\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"2272",leadTitle:null,fullTitle:"The Functioning of Ecosystems",title:"The Functioning of Ecosystems",subtitle:null,reviewType:"peer-reviewed",abstract:"The ecosystems present a great diversity worldwide and use various functionalities according to ecologic regions. In this new context of variability and climatic changes, these ecosystems undergo notable modifications amplified by domestic uses of which it was subjected to. Indeed the ecosystems render diverse services to humanity from their composition and structure but the tolerable levels are unknown. The preservation of these ecosystemic services needs a clear understanding of their complexity. The role of the research is not only to characterise the ecosystems but also to clearly define the tolerable usage levels. Their characterisation proves to be important not only for the local populations that use it but also for the conservation of biodiversity. Hence, the measurement, management and protection of ecosystems need innovative and diverse methods. For all these reasons, the aim of this book is to bring out a general view on the biogeochemical cycles, the ecological imprints, the mathematical models and theories applicable to many situations.",isbn:null,printIsbn:"978-953-51-0573-2",pdfIsbn:"978-953-51-5290-3",doi:"10.5772/2661",price:139,priceEur:155,priceUsd:179,slug:"the-functioning-of-ecosystems",numberOfPages:346,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"7e5a5f3530094a30a6870fab307c18cb",bookSignature:"Mahamane Ali",publishedDate:"April 27th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/2272.jpg",numberOfDownloads:39913,numberOfWosCitations:48,numberOfCrossrefCitations:15,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:59,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:122,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 10th 2011",dateEndSecondStepPublish:"June 7th 2011",dateEndThirdStepPublish:"October 12th 2011",dateEndFourthStepPublish:"November 11th 2011",dateEndFifthStepPublish:"March 10th 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"103960",title:"Prof.",name:"Mahamane",middleName:null,surname:"Ali",slug:"mahamane-ali",fullName:"Mahamane Ali",profilePictureURL:"https://mts.intechopen.com/storage/users/103960/images/system/103960.jpg",biography:"Prof. Ali Mahamane is a Lecturer at Abdou Moumouni University (Niger). He was born in 1964 at Kendadji, Tillabéri, Niger. He got his first degree in Agricultural Sciences from the Abdou Moumouni University and later specialised in Arid Regions Forestry (ENGREF, Montpellier, France). He pursued his studies at the University of Ouagadougou, Burkina Faso where he obtained his M. Phil in 1997. In 2000, he got a tenure appointment at the Faculty of Sciences at Abdou Moumouni University. He registered for his Ph. D thesis at the Université Libre de Bruxelles, Belgium in April 2005. He published more than 38 Scientifics articles both in national and international journals. He is National Coordinator of UNDESERT Project (Understanding and combating desertification to mitigate its impact on ecosystem services). \nPresently Ali Mahamane is Deputy Vice Chancellor and Dean of Faculty of Sciences and Technics at the University of Maradi (Niger).",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Abdou Moumouni University",institutionURL:null,country:{name:"Niger"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"841",title:"Biodiversity",slug:"environmental-sciences-ecology-biodiversity"}],chapters:[{id:"36240",title:"Autonomic Management of Networked Small-Medium Factories",doi:"10.5772/35465",slug:"autonomic-management-of-networked-small-medium-factories",totalDownloads:1448,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Flavio Bonfatti, Matteo Berselli, Luca Martinelli and Federico Stradi",downloadPdfUrl:"/chapter/pdf-download/36240",previewPdfUrl:"/chapter/pdf-preview/36240",authors:[{id:"104552",title:"Prof.",name:"Flavio",surname:"Bonfatti",slug:"flavio-bonfatti",fullName:"Flavio Bonfatti"},{id:"104561",title:"MSc",name:"Luca",surname:"Martinelli",slug:"luca-martinelli",fullName:"Luca Martinelli"},{id:"104563",title:"Dr.",name:"Federico",surname:"Stradi",slug:"federico-stradi",fullName:"Federico Stradi"},{id:"104564",title:"Dr.",name:"Matteo",surname:"Berselli",slug:"matteo-berselli",fullName:"Matteo Berselli"}],corrections:null},{id:"36241",title:"Land Cover/Use Dynamics and Vegetation Characteristics in the Rural District of Simiri (Tillabery Region, Niger)",doi:"10.5772/35335",slug:"spatial-and-temporal-dynamics-of-the-falki-pond-ecosystem-in-the-region-of-zinder-niger",totalDownloads:2005,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Karim Saley, M. 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Over the past 50 years, therapeutic advances and improvements in surgical techniques have increased the number of patients who could survive and benefit from organ transplantation. Unfortunately, the number of organs available through donation has not changed significantly. Thus, there is a growing disparity between organ supply and demand. Although efforts to enlarge the human donor pool have improved organ availability, even a massive expansion in organ donation would not ensure that a compatible organ would be available when and where necessary for a patient in need. Therefore, other alternatives besides expanded human donation are required.
A variety of efforts are making substantial progress in addressing the lack of organs. One area of research that is rapidly approaching clinical reality is xenotransplantation, the use of animal tissues and organs to treat patients [1]. Aside from the potential for creating an unlimited supply of organs, recent advancements in genome engineering technologies allows the genetic modification of animals to produce donor organs which are less prone to rejection for xenotransplantation in human patients.
Xenotransplantation experiments were described as early as the seventeenth-century [2], with sporadic attempts made to transplant a variety of animal tissues and organs into patients throughout the nineteenth and early twentieth centuries [3, 4, 5, 6, 7]. After World War II, organ transplantation from living humans was considered too high risk, and cadaveric organs were insufficient in both quality and number to meet clinical needs. Development of immunosuppressive drugs suggested the possibility that organs from more closely-related mammals could potentially be used in humans. As a consequence, xenotransplantation efforts shifted to the use of organs from primates in human patients. In the 1960s, experiments by Reemstma et al. [8, 9], Hardy et al. [10], and Starzl et al. [11, 12] showed that while it was technically possible to transplant animal organs into humans, there were still too many clinical challenges at that time for the approach to be viable. More research was required to understand and overcome the barriers to the practical application of xenotransplantation in humans.
One of the major advances in xenotransplantation research in the past few decades has been the focus on the use of pigs as donors [13]. This was based, in part, on purely practical considerations. Unlike primates, pigs are an agricultural species for which large scale breeding is well-established. In addition, the evolutionary distance between humans and pigs reduces the risk of transmission of zoonoses from pig organs to patients compared with primate organs. Most importantly, the use of porcine organs does not present the same ethical barriers as the use of non-human primate organs [14].
Although the anatomy and physiology of pig organs is closely analogous to that of humans, the advantages of porcine organ production and availability do not address the critical issue of incompatibilities of non-human tissues and organs with the human immune system [15]. Significant advancements have been made in recent years in understanding the molecular mechanisms of xenorejection responses, and a variety of genetic modifications have been made to overcome these mechanisms. Experiments transplanting pig organs into non-human primates have demonstrated a progressive improvement in organ survival and function as new genetics and drug regimens have been implemented [16]. The FDA is currently developing guidelines for clinical xenotransplantation [17], and efforts to initiate clinical trials in the near term have been announced [18].
The immune system is designed to recognize and eliminate harmful pathogens, while remaining unresponsive to host cells and beneficial microbes. The immune system can be divided into innate and adaptive responses, an interdependent set of activities which both contribute to immunity. The innate response is more immediate, broadly recognizing conserved microbial elements, such as cell wall polysaccharides, and activating a variety of cell types which attack the invading pathogens [19]. The adaptive immune response, which is typically initiated by innate response mechanisms, leads to more precise antigen-specific antibodies and immune cells that continue to control and eliminate pathogens. In addition, the adaptive response creates long-lasting immune “memory” for rapid and specific protection against future infections, as demonstrated by vaccines [20].
Despite being described as separate systems, the innate and adaptive immune responses are highly interdependent and create a layered set of defenses with increasing specificity for pathogens over time [21]. Under normal circumstances, any individual function may not eliminate a given target with 100% efficiency, but when used together in a redundant fashion can prevent nearly all infection. Although the specificity of the immune response indirectly helps to avoid recognition of host tissues, additional tolerance mechanisms are required to restrain the immune system to prevent autoreactivity. Disruptions of the balance between immunity and tolerance can lead to the immune system destroying host tissues (autoimmunity) or allowing repeated severe infections (immunodeficiency) [22].
The transplantation of foreign cells or tissues into a human host can trigger a hostile response from the immune system, leading to immune rejection. The extraordinary precision of the immune system can distinguish even minor differences between donor and recipient, so that even organs from closely related donors may be rejected. Although immunosuppressive drugs can reduce the chance of rejection of human donor organs, the massive amount of immunogenic material found in a whole organ presents an ongoing risk which requires monitoring. Because of the greater genetic differences between pigs and humans, the vigor of the rejection response is much stronger than occurs between human donors and recipients, requiring more and different solutions.
A major advantage in using pigs for xenotransplantation is the potential to manipulate the porcine genome to create donor organs that are more compatible for human patients. However, the scope of the engineering challenge in xenotransplantation is extremely large, involving a variety of genes and pathways. With so many potential targets for genetic modification, an assortment of different genome engineering strategies have been applied, including editing or deletion of porcine genes and insertion of human or engineered genes. Because of the great diversity of genome modification efforts being carried out in xenotransplantation research, representative approaches will be highlighted here as examples of the general types of the engineering strategies being employed.
Historically, mice have been subject to more and different genetic modifications than any other mammalian species, and many of the protocols described here were first developed in mice. Aside from their well-established and convenient husbandry, small size, and rapid generation times, mice also have a variety of technological advantages for genome manipulation and production. Although genetic modification has been demonstrated for multiple agricultural species, including pigs, the scale and complexity possible with mice has, until recently, not been available for pigs [23].
One advantage for the creation of mice with multiple genetic modifications is the availability of embryonic stem (ES) cells, which can be cultured
Mouse ES cells not only allow more straightforward and efficient genome engineering, but also facilitate large scale production of cloned mice. The mouse ES cells typically employed for genetic modification can be injected into very early stage embryos (blastocysts) and will aggressively populate the inner cell mass, creating viable chimeric mice which are almost entirely ES-cell derived. Since the ES cells will also contribute to the germ cells of the chimeric mice, the progeny will be highly likely to receive the genetic modifications made to the ES cells [27]. Without readily available porcine ES cells, pig cloning instead relies upon somatic cell nuclear transfer (SCNT), similar to the protocols used to create the sheep “Dolly”. In this approach, pig oocyte nuclei are replaced with nuclei from the modified primary pig cells, and embryonic development stimulated electrochemically. The embryos are transferred to female surrogates and allowed to develop. The level of complexity and effort involved leads to lower efficiencies and higher costs for porcine SCNT relative to mouse ES cell cloning. Additionally, the size and scale of the facilities required for pig cloning is significantly greater compared with mouse cloning, further limiting availability [28].
In the following sections, different types of gene modifications are described with examples of their application in porcine genome engineering for xenotransplantation.
As mentioned above, porcine cells produce molecules which are rapidly recognized by the human immune system and rejected. One straightforward approach to engineering the pig would be to simply eliminate the genes encoding reactive genes by either disrupting or removing the coding sequence. Several of the technical routes which can be employed to accomplish this are discussed below.
Gene knockout (KO) approaches developed for use in mouse ES cells generally rely upon homologous recombination to replace a region of genomic DNA with a heterologous DNA sequence, which interrupts the function of the target gene [29]. To accomplish this, a DNA vector is generated with the heterologous DNA flanked on either side by sequences identical to regions flanking the genomic region to be eliminated. When introduced into mouse ES cells, the flanking sequences of the DNA vector first align with the cognate regions of the genome on either side of the target gene, after which the homologous recombination machinery replaces the genomic target with the heterologous DNA vector sequence found between the flanking sequences.
Because homologous recombination occurs at a relatively low rate, in order to identify properly targeted cells within the larger cell population, it is common to include a gene in the heterologous DNA to be inserted into the genome, which, once properly inserted, allows selection of the desired cells. For example, genes which confer resistance to drugs which kill mammalian cells (neomycin hygromycin or puromycin resistance), or genes encoding molecules that enable cells to be isolated via flow cytometry (green fluorescent protein or novel cell surface markers), allow isolation of even extremely rare targeted cells from a large mixed population [30].
The use of gene KO approaches was one of the earliest successes in pig genetic modification for xenotransplantation [31]. The porcine genome encodes proteins that can be substantially different from their human counterparts, or that carry additional modifications which are not present in humans and can induce immune responses. These molecules are collectively referred to as “xenoantigens” [32]. Some of the most reactive of these targets are carbohydrate molecules found as post-translational modifications to proteins observed in pig, but not human, cells. Human serum can contain high levels of pre-existing antibodies specific for these porcine-specific glycan epitopes, leading to the destruction of pig cells expressing these molecules through antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) mechanisms [33]. It is not entirely clear why human serum carries antibodies to these particular carbohydrates; one proposal is that the xenoantigens are related to glycans found in the cell walls of pathogens, others suggest that the human dietary consumption of pork causes antibody generation to the porcine-specific molecules [34]. Because the novel carbohydrate structures are created by specific glycosylation enzymes, it is possible to eliminate the gene responsible for the enzymatic activity and prevent the xenoantigen from being expressed by pig cells.
The GGTA1 gene encodes the enzyme responsible for creating the highly reactive glycan Gal alpha (1,3) Gal epitope in pigs [35]. The KO of the GGTA1 gene is one of the earliest genetic modifications of pigs for application in xenotransplantation, and resulted in greatly reduced human antibody recognition of porcine cells [36, 37]. However, ablation of the GGTA1 gene alone did not completely eliminate porcine cell recognition by human serum antibodies. The enzymes responsible for other xenoantigens, such as CMAH (cytidine monophosphate-N-acetylneuraminic acid hydroxylase critical for Neu5Gc biosynthesis) and B4GALNT2 (beta 1,4 N-acetylgalactosaminyltransferase), have been identified as sources of porcine-specific epitopes bound by antibodies found in human serum. In each case, the deletion of the gene responsible for creating the specific glycan leads to greatly decreased recognition of porcine cells by antibodies in human serum, and reduction in complement-mediated destruction [38, 39].
Another subset of xenoantigens is the swine leukocyte antigens (SLA), the physical and functional equivalent of the human leukocyte antigens (HLA) [40]. Much like the case for human HLA, the SLA genes are highly diverse and individual patients will have a variable level of cross-reactive antibodies in their serum for a given set of SLA genes [41]. Although typing of patients and porcine donors to find the best HLA-SLA matches would be similar to the current system used for determining allotransplant cross-reactivity [42], use of gene targeting or editing technologies could easily eliminate the genes encoding SLA entirely. However, unlike the glycan epitopes described above, the SLA have a critical role in antigen presentation as part of the immune response, and thus the deletion of SLA could create risks of immune deficiencies that outweigh their risks as xenoantigens. Instead, alternate approaches seek to create engineered SLA proteins lacking the epitopes responsible for the immunogenicity while maintaining their antigen presentation functions [43].
The ease and efficiency of creating gene KO has improved recently through the use of engineered molecules to create genome disruptions in a process referred to as “gene editing”. These novel molecules can be designed to generate double-strand DNA breaks at virtually any chosen genomic site
The most prominent of these novel tools for gene editing are Zinc Finger Nucleases (ZFN), Transcription Activator-Like Effector Nuclease (TALEN) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), each of which consists of two regions: a sequence-specific DNA binding domain and an enzymatic function that creates a double-strand break in the target DNA [45, 46, 47]. For ZFN and TALEN, the synthetic DNA binding domain is created by repetitive protein modules which can be joined combinatorially to recognize a particular DNA sequence. Both approaches, while successful, require a significant investment of time and resources to identify functional molecules. CRISPR, like ZFN and TALEN, has the ability to generate double-strand DNA breaks, however, the DNA binding domain relies upon RNA base-pairing with target DNA for its precision. The use of an RNA to guide specificity greatly improves the speed and efficiency in identifying optimal molecules at a much lower cost, which has led to its rapid adoption in genome engineering [48, 49].
The use of CRISPR for the rapid modification of the pig genome was recently demonstrated with the ablation of porcine endogenous retroviral (PERV) sequences. The pig genome carries 25 or more copies of these gamma retroviral sequences, which are transmitted from parent to offspring through inheritance. Application of CRISPR was able to eliminate the PERV sequences from the genome of porcine cells [50]. Although the potential risk of infectious disease from porcine organs caused by PERV sequences in xenotransplantation is debatable, the results show the ability of CRISPR to target multiple, homologous loci throughout the genome. A key question that has arisen regarding large scale CRISPR targeting at multiple genomic sites is whether significant numbers of off-target double-stranded breaks were introduced, which may create unexpected mutations in the resulting pigs [51]. Nonetheless, the ease of use of CRISPR has resulted in widespread adoption for genome engineering in xenotransplantation.
Gene deletion has been instrumental in the advancement of xenotransplantation, however, there are limitations to its application; the genes of interest must be non-essential to pig viability, development, fertility and, most importantly, organ function. The number of distinct loci to be targeted is also a serious consideration, since independently-assorting alleles will be challenging to breed together in a reasonable timeframe. To address these concerns, additional engineering strategies are required as discussed below.
Gene KO and editing techniques have been used for ablation of xenoantigen genes but do not address the need to express human or synthetic genes in pig cells and organs. Unlike gene deletions, gene insertions require heterologous DNA to be introduced into the genome in a manner that allows subsequent expression of the gene(s) encoded by the inserted DNA. Because they are being transferred into the genome from another source, these novel genes are referred to as “transgenes” (TG), whether they are derived from natural or synthetic sequences. The general approaches to introduce TG into the genome are detailed below.
One of the earliest types of genetic modification described in mammals was insertion of DNA into the target genome by random integration. After transfection of DNA into nearly all mammalian cells, some portion of the heterologous DNA can be found incorporated at random sites in the genome [52]. The precise process for this is unclear, but presumably is a result of aberrant repair mechanisms. One hypothesis is that endogenous NHEJ machinery recognizes breaks in the genome and fortuitously utilizes the relatively higher concentration of the heterologous DNA vector sequences to repair the break [53], resulting in the insertion of the TG into the genome.
Agricultural species, including pig, were some of the earliest TG animals described, establishing the utility of this approach [54]. For xenotransplantation, several of the initial TG approaches focused on inhibiting human antibody-mediated damage of porcine organs. The binding of human antibodies to porcine cells leads to complement pathway activation and subsequent cell ablation [55]. The complement function is controlled by several proteins, such as CD46, CD55 and CD59, referred to as complement regulatory proteins (CRPs). The CRPs are broadly expressed on many different cell types to prevent harm from complement activity by raising the threshold of antibody binding required for complement pathway induction [56]. The transgenic expression of human CRPs in pigs appears to overcome human complement activity, and may have the potential to reduce, or even eliminate, the need for xenoantigen KOs. By placing the human CRP TGs under the control of strong gene expression elements, the CRP protein levels on the porcine cells can be much higher than CRP levels on normal human cells, further increasing resistance to complement-mediated destruction [57].
Pig lineages developed by multiple labs have been engineered to express human CRPs, individually or in combination. In most cases, the porcine cells appeared to be more resistant to complement-mediated destruction, and organs from TG animals survived longer in xenotransplant experiments in non-human primates [58, 59, 60]. Because each of the CRPs control a different part of the complement pathway, the use of multiple human TGs was more effective in protecting cells from complement-mediated destruction than individual TGs [61]. Together with the removal of key xenoantigens, the expression of human CRPs by porcine cells has greatly reduced the effects of human serum antibodies on xenografts.
Because random insertion of DNA does not require homologous recombination, it is relatively rapid and efficient to produce transgenic animals [62]. The process is so efficient that the selection methods that are critical for gene KO described above are often unnecessary for TG. Despite the speed and ease of generation, random integration of TGs has several drawbacks. Variabilities in genome structure can affect the expression level of genes inserted at distinct chromosomal regions, such that identical TGs may express at very different levels depending upon their specific location [63]. Furthermore, multiple copies of a given TG may be inserted into the genome at a single site, creating concatenated repeats which can be unstable and yield variable expression levels [64]. Random TG insertion may occur within or near endogenous genes and alter or inactivate their function, leading to tumorigenesis, instability or even lethality [65].
The development of techniques for precise gene KO by homologous recombination has been adapted for site-specific gene insertion or gene knock-in (KI). Similar to the KO vectors described above, the gene to be introduced is flanked by DNA sequences that are identical to regions of the genome to be targeted. After introduction of the heterologous DNA vector, the regions of DNA sequence identity are aligned with the target genome sequence, after which the homologous recombination machinery catalyzes reactions which swap the endogenous genomic DNA with the heterologous DNA within the construct. If the recombination event occurs with high fidelity, the gene of interest will functionally replace the gene that was removed [24]. Similar to gene KO, this approach is much less efficient than random TG integration. Therefore, vectors carrying the TG are often designed to incorporate selectable markers, similar to those used for gene KO, to allow the identification of cells carrying the desired TG in the genome. In this case, both targeted and randomly integrated TGs may be selected, requiring additional assays, such as PCR or Southern blotting, to distinguish between sequence-specific and random insertion events [30].
As described above for gene KO, specific targeting is more efficient in murine ES cells, which express the enzymatic machinery necessary for homologous recombination, than is currently possible for pig primary cells. Insertion of heterologous DNA into the mammalian genome is believed to be driven by endogenous DNA repair mechanisms, presumably in response to DNA breaks, whether randomly via NHEJ, or specifically via homologous recombination [66]. The deliberate introduction of double-stranded DNA breaks at the desired integration site should therefore improve the efficiency of heterologous DNA insertion by activating and recruiting the cellular repair machinery. Application of ZFN, TALEN and CRISPR technologies have shown that homologous recombination efficiencies are improved when one or more double-strand DNA breaks are introduced into the genome at the desired site of insertion [67] with CRISPR exhibiting bi-allelic targeting rates as high as 90% [68]. The use of these more advanced genome engineering tools has greatly improved the rates and specificity of both gene deletion and gene insertion in genomes.
Gene insertion by homologous recombination for xenotransplantation has not advanced as rapidly as other approaches, in part due to the challenges of using primary porcine cells, for which the efficiencies can be extremely low, particularly with large DNA constructs. Use of improved genome engineering tools with increased targeting efficiencies have already been applied in pig and will continue to grow in impact [69]. However, even with improved efficiencies of gene insertion, breeding pigs with multiple, independently segregating loci is challenging. The number of litters required to produce animals bearing all of the genetic modifications greatly increases with each additional locus, which can be impractical for large animals such as pigs. Therefore, the ability to insert the maximal amount of genetic information into the genome in the minimal number of steps, as discussed below, is highly valuable.
The most straightforward example of multigenic targeting at a single site takes advantage of the observation that multiple DNA vectors co-transfected into cells will tend to insert together at a given genome site. This approach was used successfully to simultaneously introduce as many as five large transgenes in a single step into porcine cells [70]. Although difficulties in producing mature cloned pigs limited the study to animals with fewer integrated genes, the study demonstrated the feasibility of rapidly making animals with multiple TG.
Another, relatively less complicated, way to introduce multiple TG is to generate large DNA constructs bearing multiple TGs for integration at random into the genome [71]. This greatly reduces the complexity of screening, while increasing the efficiency of insertion, but still relies upon random integrants which can have variable TG copy numbers and expression levels.
Multiple genomic regions have been defined, such as Rosa26, which allow expression of heterologous genes at similar levels regardless of cell type. These “safe harbor” regions are believed to have a chromatin structure that is more easily accessible to the gene expression machinery, regardless of cell type. Targeting at porcine homologs of murine safe harbor sites such as Rosa26 has been described and demonstrates the utility of this approach [70, 72]. On a practical level, the use of safe harbor sites yields more reproducible gene expression than random TG insertions, so fewer lineages are required to select animals with desired TG levels. Furthermore, the defined location and copy number of TG inserted at a safe harbor site makes breeding and genotyping more straightforward, and is expected to provide a less complicated regulatory pathway for clinical use.
As DNA synthesis and assembly has improved, increasingly large DNA constructs encoding a variety of TG are possible, however, as the size of the DNA increases, the rate of insertion decreases. Considering the lower insertion rates observed for large animals such as pig, alternate approaches are necessary to incorporate larger DNAs into the genome.
Bacteriophage- and yeast-derived site-specific recombinases are, as the name suggests, proteins which catalyze recombination between two specific DNA recognition sites, small (<50 base pair) sequences that are unique to the recombinase being used. The recombination event is highly efficient, in some cases eliminating the need for selection genes, and allowing large DNA constructs to be inserted at a much higher frequency than possible for homologous recombination [73].
One limitation for the use of site-specific recombination is the need for a recognition sequence to be present in the target genome at the desired locus. This requires a preceding step in which the recognition site is engineered into the genome using less efficient homologous recombination. Therefore, the gain in efficiency for introduction of large DNA constructs may be offset by the need for insertion of the recombinase recognition site into the genome. Despite this constraint, the potential for site-specific recombination into a defined locus has been demonstrated in pigs [70] and provides a route for more rapid complex genetic modifications.
The advancements in genome engineering, both in general and in their application to xenotransplantation, have been significant, but many needs remain to be addressed. As new genome engineering tools are identified and further refined, improvement of targeting efficiencies will allow more sophisticated modifications of the pig genome. Ideally, the pig genome will become as readily manipulated as the mouse, allowing researchers to further leverage approaches shown to be effective in murine models.
One major technological difference in the genetic modification of mice and pigs (and many other mammalian species) is the lack of ES cells possessing significant rates of homologous recombination that can be grown in culture for extended periods and subjected to multiple manipulations without losing the ability to produce viable pigs. Efforts to identify natural or induced pluripotent stem cells (iPSC) suitable for these purposes have been described, but have yet to demonstrate practical application for porcine genome engineering [74]. Ongoing work will be required to identify and validate cells which meet these needs.
The function of the TGs themselves can also be further improved. The majority of TG constructs used in pigs have used constitutive promoters to drive high level expression of the proteins encoded by the TGs. In some cases, such as CRPs, this approach may be useful, however, overexpression of TGs which inhibit critical immune processes may create risks of immune deficiency and infections. For this reason, use of expression control elements which can turn on and off TG activity is of increasing interest in xenotransplantation. There are multiple examples of inducible promoters employed in mice which can be controlled by exogenously applied small molecules (such as the tetracycline repressor system), or by endogenous signals (such as promoters for innate immune response genes) [75]. Advanced DNA synthesis and assembly methods also allow synthetic biology approaches to create novel signaling pathways and networks not present in nature.
Immune tolerance is another very active area in xenotransplantation research. As the molecular mechanisms controlling the balance between immunity and tolerance are further elucidated, manipulation of the human immune system itself to specifically reduce or eliminate responses to porcine targets, while leaving intact immunity to infectious diseases, will help overcome xenorejection. Multiple approaches are currently being tested and genome targets identified to encourage human immune tolerance of porcine cells and tissues [76, 77].
The speed and ease of genome engineering technologies has helped to overcome many of the limitations for the use of pig organs for xenotransplantation. Despite recent achievements, a key question remains: which combination of genetic modifications is most critical to make a pig organ useful for xenotransplantation? Ongoing experiments seek to address this question, but the answers are likely to be complex and dependent upon the type of organ, the specific immune mechanisms involved, and perhaps other factors that are not yet defined. It is very likely that the first set of genetic modifications of pigs used for xenotransplantation in humans will not be the final set, as the understanding of the mechanisms of xenorejection increases and better strategies developed to influence the human immune response. Continuing progress in genome engineering technologies of pigs will allow the creation of the more complex modifications necessary to meet these demands. Although much remains to be done, it is clear that given the current rate of progress, overcoming the crisis of human organ shortage with unlimited rejection-free porcine organs is rapidly growing closer to reality.
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
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\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
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The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
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\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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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. 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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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Hair is a derivative of the epidermis and consists of two distinct parts: the follicle and the hair shaft. The follicle is the essential unit for the generation of hair. The hair shaft consists of a cortex and cuticle cells, and a medulla for some types of hairs. Hair follicle has a continuous growth and rest sequence named hair cycle. The duration of growth and rest cycles is coordinated by many endocrine, vascular and neural stimuli and depends not only on localization of the hair but also on various factors, like age and nutritional habits. Distinctive anatomy and physiology of hair follicle are presented in this chapter. Extensive knowledge on anatomical and physiological aspects of hair can contribute to understand and heal different hair disorders.",book:{id:"5461",slug:"hair-and-scalp-disorders",title:"Hair and Scalp Disorders",fullTitle:"Hair and Scalp Disorders"},signatures:"Bilgen Erdoğan",authors:[{id:"193661",title:"Dr.",name:"Bilgen",middleName:null,surname:"Erdoğan",slug:"bilgen-erdogan",fullName:"Bilgen Erdoğan"}]},{id:"42520",doi:"10.5772/55026",title:"Discovery and Delineation of Dermatan 4-O-Sulfotransferase-1 (D4ST1)-Deficient Ehlers-Danlos Syndrome",slug:"discovery-and-delineation-of-dermatan-4-o-sulfotransferase-1-d4st1-deficient-ehlers-danlos-syndrome",totalDownloads:2824,totalCrossrefCites:4,totalDimensionsCites:8,abstract:null,book:{id:"3038",slug:"current-genetics-in-dermatology",title:"Current Genetics in Dermatology",fullTitle:"Current Genetics in Dermatology"},signatures:"Tomoki Kosho",authors:[{id:"153541",title:"Dr.",name:"Tomoki",middleName:null,surname:"Kosho",slug:"tomoki-kosho",fullName:"Tomoki Kosho"}]},{id:"52801",doi:"10.5772/66156",title:"Psychosocial Aspects of Hair Loss",slug:"psychosocial-aspects-of-hair-loss",totalDownloads:2525,totalCrossrefCites:6,totalDimensionsCites:7,abstract:"Hair loss (alopecia) is a common dermatological condition that affects men and women of all ages. It can be due to a wide variety of causes including scarring and non-scarring diseases. Although alopecia is not a life-threatening condition, it has significant psychological impact on the quality of life. Mental disorders such as anxiety, depression, social phobia, posttraumatic stress disorder, and suicidal thoughts are increased among alopecia patients. On the other hand, alopecia frequency increases during the course of psychological disorders. In this chapter, psychosocial aspects of hair loss and the relationship between alopecia and psychological disorders are reviewed.",book:{id:"5461",slug:"hair-and-scalp-disorders",title:"Hair and Scalp Disorders",fullTitle:"Hair and Scalp Disorders"},signatures:"Hilal Gokalp",authors:[{id:"193580",title:"M.D.",name:"Hilal",middleName:null,surname:"Gokalp",slug:"hilal-gokalp",fullName:"Hilal Gokalp"}]},{id:"62733",doi:"10.5772/intechopen.79807",title:"Ethosomes: An Exciting and Promising Alcoholic Carrier System for Treating Androgenic Alopecia",slug:"ethosomes-an-exciting-and-promising-alcoholic-carrier-system-for-treating-androgenic-alopecia",totalDownloads:1075,totalCrossrefCites:1,totalDimensionsCites:5,abstract:"Androgenetic alopecia (male-pattern hair loss) is characterized by the deposition of dihydrotestosterone at the pilosebaceous unit of the scalp. Oral administration of drugs (like finasteride) which can reverse androgenic alopecia causes undesired effects to the body. Targeting these drugs directly to the pilosebaceous unit of the scalp will enhance the pharmacological response at the desired site by reducing undesired systemic side effects. This chapter discusses about ethosomes, a specially tailored ethanolic vesicular carriers which can efficiently deliver various drugs with different physicochemical properties to and through the skin. The unique characteristics of the ethosomal carriers, their composition, preparation methods, and the mechanism of permeation, safety, and practical experience (finasteride and herbal extracts) have been discussed in detail.",book:{id:"6961",slug:"alopecia",title:"Alopecia",fullTitle:"Alopecia"},signatures:"Veintramuthu Sankar, Santhanam Ramesh and Karthik Siram",authors:[{id:"254541",title:"Prof.",name:"Sankar",middleName:null,surname:"Veintramuthu",slug:"sankar-veintramuthu",fullName:"Sankar Veintramuthu"},{id:"260986",title:"Mr.",name:"Karthik",middleName:null,surname:"Siram",slug:"karthik-siram",fullName:"Karthik Siram"},{id:"260991",title:"Dr.",name:"Santhanam",middleName:null,surname:"Ramesh",slug:"santhanam-ramesh",fullName:"Santhanam Ramesh"}]},{id:"54160",doi:"10.5772/66747",title:"Cosmetic Procedures in the Treatment of Alopecia",slug:"cosmetic-procedures-in-the-treatment-of-alopecia",totalDownloads:3367,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Alopecia has a significant negative impact on the quality of life. Unfortunately, there is no satisfactory cure for most types of alopecia. Alopecia is divided into cicatricial and noncicatricial types. Androgenetic alopecia, alopecia areata, and telogen effluvium are common forms of noncicatricial alopecias. In order to treat or improve the appearance, various procedures that are being applied for different types of alopecia including mesotherapy, microneedling, platelet‐rich plasma, low‐level light therapy, and stem‐cell therapy with variable outcomes are reviewed in this chapter.",book:{id:"5461",slug:"hair-and-scalp-disorders",title:"Hair and Scalp Disorders",fullTitle:"Hair and Scalp Disorders"},signatures:"Selda Pelin Kartal, Cemile Altunel and Bilgen Gencler",authors:[{id:"72686",title:"Prof.",name:"Selda Pelin",middleName:null,surname:"Kartal",slug:"selda-pelin-kartal",fullName:"Selda Pelin Kartal"}]}],mostDownloadedChaptersLast30Days:[{id:"53880",title:"Anatomy and Physiology of Hair",slug:"anatomy-and-physiology-of-hair",totalDownloads:7768,totalCrossrefCites:5,totalDimensionsCites:8,abstract:"Hair is one of the characteristic features of mammals and has various functions such as protection against external factors; producing sebum, apocrine sweat and pheromones; impact on social and sexual interactions; thermoregulation and being a resource for stem cells. Hair is a derivative of the epidermis and consists of two distinct parts: the follicle and the hair shaft. The follicle is the essential unit for the generation of hair. The hair shaft consists of a cortex and cuticle cells, and a medulla for some types of hairs. Hair follicle has a continuous growth and rest sequence named hair cycle. The duration of growth and rest cycles is coordinated by many endocrine, vascular and neural stimuli and depends not only on localization of the hair but also on various factors, like age and nutritional habits. Distinctive anatomy and physiology of hair follicle are presented in this chapter. Extensive knowledge on anatomical and physiological aspects of hair can contribute to understand and heal different hair disorders.",book:{id:"5461",slug:"hair-and-scalp-disorders",title:"Hair and Scalp Disorders",fullTitle:"Hair and Scalp Disorders"},signatures:"Bilgen Erdoğan",authors:[{id:"193661",title:"Dr.",name:"Bilgen",middleName:null,surname:"Erdoğan",slug:"bilgen-erdogan",fullName:"Bilgen Erdoğan"}]},{id:"53947",title:"Infections, Infestations and Neoplasms of the Scalp",slug:"infections-infestations-and-neoplasms-of-the-scalp",totalDownloads:3475,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This chapter reviews common cutaneous infections, infestations, and neoplasms of the scalp. Infections of the scalp are subdivided into three major groups. The most seen are: (1) Bacterial: Folliculitis, folliculitis decalvans, tufted hair folliculitis and acne keloidalis nuchae. (2) Fungal: Tinea capitis, favus and kerion celsi. (3) Protozoal: Syphilitic alopecia. Pediculosis capitis is the most common worldwide infestation of the scalp. The neoplasms of the scalp are large group of different diseases due to arising different origin. In the following section, trichilemmal cyst, proliferating trichilemmal cyst, nevus sebaceous and cylindroma are discussed in detail.",book:{id:"5461",slug:"hair-and-scalp-disorders",title:"Hair and Scalp Disorders",fullTitle:"Hair and Scalp Disorders"},signatures:"Filiz Canpolat",authors:[{id:"191617",title:"Associate Prof.",name:"Filiz",middleName:null,surname:"Canpolat",slug:"filiz-canpolat",fullName:"Filiz Canpolat"}]},{id:"53525",title:"Trichoscopy and Trichogram",slug:"trichoscopy-and-trichogram",totalDownloads:2609,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Hair and scalp examination techniques can be classified into three categories: noninvasive methods (clinical history, general examination, photography, hair count, weighing shed hair, pull test, global hair counts, dermoscopy, electron microscopy, laser scanning microscopy, etc.); semi‐invasive methods (the trichogram, unit areatrichogram); and invasive methods (biopsies in cicatritial alopecia). Scalp dermoscopy or trichoscopy is one of thenoninvasive techniques for the evaluation of patients with hair loss that allows for magnified visualization of the hair and scalp skin. It may be performed with a manual dermoscope (10× magnification) or a videodermoscope (up to 1000× magnification). This method is simple, quick, and easy to perform, is well‐accepted by patients, and is useful for monitoring treatment, determining severity of the disease and follow‐up. It is a simple, minimally invasive and rapid technique for measuring hair follicle activity. Trichogram represents a semi‐invasive technique for the evaluation of patients with hair loss that allows the microscopic examination of hairs plucked from the scalp and provides information about the state of the proximal end of the hair shaft and the distal end. The trichogram is a useful complementary tool for clinical evaluation, diagnosis, and the monitoring of treatment response.",book:{id:"5461",slug:"hair-and-scalp-disorders",title:"Hair and Scalp Disorders",fullTitle:"Hair and Scalp Disorders"},signatures:"Melike Kibar",authors:[{id:"189899",title:"Dr.",name:"Melike",middleName:null,surname:"Kibar Ozturk",slug:"melike-kibar-ozturk",fullName:"Melike Kibar Ozturk"}]},{id:"42524",title:"Hereditary Palmoplantar Keratosis",slug:"hereditary-palmoplantar-keratosis",totalDownloads:4547,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"3038",slug:"current-genetics-in-dermatology",title:"Current Genetics in Dermatology",fullTitle:"Current Genetics in Dermatology"},signatures:"Tamihiro Kawakami",authors:[{id:"155091",title:"Associate Prof.",name:"Tamihiro",middleName:null,surname:"Kawakami",slug:"tamihiro-kawakami",fullName:"Tamihiro Kawakami"}]},{id:"63066",title:"Pharmacological Treatment of Alopecia",slug:"pharmacological-treatment-of-alopecia",totalDownloads:1440,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"In this chapter, we will explore non-surgical treatments of alopecia. Unlike many other areas of medicine, pharmacological treatments for alopecia are relatively new. There are only two treatments which are approved by the Food and Drug Administration (FDA); the rest are drugs developed for other indications which have gained popular off-label use to promote hair growth. The reasons for this are many, including the designation of alopecia by the FDA as a cosmetic disease. This designation has restricted alopecia development programs to compounds with virtually no side effects. Unfortunately, it has also led to off-label use of far more dangerous compounds as alopecia treatments, without the benefit of controlled trials. There is a growing recognition that alopecia, particularly alopecia areata and chemotherapy-induced alopecia, are disorders which significantly alter the quality of life, similar to acne vulgaris and psoriasis, and merit treatment accordingly. There have also been several recent advances in our understanding of the hair cycle, revealing new targets for developing alopecia therapies. As a result, there is a more robust slate of programs for developing new pharmacological treatments for alopecia. 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. 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Topics include, but are not limited to: Advanced techniques of cellular and molecular biology (Molecular methodologies, imaging techniques, and bioinformatics); Biological activities at the molecular level; Biological processes of cell functions, cell division, senescence, maintenance, and cell death; Biomolecules interactions; Cancer; Cell biology; Chemical biology; Computational biology; Cytochemistry; Developmental biology; Disease mechanisms and therapeutics; DNA, and RNA metabolism; Gene functions, genetics, and genomics; Genetics; Immunology; Medical microbiology; Molecular biology; Molecular genetics; Molecular processes of cell and organelle dynamics; Neuroscience; Protein biosynthesis, degradation, and functions; Regulation of molecular interactions in a cell; Signalling networks and system biology; Structural biology; Virology and microbiology.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",keywords:"Omics (Transcriptomics; Proteomics; Metabolomics), Molecular Biology, Cell Biology, Signal Transduction and Regulation, Cell Growth and Differentiation, Apoptosis, Necroptosis, Ferroptosis, Autophagy, Cell Cycle, Macromolecules and Complexes, Gene Expression"},{id:"15",title:"Chemical Biology",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors"},{id:"17",title:"Metabolism",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation"},{id:"18",title:"Proteomics",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:null},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"chapter.detail",path:"/chapters/29416",hash:"",query:{},params:{id:"29416"},fullPath:"/chapters/29416",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()