\r\n\tGeothermal energy is recognized as a potential renewable energy source, immense and practically inexhaustible, with a solid technological maturity, clean, versatile, and useful to generate electricity, among other multiple applications. However, as in any transformation process, environmental and social impacts cannot be excluded.
\r\n
\r\n\tThis book will compile scientific research from geothermal areas where environmental and social issues have been successfully addressed as an example of social, environmental, and economic equilibrium. Based on participatory monitoring as a strategy for social acceptance or corporate responsibility from a deep-rooted environmental ethic that has become a social commitment. This natural resource is very complex therefore, environmental and social knowledge and experience are of great importance for its further sustainable development.
",isbn:"978-1-80356-999-4",printIsbn:"978-1-80356-998-7",pdfIsbn:"978-1-83880-282-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"339e74c3bcb3c7725a830d8b41278ca1",bookSignature:"D.Sc. Zayre Ivonne González Acevedo and Dr. Marco Antonio García Zarate",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11933.jpg",keywords:"Engineering Developments, Gas Filters, Reinjection, Cascade Uses, Environmental Monitoring, Greenfield, Brownfield, Environmental Indicators, Environmental Impact Assessment, Environment and Social Acceptance, Social Engagement, Corporate Social Responsibility",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 12th 2022",dateEndSecondStepPublish:"June 21st 2022",dateEndThirdStepPublish:"August 20th 2022",dateEndFourthStepPublish:"November 8th 2022",dateEndFifthStepPublish:"January 7th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"5 days",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Pioneer researcher in the analysis of the environmental, social, and economic impact of Mexican geothermal zones, with more than 15 years of experience, and awarded her Ph.D. degree from the University of Heidelberg.",coeditorOneBiosketch:"A researcher in the analysis of the total environment and its impact on society, with more than 40 years of experience in the field and awarded his Ph.D. degree from the Autonomous University of Baja, California.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"260177",title:"D.Sc.",name:"Zayre Ivonne",middleName:null,surname:"González Acevedo",slug:"zayre-ivonne-gonzalez-acevedo",fullName:"Zayre Ivonne González Acevedo",profilePictureURL:"https://mts.intechopen.com/storage/users/260177/images/system/260177.jpg",biography:"Chemical Engineer on Environment (Dec 98), Technological Institute of Toluca, Mex. Chemical Engineer Master of Process Integration (Sep 02), University of Guanajuato. Gto. Mex. Dr.rer.nat. magna cum laude Environmental Geochemistry (July 06), University of Heidelberg, BW, Germany. Sabbatical Stay (Sept 19 - 20), Department of Renewable Resources, University of Alberta, Canada. \r\nResearcher in the Department of Environmental Studies. National Institute of Nuclear Research, Mex. (Oct 07-Dec 11). Researcher Geology Department, Center of Scientific Research and High Education of Ensenada, Baja California (Jan 12 up today). \r\nResponsible Work Package 9, “Environmental, Social and Economic Impacts of Enhanced and Super-Hot Geothermal Systems” in the GEMex project, “International Cooperation in Research and Development between Mexico and the European Union in Geothermal Energy”. Responsible specific project 25, “Sustainable Development and Environmental Impact Assessment of three Geothermal Exploration Zones with Exploitation Potential in Mexico”.",institutionString:"Center for Scientific Research and Higher Education at Ensenada",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Center for Scientific Research and Higher Education at Ensenada",institutionURL:null,country:{name:"Mexico"}}}],coeditorOne:{id:"260179",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"García Zarate",slug:"marco-antonio-garcia-zarate",fullName:"Marco Antonio García Zarate",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRXp9QAG/Profile_Picture_2022-04-01T07:16:47.jpg",biography:'Course of "Technical Specialization in Optical Laboratorian" at the Applied Physics Department of CICESE, with a scholarship from CONACYT from July 1980 to July 1981. 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\n
1. Introduction
\n
Tuberculosis is a contagious disease and constitutes a global public health problem. Currently, 22 countries are heavily affected by the disease, accounting for about 80% of all cases, according to data from the World Health Organization [1] . To combat the disease, measures and strategies concerning TB treatment and ways of dealing with the patient have been conceived and disseminated by the World Health Organization (WHO), which advises countries to adhere to it.
\n
The observation and problematization of the discourse regarding these measures and strategies, as well as the relationship between the professional health subject (doctor, nurse, “clinician”) and the subject of TB, led us to construct the assumption that such measures and strategies work as “discourses on” the illness and the sick, contributing to the establishment of the “truth discourses” [2] about the illness and the sick. From this assumption, we seek to understand how the tuberculosis patient is discursive in the current medical discourse.
\n
Our theoretical and methodological foundation is based on the contributions coming from the philosophers Michel Foucault of Discourse Analysis of French matrix, a theoretical field that works not only with the structure but also with the language event.
\n
\n
\n
2. Theoretical foundation
\n
In the Collège de France, in his lecture on the History of Thought Systems, Foucault developed, through his archeological and genealogical methods, critical reflections on how the relations between knowledge and power are historically intertwined. The French philosopher focused historically, above all, on the transition from the classical to modern times. The emphasis on this period, which marks the passage from the Enlightenment to the nineteenth century, represented the period of the rise of Science which, under the positivist and empiricist methodological presuppositions, imposed itself institutionally as a producer of truths. Knowledge must now be provable in order to be recognized, and it must possess an object that can be observed, tested, and analyzed [3, 4, 5].
\n
At the end of the nineteenth century, we can mark the birth of modern medicine by the increase in value of medical knowledge, known as “biopolitical strategy” [4]. According to theorists, with the advent of capitalism, medicine gains a new status, as the body is seen as a force of production. Knowledge is, therefore, a domain where the subject is necessarily situated and dependent, and in this sense, for example, the knowledge of clinical medicine defines for the subject of medical discourse all the functions of observation, interrogation, deciphering, recording, and decision [3].
\n
In the book Birth of the Clinic, Foucault [4] conducted an archeological study of Western medical knowledge, seeking to understand the anatomical-clinical rationality that permeated the consolidation of medical knowledge in modernity, where the main investigative object is the disease or sick person [4].
\n
The philosopher describes the modifications and evolution of classical medicine until the formation of modern medicine. In the medicine of the species, the diseases were classified in species and considered entities without any connection with the body. A disease would happen if and when one of its qualities had affinities with the human body. With the emergence of disease classification medicine, medical practice was carried out according to the visible characteristics of the disease, based on a perception.
\n
Foucault’s [4] studies allow us to see how medical knowledge supports a more refined control of the individual in the new political rationality that is configured, from the nineteenth century, with the main objective being the subjection of the human being. Instituted as knowledge, medicine, through its discourse, gives a configuration to its practice, constituting the so-called “subject-of-illness” [6], which, in turn, assures the hegemony of medical knowledge. From modernity, then, there is a proliferation of fields of truth about what is the human body, which is focused on the most diverse emerging knowledge: medicine, biology, anthropology, social sciences, economics, demography, psychiatry, law, psychology, hygiene, politics, and others. In this context, the body undergoes two transforming displacements of its disposition in the field of discourses. On the one hand, it was from modernity that the body obtained depth status to be discursively searched, defined, explored, so that the tridimensionality of bodies becomes validated as a context that can be epistemically subject to research [7].
\n
It should be noted that in the light of Nietzsche studies, Foucault [4] states that truth cannot be understood as unique, fixed, and stable, but as truths that are constantly constructed and postulated moments, in given places. So if there are choices, the truth can no longer be one. Every speech is seen functioning as regimes of truth. Truth is, in a circular way, linked to systems of power, which produce and support it, and is also related to the effects of power that it induces and reproduces. We emphasize that the relations that are established between the subjects and the discourses are always inevitably relations of power that circulate and are disseminated within their meshes and plots.
\n
As highlighted, we are also based on the contributions of the Discourse Analysis of pecheuxtiana matrix. Thus, we understand discourse as the effect of meanings between sociohistorically determined interlocutors [8, 9, 10]. We also point out, based on Pêcheux [10], that we understand that the subject is spoken by both the ideology and the unconscious. We remember that the discourse is crossed by other discourses, by external voices that constitute it.
\n
Another important concept is that of conditions of production, which comprise the subjects, the situation, and the memory. In the restricted context, it involves the circumstances of the enunciation and the immediate context, and, therefore, in a broad sense, includes the sociohistorical and ideological context [11].
\n
The notion of ideological formation, in turn, serves to characterize an element susceptible of intervening as a force of confrontation with other forces in the ideological conjuncture characteristic of a social formation at a given moment. Each ideological formation constitutes a complex set of attitudes and representations that are neither individual nor universal but relate more or less directly to class positions in conflict with one another [8, 9].
\n
\n
\n
3. Methodological aspects: some notes about the constitution of the corpus
\n
Our corpus consists of cutouts of semistructured interviews conducted in 2014, with 15 health professionals who, at that time, occupied the position of “coordinator” and “clinical” subjects, directly responsible for patient observation in the drug consumption process for the cure of tuberculosis (TB). These professionals were part of the National Tuberculosis Control Program (PNCT) in Mozambique, Africa.
\n
It should be mentioned that the interviews were granted after completing all the bureaucratic steps required by the National Bioethics Commission of Mozambique. The interviews enabled us to construct a vast archive, understood here as field of pertinent and appropriate documents on a given issue [8].
\n
It is pertinent to point out that the notion of discursive clipping was formulated by Orlandi [12] to distinguish the gesture of the linguist, which segments the phrase, from the gesture of the discourse analyst who, by cutting a discursive sequence, also cuts an inseparable portion of language and situation. We can then understand what the author proposes: cut as a discursive unit [8].
\n
Another important point to emphasize is that the methodological emphasis is constituted in the relation between interdiscourse and intradiscourse. The intradiscourse refers to the linearity of saying; it is the thread of speech, according to Pêcheux [10]. The interdiscourse, in turn, refers to the complex network of discursive formations in which all say is inserted. We recall interdiscourse as a region of encounters and confrontations of meanings [13]. Observation and analysis of interdiscourse allow us to understand the functioning of discourse, the senses (re)formulated by the subjects and their relation to ideology.
\n
It should also be noted that in the period corresponding to the second half of 2014, we analyzed the raw material, that is, all the interviews we performed and the production conditions in which they were produced. From this material, we selected numerous discursive sequences of reference, SDR [14], which constituted the cutbacks. Some (five) of them were chosen for further analysis, which will be presented.
\n
We cannot fail to mention that we use the indecision paradigm, as proposed by Ginzburg [15], to search for the linguistic-discursive clues that have been examined by us, allowing us to delineate the discursive regularities of the subject’s discourse, the discursive formations in, and their respective ideological formations.
\n
Finally, we emphasize that in our analyses, we try to cross the opacity of the text, seeking to make explicit how the symbolic object produces senses, considering that the meaning can always be other.
\n
Continuing, let us focus and venture through the paths of discourse.
\n
\n
\n
4. Discursive analyses seeking to look beyond evidence of meaning
\n
\n
4.1. Clipping #1
\n
“The patient with suspected TB is observed in a normal consultation, he is asked for the Koch Bacillus (BK) exam, when the BK is positive the patient is accompanied to the PNCT sector. After starting treatment in the intensive phase, this patient is followed daily or depending on where he/she is accompanied directly to the place of the health unit until the end of the treatment” (Subject Coordinator and Clinical).
\n
\n
\n
4.2. Clipping #2
\n
“We have our volunteers who help us in the community. They are looking for coughing patients and delivering sprinklers. Bring it here and submit it for analysis in the laboratory” (Clinical Subject).
\n
\n
\n
4.3. Clipping #3
\n
“(…) they diagnose the patient, umm … he asked for the bacilloscopy in the screening, the patient is what he is, and the clinician directs the PNCT sector” (Subject Coordinator).
\n
Initially, we observed that the subjects affected by the bacillus are not identified by name, surname, cognomen, surname, or initials. They are referred to as “the patient,” which allows us to think about the enrollment of health professionals in discursive formations in which stigmatizations about the disease are prevalent, for example, TB would be associated with poor behaviors such as prostitution, alcohol consumption and other drugs, lack of hygiene, and poverty [16, 17].
\n
The medical speech strongly marks the three clippings above. We recall, based on Foucault [4], that this discourse has the power to “fabricate” the disease and its treatment and also to silence the voice of the subject who lives the experience of TB. Under these conditions of production, it can be thought of as authoritarian discourse.
\n
The discursive sequences: the patient is observed, he/she is asked, and he/she is accompanied to the laboratory. We submit the analysis to the laboratory and ask for the bacilloscopy. It indicates that the health professionals occupy the position of subjects with specific knowledge, which would assure them places hierarchically superior, in relation to the subjects affected by TB. Based on institutionally recognized and socially valued positions (coordinator, clinician), specific knowledge produces meaningful effects of “speeches of truth” [2, 3], being imagined and treated by patients who suffer from TB as speeches irrefutable, almost definitive, as we show in our doctoral thesis [17].
\n
We wish to emphasize the aspect of medical tutelage, which, if on the one hand, gives supposed assistance, in the form of care, examinations, prescriptions, examination requisitions, on the other hand, demands obedience, understood as “natural,” in a society where there is a division between those who rule and those who obey, as is the case with Mozambican women. Medical discourse enjoys both the prerogative of including or excluding those who would be under its tutelage and of charging and reinforcing obedience on the part of the subject who, under these conditions of production, becomes susceptible of being “subject-of-illness.” The actions of observing, asking, accompanying, submitting, and analyzing, under these conditions of production, allow us to think that health professionals are inscribed in discursive formations that place the patient in the position of subject that must obey and submit to what is proposed or offered. The quote below corroborates our argument. The movement toward a relationship of domination on the part of the therapist on the patient is more common in the clinical practice of traditional bias, directly linked to the pedagogical medical discourse, which the therapist intends to have as knowledge and the patient submits to the clinical treatment, or this nightmare establishes well-defined relations of domination with well-defined and unchanging hierarchical roles in principles [18].
\n
What we have discussed above refers to Foucault [3], especially his analyses and discussions about power knowledge. The philosopher shows us that power is not exercised without knowing, just as it is not possible that knowledge does not engender power; one produces the other. The philosopher also postulates that power functions and is exercised in a network, that is, it is never specifically located in this or that place, here or there. Power, as thought by the author, is relational in character, being exercised and not possessed [3].
\n
Continuing, we would like to focus on the discursive sequence of clipping number 1, which refers to the recommendation of clinical tests to the subjects supposedly infected: you are asked for the Koch Bacillus (BK). The examination, here thought as a power device, allows qualifying, evidencing, controlling, and dictating what should or can be done by the sick subject. As Foucault [5] teaches us, the examination is at the center of the processes that constitute the individual as an effect and object of power.
\n
In order to increase the present analysis, we highlight the criticisms of the French philosopher, author of Microphysics of Power [3] and “Vigiar e Punir” [5], the disease and patient are thought and treated as objects that deserve only the subjection of medication and the patient is not seen as someone capable of making decision or interfering in the treatment process [4]. In the space of the clinic, where bodies and glances intersect, the knowledge of suffering—allotted in the subjectivity of symptoms—is inserted in a reductive and objectifying discourse. Under the sovereign power of the empirical eye of medical science, one has the space of open experience, only to the evidence of visible contents. What creates the possibility of a clinical experience is precisely the application of a look at the disease that gives it objectivity. There is always in the sick body a concrete a priori, which can be unveiled, in Foucault’s words: clinical experience—from the concrete individual to the language of rationality—was taken as a simple, looking under the body [19].
\n
Patient and disease control is not the exclusive exercise of health professionals, but it also covers the family institution, as we will show in the next section.
\n
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4.4. Clipping #4
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“We involve family members; the family members control the patient. First, if the clinical picture of the patient is not serious, we make a pact with the family and inform them about the care they take with the patient and help them to provide it and this motivates the patient to take the medication until the end” (Subject Coordinator).
\n
We observe that the pedagogical and disciplinary action extends to those who occupy the positions of subject “members of the family,” who would be responsible for the patient. In this case, the family may constitute an “extension” of hospital power to the patient. According to Gonzales [20], for effective TB control, the participation and flexibility of the medical and family teams is necessary, in the follow-up of the patients, and supervision can be done at home or even in the workplace. Mobilized and authorized by hospital teams, relatives can also exercise control over the patient, who almost always enters into discursive formations marked by submission and belief in medical discourse.
\n
The discursive sequence emphasized brings linguistic-discursive indications that allow us to say that, in this case, the subject-patient position is subject to the dictates of hospital and family institutions: we make a pact with the family. The signifier “pact” instigates us to think of a reproductive scheme, that is, the family reproduces medical discourses and actions, from a discursive memory. The family, conceived as an institution, inscribes itself in discursive formations that make it believe that its function is to help to make docile, useful, disciplined, to cure TB patients.
\n
In these conditions of production, we can say that both sick subjects and family members occupy the place of “good subject,” performing their roles in the form of “freely consented” [10]. We point out that in this modality, that of “good subject,” the interdiscourse determines the discursive formation with which the subject identifies himself/herself and this subject blindly suffers this determination [10].
\n
\n
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4.5. Clipping #5
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“(…) TB is still a neglected disease unfortunately people only realize that the disease is already taking care of it when it is already at an advanced stage. And I think we still need to spread the word about TB a lot. We need to encourage people that the little cough he has, the first thing he should think about is exactly TB, and that this treatment that is given to the patient really works and he heals, but for that he should follow up and one of the strategies is the Short-Term Observed Direction Treatment Strategy that has given optimum results, people take the medicine as it should be” (Subject Coordinator).
\n
When we look at this clipping, we are going to stick to the discursive sequence “people only realize that the disease is already taking care of it when it is already at an advanced stage.” In our view, the realization of the disease when it is in an advanced state can be interpreted as a gesture of resistance from the subject-patient to accept that he is suffering from tuberculosis. As pointed out, the signifier tuberculosis refers to networks of meanings according to which being affected by the disease means “being poor,” “prostitute,” “convict,” among other senses. Resisting disease and the condition of the patient seems to be a resource that is worth the subject not to submit to institutional discourses.
\n
It is pertinent to point out that Foucault’s notion that power is found in social relations, in the form of relations of force, presupposes resistance to every form and exercise of power. If there is a relation of power, there is a possibility of resistance, Foucault teaches us. The perception of oneself as subject-of-illness causes changes in the daily life, in a particular way, and in the life and history of the subject, in a wide way. While he perceives himself as “normal man,” he feels inserted in society, being able to work, study, produce, and act. Feeling in good health is feeling more than normal, that is, not only adapted to the environment and the requirements, but also normative, capable of following new norms of life [21].
\n
On the other hand, “feeling bad” breaks with the normativity, requiring diagnosis, clinical, laboratory, and other tests that can translate its meaning (s). Admitting “feeling bad” brings pain and psychic suffering to the subject: “Why did this happen to me so soon?” leading him, in some cases, to deny the disease [20]. The subject-doctor position is the verdict, and its supposed knowledge lies in the promise of healing and/or postponing death.
\n
Our arguments can be based on the contributions of Pêcheux [10] regarding the “bad subject.” We can say that the subject, in a certain way, is counteridentified with the predetermined dictates by the health services where prescriptive functions are exercised: one of the first thing to think about is exactly in tuberculosis and he should follow up.
\n
The discourse of the “bad subject” is that in which the subject of enunciation turns against the universal subject, through the taking of a position which, in this case, consists of a separation that reflects distancing, doubt, questioning, contestation, or revolt in relation to what the universal subject gives to think. In this case, then, the bad subject is counteridentified by the discursive formation imposed on him by “interdiscourse” as an external determination of his subjective interiority, which produces philosophical and political forms of discourse-against (i.e., “counter-discourse”) [10].
\n
Whether it occupies the position of the subject that fully identifies itself with the discursive formation in which one becomes aware, or occupy the position of the one who is counteridentified, the subject continues to be discoursed as “the patient,” the “tuberculous,” “the one who must obey and follow” what is recommended to him (imposed) by the medical discourse, whose specific knowledge, prestige, and condition of irrefutability assure him legitimacy and power.
\n
According to our hypothesis, this discursivization contributes to the construction of a discursive memory whose senses can negatively affect the identity of the subject. It should be remembered that the senses become enunciable and readable by the action of discursive memory [14].
\n
Knowing that the term identity carries multiple meanings, we emphasize that here we use it in the sense of identification, because we understand that identities can function as points of identification and attachment.
\n
According to Hall [22], we can cite three types of identities: the Enlightenment, the Sociological, and the Postmodern. In the first, identity is centered, unified, and endowed with reason. It consists of an inner core that is born with the subject and in it develops, although it remains essentially the same (identical) throughout its existence. In the second, the subjects and the cultural world in which they live are treated as unified and predictable. However, gradually, the subject, thought as having a unique and stable identity, is perceived as fragmented, composed not of a single but of several identities, sometimes contradictory and incoherent. Finally, in the third, the subject does not have a fixed or permanent identity, being conceived as a mobile celebration, formed and transformed continuously. It is an identity marked by heterogeneity and dispersion.
\n
From these considerations, we understand that identities are always fragmented and fractured; they are never singular but multiply constructed along discourses, practices, and positions that can cross and be antagonistic. They are subject to a radical historicization, constantly being in the process of change and transformation [22].
\n
We would like to emphasize that, given the fluidity of the identities emphasized by Hall [21] and the notion of discourse adopted here, that is, that all say is constitutively crossed by the discourse of the other, we will use the term identity in the sense of identification.
\n
To understand oneself as subject-patient of tuberculosis, makes the subject mainly occupy the place of being sick the one of the needs help from others, allows him to produce predominantly stereotyped senses, seeing himself as incapacitate to act upon himself about the disease [10, 22].
\n
\n
\n
\n
5. Final considerations: a few brief considerations
\n
Medical discourse, in particular the discourse of health professionals of those working with patients with TB, has different forms of control over the patient. One of the ways in which the exercise of power is effective is through specific, institutionalized, and legitimized knowledge. This knowledge circulating in the discourses on disease and the patient contribute to the formation of an interdiscourse in which the sick subject is spoken, interpreted, and watched but never listened to. These discourses focus only on what is visible, apparent, and “rational” in disease.
\n
We observed a reproductive pattern, that is, health professionals reproduce in their speeches words and forms not only of control of medical discourse but also of organs such as the WHO. Families, on the other hand, are called to collaborate with the treatment, reproducing words and devices of vigilance about the patient.
\n
Being discursive as “sick,” “tuberculous,” “carrier of disease” can contribute to the constitution of a discursive memory where stereotyped and negative senses predominate about the disease. When updated, in the words of the subjects, they can revere these senses, negatively influencing the constitution of their identity, once the senses produced become circulating and accepted, not only by the patients and professionals but also by the family and community as such.
\n
Reflecting on the discourses on tuberculosis, the sick and the constitution of their identity can contribute to the resignification of meanings and positions to be assumed by the subjects who could move from the subject-from-disease to the subject-from-healthy.
\n
\n\n',keywords:"tuberculosis, health system, discourse analysis, Mozambique",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/65347.pdf",chapterXML:"https://mts.intechopen.com/source/xml/65347.xml",downloadPdfUrl:"/chapter/pdf-download/65347",previewPdfUrl:"/chapter/pdf-preview/65347",totalDownloads:752,totalViews:175,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:13,impactScoreQuartile:1,hasAltmetrics:0,dateSubmitted:"July 28th 2018",dateReviewed:"October 7th 2018",datePrePublished:null,datePublished:"April 3rd 2019",dateFinished:"January 24th 2019",readingETA:"0",abstract:"Tuberculosis is one of the diseases that kills most in developing countries, especially in Mozambique, where there is a shortage of hospitals and health professionals and where the knowledge about the disease is centralized in the health professional and the patient is only the subject with the disease without the right to question or decide about you. Under these conditions of production, in the treatment process, speeches are produced, which signify and symbolize and classify the patient. The study aimed to understand how the discourse of tuberculosis is constituted in the current medical discourse. This is a qualitative study and uses the theoretical framework of French-speaking discourse analysis. The narratives of the subjects enrolled in the study bring statements that lead us to consider that the exercise of power over the patient is effective through the specific, institutionalized, and legitimized knowledge within the hospital.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/65347",risUrl:"/chapter/ris/65347",book:{id:"8632",slug:"advances-in-discourse-analysis"},signatures:"Fernando Mitano, João Miguel Fernandes, Filomena Elaine Assolini\nand Pedro Fredemir Palha",authors:[{id:"260900",title:"Ph.D.",name:"Fernando",middleName:null,surname:"Mitano",fullName:"Fernando Mitano",slug:"fernando-mitano",email:"piqinamita@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"269653",title:"Prof.",name:"Elaine",middleName:null,surname:"Paiva",fullName:"Elaine Paiva",slug:"elaine-paiva",email:"elainefdoc@ffclrp.usp.br",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"269654",title:"Prof.",name:"Pedro",middleName:null,surname:"Palha",fullName:"Pedro Palha",slug:"pedro-palha",email:"palha2012@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"271799",title:"MSc.",name:"Jão",middleName:null,surname:"Fernandes",fullName:"Jão Fernandes",slug:"jao-fernandes",email:"joao.fernandes@unilurio.ac.mz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Theoretical foundation",level:"1"},{id:"sec_3",title:"3. Methodological aspects: some notes about the constitution of the corpus",level:"1"},{id:"sec_4",title:"4. Discursive analyses seeking to look beyond evidence of meaning",level:"1"},{id:"sec_4_2",title:"4.1. Clipping #1",level:"2"},{id:"sec_5_2",title:"4.2. Clipping #2",level:"2"},{id:"sec_6_2",title:"4.3. Clipping #3",level:"2"},{id:"sec_7_2",title:"4.4. Clipping #4",level:"2"},{id:"sec_8_2",title:"4.5. Clipping #5",level:"2"},{id:"sec_10",title:"5. Final considerations: a few brief considerations",level:"1"}],chapterReferences:[{id:"B1",body:'World Health Organization. Tuberculosis Report. Genebra: World Health Organization; 2017. 147 p. Available from: http://www.who. int/tb/publications/global_report/ gtbr2017_main_text.pdf\n\n\n\n'},{id:"B2",body:'Foucault M. A ordem do discurso. São Paulo: Edições Loyola; 2000. 74 p\n'},{id:"B3",body:'Foucault M. Microfísica do poder. 28th ed. Rio de Janeiro: Paz e Terra; 2014. 431 p\n'},{id:"B4",body:'Foucault M. O nascimento da clínica. Tradução de Roberto Machado. Rio de Janeiro: Forense Universitária; 2011\n'},{id:"B5",body:'Foucault M. Vigiar e punir: nascimento da prisão. Tradução de Raquel Ramalhete. 42a ed. RJ: Vozes; 2014. 302 p\n'},{id:"B6",body:'Herzog R. A percepção de si como sujeito da doença. PHISYIS. Revista de Saúde coletiva. 1991;1(2):144-156\n'},{id:"B7",body:'Silveira F. Michel Foucault e a construção discursiva do corpo do sujeito moderno e sua relação com a Psicologia. Psicologia em estudo. 2008;13:733-742\n'},{id:"B8",body:'Pêcheux M. Análise automática do discurso. Tradução de Eni P. Orlandi. In: Gadet F, Hak T, editors. Por uma análise automática do discurso: uma introdução à obra de Michel Pêcheux. 2nd ed. Campinas: Unicamp; 1990. pp. 61-161\n'},{id:"B9",body:'Pêcheu M. Ler o arquivo hoje. In: Gestos de leitura: da história no discurso. 2nd ed. Campinas: Editora da UNICAMP; 1997. pp. 56-62\n'},{id:"B10",body:'Pêcheux M. Semântica e discurso: uma crítica à afirmação do óbvio. 4ª ed. Campinas: Unicamp; 1995. 287 p\n'},{id:"B11",body:'Orlandi EP. Análise do discurso: Princípios e procedimentos. 8ª ed. Campinas: Pontos; 2009. 100 p\n'},{id:"B12",body:'Orlandi EP. As formas do silêncio: no movimento dos sentidos. Campinas, Unicamp; 2007. 177 p\n'},{id:"B13",body:'Gregolin MR, Baronas R. Análise de Discurso: as materialidades do sentido. 3rd ed. São Carlos: Editora Clara Luz; 2007. 180 p\n'},{id:"B14",body:'Courtine JJ. Analyse du discours politique. In: Language. Vol. 62. Paris: Larouse; 1981. 127 p\n'},{id:"B15",body:'Ginzburg C. Mitos, emblemas, sinais: morfologia e histórico. São Paulo: Companhia das letras; 2012. 281 p\n'},{id:"B16",body:'Mitano F, Sicsú AN, Sousa LO, Silva LMC, Palha PF. Discourses of healthcare professionals about health surveillance actions for tuberculosis control. Revista da Escola de Enfermagem da U.S.P. 2017;51:e03213. DOI: 10.1590/S1980-220X2016018203213\n'},{id:"B17",body:'Mitano F, Sicsú AN, Lima MCRAD, Peruhype RC, Protti ST, Palha PF. Discourses on short-course therapy for tuberculosis control. Revista Brasileira de Enfermagem. 2017;70(1):120-125. DOI: 10.1590/0034-7167-2016-0463\n'},{id:"B18",body:'Barroni DPM, Cunha CS. Reflexão sobre a resistência na clínica a partir de Michel Foucault. Psicologia Ciência e Profissão. 2008;(4):682-695\n'},{id:"B19",body:'Foucault M. A verdade e as formas jurídicas. 2nd ed. Rio de Janeiro: Nau; 2001. 130 p\n'},{id:"B20",body:'Gonzales RIC, Monroe AA, Assis EG, Palha PF, Villa TCS, Netto AR. Desempenho de Serviços de saúde no domicílio para controle da tuberculose. Revista da Escola de Enfermagem da U.S.P. 2008;42(4):628-634\n'},{id:"B21",body:'Canguinhes G. O normal e o patológico. Rio de Janeiro: Forense Universitária; 1988. 120 p\n'},{id:"B22",body:'Hall S. A identidade cultural na pós-modernidade. 11th ed. Rio de Janeiro: DP&A; 2000. 102 p\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Fernando Mitano",address:"piqinamita@gmail.com",affiliation:'
Faculty of Health Science, Lúrio University, Nampula, Mozambique
'},{corresp:null,contributorFullName:"João Miguel Fernandes",address:null,affiliation:'
Faculty of Health Science, Lúrio University, Nampula, Mozambique
School of Nursing, University of São Paulo, Brazil
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1. Introduction
Cardiac transplantation is the gold standard therapy for end-stage heart failure. The perfection of surgical interventions, development of modern immunosuppressive therapies, and implementation of rigorous transplant care protocols have contributed to better outcomes over the last several years [1, 2]. However, cardiac transplantation is limited by the number of available donor hearts, primary graft dysfunction (PGD), rejection of the heart, as well as by the side effects caused by immunosuppression therapy [3]. Gene therapy is an advanced treatment intervention that can potentially bridge the gap to overcome these common post-transplantation complications. The success of commercially available gene therapy interventions, such as Zolgensma for spinal muscular atrophy and Luxturna for Leber congenital amaurosis, demonstrates that gene therapy provides a viable treatment option for people who would otherwise suffer from diseases that have traditionally been thought of as impossible to treat.
Gene therapy works by altering the genetic composition of cells to confer therapeutic protein or RNA expression to the target organ. To date, it has been commercially used to treat spinal muscular atrophy, Duchenne muscular dystrophy, and for various types of ocular disorders [4]. There are currently many gene therapy clinical trials underway and growing in number (clinicaltrials.gov). Gene therapy based interventions have been studied for various cardiovascular diseases, such as coronary artery disease (CAD), heart failure (HF), and myocardial ischemia (MI) [5]. However, no intervention has yet been able to attain robust or long-term transgene expression in the heart in clinical practice. One promising intervention for HF was the AAV1-SERCA2a therapeutic which was evaluated in human clinical trials (CUPID, AGENT-HF, SERCA-LVAD). The trials, unfortunately, failed to demonstrate that the intervention led to a statistically significant difference in the primary endpoint of time to recurrent HF and secondary endpoint of time to first terminal events [6, 7, 8].
The heart is a complex target for gene therapy interventions due to its location in the body, the mechanical force of blood flow, endothelial barriers, cellular barriers, and the body’s immune response [9]. A cardiac graft being treated prior to transplantation is uniquely amenable to gene therapy as most of these traditional barriers of gene delivery to the heart can be overcome. Through gene therapy, a cardiac allograft can be engineered to express selected therapeutic genes that could prevent the onset of post-transplantation complications and potentially minimize or eliminate the need for traditional systemic immunosuppression medications [10, 11]. Gene therapy for heart transplantation, though attractive, has not been translated clinically.
There are major challenges that need to be overcome for gene therapy to be able to be applied for cardiac transplantation. One of them is that, despite major advances in the understanding of transplant immunology, there remains an incomplete understanding of the mechanisms of both rejection and tolerance. This includes the understanding of the details of regulatory cytokine networks, MHC-antigen interactions during the rejection process, and a complete understanding of co-stimulatory factors and their functions [12]. Another challenge is that most current gene delivery mechanisms confer a transient, low level of gene expression [13]. With the current understanding of gene therapy in the context, it also is unclear what is the optimal dose of the therapeutic transgene needed to confer an appreciable clinical effect. However, recent investigations describe methods of robust and global gene delivery to cardiac grafts that offer promise to overcome this challenge. Similarly, viral vector delivery systems pose risks to the host and allograft via eliciting undesired immune reactions, off-target gene delivery, and genome integration. With the recent success and clinical adoption of ex vivo normothermic perfusion, the possibility of gene delivery that is isolated to the cardiac graft is feasible and promising for translation into clinical practice. Ex vivo normothermic perfusion also provides the optimal environment for viral vectors to be able to attach and enter cardiac cells for efficient transduction. With the advances that have been made to address these challenges, it will not be long before we witness the successful application of gene therapy to cardiac transplantation.
To achieve a successful gene therapy intervention for cardiac transplantation, several components need to be addressed: disease or indication and therapeutic target, use of an appropriate animal to test the therapeutic, selection of the vector for gene delivery, and method for vector delivery. Here we review select post-transplantation complications and potential targets where gene therapy can be implemented to prevent them. We will also review translational animal models that have been developed for investigating gene therapeutic targets. Finally, we will discuss the different viral and non-viral vectors that can be used for gene delivery, the selection of promoters, and the different modalities that have been investigated for the delivery of vectors to cardiac grafts.
2. Disease and therapeutic targets for cardiac transplantation
There are various insults that a cardiac graft experiences prior to, during, and after transplantation. Early damage to the cardiac graft can happen during the brain or cardiac death of the donor, organ procurement, organ preservation time, the implantation procedure, or as a result of reperfusion injury. These points of insult to the cardiac graft can trigger both innate and adaptive immune responses that result in injury. Common complications that occur following transplantation include primary graft dysfunction (PGD), coronary allograft vasculopathy (CAV), and rejection.
2.1 Primary graft dysfunction
PGD is a leading cause of early mortality post-transplantation [14]. The diagnosis of PGD occurs in the first 24 hours following heart transplantation. It presents as severe ventricular dysfunction of the cardiac graft in the immediate post-transplant period, resulting in low cardiac output and hypotension despite the presence of adequate filling pressures [15]. Either the left, right, or both ventricles can be involved, and the severity of the dysfunction can range from mild to moderate to severe depending on the extent of circulatory support that is needed to maintain hemodynamic stability [16].
Numerous causative factors, starting from donor death to weaning the heart from cardiopulmonary bypass in the recipient, have been identified that contribute to the cause of PGD [17]. These factors relate to ischemic and ischemic-reperfusion injury of the cardiac graft. Additionally, the onset of systemic inflammatory response syndrome and the development of vasoplegic syndrome in the recipient have also been identified as significant causes [18]. Finally, the use of extended criteria donors, such as donation after cardiac death (DCD), has also been identified as a significant risk factor for PGD [19].
The treatment of PGD is primarily through supportive care. It is typically initially managed with the use of inotropic support using catecholamines and phosphodiesterase inhibitors. The next escalation in care is typically the use of an intra-aortic balloon pump, followed by the initiation of advanced mechanical support using extracorporeal membranous oxygenation.
2.2 Cardiac allograft Vasculopathy
Cardiac allograft vasculopathy (CAV) is a major cause of late heart graft failure [20]. It is characterized by diffuse and concentric narrowing of large epicardial and small intramyocardial arteries due to intimal fibromuscular hyperplasia, atherosclerosis, and vasculitis. As a result, the transplant recipient develops pathological changes within the donor blood vessels leading to a spectrum of diseases ranging from MI to HF. CAV is often unable to be diagnosed by coronary angiography and requires intravascular ultrasound for diagnosis.
The main driver of CAV is believed to be the immune system of the host. The intimal thickening seen in CAV results from an accumulation of smooth muscle cells (SMC) accompanied by the infiltration of T cells and macrophages which further contribute to intimal expansion [21, 22]. Yet CAV lesions characteristically stop at the suture line between the donor and the recipient. The endothelial lining of the vessels remains intact in CAV lesions suggesting that SMC injury may result from sterile inflammation as is seen during cold and warm ischemia effects and ischemia–reperfusion injuries [23].
Current treatments are based on vascular risk factor management and the use of statins and mTOR inhibitors (sirolimus and everolimus) to reduce the development of the disease. Percutaneous revascularization is used to treat focal obstructive coronary stenosis but repeat revascularization rates are high due to restenosis and disease progression [24]. However, patients who go on to develop allograft dysfunction require re-transplantation [25, 26].
2.3 Rejection and immunosuppression
Cardiac allograft rejection is among the most common causes of death in heart transplant recipients [1]. Acute rejection is categorized into hyperacute rejection acute cellular rejection (ACR), and antibody mediated rejection (AMR). Currently, recipients undergo routine screening for rejection with endomyocardial biopsies obtained by a bioptome. Hyperacute rejection is due to the presence of preformed host antibodies against the graft and portends an inevitable immediate immune rejection resulting in death [27]. ACR and AMR take longer to manifest and are thus amenable to potential gene therapy intervention and we will focus our discussion on these forms of rejection. To prevent rejection of the cardiac allograft, patients are treated with systemic multidrug immunotherapies. Multidrug immunosuppressive regimens currently used in human transplant recipients are associated with an increased risk of malignancy and opportunistic infections, a metabolic syndrome characterized by insulin resistance and dyslipidemia, and drug-specific toxicity [11].
2.4 Potential targets for gene therapy
An understanding of the different insults that the cardiac graft experiences during the different steps of transplantation helps to identify potential targets for gene therapy for cardiac transplantation. The cardiac graft endothelium is vulnerable to ischemic reperfusion injury. In this setting, leukocytes adhere to the activated endothelium. The complement system becomes activated, neutrophils migrate into the cardiac graft, subsequently followed by natural killer cells and macrophage infiltration. These early non-specific inflammatory reactions are then followed by alloimmune reactions that result in massive graft infiltration by dendritic cells, T-cells, B-cells, and macrophages. Donor-derived dendritic cells leave the cardiac graft and migrate to recipient lymph nodes and the spleen. There they present donor antigen to recipient T cells directly and trigger acute rejection.
2.4.1 Inflammatory targets
Many candidate genes that interfere with one of these inflammatory mechanisms have been investigated in the context of cardiac transplantation. One such gene is endothelial nitric oxide synthase (eNOS). eNOS produces nitric oxide which is vasoprotective. Delivery of eNOS into the donor heart attenuated ischemic reperfusion injury, leukocyte infiltration, and cardiac graft rejection in a rabbit model [28]. Similarly, superoxide dismutase (SOD) gene delivery into a donor heart attenuated ischemic reperfusion injury after organ preservation and transplantation in a rabbit model [29]. SOD functions as a free radical scavenger that neutralizes reactive oxygen species generated during ischemic reperfusion injuries. Another target, nuclear factor-kappa B (NFkB), is a transcription factor involved in the up-regulation of pro-inflammatory gene products. One possible therapeutic intervention is to block NFkB in endothelial cells to attenuate ischemia–reperfusion injury in the myocardium. Sakaguchi et al. blocked NFkB by using double-stranded oligodeoxynucleotides with a specific affinity for NFkB (NFkB decoy group) to transduce rat hearts utilizing HVJ envelope [30]. The hearts were then preserved for 16 hours in hypothermic preservation solution before being heterotopically transplanted into a recipient rat. What they found is that the intervention attenuated ischemic reperfusion injury after prolonged heart preservation in hypothermic solution. Another protein that is up-regulated during inflammation and serves as a potential target for gene therapy is heat shock protein-70 (HSP-70). It has an essential role in protein folding and translocation and as chaperones for intracellular proteins. HSP-70 has particularly been shown to be associated with protection against ischemia–reperfusion injury. Jayakumar et al. infused rat hearts using 1 mL of the gene vector solution then incubated the hearts on ice for 10 minutes before heterotopically transplanting them into a recipient rat [31]. 4 days after the intervention, the hearts were perfused on a Langendorff apparatus for 45 minutes followed by reperfusion for 1 hour. They found that post-ischemic recovery of mechanical function was greater in the treatment arm versus control, recovery of coronary flow was greater as well. The conclusion was that HSP-70 gene transduction protects both the mechanical and endothelial function of the cardiac graft.
2.4.2 Rejection targets
The most direct and immediate barrier to the success of cardiac transplantation is the recipient immune response. Currently, the most effective clinical therapy is lifetime immunosuppressive therapy. Knowledge about the immune response in transplantation has grown tremendously in recent years such that gene therapy can be used to intervene on different targets of the immune response. Both cell and antibody mediated effector mechanisms are responsible for acute rejection [32]. A strategy to protect the cardiac graft from recipient immune responses is through the delivery of genes that confer proteins to the graft that modulate host immune responses. These would include cytokines or soluble ligands. Qin et al. utilized a retrovirus and a plasmid delivery system to transfer genes that encode transforming growth factor beta-1 (TGF-β and interleukin 10 (IL-10) to a mouse myoblast and non-vascularized cardiac graft [33]. Grafts transduced with either of these genes had significantly prolonged survival when compared with the vector alone (39 days with IL-10 vs. 26 days with TGF-β vs. 12 days with vector alone). The therapeutic effect of transduced IL-10 and TGF-β1 has been demonstrated in follow-up investigations using different types of vectors [34, 35, 36].
Another point of gene intervention would be at the point of T-cell costimulatory activation. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a protein that modulates T-cell costimulatory activation. It becomes upregulated on T-cells upon T-cell activation. Gene delivery of a soluble CTLA-4 immunoglobulin fusion protein (CTLA4Ig) into the donor heart was associated with detectable CTLA4Ig serum levels 120 days after transplantation as well as long-term cardiac graft survival, >100 days in a rat model [37]. However, the expression of CTLA4Ig did enter systemic circulation causing some systemic immunosuppression in the rats. Another similar target is the programmed death-1 (PD-1) gene. It is expressed on activated T-cells, B-cells, and myeloid cells. When PD-1 binds one of its ligands, PD-L1 or PD-L2, it leads to the inhibition of activated T-cells. PD-L1 and PD-1 play an important role in both acute and chronic rejection of transplanted hearts in animal studies [38, 39, 40]. In rejecting human transplanted hearts, PD-L1 expression is decreased relative to PD-1 expression [41]. Gene delivery of soluble PDL1Ig fusion protein into the donor heart moderately prolonged cardiac graft survival in rats [42].
2.4.3 Cardiac ischemic disease targets
An additional example of gene therapy applied to treat cardiac disease involves targeting angiogenic gene therapy that facilitates neovascularization to augment blood flow in ischemic myocardium. These include vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF). In particular, these targets have been assessed for treating ischemic disease caused by MI or congestive heart failure. Rosengart et al. delivered 4 x 108 to 4 x 1010 particle units of an adenoviral vector encoding the VEGF gene to individuals undergoing bypass graft surgery and as the sole therapy to the experimental group via mini-thoracotomy. The intervention demonstrated no adverse events and there was symptomatic improvement in both groups [43].
The Angiogenic Gene Therapy (AGENT) clinical trials were the first randomized control trial studies investigating the benefits of stimulating coronary angiogenesis with gene therapy using FGF-4 [44]. FGF-4 was delivered using adenovirus administered by infusion into the coronary arteries of patients with chronic stable angina. AGENT evaluated incremental doses of 3 x 108 to 1 x 1011 particle units. The overall improvement in exercise treadmill time was similar for those in the treatment and the control arms. However, post-hoc analysis showed that when baseline neutralizing antibody titer was controlled for, patients with titers less than 1:100, 44% had increased their exercise treadmill time by more than 30%. In patients with titers greater than 1:100, only 7% had increased their exercise treadmill time by more than 30%. AGENT 2 investigated whether FGF-4 improved myocardial perfusion compared with placebo. A significant decrease in ischemic defect size was observed in the treatment arm (21% relative decrease) that was not observed in the placebo group. AGENT 3 and 4 were planned to determine the efficacy and safety of FGF-4 in the larger population, however, an interim review of the data demonstrated no differences in exercise treadmill time and therefore recruitment was stopped.
HGF as a therapeutic target has been evaluated in numerous studies. In the context of therapy for MI, Jin et al. investigated the long-term effects of HGF in a rat MI model [45]. Utilizing an adenoviral vector for delivery of HGR, the vector was injected directly into the infarct border zone immediately after permanent coronary ligation. 10 weeks post-intervention, there was no significant difference in the left ventricular ejection fraction, but capillary density was significantly higher in the treatment groups, whereas arteriole density was unchanged. Masahiro et al. describe the use of recombinant HGF delivered by HVJ envelope for prolonged cardiac graft preservation in rats during hypothermic storage [46]. The rationale for this choice is that HGF functions as an antiapoptotic factor in the heart. They concluded that the administration of HGF prevented myocardial apoptosis and improved cardiac function after prolonged myocardial preservation in hypothermic solution.
3. Animal models
Selection of an appropriate animal model for heart transplantation is critical to be able to translate a potential gene therapy intervention from the laboratory bench to the patient bedside. Numerous small animal models using rodents have been described where the heart is transplanted either heterotopically or orthotopically in the recipient animal. Similarly, there have been numerous large animal models described using pigs, sheep, and non-human primates (NHP). We will discuss examples of different types of small and large animal models in heart transplantation and in what instances an investigator may choose one over the other.
3.1 Heterotopic heart transplantation
Heterotopic heart transplantation (HHT) is when the transplanted heart is placed in an ectopic position inside of the recipient without the removal of the recipient’s native heart. Intra-abdominal HHT is primarily used to investigate transplantation biology and is also suitable for studying unloading induced changes in the heart [47]. The heart of a donor animal is explanted and subsequently transplanted into the abdomen of a recipient animal. To accomplish this the donor ascending aorta is anastomosed to the recipient infrarenal aorta and the donor pulmonary aorta is anastomosed to the recipient inferior vena cava. The result of this configuration is that the graft beats with reduced left ventricular filling while coronary perfusion is preserved. It offers several advantages over orthotopic transplantation in research applications such as technical simplicity, better accessibility for biopsies, and survival of the recipient even in cases of graft rejection [48].
The first heterotopic abdominal heart transplantation was published using rats by Abbott et al. [49] in 1964 and subsequently modified by Ono et al. [50]. The technique of the latter has been widely adopted as the standard HHT rodent model. Heterotopic heart transplantation in mice is more challenging than in rats, however, testing mechanistic hypotheses is more practical in mice given the greater diversity of genetic modifications available in mice. The advantage of using a small animal model is that they are less costly when compared to the cost of a large animal. A larger number of small animals can be used to assess and describe the effects of a therapeutic transgene. It also allows for several transgenes to be tested in parallel to study the differences in efficacy between them. The main challenge in using small animals is that the micro-surgical implantation technique is very challenging given their smaller size. Another aspect that makes this surgery more challenging to do in smaller animals is that they have a lower tolerance for blood loss. Because of this, it is especially important that there be minimal blood loss during the procedure and that the anastomoses be hemostatic at the time of procedure completion.
The advantage of large animals is that the results of the gene therapy intervention are able to be translated more quickly into clinical practice than are the results obtained from small animal studies. However, large animals are very costly to acquire and maintain in comparison to small models. In the setting of small primates, Minanov et al. positioned NHP hearts into the iliac fossa of primate recipients [51]. More recently this transplant configuration has been used to investigate interventions in xenotransplantation using a porcine heart transplanted into a baboon [52, 53, 54]. Porcine to porcine heart transplantation is also used in the research setting to investigate the immune system effects of cardiac transplantation as well as gene therapy interventions (Figure 1) [55, 56, 57]. This surgical research model is also amenable for modeling post-cardiac transplantation complications, such as CAV and rejection, without subjecting the animal to a high risk of morbidity or mortality [55, 58]. The recent success of a porcine to human xenotransplantation using genetically modified pigs to minimize rejection by the human immune system of the xenograft stresses the importance of the selection of the appropriate animal model. After procuring the heart, the xenograft was preserved utilizing an ex vivo perfusion device until the time of implantation. The experiments leading up to this milestone utilized the heterotopic heart transplantation model to establish the longevity of the graft against rejection [53, 59].
Figure 1.
Heterotopic heart transplantation in the intra-abdominal position in a large animal porcine model. The donor aorta is anastomosed to the recipient infrarenal aorta and the donor pulmonary artery is anastomosed to the recipient inferior vena cava.
3.2 Orthotopic heart transplantation
Orthotopic heart transplantation is when the transplanted heart is placed in the position of the recipient’s native heart. As such, the cardiac graft takes over providing the cardiovascular support of the recipient. This transplant configuration in research is most useful to investigate the cardiac graft’s overall ability to support the recipient following an administration of a new intervention. The pros of this design are that it most closely reflects clinical practice so one can investigate beyond the immunopathologic changes the heart undergoes after transplantation. This approach allows the investigator to determine whether an intervention permits the transplanted heart to perform its intended function to support the recipient’s cardiovascular system. This has been successfully described in porcine to porcine models, as well as in pig to baboon xenotransplantation models [60, 61, 62].
4. Vectors for gene delivery
Vectors for gene delivery comprise viral and non-viral vectors. Viral vectors are the more efficient of the two but are also associated with more side effects than non-viral vectors. Each type of viral vector confers different gene expression characteristics, such as the length of time for transgene expression and the intensity of transgene expression (Table 1). Additionally, when constructing the optimal vector for cardiac gene delivery consideration must be given to the selection of promoter. Constitutively active promoters, such as CMV or RSV promoters, confer broad tissue tropism and strong expression. However, cardiac-specific promoters, such as myosin heavy chain promoter, myosin light chain promoter, and troponin T promoter have been used to restrict transgene expression in the heart [63]. While the cardiac-specific promoters focus gene delivery to cardiac tissue, they confer weaker expression when compared with constitutively active promoters (Table 2).
Viral vector
Genetic material
Capacity
Transduction ability
Peak gene expression
Main advantages
Characteristics
Adenovirus
dsDNA
4.5–36 kb
Transduces both dividing and non-dividing cells.
1–7 days
Efficiently delivers genes to most tissues.
Short-term but highly efficient gene delivery. Can elicit a strong inflammatory response.
Adeno-associated virus
ssDNA
4.7 kb
Transduces both dividing and non-dividing cells.
2–4 weeks
Low immunogenicity. Broad but specific tropism.
Long-term gene expression. Low immunogenicity.
Lentivirus
RNA
8 kb
Transduces both dividing and non-dividing cells.
4–6 days
Can carry multiple transgenes. Persistent gene transfer in dividing cells.
Persistent gene expression in dividing cells. Low but potential risk of mutagenesis.
Table 1.
Summary of common viral vectors used in gene therapy.
Allogeneic rabbit heart transplant model demonstrated that intramyocardial neutrophil and T-cell populations were halved in eNOS transduced hearts. NF-kB activation in microvascular endothelial cells and cardiomyocytes was significantly reduced.
Heterotopic heart transplant model in rats demonstrated positive immunoreactivity for SOD and 86.8% +/− recovery of pre-ischemic left ventricular pressure.
Heterotopic heart transplant model in rats demonstrated greater post-ischemic recovery of mechanical function and greater recovery of coronary flow in HSP-70 treated mice.
Heterotopic heart transplant model in rats demonstrated introduction of NF-kB decoy into the nuclei of endothelial cells and cardiomyocytes. After 1 hour of reperfusion the NF-kB decoy group showed significantly higher degrees of recovery of left ventricular function.
Heterotopic heart transplant model in rats demonstrated indefinite graft survival (>100 days) and could be detected in the graft at least 1 year after gene transfer. Evident suppression of antibody production against donor alloantigens up to at least 120 days after gene transfer.
Heterotopic heart transplant model in rats demonstrated a prolonged median survival time (17 days vs. 11 days). Also demonstrated a decreased number of CD4 cells and monocytes/macrophages infiltrating the graft.
Randomized controlled trial that enrolled patients with chronic stable angina demonstrated improved exercise time on a treadmill for those treated with intervention and had a baseline time < or equal to 10 minutes. Intervention decreased the ischemic defect size. Larger efficacy studies failed to demonstrate significant differences in exercise time on a treadmill so the trial was stopped.
Phase I clinical study that enrolled patients with clinically significant coronary artery disease. There were no systemic or cardiac related adverse events related to vector administration. Coronary angiography and stress sestamibi scan showed improvement in the treated area. All patients reported improvement in angina class after therapy.
Myocardial infarction model in rats demonstrated no significant difference in the left ventricular ejection fraction. It did observe increased capillary density in the treatment group.
Cardiac grafts procured from rats demonstrated that HGF treated hearts had a significantly higher recovery rate of left ventricular developed pressure. c-MET/HGF receptor expression was stronger in the treatment group.
Table 2.
Summary of investigations of gene therapy for cardiac transplantation.
4.1 Adenoviral vectors
Adenovirus (Ad) vectors have high transduction efficiency. They are able to transduce both quiescent and dividing cells and maintain epichromosomal persistence in the host cell [64]. Ad vectors also have a broad tropism profile and large packaging capacity (4.5-36 kb). They offer efficient transduction of cardiomyocytes. However, gene expression is transient, peaking 1–7 days after delivery and then diminishing until it ceases at about 2–3 weeks after transduction [65]. They carry double-stranded DNA. Their main disadvantage is the widely pre-existing viral immunity among the general population. Since Ad is strongly immunogenic it causes undesired immune responses in treated subjects [66]. In order to overcome this and improve their capacity, Ad vectors have undergone several generations of engineering.
The first generation of Ad vectors was designed by removing the E1A gene which makes it so the recombinant Ad is unable to replicate within the host cell [67]. With the deletion of this gene, complementary cell lines, such as HEK293, had to be designed to express E1A and E1B in order to produce the viral vector. The main disadvantages of the first generation of Ad were that de novo expression of Ad proteins could activate the host immune response and there was still the possibility of spontaneous homologous recombination between the vector and engineered E1 region from HEK293 that could generate replication-competent adenovirus [68].
In the second generation of Ad vectors, further early gene regions (E2a, E2b, or E4) of the vector were deleted to permit additional space for the transgenes. As in the first generation, the deleted genes needed to be complemented by engineered production cell lines. However, the deletion of these genes led to inefficient complementation of E2/4 with engineered cell lines thus negatively affecting viral vector amplification, resulting in lower titers. Another disadvantage was that the native Ad late genes that were still retained within the viral genome could trigger host immunogenicity and cellular toxicity [69].
Finally, the third generation of Ad vectors have all Ad viral sequences deleted except for the inverted terminal repeat sequences and packaging signal. As such, these are referred to as “gutless” or “high capacity” Ad vectors (HCAd). The production of HCAds in cell culture requires an adenoviral helper virus similar to the first-generation Ad vectors. Compared with the previous Ad vector generations, HCAds have reduced immunogenicity, prolonged transduction in the host cell, and a significantly larger transgene capacity [64]. Their large transgene capacity makes it so that multiple transgenes could be delivered. The main disadvantage of HCAds is the challenge of ensuring that the helper virus is eliminated from the final vector preparation.
4.2 Adeno-associated viral vectors
Adeno-associated viral (AAV) vectors were discovered as a contaminant of Ad preparations in 1965 [70]. They lack essential genes needed for replication and expression of their own genome. They are not known to cause any human diseases. AAV vector was first used in humans in 1995 to deliver the cystic fibrosis transmembrane regulator (CFTR) gene into a patient with cystic fibrosis using the AAV2 capsid [71]. Today, recombinant AAVs are the leading vectors for the delivery of gene therapies. The first recombinant AAV gene therapy product, Glybera, was approved by the European Medicines Agency to treat lipoprotein lipase deficiency in 2012. Five years later, Luxturna was approved as the first recombinant AAV gene therapy product in the United States [72, 73].
AAVs carry single-stranded DNA (ssDNA). However, the efficiency of AAVs are limited by ssDNA in that it needs to be converted to double-stranded DNA (dsDNA) prior to expression. This step is circumvented through the use of self-complementary vectors which package an inverted repeat genome that can fold into dsDNA without the requirement for DNA synthesis or base-pairing between multiple vector genomes [74]. Transgene expression peaks at around 2–4 weeks after delivery. AAVs can carry transgenes up to 4.7 kb in size.
There are 13 natural AAV serotypes. These have been isolated from laboratory Ad stocks and mostly from human or non-human primate origin [75]. Engineering or recombinant AAV capsids confer the vector the capability to transduce multiple tissue types. Recombinant AAVs are composed of the same capsid sequence and structure as found in wild-type AAVs. Recombinant AAVs encapsidate genomes that are devoid of all AAV protein-coding sequences and that have therapeutic genes designed in their place. The complete removal of viral coding sequences maximizes the packaging capacity of these AAVs and contributes to their low immunogenicity and cytotoxicity [73].
Capsid development approaches are based on rational design and directed evolution. The rational design was among the first approaches to improve vector capsids. This entailed adding peptide sequences onto the surface of the capsid to direct the tropism of the vector and deter immunological recognition [76]. While rational design allowed for the early development of specialized AAVs, a major limitation of that approach is that there oftentimes is insufficient knowledge regarding AAV cell surface binding, internalization, trafficking, uncoating, and gene expression. The basis of directed evolution is in the simulation of natural evolution. Capsid libraries are placed under selective pressure to yield genetic variants with specific biological properties and advantageous characteristics. This way directed evolution of the capsid does not require a prior understanding of the molecular mechanisms involved in the selection criteria [73].
Cell-type specific transgene expression, however, is conferred at the level of gene transcription by the promoters used in AAV vectors. The serotype AAV9 has been shown to have the highest cardiac gene transduction efficacy in mice and rats with either systemic or direct cardiac injection [77, 78]. Meanwhile, the serotype AAV6 has proven to be a more effective vector when injected into the myocardium of pigs and non-human primates [79, 80]. Piacentino et al. described a recombinant AAV serotype engineered via rational design, termed SASTG, which has extremely high-level cardiac transduction and tropism [81]. A challenge for AAV-mediated gene therapy is overcoming the negative effect that innate immunity has on transgene expression. Yet adaptive immunity to the capsid and the foreign transgene is the main factor for decreased efficacy. Notwithstanding, recombinant AAVs are accepted as the least immunogenic when compared to other viral vectors. Patients that have been exposed to AAV serotypes that gene therapy is based on will have a high chance of forming antibodies against the vector capsid [82]. One plausible way of removing these anti-AAV antibodies from the bloodstream is by using plasmapheresis [83]. Another described pre-treatment is the use of IgG-cleaving endopeptidases which reduce IgG antibodies from the serum [84]. Besides removing the neutralizing antibodies, investigators have also utilized rational design and directed evolution to develop AAV capsids that evade neutralizing antibodies [85, 86, 87, 88].
4.3 Lentivirus
Lentiviral vectors constitute a genus of the retrovirus family. They permit long-term transgene expression by integrating the delivered genes into the host genome and can carry transgenes up to 8 kb in size [89]. They can deliver single-stranded RNA to both dividing and non-dividing cells and display robust transduction efficiency [90]. A unique advantage of lentiviral vectors is the ability to express multiple genes from a single vector [91, 92]. Transgene expression peaks after 4–6 days. The immune response to lentiviral vectors is low but concerns remain about potential insertional mutagenesis and off-target gene expression [93]. They have a preference for targeting the coding regions of genes, carrying the risk of insertional oncogenesis [94]. Additionally, the vector lacks tropism for the heart, making it unideal for heart-specific delivery through in vivo delivery, however, may have a role in ex vivo delivery [95, 96].
4.4 Non-viral vectors
Naked nucleic acids allow for the delivery of large genes in high quantities. These include DNAs, mRNAs, micro RNAs, and siRNAs. However, the lack of protection from endonuclease degradation makes them unreliable with low cellular internalization of the transgene [97]. Additionally, naked nucleic acids have an uncondensed shape and polyanionic charge that does not allow for their efficient uptake into cells. The half-life of plasmid DNA is about 10 minutes following systemic injection into mice [98].
Nanoparticles have been developed to interact with nucleic acids to protect them from degradation and condense them into nano-sized complexes that can be internalized by cells. Two main types of nanoparticles being used in investigations are lipid-based and cationic polymer-based. Another modification that is being used to improve the uptake of naked nucleic acids by cells is through chemical modification to mRNA to reduce the activation of the immune system and improve the stability of the RNA. These modified mRNAs are attractive agents for short-term gene delivery to the myocardium [99].
4.5 Hemagglutinating virus of Japan envelope vector
Wild-type hemagglutinating virus of Japan (HVJ) was discovered in 1953 and is a member of the paramyxovirus family. The envelope of HVJ is composed of a lipid bilayer and two integral membrane glycoproteins, F and HN, that project from the viral surface [100, 101]. HVJ envelope vector is constructed by incorporation of plasmid DNA into inactivated HVJ-containing liposomes [102]. During the preparation of the envelope vector, HN and F are retained but all the genome inside of HVJ is removed. It has high efficacy to induce a molecule into a target cell by the strong action of fusing cells on its membrane. Additionally, the removal of all the virus genomes confers low immunogenicity to the vector and eliminates replication and viral gene expression in cells. It is in essence a “viral, non-viral hybrid vector” [101]. HVJ can be used to deliver DNA, RNA, and oligonucleotides efficiently both in vitro and in vivo. The genetic material is entrapped within the HVJ liposomes and directly introduced into the cellular cytoplasm by means of the fusion activity of HVJ and not by endocytosis.
5. Methods for delivery of vectors for cardiac gene therapy
Gene delivery to any organ is a challenging feat. Gene delivery to the whole cardiac allograft is an especially challenging task given numerous obstacles. In vivo physiologic barriers include the heart’s location in the body, the mechanical force of blood flow, endothelial barriers, cellular barriers, and the body’s immune response [9]. Additional barriers involve the limited spread of the vectors from the site of vector exposure to achieve widespread transgene expression as well as the lack of an effective procedure for delivering the vectors without causing significant injury to the cardiac tissue that also maximizes the exposure time to cardiac tissue to the vector.
5.1 Intramyocardial injection
Direct intramyocardial injection of the vector into the myocardium is one such technique for vector delivery. It is easy to perform the injections and could theoretically be performed during graft procurement or after cardiac transplantation. Guzman et al. described the use of this technique for the delivery of adenovirus injected through a 25-gauge needle into the cardiac apex [103]. The intramyocardial injection has also been described in a clinical trial where subjects underwent a thoracotomy with the injection of vascular endothelial growth factor-2 naked deoxyribonucleic acid. They found that the procedure is well tolerated and reported few major adverse cardiac events at 1 year [104]. The major limitation of this technique for cardiac transplantation is that it only allows for limited focal delivery and the inability to target deeper muscular structures of the heart, such as the septum. Additionally, it is challenging to keep all of the injected material inside of the myocardium, leading to leakage from the needle holes and causing injury to the heart [105].
5.2 Intracoronary infusion
Intracoronary infusion of the vector is another described technique. By this method, the vectors are infused directly into the coronary arteries and reach the target cells for transduction by transit through the coronary arterial tree. Intracoronary infusion can be achieved by several methods: coronary catheterization prior to procurement, in vivo coronary infusion through the cardioplegia catheter prior to explantation, and ex vivo coronary infusion.
Catheterization of the coronary arteries for delivery and infusion through the cardioplegia catheter at the time of the graft procurement allows for a more dispersed and homogenous distribution of transgene delivery than is achieved through intramyocardial injections. Generally, transgene expression is able to be observed along with the distribution of the coronary arteries [2]. Several disadvantages exist with these delivery techniques. One is the negative effect pre-existing coronary artery disease has on the ability of vectors to reach their cellular target. Another is that since the infusion of the vector is based on a single bolus delivery when using a catheter-based approach, there is a large amount of vector that is lost to the systemic circulation resulting in poor transduction efficacy of the heart and a significant amount of off-target transduction. Finally, transduction efficacy is hampered by the presence of circulating neutralizing antibodies in the recipient against viral vectors. Vector particles containing proteins that are similar to antigens that humans are exposed to following natural infection may be neutralized by antibodies upon injection in some humans because of pre-existing immunity [106].
5.3 Complete heart isolation by cardiopulmonary bypass
Administration of the vectors during cardiopulmonary bypass featuring complete heart isolation and continuous cardiac perfusion addresses the issues associated with the catheter-based intracoronary infusion. The technique for achieving this was described by Katz et al. using separate pumps for the systemic and cardiac circuits permitting continuous isolated arrested heart perfusion [8]. This allows for the vectors to be recirculated through the coronary circulation of the heart, allowing for additional opportunities for the vectors to attach to cells and achieve entry. However, cardioplegia arrest requires for the heart and circulation to be maintained at a cold temperature (4°C) which is not favorable for vector attachment and entry into the target cells [107].
5.4 Ex vivo perfusion
The procedure for cardiac transplantation offers a unique opportunity for gene delivery that does not exist for other indications for therapeutic intervention for heart disease. The cardiac graft is removed from the recipient and preserved for a period of time ex vivo until it is implanted into the recipient. During this time the heart can be treated in isolation, obviating the need for additional procedures on the donor or recipient and minimizing or potentially eliminating the risk of off-target transduction by the gene delivering vector. With the recent FDA approval of ex vivo perfusion devices for organ preservation during transplantation, the ability to deliver vectors via ex vivo coronary perfusion seems plausible for introducing gene therapy interventions to the cardiac allograft that confer global transgene expression to the whole graft. Currently, there are two methods of ex vivo heart perfusion: hypothermic (4°C) and normothermic (>32°C). Hypothermic ex vivo perfusion involves pumping a cold crystalloid solution into the coronary arteries of the arrested heart to deliver oxygen and nutrients while removing toxic metabolites [108]. Normothermic ex vivo perfusion maintains the donor heart in a warm, contractile, near physiologic state during transport from the donor to the recipient. The donor heart is arrested prior to being placed on the perfusion device and then prepared by cannulation of the aorta and pulmonary artery and ligation of the superior vena cava and inferior vena cava. The circuit is primed with 1–1.2 L of donor blood mixed with a crystalloid perfusate solution. The cannulated heart is reanimated by pumping oxygenated blood mixed with the perfusate solution that enters the aorta to perfuse the coronary arteries. The coronary sinus effluent then crosses the tricuspid valve and gets pumped by the right ventricle into the cannulated pulmonary artery [109].
Gene delivery to a whole cardiac graft has been described in both small and large animal models utilizing ex vivo perfusion methods. Kypson et al. described a successful adenovirus-mediated transfer of the marker genes LacZ and Luciferase that was accomplished by flushing the rat heart before performing implantation of the heart into the recipient rat [110]. Similarly, utilizing a pig model Bishawi et al. described a successful adenovirus-mediated transfer of the marker gene Luciferase that was accomplished by utilizing the Organ Care System™ ex vivo perfusion device (TransMedics, Inc) [56]. The porcine heart was perfused ex vivo with normothermic, sanguinous perfusate containing the adenoviral-luciferase vector for two hours prior to implantation into the recipient pig (Figure 2).
Figure 2.
Schematic for delivery of viral vectors to a cardiac allograft using normothermic, sanguinous ex vivo perfusion. The heart and blood are collected from the donor (a). The blood is then washed to remove any vector neutralizing components from the donor serum (B). The cardiac graft is perfused on the ex vivo perfusion device (C) and the viral vectors are added to the perfusion circuit to transduce cardiac graft (D). After completion of the perfusion/transduction period, the cardiac allograft is transplanted into the recipient pig in the heterotopic, intra-abdominal position.
There are several advantages that make ex vivo normothermic, sanguinous perfusion the ideal platform for translating gene therapy into clinical practice. The ability to recirculate the perfusate through the coronary arteries multiple times over a prolonged period of time optimizes the chances the delivery vectors attach to the target cells and enter. Normothermic perfusion provides a favorable environment for viral vectors to be able to efficiently transduce cells, enabling receptor-mediated vector entry and optimizing the downstream processes of transductions [107]. The main obstacle to overcome with this vector delivery modality is the use of whole blood from the donor to make the circulating perfusate. The presence of preformed antibodies to different viral vectors could effectively neutralize the ability of the viral vectors to achieve cellular attachment. One successful intervention to overcome this is the addition of a blood washing step prior to adding the donor blood to the perfusion device and this way remove any neutralizing blood components [56].
6. Conclusion
Gene therapy for cardiac transplantation promises to transform clinical practice in the near future with cardiac grafts that are more robust and lasting than ever. However, in order to achieve its widespread adoption, there are various factors that need to be taken into consideration for how to achieve successful vector delivery and transgene expression to the cardiac graft. Here, we discussed several considerations such as choice of vector, choice of the therapeutic gene, and choice of vector delivery mechanism. Just as important is the selection of the appropriate animal model for determining the efficacy and therapeutic effect of a gene therapy construct. The successful translation of gene therapy interventions for cardiac transplantation can potentially minimize or eliminate the incidence of post-transplantation complications and the need for systemic immunosuppression therapy.
\n',keywords:"gene therapy, cardiac transplantation, gene delivery, viral vectors, non-viral vectors",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/80721.pdf",chapterXML:"https://mts.intechopen.com/source/xml/80721.xml",downloadPdfUrl:"/chapter/pdf-download/80721",previewPdfUrl:"/chapter/pdf-preview/80721",totalDownloads:82,totalViews:0,totalCrossrefCites:0,dateSubmitted:"January 17th 2022",dateReviewed:"January 26th 2022",datePrePublished:"March 4th 2022",datePublished:null,dateFinished:"March 4th 2022",readingETA:"0",abstract:"Gene therapy is an advanced treatment approach that alters the genetic composition of cells to confer therapeutic protein or RNA expression to the target organ. It has been successfully introduced into clinical practice for the treatment of various diseases. Cardiac transplantation stands to benefit from applications of gene therapy to prevent the onset of post-transplantation complications, such as primary graft dysfunction, cardiac allograft vasculopathy, and rejection. Additionally, gene therapy can be used to minimize or potentially eliminate the need for immunosuppression post-transplantation. Several animal models and delivery strategies have been developed over the years with the goal of achieving robust gene expression in the heart. However, a method for doing this has yet to be successfully translated into clinical practice. The recent advances in ex vivo perfusion for organ preservation provide potential ways to overcome several barriers to achieving gene therapy for cardiac transplantation into clinical practice. Optimizing the selection of the gene-carrying vector for gene delivery and selection of the therapeutic gene to be conferred is also crucial for being able to implement gene therapy in cardiac transplantation. Here, we discuss the history and current state of research on gene therapy for cardiac transplantation.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80721",risUrl:"/chapter/ris/80721",signatures:"Michelle Mendiola Pla, Yuting Chiang, Jun-Neng Roan and Dawn E. Bowles",book:{id:"11236",type:"book",title:"Heart Transplantation - New Insights in Therapeutic Strategies",subtitle:null,fullTitle:"Heart Transplantation - New Insights in Therapeutic Strategies",slug:null,publishedDate:null,bookSignature:"Prof. Norihide Fukushima",coverURL:"https://cdn.intechopen.com/books/images_new/11236.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-433-4",printIsbn:"978-1-80355-432-7",pdfIsbn:"978-1-80355-434-1",isAvailableForWebshopOrdering:!0,editors:[{id:"284629",title:"Prof.",name:"Norihide",middleName:null,surname:"Fukushima",slug:"norihide-fukushima",fullName:"Norihide Fukushima"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Disease and therapeutic targets for cardiac transplantation",level:"1"},{id:"sec_2_2",title:"2.1 Primary graft dysfunction",level:"2"},{id:"sec_3_2",title:"2.2 Cardiac allograft Vasculopathy",level:"2"},{id:"sec_4_2",title:"2.3 Rejection and immunosuppression",level:"2"},{id:"sec_5_2",title:"2.4 Potential targets for gene therapy",level:"2"},{id:"sec_5_3",title:"2.4.1 Inflammatory targets",level:"3"},{id:"sec_6_3",title:"2.4.2 Rejection targets",level:"3"},{id:"sec_7_3",title:"2.4.3 Cardiac ischemic disease targets",level:"3"},{id:"sec_10",title:"3. Animal models",level:"1"},{id:"sec_10_2",title:"3.1 Heterotopic heart transplantation",level:"2"},{id:"sec_11_2",title:"3.2 Orthotopic heart transplantation",level:"2"},{id:"sec_13",title:"4. Vectors for gene delivery",level:"1"},{id:"sec_13_2",title:"4.1 Adenoviral vectors",level:"2"},{id:"sec_14_2",title:"4.2 Adeno-associated viral vectors",level:"2"},{id:"sec_15_2",title:"4.3 Lentivirus",level:"2"},{id:"sec_16_2",title:"4.4 Non-viral vectors",level:"2"},{id:"sec_17_2",title:"4.5 Hemagglutinating virus of Japan envelope vector",level:"2"},{id:"sec_19",title:"5. Methods for delivery of vectors for cardiac gene therapy",level:"1"},{id:"sec_19_2",title:"5.1 Intramyocardial injection",level:"2"},{id:"sec_20_2",title:"5.2 Intracoronary infusion",level:"2"},{id:"sec_21_2",title:"5.3 Complete heart isolation by cardiopulmonary bypass",level:"2"},{id:"sec_22_2",title:"5.4 Ex vivo perfusion",level:"2"},{id:"sec_24",title:"6. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Stehlik J, Kobashigawa J, Hunt SA, Reichenspurner H, Kirklin JK. Honoring 50 Years of Clinical Heart Transplantation in Circulation: In-Depth State-of-the-Art Review. 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Molecular Therapy. 2020;28(3):709-722'},{id:"B107",body:'Pellegrini C. Influence of temperature on adenovirus-mediated gene transfer. European Journal of Cardio-Thoracic Surgery. 1998;13(5):599-603'},{id:"B108",body:'Van Raemdonck D, Rega F, Rex S, Neyrinck A. Machine perfusion of thoracic organs. Journal of Thoracic Disease. 2018;10(Suppl 8):S910-SS23'},{id:"B109",body:'Ragalie WS, Ardehali A. Current status of normothermic ex-vivo perfusion of cardiac allografts. Current Opinion in Organ Transplantation. 2020;25(3):237-240'},{id:"B110",body:'Kypson AP, Peppel K, Akhter SA, Lilly RE, Glower DD, Lefkowitz RJ, et al. Ex vivo adenovirus-mediated gene transfer to the adult rat heart. The Journal of Thoracic and Cardiovascular Surgery. 1998;115(3):623-630'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Michelle Mendiola Pla",address:null,affiliation:'
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Duke University, USA
'}],corrections:null},book:{id:"11236",type:"book",title:"Heart Transplantation - New Insights in Therapeutic Strategies",subtitle:null,fullTitle:"Heart Transplantation - New Insights in Therapeutic Strategies",slug:null,publishedDate:null,bookSignature:"Prof. Norihide Fukushima",coverURL:"https://cdn.intechopen.com/books/images_new/11236.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-433-4",printIsbn:"978-1-80355-432-7",pdfIsbn:"978-1-80355-434-1",isAvailableForWebshopOrdering:!0,editors:[{id:"284629",title:"Prof.",name:"Norihide",middleName:null,surname:"Fukushima",slug:"norihide-fukushima",fullName:"Norihide Fukushima"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},profile:{item:{id:"320721",title:"Dr.",name:"Wajid",middleName:null,surname:"Nasim",email:"wajidnasim@ciitvehari.edu.pk",fullName:"Wajid Nasim",slug:"wajid-nasim",position:null,biography:null,institutionString:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",totalCites:0,totalChapterViews:"0",outsideEditionCount:0,totalAuthoredChapters:"3",totalEditedBooks:"0",personalWebsiteURL:null,twitterURL:null,linkedinURL:null,institution:null},booksEdited:[],chaptersAuthored:[{id:"71856",title:"Consequences and Mitigation Strategies of Heat Stress for Sustainability of Soybean (Glycine max L. Merr.) Production under the Changing Climate",slug:"consequences-and-mitigation-strategies-of-heat-stress-for-sustainability-of-soybean-em-glycine-max-e",abstract:"Increasing ambient temperature is a major climatic factor that negatively affects plant growth and development, and causes significant losses in soybean crop yield worldwide. Thus, high temperatures (HT) result in less seed germination, which leads to pathogenic infection, and decreases the economic yield of soybean. In addition, the efficiency of photosynthesis and transpiration of plants are affected by high temperatures, which have negative impact on the physio-biochemical process in the plant system, finally deteriorate the yield and quality of the affected crop. However, plants have several mechanisms of specific cellular detection of HT stress that help in the transduction of signals, producing the activation of transcription factors and genes to counteract the harmful effects caused by the stressful condition. Among the contributors to help the plant in re-establishing cellular homeostasis are the applications of organic stimulants (antioxidants, osmoprotectants, and hormones), which enhance the productivity and quality of soybean against HT stress. In this chapter, we summarized the physiological and biochemical mechanisms of soybean plants at various growth stages under HT. Furthermore, it also depicts the mitigation strategies to overcome the adverse effects of HT on soybean using exogenous applications of bioregulators. These studies intend to increase the understanding of exogenous biochemical compounds that could reduce the adverse effects of HT on the growth, yield, and quality of soybean.",signatures:"Ayman EL Sabagh, Akbar Hossain, Mohammad Sohidul Islam, Muhammad Aamir Iqbal, Shah Fahad, Disna Ratnasekera, Faraz Azeem, Allah Wasaya, Oksana Sytar, Narendra Kumar, Analía Llanes, Murat Erman, Mustafa Ceritoğlu, Huseyin Arslan, Doğan Arslan, Sajjad Hussain, Muhammad Mubeen, Muhammad Ikram, Ram Swaroop Meena, Hany Gharib, Ejaz Waraich, Wajid Nasim, Liyun Liu and Hirofumi Saneoka",authors:[{id:"79255",title:"Dr.",name:"Ejaz",surname:"Waraich",fullName:"Ejaz Waraich",slug:"ejaz-waraich",email:"uaf_ewarraich@yahoo.com"},{id:"215584",title:"Dr.",name:"Ayman",surname:"EL Sabagh",fullName:"Ayman EL Sabagh",slug:"ayman-el-sabagh",email:"aymanelsabagh@gmail.com"},{id:"239094",title:"Dr.",name:"Shah",surname:"Fahad",fullName:"Shah Fahad",slug:"shah-fahad",email:"shah_fahad80@yahoo.com"},{id:"280755",title:"Dr.",name:"Akbar",surname:"Hossain",fullName:"Akbar Hossain",slug:"akbar-hossain",email:"akbarhossainwrc@gmail.com"},{id:"309311",title:"Dr.",name:"Mohammad Sohidul",surname:"Islam",fullName:"Mohammad Sohidul Islam",slug:"mohammad-sohidul-islam",email:"shahid_sohana@yahoo.com"},{id:"315343",title:"Dr.",name:"Ram Swaroop",surname:"Meena",fullName:"Ram Swaroop Meena",slug:"ram-swaroop-meena",email:"rsmeenaagro@gmail.com"},{id:"317875",title:"Prof.",name:"Murat",surname:"Erman",fullName:"Murat Erman",slug:"murat-erman",email:"rektor@siirt.edu.tr"},{id:"317878",title:"Prof.",name:"Hirofumi",surname:"Saneoka",fullName:"Hirofumi Saneoka",slug:"hirofumi-saneoka",email:"saneoka@hiroshima-u.ac.jp"},{id:"317879",title:"Dr.",name:"Muhammad",surname:"Mubeen",fullName:"Muhammad Mubeen",slug:"muhammad-mubeen",email:"muhammadmubeen@ciitvehari.edu.pk"},{id:"317888",title:"Prof.",name:"Oksana",surname:"Sytar",fullName:"Oksana Sytar",slug:"oksana-sytar",email:"oksana.sytar@gmail.com"},{id:"317892",title:"Dr.",name:"Huseyin",surname:"Arslan",fullName:"Huseyin Arslan",slug:"huseyin-arslan",email:"huarslan@siirt.edu.tr"},{id:"318779",title:"Dr.",name:"Muhammad",surname:"Aamir Iqbal",fullName:"Muhammad Aamir Iqbal",slug:"muhammad-aamir-iqbal",email:"aamir1801@yahoo.com"},{id:"318780",title:"Dr.",name:"Allah",surname:"Wasaya",fullName:"Allah Wasaya",slug:"allah-wasaya",email:"wasayauaf@gmail.com"},{id:"319587",title:"Dr.",name:"Liyun",surname:"Liu",fullName:"Liyun Liu",slug:"liyun-liu",email:"liuly@hiroshima-u.ac.jp"},{id:"319588",title:"Ph.D. Student",name:"Mustafa",surname:"Ceritoğlu",fullName:"Mustafa Ceritoğlu",slug:"mustafa-ceritoglu",email:"ceritoglu@siirt.edu.tr"},{id:"319589",title:"Dr.",name:"Doğan",surname:"Arslan",fullName:"Doğan Arslan",slug:"dogan-arslan",email:"doganarslan@siirt.edu.tr"},{id:"320718",title:"Ms.",name:"Faraz",surname:"Azeem",fullName:"Faraz Azeem",slug:"faraz-azeem",email:"faraza621@gmail.com"},{id:"320719",title:"Mr.",name:"Muhammad",surname:"Ikram",fullName:"Muhammad Ikram",slug:"muhammad-ikram",email:"r4rana88@gmail.com"},{id:"320721",title:"Dr.",name:"Wajid",surname:"Nasim",fullName:"Wajid Nasim",slug:"wajid-nasim",email:"wajidnasim@ciitvehari.edu.pk"},{id:"320877",title:"Dr.",name:"Disna",surname:"Ratnasekera",fullName:"Disna Ratnasekera",slug:"disna-ratnasekera",email:"disnaratnasekera@gmail.com"},{id:"320878",title:"Dr.",name:"Narendra",surname:"Kumar",fullName:"Narendra Kumar",slug:"narendra-kumar",email:"nkumar.icar@gmail.com"},{id:"320879",title:"Dr.",name:"Analía",surname:"Llanes",fullName:"Analía Llanes",slug:"analia-llanes",email:"analiallanes9@gmail.com"},{id:"320880",title:"Dr.",name:"Sajjad",surname:"Hussain",fullName:"Sajjad Hussain",slug:"sajjad-hussain",email:"mubeenagri@gmail.com"},{id:"320881",title:"Prof.",name:"Hany",surname:"Gharib",fullName:"Hany Gharib",slug:"hany-gharib",email:"hanysony@yahoo.com"}],book:{id:"10118",title:"Plant Stress Physiology",slug:"plant-stress-physiology",productType:{id:"1",title:"Edited Volume"}}},{id:"72199",title:"Maize Adaptability to Heat Stress under Changing Climate",slug:"maize-adaptability-to-heat-stress-under-changing-climate",abstract:"The rapidly increasing human population is an alarming issue and would need more food production under changing climate. Abiotic stresses like heat stress and temperature fluctuation are becoming key issues to be addressed for boosting crop production. Maize growth and productivity are sensitive to temperature fluctuations. Grain yield losses in maize from heat stress are expected to increase owing to higher temperatures during the growing season. This situation demands the development of maize hybrids tolerant to heat and drought stresses without compromising grain yield under stress conditions. The chapter aimed to assess the updates on the influence of high-temperature stress (HTS) on the physio-biochemical processes in plants and to draw an association between yield components and heat stress on maize. Moreover, exogenous applications of protectants, antioxidants, and signaling molecules induce HTS tolerance in maize plants and could help the plants cope with HTS by scavenging reactive oxygen species, upregulation of antioxidant enzymes, and protection of cellular membranes by the accrual of compatible osmolytes. It is expected that a better thought of the physiological basis of HTS tolerance in maize plants will help to develop HTS maize cultivars. Developing HTS-tolerant maize varieties may ensure crops production sustainability along with promoting food and feed security under changing climate.",signatures:"Ayman EL Sabagh, Akbar Hossain, Muhammad Aamir Iqbal, Celaleddin Barutçular, Mohammad Sohidul Islam, Fatih Çiğ, Murat Erman, Oksana Sytar, Marian Brestic, Allah Wasaya, Tasmiya Jabeen, Maham Asif Bukhari, Muhammad Mubeen, Habib-ur-Rehman Athar, Faraz Azeem, Hakki Akdeniz, Ömer Konuşkan, Ferhat Kizilgeci, Muhammad Ikram, Sobhy Sorour, Wajid Nasim, Mabrouk Elsabagh, Muhammad Rizwan, Ram Swaroop Meena, Shah Fahad, Akihiro Ueda, Liyun Liu and Hirofumi Saneoka",authors:[{id:"215584",title:"Dr.",name:"Ayman",surname:"EL Sabagh",fullName:"Ayman EL Sabagh",slug:"ayman-el-sabagh",email:"aymanelsabagh@gmail.com"},{id:"239094",title:"Dr.",name:"Shah",surname:"Fahad",fullName:"Shah Fahad",slug:"shah-fahad",email:"shah_fahad80@yahoo.com"},{id:"280755",title:"Dr.",name:"Akbar",surname:"Hossain",fullName:"Akbar Hossain",slug:"akbar-hossain",email:"akbarhossainwrc@gmail.com"},{id:"309311",title:"Dr.",name:"Mohammad Sohidul",surname:"Islam",fullName:"Mohammad Sohidul Islam",slug:"mohammad-sohidul-islam",email:"shahid_sohana@yahoo.com"},{id:"315343",title:"Dr.",name:"Ram Swaroop",surname:"Meena",fullName:"Ram Swaroop Meena",slug:"ram-swaroop-meena",email:"rsmeenaagro@gmail.com"},{id:"317875",title:"Prof.",name:"Murat",surname:"Erman",fullName:"Murat Erman",slug:"murat-erman",email:"rektor@siirt.edu.tr"},{id:"317878",title:"Prof.",name:"Hirofumi",surname:"Saneoka",fullName:"Hirofumi Saneoka",slug:"hirofumi-saneoka",email:"saneoka@hiroshima-u.ac.jp"},{id:"317879",title:"Dr.",name:"Muhammad",surname:"Mubeen",fullName:"Muhammad Mubeen",slug:"muhammad-mubeen",email:"muhammadmubeen@ciitvehari.edu.pk"},{id:"317888",title:"Prof.",name:"Oksana",surname:"Sytar",fullName:"Oksana Sytar",slug:"oksana-sytar",email:"oksana.sytar@gmail.com"},{id:"318779",title:"Dr.",name:"Muhammad",surname:"Aamir Iqbal",fullName:"Muhammad Aamir Iqbal",slug:"muhammad-aamir-iqbal",email:"aamir1801@yahoo.com"},{id:"318780",title:"Dr.",name:"Allah",surname:"Wasaya",fullName:"Allah Wasaya",slug:"allah-wasaya",email:"wasayauaf@gmail.com"},{id:"319587",title:"Dr.",name:"Liyun",surname:"Liu",fullName:"Liyun Liu",slug:"liyun-liu",email:"liuly@hiroshima-u.ac.jp"},{id:"320718",title:"Ms.",name:"Faraz",surname:"Azeem",fullName:"Faraz Azeem",slug:"faraz-azeem",email:"faraza621@gmail.com"},{id:"320719",title:"Mr.",name:"Muhammad",surname:"Ikram",fullName:"Muhammad Ikram",slug:"muhammad-ikram",email:"r4rana88@gmail.com"},{id:"320721",title:"Dr.",name:"Wajid",surname:"Nasim",fullName:"Wajid Nasim",slug:"wajid-nasim",email:"wajidnasim@ciitvehari.edu.pk"},{id:"242174",title:"Dr.",name:"Habib-ur-Rehman",surname:"Athar",fullName:"Habib-ur-Rehman Athar",slug:"habib-ur-rehman-athar",email:"habibathar@yahoo.com"},{id:"310541",title:"Dr.",name:"Ferhat",surname:"Kizilgeci",fullName:"Ferhat Kizilgeci",slug:"ferhat-kizilgeci",email:"ferhat_kizilgeci@hotmail.com"},{id:"317876",title:"Dr.",name:"Fatih",surname:"Çiğ",fullName:"Fatih Çiğ",slug:"fatih-cig",email:"fatihcig@hotmail.com"},{id:"317880",title:"Prof.",name:"Celaleddin",surname:"Barutçular",fullName:"Celaleddin Barutçular",slug:"celaleddin-barutcular",email:"cbarutcular@gmail.com"},{id:"317887",title:"Dr.",name:"Ömer",surname:"Konuşkan",fullName:"Ömer Konuşkan",slug:"omer-konuskan",email:"okonuskan@mku.edu.tr"},{id:"318781",title:"Dr.",name:"Hakki",surname:"Akdeniz",fullName:"Hakki Akdeniz",slug:"hakki-akdeniz",email:"hakki_akdeniz@hotmail.com"},{id:"320715",title:"Dr.",name:"Marian",surname:"Brestic",fullName:"Marian Brestic",slug:"marian-brestic",email:"Marian.Brestic@uniag.sk"},{id:"320716",title:"Dr.",name:"Tasmiya",surname:"Jabeen",fullName:"Tasmiya Jabeen",slug:"tasmiya-jabeen",email:"tasmiyajabeen124@gmail.com"},{id:"320717",title:"Dr.",name:"Maham Asif",surname:"Bukhari",fullName:"Maham Asif Bukhari",slug:"maham-asif-bukhari",email:"mahambukhari998@gmail.com"},{id:"320720",title:"Dr.",name:"Sobhy",surname:"Sorour",fullName:"Sobhy Sorour",slug:"sobhy-sorour",email:"sobhysor@yahoo.com"},{id:"320722",title:"Dr.",name:"Mabrouk",surname:"Elsabagh",fullName:"Mabrouk Elsabagh",slug:"mabrouk-elsabagh",email:"mabroukelsabagh@yahoo.com"},{id:"320723",title:"Dr.",name:"Muhammad",surname:"Rizwan",fullName:"Muhammad Rizwan",slug:"muhammad-rizwan",email:"mrizwan@gcuf.edu.pk"},{id:"320724",title:"Dr.",name:"Akihiro",surname:"Ueda",fullName:"Akihiro Ueda",slug:"akihiro-ueda",email:"akiueda@hiroshima-u.ac.jp"}],book:{id:"10118",title:"Plant Stress Physiology",slug:"plant-stress-physiology",productType:{id:"1",title:"Edited Volume"}}},{id:"73636",title:"Elevated CO2 Concentration Improves Heat-Tolerant Ability in Crops",slug:"elevated-co-sub-2-sub-concentration-improves-heat-tolerant-ability-in-crops",abstract:"The rising concentration of atmospheric carbon dioxide (aCO2) and increasing temperature are the main reasons for climate change, which are significantly affecting crop production systems in this world. However, the elevated carbon dioxide (CO2) concentration can improve the growth and development of crop plants by increasing photosynthetic rate (higher availability of photoassimilates). The combined effects of elevated CO2 (eCO2) and temperature on crop growth and carbon metabolism are not adequately recognized, while both eCO2 and temperature triggered noteworthy changes in crop production. Therefore, to increase crop yields, it is important to identify the physiological mechanisms and genetic traits of crop plants which play a vital role in stress tolerance under the prevailing conditions. The eCO2 and temperature stress effects on physiological aspects as well as biochemical profile to characterize genotypes that differ in their response to stress conditions. The aim of this review is directed the open-top cavities to regulate the properties like physiological, biochemical, and yield of crops under increasing aCO2, and temperature. Overall, the extent of the effect of eCO2 and temperature response to biochemical components and antioxidants remains unclear, and therefore further studies are required to promote an unperturbed production system.",signatures:"Ayman EL Sabagh, Akbar Hossain, Mohammad Sohidul Islam, Muhammad Aamir Iqbal, Ali Raza, Çetin Karademir, Emine Karademir, Abdul Rehman, Md Atikur Rahman, Rajesh Kumar Singhal, Analía Llanes, Muhammad Ali Raza, Muhammad Mubeen, Wajid Nasim, Celaleddin Barutçular, Ram Swaroop Meena and Hirofumi Saneoka",authors:[{id:"215584",title:"Dr.",name:"Ayman",surname:"EL Sabagh",fullName:"Ayman EL Sabagh",slug:"ayman-el-sabagh",email:"aymanelsabagh@gmail.com"},{id:"280755",title:"Dr.",name:"Akbar",surname:"Hossain",fullName:"Akbar Hossain",slug:"akbar-hossain",email:"akbarhossainwrc@gmail.com"},{id:"309311",title:"Dr.",name:"Mohammad Sohidul",surname:"Islam",fullName:"Mohammad Sohidul Islam",slug:"mohammad-sohidul-islam",email:"shahid_sohana@yahoo.com"},{id:"315343",title:"Dr.",name:"Ram Swaroop",surname:"Meena",fullName:"Ram Swaroop Meena",slug:"ram-swaroop-meena",email:"rsmeenaagro@gmail.com"},{id:"317878",title:"Prof.",name:"Hirofumi",surname:"Saneoka",fullName:"Hirofumi Saneoka",slug:"hirofumi-saneoka",email:"saneoka@hiroshima-u.ac.jp"},{id:"317879",title:"Dr.",name:"Muhammad",surname:"Mubeen",fullName:"Muhammad Mubeen",slug:"muhammad-mubeen",email:"muhammadmubeen@ciitvehari.edu.pk"},{id:"318779",title:"Dr.",name:"Muhammad",surname:"Aamir Iqbal",fullName:"Muhammad Aamir Iqbal",slug:"muhammad-aamir-iqbal",email:"aamir1801@yahoo.com"},{id:"320721",title:"Dr.",name:"Wajid",surname:"Nasim",fullName:"Wajid Nasim",slug:"wajid-nasim",email:"wajidnasim@ciitvehari.edu.pk"},{id:"320879",title:"Dr.",name:"Analía",surname:"Llanes",fullName:"Analía Llanes",slug:"analia-llanes",email:"analiallanes9@gmail.com"},{id:"317880",title:"Prof.",name:"Celaleddin",surname:"Barutçular",fullName:"Celaleddin Barutçular",slug:"celaleddin-barutcular",email:"cbarutcular@gmail.com"},{id:"320400",title:"Dr.",name:"Rajesh",surname:"Singhal",fullName:"Rajesh Singhal",slug:"rajesh-singhal",email:"rajasinghal151@gmail.com"},{id:"329978",title:"Dr.",name:"Ali",surname:"Raza",fullName:"Ali Raza",slug:"ali-raza",email:"alirazamughal143@gmail.com"},{id:"329979",title:"Prof.",name:"Çetin",surname:"Karademir",fullName:"Çetin Karademir",slug:"cetin-karademir",email:"cetin_karademir@hotmail.com"},{id:"329980",title:"Prof.",name:"Emine",surname:"Karademir",fullName:"Emine Karademir",slug:"emine-karademir",email:"emine_karademir@hotmail.com"},{id:"329981",title:"Dr.",name:"Abdul",surname:"Rehman",fullName:"Abdul Rehman",slug:"abdul-rehman",email:"abdurehmanuaf@gmail.com"},{id:"329982",title:"Dr.",name:"Md. Atikur",surname:"Rahman",fullName:"Md. Atikur Rahman",slug:"md.-atikur-rahman",email:"atikbt@korea.kr"},{id:"329983",title:"Dr.",name:"Muhammad",surname:"Ali Raza",fullName:"Muhammad Ali Raza",slug:"muhammad-ali-raza",email:"razaali0784@yahoo.com"}],book:{id:"10363",title:"Abiotic Stress in Plants",slug:"abiotic-stress-in-plants",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"242124",title:"Dr.",name:"Shalim",surname:"Uddin",slug:"shalim-uddin",fullName:"Shalim Uddin",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"268014",title:"Dr.",name:"Te-Ming",surname:"Tseng",slug:"te-ming-tseng",fullName:"Te-Ming Tseng",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"273965",title:"MSc.",name:"Shandrea",surname:"Stallworth",slug:"shandrea-stallworth",fullName:"Shandrea Stallworth",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"315969",title:"Dr.",name:"Brooklyn",surname:"Schumaker",slug:"brooklyn-schumaker",fullName:"Brooklyn Schumaker",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Mississippi State University",institutionURL:null,country:{name:"United States of America"}}},{id:"317036",title:"Ms.",name:"Mary Gracen",surname:"Fuller",slug:"mary-gracen-fuller",fullName:"Mary Gracen Fuller",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Mississippi State University",institutionURL:null,country:{name:"United States of America"}}},{id:"317170",title:"Mr.",name:"Abu Sayeed Md.",surname:"Hasibuzzaman",slug:"abu-sayeed-md.-hasibuzzaman",fullName:"Abu Sayeed Md. Hasibuzzaman",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Bangabandhu Sheikh Mujibur Rahman Agricultural University",institutionURL:null,country:{name:"Bangladesh"}}},{id:"317171",title:"Mrs.",name:"Farzana",surname:"Akter",slug:"farzana-akter",fullName:"Farzana Akter",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Bangabandhu Sheikh Mujibur Rahman Agricultural University",institutionURL:null,country:{name:"Bangladesh"}}},{id:"317172",title:"Mrs.",name:"Shamim Ara",surname:"Bagum",slug:"shamim-ara-bagum",fullName:"Shamim Ara Bagum",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Bangladesh Agricultural Research Institute",institutionURL:null,country:{name:"Bangladesh"}}},{id:"317173",title:"Mrs.",name:"Nilima",surname:"Hossain",slug:"nilima-hossain",fullName:"Nilima Hossain",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Bangladesh Agricultural Research Institute",institutionURL:null,country:{name:"Bangladesh"}}},{id:"317174",title:"M.Sc.",name:"Tahmina",surname:"Akter",slug:"tahmina-akter",fullName:"Tahmina Akter",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Bangladesh Agricultural Research Institute",institutionURL:null,country:{name:"Bangladesh"}}}]},generic:{page:{slug:"attribution-policy",title:"Attribution Policy",intro:"
Definition of Terms:
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Work - a book Chapter (as well as Conference Papers), including any and all content, graphics, images and/or other materials forming part of, or accompanying, the Chapter/Conference Paper.
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Rules of Attribution for Works Published by IntechOpen
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With the purpose of protecting Authors' copyright and the transparent reuse of OA (Open Access) content, IntechOpen has developed Rules of Attribution of Works licensed under Creative Commons licenses.
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All Chapters published in IntechOpen books prior to October 2011 are licensed under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported license (CC BY-NC-SA 3.0);
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All Chapters published in IntechOpen books after October 2011 are licensed under the Creative Commons Attribution 3.0 Unported license (CC BY 3.0);
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In case you reuse or republish any of the Works licensed under CC licenses, you must abide by the guidelines outlined below:
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1. Rules for reusing of books in their entirety or significant parts of books
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All rights to Books and other compilations published on the IntechOpen platform and in print are reserved by IntechOpen. The Copyright to Books and other compilations is subject to a separate Copyright from any that exists in the included Works.
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A Book in its entirety or a significant part of a Book cannot be translated freely without specific written consent by the publisher. Further information can be obtained at permissions@intechopen.com.
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In instances where permission is obtained from the publisher for reusing or republishing the Book, or significant parts of the Book, all of the following conditions apply:
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Information about the first publisher must be provided – please note the fact that the material was originally published by IntechOpen as an OA (Open Access) publication must be acknowledged;
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All original Academic Editor(s) must be credited;
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Since you are reusing content that someone else created and allowed you to use freely, you must credit all Authors involved;
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The type of license that is available for the Works must be indicated, as well as a link to the license provided, so that others can investigate the terms of the license. You will be aware that the material can be used for free in consequence of the CC license attribution, so you must acknowledge that fact. It is not sufficient that the material is Creative Commons, because that says nothing about how the material can actually be used. There are different CC licenses and you have to identify the specific license that is being used;
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Any original Copyright Notices associated, with the Works which constitute the Book must be kept intact;
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Provision of the original title of the Book, as well as the original titles of any individual Works;
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Provision of the URL where the Book is hosted, with a notice to the effect that the Book is an OA (Open Access) publication;
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Provision of the URL to every individual Work which constitutes the Book with a notice that the Work is an OA (Open Access) publication. As the material has been accessed for free, it is incumbent upon you to provide the source so that others can also access it for free.
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Every single Work that is used has to be attributed in the way described. If you are unsure about proper attribution, please write to permissions@intechopen.com.
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2. Rules of attribution for works published by IntechOpen
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Individual Works originally published in IntechOpen books are licensed under Creative Commons licenses and can be freely used under terms of the respective CC license, if properly attributed. In order to properly attribute the Work you must respect all the conditions outlined below:
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Credit all Authors – since you are reusing contents that someone created and allowed you to use freely, you have to acknowledge authorship;
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Indicate the type of license under which the Work is available and provide the URL to the license so others can find out the license terms. Preferably keep intact any original Copyright Notice associated with the Chapter (if any). You will be aware that the material can be used for free in consequence of the CC license attribution, so you must acknowledge that fact. It is not sufficient that the material is Creative Commons, because that says nothing about how the material can actually be used. There are different CC licenses and you have to identify the specific license that is being used;
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Provide the URL where the Work is hosted, preferably providing the original title of the Work, as well as the original title of the Book with a notification that the Work is an OA (Open Access) publication. As the material has been accessed for free, it is incumbent upon you to provide the source so that others can also access it for free;
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Provide information about the first publisher – please note the fact that the material was originally published by IntechOpen as an OA (Open Access) Work must be acknowledged.
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Every single Work that is used has to be attributed in the way as described. If you are unsure about proper attribution, please contact Us at permissions@intechopen.com.
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In the event that you use more than one of IntechOpen's Works published in one or more books (but not a significant part of the book that is under separate Copyright), each of these have to be properly attributed in the way described.
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IntechOpen does not have any claims on newly created copyrighted Works, but the Works originally published by IntechOpen must be properly attributed.
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All these rules apply to BOTH online and offline use.
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Parts of the Rules of Attribution are based on Work Attributing Creative Commons Materials published by the Australian Research Council Centre of Excellence for Creative Industries and Innovation, in partnership with Creative Commons Australia, which can be found at creativecommons.org.au licensed under Creative Commons Attribution 2.5 Australia license, and Best practices for attribution published by Creative Commons, which can be found at wiki.creativecommons.org under the Creative Commons Attribution 4.0 license.
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All the above rules are subject to change, IntechOpen reserves the right to take appropriate action if any of the conditions outlined above are not met.
Work - a book Chapter (as well as Conference Papers), including any and all content, graphics, images and/or other materials forming part of, or accompanying, the Chapter/Conference Paper.
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Attribution – appropriate credit for the used Work or book.
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Creative Commons licenses – enable licensors to retain copyright while allowing others to use their Works in an appropriate way.
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Rules of Attribution for Works Published by IntechOpen
\n\n
With the purpose of protecting Authors' copyright and the transparent reuse of OA (Open Access) content, IntechOpen has developed Rules of Attribution of Works licensed under Creative Commons licenses.
\n\n
\n\t
All Chapters published in IntechOpen books prior to October 2011 are licensed under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported license (CC BY-NC-SA 3.0);
\n\t
All Chapters published in IntechOpen books after October 2011 are licensed under the Creative Commons Attribution 3.0 Unported license (CC BY 3.0);
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In case you reuse or republish any of the Works licensed under CC licenses, you must abide by the guidelines outlined below:
\n\n
1. Rules for reusing of books in their entirety or significant parts of books
\n\n
All rights to Books and other compilations published on the IntechOpen platform and in print are reserved by IntechOpen. The Copyright to Books and other compilations is subject to a separate Copyright from any that exists in the included Works.
\n\n
A Book in its entirety or a significant part of a Book cannot be translated freely without specific written consent by the publisher. Further information can be obtained at permissions@intechopen.com.
\n\n
In instances where permission is obtained from the publisher for reusing or republishing the Book, or significant parts of the Book, all of the following conditions apply:
\n\n
\n\t
Information about the first publisher must be provided – please note the fact that the material was originally published by IntechOpen as an OA (Open Access) publication must be acknowledged;
\n\t
All original Academic Editor(s) must be credited;
\n\t
Since you are reusing content that someone else created and allowed you to use freely, you must credit all Authors involved;
\n\t
The type of license that is available for the Works must be indicated, as well as a link to the license provided, so that others can investigate the terms of the license. You will be aware that the material can be used for free in consequence of the CC license attribution, so you must acknowledge that fact. It is not sufficient that the material is Creative Commons, because that says nothing about how the material can actually be used. There are different CC licenses and you have to identify the specific license that is being used;
\n\t
Any original Copyright Notices associated, with the Works which constitute the Book must be kept intact;
\n\t
Provision of the original title of the Book, as well as the original titles of any individual Works;
\n\t
Provision of the URL where the Book is hosted, with a notice to the effect that the Book is an OA (Open Access) publication;
\n\t
Provision of the URL to every individual Work which constitutes the Book with a notice that the Work is an OA (Open Access) publication. As the material has been accessed for free, it is incumbent upon you to provide the source so that others can also access it for free.
\n
\n\n
Every single Work that is used has to be attributed in the way described. If you are unsure about proper attribution, please write to permissions@intechopen.com.
\n\n
2. Rules of attribution for works published by IntechOpen
\n\n
Individual Works originally published in IntechOpen books are licensed under Creative Commons licenses and can be freely used under terms of the respective CC license, if properly attributed. In order to properly attribute the Work you must respect all the conditions outlined below:
\n\n
\n\t
Credit all Authors – since you are reusing contents that someone created and allowed you to use freely, you have to acknowledge authorship;
\n\t
Indicate the type of license under which the Work is available and provide the URL to the license so others can find out the license terms. Preferably keep intact any original Copyright Notice associated with the Chapter (if any). You will be aware that the material can be used for free in consequence of the CC license attribution, so you must acknowledge that fact. It is not sufficient that the material is Creative Commons, because that says nothing about how the material can actually be used. There are different CC licenses and you have to identify the specific license that is being used;
\n\t
Provide the URL where the Work is hosted, preferably providing the original title of the Work, as well as the original title of the Book with a notification that the Work is an OA (Open Access) publication. As the material has been accessed for free, it is incumbent upon you to provide the source so that others can also access it for free;
\n\t
Provide information about the first publisher – please note the fact that the material was originally published by IntechOpen as an OA (Open Access) Work must be acknowledged.
\n
\n\n
Every single Work that is used has to be attributed in the way as described. If you are unsure about proper attribution, please contact Us at permissions@intechopen.com.
\n\n
In the event that you use more than one of IntechOpen's Works published in one or more books (but not a significant part of the book that is under separate Copyright), each of these have to be properly attributed in the way described.
\n\n
IntechOpen does not have any claims on newly created copyrighted Works, but the Works originally published by IntechOpen must be properly attributed.
\n\n
All these rules apply to BOTH online and offline use.
\n\n
Parts of the Rules of Attribution are based on Work Attributing Creative Commons Materials published by the Australian Research Council Centre of Excellence for Creative Industries and Innovation, in partnership with Creative Commons Australia, which can be found at creativecommons.org.au licensed under Creative Commons Attribution 2.5 Australia license, and Best practices for attribution published by Creative Commons, which can be found at wiki.creativecommons.org under the Creative Commons Attribution 4.0 license.
\n\n
All the above rules are subject to change, IntechOpen reserves the right to take appropriate action if any of the conditions outlined above are not met.
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Policy last updated: 2016-06-09
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On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. 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After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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In recent years, many developed countries as well as some developing ones have extensively investigated all aspects of the carbon dioxide geological storage (CGS) process such as the potential of storage sites, understanding the behavior of CO2, and its interaction with various formations comprising trapping mechanisms, flow pattern, and interactions with formation rocks and so on. This review presents a summary of recent research efforts on storage capacity estimation techniques in most prominent storage options (depleted oil and gas reservoir, saline aquifers and coal beds), modeling and simulation means followed by monitoring and verification approaches. 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Principles of green architecture and building physics are not given enough thought and consideration. In the best cases, some thought is given to such factors but without a scientific methodology, which takes into consideration appropriate climatic data and appropriate assessment tools. Most importantly, the interference of the environmentalist in architecture projects comes usually very late in the design processes. Facing these facts has driven most countries to adopt official strategies and policies to deal with building’s performance. The rating systems are among these initiatives. The author of this chapter adapts a detailed methodology to aid the integration of the principles of the green architecture in the early stages of design using rating systems. The Leadership in Energy and Environmental Design (LEED) 1 that was developed in the USA by the U.S. Green Building Council (USGBC) for Core and Shell has been employed as the main design target. 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The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null,scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
\r\n
\r\n\t
\r\n
\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n
\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
\r\n
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
\r\n
\r\n\t
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
\r\n
\r\n\t
\r\n
\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
\r\n
\r\n\t
\r\n
\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
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Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334239",title:"Prof.",name:"Leung",middleName:null,surname:"Wai Keung",slug:"leung-wai-keung",fullName:"Leung Wai Keung",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Hong Kong",country:{name:"China"}}}]}},subseries:{item:{id:"20",type:"subseries",title:"Animal Nutrition",keywords:"Sustainable Animal Diets, Carbon Footprint, Meta Analyses",scope:"An essential part of animal production is nutrition. Animals need to receive a properly balanced diet. One of the new challenges we are now faced with is sustainable animal diets (STAND) that involve the 3 P’s (People, Planet, and Profitability). We must develop animal feed that does not compete with human food, use antibiotics, and explore new growth promoters options, such as plant extracts or compounds that promote feed efficiency (e.g., monensin, oils, enzymes, probiotics). These new feed options must also be environmentally friendly, reducing the Carbon footprint, CH4, N, and P emissions to the environment, with an adequate formulation of nutrients.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/20.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11416,editor:{id:"175967",title:"Dr.",name:"Manuel",middleName:null,surname:"Gonzalez Ronquillo",slug:"manuel-gonzalez-ronquillo",fullName:"Manuel Gonzalez Ronquillo",profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",biography:"Dr. Manuel González Ronquillo obtained his doctorate degree from the University of Zaragoza, Spain, in 2001. He is a research professor at the Faculty of Veterinary Medicine and Animal Husbandry, Autonomous University of the State of Mexico. He is also a level-2 researcher. He received a Fulbright-Garcia Robles fellowship for a postdoctoral stay at the US Dairy Forage Research Center, Madison, Wisconsin, USA in 2008–2009. He received grants from Alianza del Pacifico for a stay at the University of Magallanes, Chile, in 2014, and from Consejo Nacional de Ciencia y Tecnología (CONACyT) to work in the Food and Agriculture Organization’s Animal Production and Health Division (AGA), Rome, Italy, in 2014–2015. He has collaborated with researchers from different countries and published ninety-eight journal articles. He teaches various degree courses in zootechnics, sheep production, and agricultural sciences and natural resources.\n\nDr. Ronquillo’s research focuses on the evaluation of sustainable animal diets (StAnD), using native resources of the region, decreasing carbon footprint, and applying meta-analysis and mathematical models for a better understanding of animal production.",institutionString:null,institution:{name:"Universidad Autónoma del Estado de México",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,series:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517"},editorialBoard:[{id:"175762",title:"Dr.",name:"Alfredo J.",middleName:null,surname:"Escribano",slug:"alfredo-j.-escribano",fullName:"Alfredo J. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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