stimulates AngII release [30]. Studies have determined that smooth muscle cells are also critical in the regulation of AngII-mediated blood pressure. A study in mice found that 22α protein deficiency in smooth muscle reduces hypertension that can occur with AngII [31]. This is an indication that the RAAS system plays an important role in hypertension.
AngII has been determined to induce endothelial dysfunction and increase oxidative stress in the endothelium by stimulating the production of reactive oxygen species (ROS) such as superoxide anions (O2−) derived from nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase). This is especially the result of endothelial AT1R stimulation that interacts with the Nox5/Ca2 + calmodulin binding site, which will increase Ca + concentration in the endothelial cell [32, 33]. Nox5 is a member of the NADPH oxidase family and plays an important role in the development of atherosclerosis, inflammation, and oxidative stress [33, 34]. It also plays a role in the adhesion of mononuclear cells to the arterial endothelium and recruitment of mononuclear cells by stimulating the increase in CAM expression of TNF-α, which is released as a result of stimulation of AT1R with AngII, in combination with IL-6 [35]. One study reported that AngII induced monocyte chemotactic protein-derived protein expression (MCPIP1) via an AMPK/p38 MAPK-dependent pathway [36]. Increased MCPIP1 expression contributes to atherosclerotic plaque formation by triggering apoptosis in macrophages [37]. Another thing related to the formation of atherosclerosis is that AngII induces the expression of a multifunctional protein found in macrophages, endothelial cells, smooth muscle cells (SMCs), and epithelial cells called osteopontin. Osteopontin plays an important role in the development and development of atherosclerosis [38]. The cell membrane has a transmembrane glycoprotein called LOX. LOX acts as a receptor for oxidised LDL (oxLDL). It increases the expression of AngII LOX-1 gene. Binding of oxLDL to LOX-1 in the endothelium causes an increase in leukocyte adhesion molecules, activates apoptosis pathways, increases ROS and induces endothelial dysfunction. This situation contributes to the development of atherosclerosis. Also, oxLDL increases the formation of ACE, which induces the formation of AngII (Figure 2). This increases LOX-1 expression, which positively regulates the expression of AT1R, and contributes to a self-sustaining pro-atherogenic cycle [39]. Thus, it has been determined that ACE and ATR1 inhibitors prevent the development of atherosclerosis.
Mechanism of AngII-mediated atherosclerosis formation. Involvement of Ang-II, ACE2, and Ang-1–7 in atherogenic pathways. The Ang-II binding into AT1R can activate Nox5 through a calcium/calmodulin-dependent pathway.
RAAS plays an important role in shaping vascular inflammation. Vascular inflammation causes endothelial dysfunction. This dysfunction causes tissue damage. Endothelial dysfunction also results in the accumulation of inflammatory cells in the area. This situation triggers atherosclerosis. Also, studies have shown that AngII-mediated inflammation and hypertension and atherosclerosis develop [40]. In another study, it was determined that AngII administration in human vascular smooth muscle cells increased NF-KB activation, thus increasing IL-6, MCP-1 and TNF-expression [41]. Again, although it is a vasoconstrictor, AngII was determined to induce endothelial damage by inhibiting endothelial cell regeneration. AngII has been reported to act as a second messenger to activate intracellular signalling pathways such as mitogen-activated protein kinase (MAPK) and protein kinase Akt/protein kinase B (Akt/PKB), pathways that mediate cell proliferation and apoptosis, and thus vascular dysfunction [42]. AngII is also stated to be a potent pro-oxidant. Ang II induces the production of superoxide anions and activates NADH/NADPH signalling [43]. AngII lowers nitric oxide (NO) levels and activates redox-sensitive genes, particularly cytokines and adhesion molecules [44]. Ang II is also a profibrotic factor. Chronic AngII administration in mice has been shown to cause an increase in blood pressure, infiltration of inflammatory cells into the myocardium and cardiac fibrosis [45]. Another factor that provides the proinflammatory and profibrinolytic effect of RAAS in vessels is aldosterone [46]. Aldosterone affects insulin resistance and the development of atherosclerosis. In vascular smooth muscle cells, aldosterone alters insulin signalling, increases insulin-like growth factor-1 expression.
Oxidative stress is defined as the disproportion between the presence of antioxidants and free radicals or prooxidants in a biological system. ROS and reactive nitrogen species (RNTs) are by-products of a variety of cellular processes, including aerobic metabolism [47, 48, 49, 50, 51]. These by-products cause damage to various tissues [52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73]. RAAS has a direct relationship with oxidative stress that may occur in the cardiovascular system. It has been determined that chronic administration of aldosterone, one of the components of RAAS, causes oxidative stress in the rat aorta [74]. AngII represents one of the major vasoactive peptides involved in the regulation and activation of NADPH oxidase. Ang II stimulates the activation of NADPH oxidase, increases the expression of NADPH oxidase subunits, and induces ROS formation in vascular smooth muscle cells, endothelial cells and fibroblasts. ACE2 shows an effect of reducing oxidative stress by inhibition of ROS synthesis by reducing AngII to Ang 1–7. Ang 1–7 therapy can have a curative effect on vascular disease models. It is reported that solutions that can increase Ang 1–7 levels may be beneficial to alleviate endothelial dysfunction [75]. This is supported by studies showing that overexpression of ACE2 leads to attenuating the effects of hypertension in animal models [76, 77]. It supports the argument that hypertension is a side effect directly related to oxidative stress, thus overexpression of ACE2 leads to a reduction of oxidative stress in a biological system [78].
RAAS plays an important role in the pathogenesis of many kidney diseases characterised by proteinuria. In a study, it was stated that AngII induces the formation of proteinuria. It has also been determined that AngII stimulates the formation of TGF-1 in various kidney cells [79]. TGF-1 has been found to impair autoregulation by afferent arterioles [80]. Vasoconstriction occurs after increased arterial pressure in afferent arterioles. In case of impaired autoregulation in the presence of TGF-1, especially systemic hypertension occurs, an increase in transcapillary pressure occurs. Thus, AngII increases capillary filtration pressure by causing efferent vasoconstriction and TGF-1-mediated impaired afferent arteriole autoregulation. Also, AngII has been found to have a direct effect on the integrity of the filtration barrier. Again, AngII has been shown to reduce the synthesis of negatively charged proteoglycans and additionally suppress nephrin synthesis [81]. It has been observed that this situation causes apoptosis in podocytes. Vascular endothelial growth factor (VEGF) has been identified to be an important factor in increasing the permeability of the filtration barrier in the kidneys [82]. It has been determined to stimulate VEGF expression via the AngII, AT1 and AT 2 receptors. It is thought that the increase in VEGF expression via AT2 receptors may be mediated by an increase in hypoxia-inducible factor 1. Also, VEGF and TGF-1 mediate the AngII-mediated synthesis of the 3rd chain of collagen type IV, which is a component of the glomerular basement membrane [83, 84]. As a result, it is seen that AngII causes proteinuria by causing changes in hemodynamic and non-hemodynamic mechanisms. AngII stimulates albumin reabsorption in proximal tubule cells through AT2 receptor-mediated protein kinase B activation [85]. Albumin uptake induces a selection of proinflammatory and profibrogenic cytokines such as monocyte chemoattractant protein-1, IL-8, endothelin, and TGF-1 [86]. This situation stimulates the migration of cells into the interstitium. Ultimately it causes inflammation in the interstitial area.
In a study, ECM proteins induce type I procollagen and mRNA encoding fibronectin in cultured mesangial cells of AngII, and also stimulates the synthesis of type I collagen types 1 and 3 in cultured proximal tubular cells [79]. It has been determined that the stimulatory effect of AngII on collagen expression is dependent on TGF-1 expression. As a result of the studies, it has been reported that AngII stimulates the proliferation of cultured renal fibroblasts and increases mRNA expression of TGF-β1, fibronectin and type I collagen. It has also been observed that renin increases TGF-1 expression by stimulating a particular receptor in cultured mesangial cells [87]. These findings suggest that increased renin as a result of ACE inhibitor therapy may directly contribute to renal fibrosis through increased TGF-1 despite AngII blockade. It was also determined that AngII increased connective tissue growth factor (CTGF) in kidney tissue. CTGF is a fibrinolytic mediator and is also stimulated by TGF-β. However, AngII also stimulates CTGF synthesis independently of TGF-β [88]. These findings suggest that increased renin as a result of ACE inhibitor therapy may directly contribute to renal fibrosis through increased TGF-1 despite AngII blockade. It was also determined that AngII increased connective tissue growth factor (CTGF) in kidney tissue. CTGF is a fibrinolytic mediator and is also stimulated by TGF-β. However, AngII also stimulates CTGF synthesis independently of TGF-β [89]. Studies have shown that more than one-third of local fibroblasts in renal interstitial fibrosis originate from tubular epithelial cells through a process called epithelial to mesenchymal transition (EMT). Again, AngII can be effective on EMT [90].
Studies have shown that AngII activates the proinflammatory transcription factor NF-KB via AT1 and AT2 [91]. It has also been stated that it can stimulate NF-KB in AngIII and AngIV [86]. It has been determined that Rho-kinase plays a role in AngII mediated NF-KB activation. Also, AngII stimulates the transcription factor Ets. This factor regulates vascular inflammation by the transport of T cells and macrophages to the vascular wall. AngII has been reported to increase the level of Toll-like 4 receptors that bind LPS on mesangial cells. It has been observed that this receptor has an increasing effect on NF-KB activation [92]. The penetration of inflammatory cells into the glomerulus as well as the tubulointerstitium plays an important role in the progression of chronic kidney disease. Also, AngII induces the adhesion of circulating immune cells to capillaries by stimulating the increase of adhesion molecules such as vascular cellular adhesion molecule-1, intracellular adhesion molecule-1 and integrins. This situation shows the relationship of AngII with renal inflammation. It has also been determined that AngII has a stimulating effect on lymphocyte production [86, 93].
Studies explaining the relation of RAAS with CKD were made in the 1980s and important data were obtained in these studies [94]. AngII has emerged as a central mediator of kidney damage because it can induce glomerular capillary hypertension that damages endothelial, glomerular epithelial cells, and mesangial cells [94, 95]. Also, AngII/aldosterone has non-haemodynamic effects that are important in the pathogenesis of CKD, such as inflammation, fibrosis, ROS production, and activation of pathways associated with endothelial dysfunction [94]. One of the most common causes of CKD is diabetic nephropathy. RAAS has an important role in diabetic nephropathy. Plasma renin activity is lower than normal in patients with diabetes [96]. However, intra-renal RAAS activity is high [97, 98]. This is an indication that diabetic nephropathy has one of the most important roles in the formation of CKD.
Studies show that the RAAS system is associated with renal hypertrophy and apoptosis. It has been determined that AngII, one of the components of RAAS, induces apoptosis in vivo and in vitro conditions [99]. It has been reported that AT1 and AT2 receptors are involved in these effects. Studies have reported that Ang II plays an important role in tubular cells and podocytes in (Endoplasmic reticulum) ER stress-induced renal apoptosis, especially in diabetic nephropathy [100]. It has been shown that Ang II can induce podocyte ER stress via the PERK-eIf2-α-ATF4 axis and the PI3-kinase pathway [101]. Another study found an AT1R-mediated increase in glomerular GRP 78 in rats chronically treated with AngII. These data support the relationship between the AngII/AT1R signal and ER stress on podocyte damage. In the same study, Ang II treatment was reported to induce p38 MAPK-dependent apoptosis in podocytes associated with Bax protein activation. In addition, Na+/H+ exchanger isoform 1 (NHE1) activity increases. As a result, it triggers cellular apoptosis (Figure 3), [102].
Mechanism of AngII-mediated apoptosis formation in the podocyte. AT1R signalling induces ER stress through increased GRP 78 and p-elf2α expression and PKC-δ phosphorylation. p38 MAPK and PKC-δ activation lead to increased Bax expression and enhanced NHE1 activity, triggering cellular apoptosis.
As a result of RAAS activation, inflammation [103] and vascular permeability increase [104] due to Ang II stimulation of AT1 receptor and thus severe acute lung damage occurs [105, 106]. In mice, administration of losartan prevents acute lung injury caused by Ang II and decreases AT1R expression [107, 108]. Pneumonia is associated with RAAS, especially in influenza-induced types of pneumonia RAAS system plays a very important role. In patients with pneumonia, the use of RAAS inhibitors reduces the mortality rate and the likelihood of intubation [109]. As with other viral types of pneumonia, children infected with the Respiratory syncytial virus (RSV) tend to have higher Ang II levels than healthy children [110]. The benefit of recombinant ACE2 treatment on RSV infection has been demonstrated in a preclinical mouse model in animal experiments [111]. H7N9 and H5N1 influenza reduce the level of ACE2, increase the level of Ang II, and thus cause lung damage via the AT1 receptor [112]. In H5N1 and H7N9 mouse models, treatment with losartan results in a decrease in IL-6 level and lung oedema, thus preventing lung damage [113]. It was concluded that losartan prevents lung damage by inhibiting RAAS activity.
The Spike protein [S protein] on the SARS-CoV Virus surface attaches to the ACE2 receptor and enters the body in this way. Moreover, ACE2 improves the efficiency of SARS-CoV replication [114]. Transmembrane protease serine 2 (TMPRSS2) can degrade ACE2 and S protein for membrane fusion and the entry of SARS-CoV into cells. Therefore, the concentration of ACE2 in the membrane decreases, but the number of cells infected with SARS-CoV with cessation increases [115]. Ang-II level increases in lung tissue of mice infected with SARS-CoV. Also, the use of angiotensin receptor blockers in these animals significantly reduces pulmonary oedema. This indicates that lung failure caused by SARS-CoV is caused by an increase in Ang-II level and overactivation of the AT1 receptor [116]. Increased ACE level and decreased ACE2 levels in SARS patients cause increased Ang II level and AT1 receptor expression, which accelerates lung damage and can lead to death [117]. Also, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), caspase 3 (CASP3), caspase 9 (CASP9) and fibroblast growth factor-7 (FGF-7) increase in the lung tissue of these patients [118].
SARS-CoV-2 (Covid-19) Similar to SARS-CoV, the S protein uses the ACE2 cellular membrane for input and uses TMPRSS2 for S protein preparation to facilitate the fusion of viral and cellular membranes [119, 120, 121]. Compared to other coronaviruses, the affinity of S protein to ACE2 is higher in SARS-CoV and SARS-CoV-2. Looking at the distribution of ACE2 receptors in the body, it is found on the endothelial cells and smooth muscle cells of organs and tissues, including the oral and nasal mucosa, lung, small intestine, kidney, heart and blood vessels. The widespread distribution of ACE2 receptors in the body is an indicator of multi-organ failure in COVID-19 patients [122, 123, 124]. SARS-CoV-2 infection causes RAAS disorders and systemic inflammatory response. The plasma Ang II level of COVID-19 patients is significantly higher than that of healthy individuals. This condition is linearly related to viral load and lung injury [125]. A clinical study has shown that cytokine storm syndrome (CSS) occurs in patients with COVID-19 and severe pneumonia. Also, it showed that some cases can progress rapidly to Acute respiratory distress syndrome (ARDS) and even to multiple organ failure [126]. Inflammatory cytokines and chemokines are synthesised in Covid-19 patients, including IL-6, IL-2, IL-1β, IL-8, IL-17, IFN-γ, TNF-α and monocyte chemoattractant protein-1 (MCP-1) (Figure 4). Among them, however, IL-6 in particular plays a key role in triggering the inflammatory response, increasing the mortality rate in patients [125]. In Covid-19 infection, after the virus binds to ACE2 on the cell surface, Ang II cannot convert to Ang1–7, and thus more and more binding occurs to AT1 receptors. This situation causes an imbalance in the ACE/ Ang II/AT1R axis. As a result, the pulmonary endothelium and epithelial cells are damaged by stimulating inflammatory signalling pathways, resulting in an increase in the permeability of pulmonary capillaries [127].
Effects of the renin-angiotensin system during SARS-CoV-2 infection.
Brain RAAS irregularity may contribute to neurodegeneration due to neuroinflammation, oxidative stress and pathophysiological changes due to ageing. Several studies have reported that irregular RAAS plays a key role in numerous degenerative diseases of the brain, including Alzheimer’s, Parkinson’s disease, Huntington’s disease, dementia, amyotrophic lateral sclerosis, Multiple sclerosis, Traumatic brain injury, and Stroke [128, 129, 130].
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterised by impaired daily functions and behaviour, especially memory [131]. The most important change in AD neuropathology is Aβ-centred senile amyloid plaques formed in the hippocampus, amygdala and cortex. Neurovascular disorders and chronic neurodegeneration occur in the surrounding brain tissues and vessels as a result of the toxic effects of these plaques [132]. Besides these plaque formations; Neurofibrillary tangles, oxidative stress in cell membranes and organelles, inflammation, gliosis, excitotoxicity due to excessive intracellular Ca + 2 increase and neuron death by many mechanisms that trigger each other such as disruption in membrane cation channels are encountered [133, 134]. The amyloid-beta (Aβ) peptide triggers O2 radical production in endothelial cells and induces oxidative and peroxidative reactions, causing cell death. As an example of these reactions; the oxidative reaction catalysed by the combination of amyloid plaques with heavy metal ions and lipid membrane peroxidation by various mechanisms can be given. It has been observed that the increased ROS activity via Aβ in tissue taken from the hippocampus caused synaptic disruption and cell death as a result of increased Ca + 2 increase with N-methyl-D-aspartate (NMDA) channel activation. Besides, mitochondria dysfunction is an important point in AD pathology. In biopsy studies, it was found that mitochondria shrank and protein and DNA dispersed into the cytoplasm [135, 136].
One of the brain RAAS products, the Ang- (1–7) peptide is a Mas receptor [MASR] agonist [137]. MASRs are abundant in memory-related areas of the brain and accelerate hippocampal long-term potentiation (LTP) together with Ang- (1–7). Also, it is known that the neuroinflammatory effects of Ang II, another RAAS product, contribute to cognitive disorders. Reversing the biological effects of Ang II with the anti-inflammatory, anti-fibrotic, vasodilator and anti-proliferative biological effects of Ang- (1–7); supports memory and learning [138]. In brain tissue studies in AD, it has been shown that the expression and activity of ACE, the metabolic enzyme of Ang-II, changes significantly in certain regions of the brain, including the frontal cortex and hippocampus. It has been reported that when centrally acting ACE inhibitors are used, they have reduced cognitive decline and have memory-enhancing effects [139, 140]. ACE2 activity decreases in AD pathology [141]. Ang- (1–7) improves memory functions without affecting hippocampal or cortical amyloid peptide storage [142].
Ang II causes oxidative stress through the AT1 receptor [143] and increases superoxide. Thus, it causes neuroinflammation and vascular diseases [144]. As a result, it causes Aβ accumulation due to AD. However, the AT2 receptor signal produces beneficial effect including learning and memory. Angiotensin receptor blockers (ARBs) inhibit AT1R signalling, which shifts the effect of Ang-II towards the beneficial path (AT2R signal) (Figure 5) [144].
Effect of AngII on the nervous system. Amyloid plaque (Aβ), angiotensin II (AngII), angiotensin I (AngI), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), angiotensin (AT), AT2 receptor (AT2R), AT1 receptor (ATR1R).
ACE inhibitors have a protective effect against AD. It shows this effect by suppressing brain-derived neurotrophic factor reduction and TNF-α release. ACE inhibitors also improve oxidative-nitrosative stress and nitrotyrosine production, which reduces amyloidogenesis and subsequent Aβ accumulation [145, 146]. On the other hand, ACE inhibitor (Captopril) and Angiotensin receptor blockers (Telmisartan, Candesartan, Losartan) ameliorate oxidative stress [147, 148, 149, 150, 151]. Telmisartan normalises the decreased thioredoxin (TRX) system in addition to attenuating the expression of the protein (TXNIP) that interacts with thioredoxin. Thus, it reduces the formation of endogenous ROS [149]. Similarly, telmisartan reduces improved glycation end products and 4-hydroxynonenal, which are markers of oxidative stress and are associated with Neurodegeneration [150]. Candesartan lowers the level of free radicals in the brain by decreasing malondialdehyde and increasing glutathione levels [151].
Ang II levels are high in the striatum and substantia nigra of Parkinson’s disease (PD) patients. Ang II and AT1R trigger apoptosis by activating autophagy in a dopaminergic neuronal cell. These findings suggest that Ang II plays a role in the pathogenesis of PD [152]. In animal models of PD, it has been found that the signalling of AT2Rs is decreased with the loss of function in dopaminergic neurons [153]. Also, ACE and ACE2 were detected in the cerebrospinal fluid of PD patients. ACE levels are decreased in the cerebrospinal fluid of PD patients [154].
Multiple sclerosis (MS) is defined as an autoimmune neurodegenerative disease that typically occurs in the third or fourth decade of life [155]. Although the aetiology of the disease is not fully known, both environmental and genetic factors are thought to play an important role in the development of MS [156]. Blocking angiotensin II production by ACE inhibitors and inhibition of angiotensin II signalling by AT1 receptor blockers suppresses T-helper 17 (Th17) cells [157]. Th17 cells play an important role in the development and relapse of MS [158]. In a study, ACE activity in the blood serum of MS patients was reported to be higher than in healthy controls [159]. In another study, ACE and ACE2 levels were found to be reduced in the cerebrospinal fluid of MS patients [160].
As understood, the renin-angiotensin-aldosterone system plays a very important role in regulating the fluid-electrolyte balance and blood pressure in the body. RAAS has receptors in many organs and tissues and can show various effects here. RAAS can be affected by various diseases affecting the cardiovascular, renal, nervous and respiratory systems and plays a major role in the formation of damage that may occur in these systems. Drugs that can affect the components or receptors of RAAS can prevent damage that may occur. The presented study shows the importance of the role of this system in the mentioned diseases. Understanding the role of this system in the mentioned diseases is of great importance in the development of new treatment protocols and new therapeutic agents.
The Internet has irrevocably changed the dynamics of scholarly communication and publishing. Consequently, we find it necessary to indicate, unambiguously, our definition of what we consider to be a published scientific work.
",metaTitle:"Prior Publication Policy",metaDescription:"Prior Publication Policy",metaKeywords:null,canonicalURL:"/page/prior-publication-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"A significant number of working papers, early drafts, and similar work in progress are openly shared online between members of the scientific community. It has become common to announce one’s own research on a personal website or a blog to gather comments and suggestions from other researchers. Such works and online postings are, indeed, published in the sense that they are made publicly available. However, this does not mean that if submitted for publication by IntechOpen they are not original works. We differentiate between reviewed and non-reviewed works when determining whether a work is original and has been published in a scholarly sense or not.
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\\n\\nIn order to facilitate the tracking of a manuscript’s publishing history and its development from its earliest draft to the manuscript submitted, we encourage Authors to disclose any instances of a manuscript’s prior publication, whether it be through a conference presentation, a newspaper article, a working paper publicly available in a repository or a blog post.
\\n\\nA note to the Academic Editor containing detailed information about a submitted manuscript’s previous public availability is the preferred means of reporting prior publication. This helps us determine if there are any earlier versions of a manuscript that should be disclosed to our readers or if any of those earlier versions should be cited and listed in a manuscript’s references.
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\\n\\nAll submitted manuscripts originating from a previously published conference paper must contain at least 50% of new original content to be accepted for review and considered for publication.
\\n\\nAuthors are required to report any links their manuscript might have with their earlier conference papers and presentations in a note to the Academic Editor, as well as in the manuscript itself. Additionally, Authors should obtain any necessary permissions from the publisher of their conference paper if copyright transfer occurred during the publishing process. Failure to do so may prevent Us from publishing an otherwise worthy work.
\\n\\n2. NEWSPAPER & MAGAZINE ARTICLES
\\n\\nNewspaper and magazine articles usually do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense. Articles appearing in newspapers and magazines rarely possess the depth and structure characteristic of scholarly articles.
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\\n\\nAs with the conference papers and presentations, Authors should obtain any necessary permissions from the newspaper or magazine that published the work, and indicate that they have done so in a note to the External Editor.
\\n\\n3. GREY LITERATURE
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\\n\\nAlthough such papers are regularly made publicly available via personal websites and institutional repositories, their general purpose is to gather comments and feedback from Authors’ colleagues in order to further improve a manuscript intended for future publication.
\\n\\nWhen submitting their work, Authors are required to disclose the existence of any publicly available earlier drafts in a note to the Academic Editor. In cases where earlier drafts of the submitted version of the manuscript are publicly available, any overlap between the versions will generally not be considered an instance of self-plagiarism.
\\n\\n4. SOCIAL MEDIA, BLOG & MESSAGE BOARD POSTINGS
\\n\\nWe feel that social media, blogs and message boards are generally used with the same intention as grey literature, to formulate ideas for a manuscript and gather early feedback from like-minded researchers in order to improve a particular piece of work before submitting it for publication. Therefore, we do not consider such internet postings to be publication in the scholarly sense.
\\n\\nNevertheless, Authors are encouraged to disclose the existence of any internet postings in which they outline and describe their research or posted passages of their manuscripts in a note to the Academic Editor. Please note that we will not strictly enforce this request in the same way that we would instructions we consider to be part of our conditions of acceptance for publication. We understand that it may be difficult to keep track of all one’s internet postings in which the researcher´s current work might be mentioned.
\\n\\nIn cases where there is any overlap between the Author´s submitted manuscript and related internet postings, we will generally not consider it to be an instance of self-plagiarism. This also holds true for any co-Author as well.
\\n\\nFor more information on this policy please contact permissions@intechopen.com.
\\n\\nPolicy last updated: 2017-03-20
\\n"}]'},components:[{type:"htmlEditorComponent",content:'A significant number of working papers, early drafts, and similar work in progress are openly shared online between members of the scientific community. It has become common to announce one’s own research on a personal website or a blog to gather comments and suggestions from other researchers. Such works and online postings are, indeed, published in the sense that they are made publicly available. However, this does not mean that if submitted for publication by IntechOpen they are not original works. We differentiate between reviewed and non-reviewed works when determining whether a work is original and has been published in a scholarly sense or not.
\n\nThe significance of Peer Review cannot be overstated when it comes to defining, in our terms, what constitutes a published scientific work. Peer Review is widely considered to be the cornerstone of modern publishing processes and the key value-adding contribution to a scholarly manuscript that a publisher can make.
\n\nOther than the issue of originality, research misconduct is another major issue that all publishers have to address. IntechOpen’s Retraction & Correction Policy and various publication ethics guidelines identify both redundant publication and (self)plagiarism to fall within the definition of research misconduct, thus constituting grounds for rejection or the issue of a Retraction if the work has already been published.
\n\nIn order to facilitate the tracking of a manuscript’s publishing history and its development from its earliest draft to the manuscript submitted, we encourage Authors to disclose any instances of a manuscript’s prior publication, whether it be through a conference presentation, a newspaper article, a working paper publicly available in a repository or a blog post.
\n\nA note to the Academic Editor containing detailed information about a submitted manuscript’s previous public availability is the preferred means of reporting prior publication. This helps us determine if there are any earlier versions of a manuscript that should be disclosed to our readers or if any of those earlier versions should be cited and listed in a manuscript’s references.
\n\nSome basic information about the editorial treatment of different varieties of prior publication is laid out below:
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\n\nGiven that conference papers and presentations generally pass through some sort of peer or editorial review, we consider them to be published in the accepted scholarly sense, particularly if they are published as a part of conference proceedings.
\n\nAll submitted manuscripts originating from a previously published conference paper must contain at least 50% of new original content to be accepted for review and considered for publication.
\n\nAuthors are required to report any links their manuscript might have with their earlier conference papers and presentations in a note to the Academic Editor, as well as in the manuscript itself. Additionally, Authors should obtain any necessary permissions from the publisher of their conference paper if copyright transfer occurred during the publishing process. Failure to do so may prevent Us from publishing an otherwise worthy work.
\n\n2. NEWSPAPER & MAGAZINE ARTICLES
\n\nNewspaper and magazine articles usually do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense. Articles appearing in newspapers and magazines rarely possess the depth and structure characteristic of scholarly articles.
\n\nSubmitted manuscripts stemming from a previous newspaper or magazine article will be accepted for review and considered for publication. However, Authors are strongly advised to report any such publication in an accompanying note to the External Editor.
\n\nAs with the conference papers and presentations, Authors should obtain any necessary permissions from the newspaper or magazine that published the work, and indicate that they have done so in a note to the External Editor.
\n\n3. GREY LITERATURE
\n\nWhite papers, working papers, technical reports and all other forms of papers which fall within the scope of the ‘Luxembourg definition’ of grey literature do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense.
\n\nAlthough such papers are regularly made publicly available via personal websites and institutional repositories, their general purpose is to gather comments and feedback from Authors’ colleagues in order to further improve a manuscript intended for future publication.
\n\nWhen submitting their work, Authors are required to disclose the existence of any publicly available earlier drafts in a note to the Academic Editor. In cases where earlier drafts of the submitted version of the manuscript are publicly available, any overlap between the versions will generally not be considered an instance of self-plagiarism.
\n\n4. SOCIAL MEDIA, BLOG & MESSAGE BOARD POSTINGS
\n\nWe feel that social media, blogs and message boards are generally used with the same intention as grey literature, to formulate ideas for a manuscript and gather early feedback from like-minded researchers in order to improve a particular piece of work before submitting it for publication. Therefore, we do not consider such internet postings to be publication in the scholarly sense.
\n\nNevertheless, Authors are encouraged to disclose the existence of any internet postings in which they outline and describe their research or posted passages of their manuscripts in a note to the Academic Editor. Please note that we will not strictly enforce this request in the same way that we would instructions we consider to be part of our conditions of acceptance for publication. We understand that it may be difficult to keep track of all one’s internet postings in which the researcher´s current work might be mentioned.
\n\nIn cases where there is any overlap between the Author´s submitted manuscript and related internet postings, we will generally not consider it to be an instance of self-plagiarism. This also holds true for any co-Author as well.
\n\nFor more information on this policy please contact permissions@intechopen.com.
\n\nPolicy last updated: 2017-03-20
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Al-Bat’hi",authors:[{id:"174793",title:"Dr.",name:"Mohamad",middleName:null,surname:"Souad",slug:"mohamad-souad",fullName:"Mohamad Souad"}]},{id:"54226",title:"Localized Surface Plasmon Resonance for Optical Fiber-Sensing Applications",slug:"localized-surface-plasmon-resonance-for-optical-fiber-sensing-applications",totalDownloads:2265,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"It is well known that optical fiber sensors have attracted the attention of scientific community due to its intrinsic advantages, such as lightweight, small size, portability, remote sensing, immunity to electromagnetic interferences and the possibility of multiplexing several signals. This field has shown a dramatic growth thanks to the creation of sensitive thin films onto diverse optical fiber configurations. In this sense, a wide range of optical fiber devices have been successfully fabricated for monitoring biological, chemical, medical or physical parameters. In addition, the use of nanoparticles into the sensitive thin films has resulted in an enhancement in the response time, robustness or sensitivity in the optical devices, which is associated to the inherent properties of nanoparticles (high surface area ratio or porosity). Among all of them, the metallic nanoparticles are of great interest for sensing applications due to the presence of strong absorption bands in the visible and near-infrared regions, due to their localized surface plasmon resonances (LSPR). These optical resonances are due to the coupling of certain modes of the incident light to the collective oscillation of the conduction electrons of the metallic nanoparticles. The LSPR extinction bands are very useful for sensing applications as far as they can be affected by refractive index variations of the surrounding medium of the nanoparticles, and therefore, it is possible to create optical sensors with outstanding properties such as high sensitivity and optical self-reference. In this chapter, the attractive optical properties of metal nanostructures and their implementation into different optical fiber configuration for sensing or biosensing applications will be studied.",book:{id:"5721",slug:"nanoplasmonics-fundamentals-and-applications",title:"Nanoplasmonics",fullTitle:"Nanoplasmonics - Fundamentals and Applications"},signatures:"Pedro J. Rivero, Javier Goicoechea and Francisco J. Arregui",authors:[{id:"69816",title:"Dr.",name:"Javier",middleName:null,surname:"Goicoechea",slug:"javier-goicoechea",fullName:"Javier Goicoechea"},{id:"188796",title:"Dr.",name:"Pedro J.",middleName:null,surname:"Rivero",slug:"pedro-j.-rivero",fullName:"Pedro J. Rivero"},{id:"197277",title:"Dr.",name:"Francisco",middleName:null,surname:"Arregui",slug:"francisco-arregui",fullName:"Francisco Arregui"}]},{id:"25297",title:"Nanofabrication of Metal Oxide Patterns Using Self-Assembled Monolayers",slug:"nanofabrication-of-metal-oxide-patterns-using-self-assembled-monolayers",totalDownloads:3443,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"860",slug:"nanofabrication",title:"Nanofabrication",fullTitle:"Nanofabrication"},signatures:"Yoshitake Masuda",authors:[{id:"12385",title:"Dr.",name:"Yoshitake",middleName:null,surname:"Masuda",slug:"yoshitake-masuda",fullName:"Yoshitake Masuda"}]},{id:"77225",title:"Piezoelectricity and Its Applications",slug:"piezoelectricity-and-its-applications",totalDownloads:510,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The piezoelectric effect is extensively encountered in nature and many synthetic materials. Piezoelectric materials are capable of transforming mechanical strain and vibration energy into electrical energy. This property allows opportunities for implementing renewable and sustainable energy through power harvesting and self-sustained smart sensing in buildings. As the most common construction material, plain cement paste lacks satisfactory piezoelectricity and is not efficient at harvesting the electrical energy from the ambient vibrations of a building system. In recent years, many techniques have been proposed and applied to improve the piezoelectric capacity of cement-based composite, namely admixture incorporation and physical. The successful application of piezoelectric materials for sustainable building development not only relies on understanding the mechanism of the piezoelectric properties of various building components, but also the latest developments and implementations in the building industry. Therefore, this review systematically illustrates research efforts to develop new construction materials with high piezoelectricity and energy storage capacity. In addition, this article discusses the latest techniques for utilizing the piezoelectric materials in energy harvesters, sensors and actuators for various building systems. With advanced methods for improving the cementations piezoelectricity and applying the material piezoelectricity for different building functions, more renewable and sustainable building systems are anticipated.",book:{id:"10511",slug:"multifunctional-ferroelectric-materials",title:"Multifunctional Ferroelectric Materials",fullTitle:"Multifunctional Ferroelectric Materials"},signatures:"B. Chandra Sekhar, B. Dhanalakshmi, B. Srinivasa Rao, S. Ramesh, K. Venkata Prasad, P.S.V. Subba Rao and B. Parvatheeswara Rao",authors:[{id:"335022",title:"Dr.",name:"B. Chandra",middleName:null,surname:"Sekhar",slug:"b.-chandra-sekhar",fullName:"B. Chandra Sekhar"},{id:"422021",title:"Dr.",name:"B.",middleName:null,surname:"Dhanalakshmi",slug:"b.-dhanalakshmi",fullName:"B. Dhanalakshmi"},{id:"422022",title:"Dr.",name:"B.Srinivasa",middleName:null,surname:"Rao",slug:"b.srinivasa-rao",fullName:"B.Srinivasa Rao"},{id:"422023",title:"Dr.",name:"S.",middleName:null,surname:"Ramesh",slug:"s.-ramesh",fullName:"S. Ramesh"},{id:"422024",title:"Dr.",name:"K.Venkata",middleName:null,surname:"Prasad",slug:"k.venkata-prasad",fullName:"K.Venkata Prasad"},{id:"422025",title:"Dr.",name:"P.S.V",middleName:null,surname:"Subba Rao",slug:"p.s.v-subba-rao",fullName:"P.S.V Subba Rao"},{id:"422026",title:"Dr.",name:"B.Parvatheeswara",middleName:null,surname:"Rao",slug:"b.parvatheeswara-rao",fullName:"B.Parvatheeswara Rao"}]}],onlineFirstChaptersFilter:{topicId:"1169",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81438",title:"Research Progress of Ionic Thermoelectric Materials for Energy Harvesting",slug:"research-progress-of-ionic-thermoelectric-materials-for-energy-harvesting",totalDownloads:23,totalDimensionsCites:0,doi:"10.5772/intechopen.101771",abstract:"Thermoelectric material is a kind of functional material that can mutually convert heat energy and electric energy. It can convert low-grade heat energy (less than 130°C) into electric energy. Compared with traditional electronic thermoelectric materials, ionic thermoelectric materials have higher performance. The Seebeck coefficient can generate 2–3 orders of magnitude higher ionic thermoelectric potential than electronic thermoelectric materials, so it has good application prospects in small thermoelectric generators and solar power generation. According to the thermoelectric conversion mechanism, ionic thermoelectric materials can be divided into ionic thermoelectric materials based on the Soret effect and thermocouple effect. They are widely used in pyrogen batteries and ionic thermoelectric capacitors. The latest two types of ionic thermoelectric materials are in this article. The research progress is explained, and the problems and challenges of ionic thermoelectric materials and the future development direction are also put forward.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Jianwei Zhang, Ying Xiao, Bowei Lei, Gengyuan Liang and Wenshu Zhao"},{id:"77670",title:"Thermoelectric Elements with Negative Temperature Factor of Resistance",slug:"thermoelectric-elements-with-negative-temperature-factor-of-resistance",totalDownloads:71,totalDimensionsCites:0,doi:"10.5772/intechopen.98860",abstract:"The method of manufacturing of ceramic materials on the basis of ferrites of nickel and cobalt by synthesis and sintering in controllable regenerative atmosphere is presented. As the generator of regenerative atmosphere the method of conversion of carbonic gas is offered. Calculation of regenerative atmosphere for simultaneous sintering of ceramic ferrites of nickel and cobalt is carried out. It is offered, methods of the dilated nonequilibrium thermodynamics to view process of distribution of a charge and heat along a thermoelement branch. The model of a thermoelement taking into account various relaxation times of a charge and warmth is constructed.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Yuri Bokhan"},{id:"79236",title:"Processing Techniques with Heating Conditions for Multiferroic Systems of BiFeO3, BaTiO3, PbTiO3, CaTiO3 Thin Films",slug:"processing-techniques-with-heating-conditions-for-multiferroic-systems-of-bifeo3-batio3-pbtio3-catio",totalDownloads:96,totalDimensionsCites:0,doi:"10.5772/intechopen.101122",abstract:"In this chapter, we have report a list of synthesis methods (including both synthesis steps & heating conditions) used for thin film fabrication of perovskite ABO3 (BiFeO3, BaTiO3, PbTiO3 and CaTiO3) based multiferroics (in both single-phase and composite materials). The processing of high quality multiferroic thin film have some features like epitaxial strain, physical phenomenon at atomic-level, interfacial coupling parameters to enhance device performance. Since these multiferroic thin films have ME properties such as electrical (dielectric, magnetoelectric coefficient & MC) and magnetic (ferromagnetic, magnetic susceptibility etc.) are heat sensitive, i.e. ME response at low as well as higher temperature might to enhance the device performance respect with long range ordering. The magnetoelectric coupling between ferromagnetism and ferroelectricity in multiferroic becomes suitable in the application of spintronics, memory and logic devices, and microelectronic memory or piezoelectric devices. In comparison with bulk multiferroic, the fabrication of multiferroic thin film with different structural geometries on substrate has reducible clamping effect. A brief procedure for multiferroic thin film fabrication in terms of their thermal conditions (temperature for film processing and annealing for crystallization) are described. Each synthesis methods have its own characteristic phenomenon in terms of film thickness, defects formation, crack free film, density, chip size, easier steps and availability etc. been described. A brief study towards phase structure and ME coupling for each multiferroic system of BiFeO3, BaTiO3, PbTiO3 and CaTiO3 is shown.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Kuldeep Chand Verma and Manpreet Singh"},{id:"78034",title:"Quantum Physical Interpretation of Thermoelectric Properties of Ruthenate Pyrochlores",slug:"quantum-physical-interpretation-of-thermoelectric-properties-of-ruthenate-pyrochlores",totalDownloads:74,totalDimensionsCites:0,doi:"10.5772/intechopen.99260",abstract:"Lead- and lead-yttrium ruthenate pyrochlores were synthesized and investigated for Seebeck coefficients, electrical- and thermal conductivity. Compounds A2B2O6.5+z with 0 ≤ z < 0.5 were defect pyrochlores and p-type conductors. The thermoelectric data were analyzed using quantum physical models to identify scattering mechanisms underlying electrical (σ) and thermal conductivity (κ) and to understand the temperature dependence of the Seebeck effect (S). In the metal-like lead ruthenates with different Pb:Ru ratios, σ (T) and the electronic thermal conductivity κe (T) were governed by ‘electron impurity scattering’, the lattice thermal conductivity κL (T) by the 3-phonon resistive process (Umklapp scattering). In the lead-yttrium ruthenate solid solutions (Pb(2-x)YxRu2O(6.5±z)), a metal–insulator transition occurred at 0.2 moles of yttrium. On the metallic side (<0.2 moles Y) ‘electron impurity scattering’ prevailed. On the semiconductor/insulator side between x = 0.2 and x = 1.0 several mechanisms were equally likely. At x > 1.5 the Mott Variable Range Hopping mechanism was active. S (T) was discussed for Pb-Y-Ru pyrochlores in terms of the effect of minority carrier excitation at lower- and a broadening of the Fermi distribution at higher temperatures. The figures of merit of all of these pyrochlores were still small (≤7.3 × 10−3).",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Sepideh Akhbarifar"},{id:"77635",title:"Optimization of Thermoelectric Properties Based on Rashba Spin Splitting",slug:"optimization-of-thermoelectric-properties-based-on-rashba-spin-splitting",totalDownloads:124,totalDimensionsCites:0,doi:"10.5772/intechopen.98788",abstract:"In recent years, the application of thermoelectricity has become more and more widespread. Thermoelectric materials provide a simple and environmentally friendly solution for the direct conversion of heat to electricity. The development of higher performance thermoelectric materials and their performance optimization have become more important. Generally, to improve the ZT value, electrical conductivity, Seebeck coefficient and thermal conductivity must be globally optimized as a whole object. However, due to the strong coupling among ZT parameters in many cases, it is very challenging to break the bottleneck of ZT optimization currently. Beyond the traditional optimization methods (such as inducing defects, varying temperature), the Rashba effect is expected to effectively increase the S2σ and decrease the κ, thus enhancing thermoelectric performance, which provides a new strategy to develop new-generation thermoelectric materials. Although the Rashba effect has great potential in enhancing thermoelectric performance, the underlying mechanism of Rashba-type thermoelectric materials needs further research. In addition, how to introduce Rashba spin splitting into current thermoelectric materials is also of great significance to the optimization of thermoelectricity.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Zhenzhen Qin"},{id:"75364",title:"Challenges in Improving Performance of Oxide Thermoelectrics Using Defect Engineering",slug:"challenges-in-improving-performance-of-oxide-thermoelectrics-using-defect-engineering",totalDownloads:214,totalDimensionsCites:0,doi:"10.5772/intechopen.96278",abstract:"Oxide thermoelectric materials are considered promising for high-temperature thermoelectric applications in terms of low cost, temperature stability, reversible reaction, and so on. Oxide materials have been intensively studied to suppress the defects and electronic charge carriers for many electronic device applications, but the studies with a high concentration of defects are limited. It desires to improve thermoelectric performance by enhancing its charge transport and lowering its lattice thermal conductivity. For this purpose, here, we modified the stoichiometry of cation and anion vacancies in two different systems to regulate the carrier concentration and explored their thermoelectric properties. Both cation and anion vacancies act as a donor of charge carriers and act as phonon scattering centers, decoupling the electrical conductivity and thermal conductivity.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Jamil Ur Rahman, Gul Rahman and Soonil Lee"}],onlineFirstChaptersTotal:6},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188",scope:"This series will provide a comprehensive overview of recent research trends in various Infectious Diseases (as per the most recent Baltimore classification). Topics will include general overviews of infections, immunopathology, diagnosis, treatment, epidemiology, etiology, and current clinical recommendations for managing infectious diseases. Ongoing issues, recent advances, and future diagnostic approaches and therapeutic strategies will also be discussed. This book series will focus on various aspects and properties of infectious diseases whose deep understanding is essential for safeguarding the human race from losing resources and economies due to pathogens.",coverUrl:"https://cdn.intechopen.com/series/covers/6.jpg",latestPublicationDate:"May 19th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:13,editor:{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"3",title:"Bacterial Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/3.jpg",isOpenForSubmission:!1,editor:null,editorTwo:null,editorThree:null},{id:"4",title:"Fungal Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",isOpenForSubmission:!0,editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",slug:"yuping-ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",biography:"Dr. Yuping Ran, Professor, Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China. Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. Vice-chief of the editorial board of Chinses Journal of Mycology, China. Board Member and Chair of Mycology Group of Chinese Society of Dermatology.",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null},{id:"5",title:"Parasitic Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",isOpenForSubmission:!0,editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",slug:"amidou-samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",biography:"Dr. Amidou Samie is an Associate Professor of Microbiology at the University of Venda, in South Africa, where he graduated for his PhD in May 2008. He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. He is currently a rated researcher by the National Research Foundation of South Africa at category C2. He has published widely in the field of infectious diseases and has overseen several MSc’s and PhDs. His research activities mostly cover topics on infectious diseases from epidemiology to control. His particular interest lies in the study of intestinal protozoan parasites and opportunistic infections among HIV patients as well as the potential impact of childhood diarrhoea on growth and child development. He also conducts research on water-borne diseases and water quality and is involved in the evaluation of point-of-use water treatment technologies using silver and copper nanoparticles in collaboration with the University of Virginia, USA. He also studies the use of medicinal plants for the control of infectious diseases as well as antimicrobial drug resistance.",institutionString:null,institution:{name:"University of Venda",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},{id:"6",title:"Viral Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",isOpenForSubmission:!0,editor:{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. 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