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Yasin, Sulaiman W. Harun and Hamzah Arof",coverURL:"https://cdn.intechopen.com/books/images_new/2019.jpg",editedByType:"Edited by",editors:[{id:"294347",title:"Dr.",name:"Moh",surname:"Yasin",slug:"moh-yasin",fullName:"Moh Yasin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"28574",title:"Rare-Earth Doped Optical Fibers",slug:"rare-earth-doped-optical-fibers",signatures:"Efraín Mejía-Beltrán",authors:[{id:"68890",title:"Dr.",name:"Efraín",middleName:null,surname:"Mejía Beltrán",fullName:"Efraín Mejía Beltrán",slug:"efrain-mejia-beltran"}]},{id:"28575",title:"Fabrication of Large Core Yb2O3 Doped Phase Separated Yttria-Alumino Silicate Nano-Particles Based Optical Fiber for Use as Fiber Laser",slug:"fabrication-of-large-core-yb2o3-doped-phase-separated-yttria-alumino-silicate-nano-particles-based-o",signatures:"M. C. Paul, A. V. Kir’yanov, S. Bysakh, S. Das, M. Pal, S. K. Bhadra, M. S. Yoo, A. J. Boyland and J. K. 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Kashou",authors:[{id:"77988",title:"Dr.",name:"Nasser",middleName:"H",surname:"Kashou",fullName:"Nasser Kashou",slug:"nasser-kashou"},{id:"83317",title:"Dr.",name:"Chemseddine",middleName:null,surname:"Mansouri",fullName:"Chemseddine Mansouri",slug:"chemseddine-mansouri"}]},{id:"28585",title:"Novel Conductive and Transparent Optical Fiber Probe for Multifunctional Scanning Tunneling Microscopy",slug:"multifunctional-fiber-",signatures:"Guo Xinli and Fujita Daisuki",authors:[{id:"68602",title:"Prof.",name:"Xinli",middleName:null,surname:"Guo",fullName:"Xinli Guo",slug:"xinli-guo"}]},{id:"28586",title:"Applications of Optical Fibers to Spectroscopy: Detection of High Explosives and Other Threat Chemicals",slug:"applications-of-optical-fibers-to-spectroscopy",signatures:"Natalie Gaensbauer, Madeline Wrable-Rose, Gabriel Nieves-Colón, Migdalia Hidalgo-Santiago, Michael Ramírez, William Ortiz, Leonardo C. Pacheco-Londoño and Samuel P. Hernandez-Rivera",authors:[{id:"23018",title:"Dr.",name:"Samuel P.",middleName:null,surname:"Hernandez-Rivera",fullName:"Samuel P. Hernandez-Rivera",slug:"samuel-p.-hernandez-rivera"},{id:"77313",title:"Ms.",name:"Natalie",middleName:null,surname:"Gaensbauer",fullName:"Natalie Gaensbauer",slug:"natalie-gaensbauer"},{id:"77315",title:"Mr.",name:"William",middleName:null,surname:"Ortiz-Rivera",fullName:"William Ortiz-Rivera",slug:"william-ortiz-rivera"},{id:"77317",title:"Dr.",name:"Leonardo C.",middleName:null,surname:"Pacheco-Londoño",fullName:"Leonardo C. Pacheco-Londoño",slug:"leonardo-c.-pacheco-londono"},{id:"77318",title:"Dr.",name:"Michael L.",middleName:null,surname:"Ramirez-Cedeno",fullName:"Michael L. 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S. Lim, S. W. Harun, H. Arof and H. Ahmad",authors:[{id:"14201",title:"Dr.",name:"Sulaiman Wadi",middleName:null,surname:"Harun",fullName:"Sulaiman Wadi Harun",slug:"sulaiman-wadi-harun"}]},{id:"28591",title:"Influence of Current Pulse Shape on Directly Modulated Systems using Positive and Negative Dispersion Fibers",slug:"influence-of-current-pulse-shape-on-directly-modulated-systems-using-positive-and-negative-dispersio",signatures:"Paloma R. Horche and Carmina del Río Campos",authors:[{id:"44022",title:"Dr.",name:"Paloma",middleName:null,surname:"Rodríguez Horche",fullName:"Paloma Rodríguez Horche",slug:"paloma-rodriguez-horche"},{id:"98353",title:"Dr.",name:"Carmina",middleName:null,surname:"Del Rio Campos",fullName:"Carmina Del Rio Campos",slug:"carmina-del-rio-campos"}]},{id:"28592",title:"Mechanical Properties of Optical Fibers",slug:"mechanical-properties-of-optical-fibers",signatures:"Paulo Antunes, Fátima Domingues, Marco Granada and Paulo André",authors:[{id:"49291",title:"Dr.",name:"Paulo",middleName:null,surname:"André",fullName:"Paulo André",slug:"paulo-andre"},{id:"52661",title:"Dr.",name:"Maria",middleName:"Fátima",surname:"Domingues",fullName:"Maria Domingues",slug:"maria-domingues"},{id:"72988",title:"Dr.",name:"Paulo",middleName:"Fernando Da Costa",surname:"Antunes",fullName:"Paulo Antunes",slug:"paulo-antunes"},{id:"72989",title:"BSc.",name:"Marco",middleName:null,surname:"Granada",fullName:"Marco Granada",slug:"marco-granada"}]},{id:"28593",title:"Fiber Fuse Propagation Behavior",slug:"fiber-fuse-propagation-behavior",signatures:"Shin-ichi Todoroki",authors:[{id:"66429",title:"Dr.",name:"Shin-Ichi",middleName:null,surname:"Todoroki",fullName:"Shin-Ichi Todoroki",slug:"shin-ichi-todoroki"}]},{id:"28594",title:"Radiation Induced by Charged Particles in Optical Fibers",slug:"radiation-induced-by-charged-particles-in-optical-fibres",signatures:"Xavier Artru and Cédric Ray",authors:[{id:"76878",title:"Dr.",name:"Xavier",middleName:null,surname:"Artru",fullName:"Xavier Artru",slug:"xavier-artru"},{id:"77456",title:"Prof.",name:"Cédric",middleName:null,surname:"Ray",fullName:"Cédric Ray",slug:"cedric-ray"}]},{id:"28595",title:"Non Linear Optic in Fiber Bragg Grating",slug:"non-linear-optic-in-fiber-bragg-grating",signatures:"Toto Saktioto and Jalil Ali",authors:[{id:"103613",title:"Dr.",name:"Toto",middleName:null,surname:"Saktioto",fullName:"Toto Saktioto",slug:"toto-saktioto"}]},{id:"28596",title:"Optical Fibers and Optical Fiber Sensors Used in Radiation Monitoring",slug:"optical-fibers-and-optical-fiber-sensors-used-in-radiation-monitoring",signatures:"Dan Sporea, Adelina Sporea, Sinead O’Keeffe, Denis McCarthy and Elfed Lewis",authors:[{id:"5392",title:"Dr.",name:"Dan",middleName:null,surname:"Sporea",fullName:"Dan Sporea",slug:"dan-sporea"},{id:"85843",title:"Dr.",name:"Adelina",middleName:null,surname:"Sporea",fullName:"Adelina Sporea",slug:"adelina-sporea"},{id:"85844",title:"Dr.",name:"Sinéad",middleName:null,surname:"O'Keeffe",fullName:"Sinéad O'Keeffe",slug:"sinead-o'keeffe"},{id:"85845",title:"BSc.",name:"Denis",middleName:null,surname:"McCarthy",fullName:"Denis McCarthy",slug:"denis-mccarthy"},{id:"85846",title:"Prof.",name:"Elfed",middleName:null,surname:"Lewis",fullName:"Elfed Lewis",slug:"elfed-lewis"}]},{id:"28597",title:'Nanoparticles On A String – Fiber Probes as "Invisible" Positioners for Nanostructures',slug:"nanoparticles-on-a-string-fiber-probes-as-invisible-positioners-for-nanostructures",signatures:"Phillip Olk",authors:[{id:"73889",title:"Dr.",name:"Phillip",middleName:null,surname:"Olk",fullName:"Phillip Olk",slug:"phillip-olk"}]}]}],publishedBooks:[{type:"book",id:"1533",title:"Nd YAG Laser",subtitle:null,isOpenForSubmission:!1,hash:"db0c2af1b51a92668c5ab54719f12745",slug:"nd-yag-laser",bookSignature:"Dan C. Dumitras",coverURL:"https://cdn.intechopen.com/books/images_new/1533.jpg",editedByType:"Edited by",editors:[{id:"114118",title:"Dr.",name:"Dan C.",surname:"Dumitras",slug:"dan-c.-dumitras",fullName:"Dan C. Dumitras"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1537",title:"Solid State Laser",subtitle:null,isOpenForSubmission:!1,hash:"d1bd2eb05971cc7dd6487b76b2df1279",slug:"solid-state-laser",bookSignature:"Amin H. Al-Khursan",coverURL:"https://cdn.intechopen.com/books/images_new/1537.jpg",editedByType:"Edited by",editors:[{id:"99105",title:"Prof.",name:"Amin",surname:"Al-Khursan",slug:"amin-al-khursan",fullName:"Amin Al-Khursan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1568",title:"Photodetectors",subtitle:null,isOpenForSubmission:!1,hash:"92efb7e38a0edd4d28c7dbb530b14212",slug:"photodetectors",bookSignature:"Sanka Gateva",coverURL:"https://cdn.intechopen.com/books/images_new/1568.jpg",editedByType:"Edited by",editors:[{id:"103718",title:"Dr.",name:"Sanka",surname:"Gateva",slug:"sanka-gateva",fullName:"Sanka Gateva"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1611",title:"Nonlinear Optics",subtitle:null,isOpenForSubmission:!1,hash:"1996056f2eafba51ac41d52290731f92",slug:"nonlinear-optics",bookSignature:"Natalia Kamanina",coverURL:"https://cdn.intechopen.com/books/images_new/1611.jpg",editedByType:"Edited by",editors:[{id:"28159",title:"Dr.",name:"Natalia",surname:"Kamanina",slug:"natalia-kamanina",fullName:"Natalia Kamanina"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1612",title:"Recent Interferometry Applications in Topography and Astronomy",subtitle:null,isOpenForSubmission:!1,hash:"dce41f98bb81e7d2e49a3c9ddda734ff",slug:"recent-interferometry-applications-in-topography-and-astronomy",bookSignature:"Ivan Padron",coverURL:"https://cdn.intechopen.com/books/images_new/1612.jpg",editedByType:"Edited by",editors:[{id:"105600",title:"Dr.",name:"Ivan",surname:"Padron",slug:"ivan-padron",fullName:"Ivan Padron"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],publishedBooksByAuthor:[]},onlineFirst:{chapter:{type:"chapter",id:"81691",title:"Function and Therapeutic Intervention of Regulatory T Cells in Immune Regulation",doi:"10.5772/intechopen.104914",slug:"function-and-therapeutic-intervention-of-regulatory-t-cells-in-immune-regulation",body:'Regulatory T cells (Tregs), as a subgroup of T cells with immunosuppressive function, were first reported in 1970s by Gershon and Kondo [1]. According to the developmental origin, Tregs can be broadly classified into two groups. Tregs that grow in the thymus are called natural (nTregs) or thymic (tTregs) Tregs, and that develop at the periphery by specific stimuli of conventional CD4+ T cells are termed peripheral Treg (pTregs). When Tregs are induced by specific factors, such as interleukin-2 (IL-2) and transforming growth factor (TGF)-β,
Every manifestation stemming from Tregs paucity highlights a vital function of Tregs in preventing fatal autoimmune inflammation. The immunosuppressive function of Tregs is mainly dependent on continuous expression of the transcription factor forkhead box protein 3 (Foxp3), which is a critical regulator of CD4+CD25+ Tregs development and function. Loss function of Foxp3 results in a fatal autoimmune disease featuring all known types of inflammatory responses. Studies have demonstrated that the typical or fatal autoimmune responses that occurred in the Foxp3-mutant scurfy mice or Foxp3-null mice are related to the deficiency of CD4+CD25+ Tregs, but not to the cell-intrinsic dysfunction of CD4+CD25− T cells. When being transferred into the neonatal Foxp3-deficient mice, Tregs can preferentially expand and control the development of autoimmune disease. Furthermore, ectopic expression of Foxp3 can confer suppressor function on peripheral CD4+CD25− T cells [4]. Even in severely diseased mice, by reinstating Foxp3 protein expression and suppressor function in cells expressing a reversible Foxp3 null allele, the rescued Tregs normalized immune activation, quelled severe tissue inflammation, reversed fatal autoimmune disease, and provided long-term protection against them. It is indicated that Tregs are capable of resetting the immune homeostasis in broad-spectrum systemic inflammation and autoimmune diseases [5].
X-linked autoimmunity-allergic dysregulation syndrome (XLAAD), which has been renamed as Immunodysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome (IPEX), was a rare inborn error of immune regulation and autoimmune lymphoproliferative illness in humans [6]. As one of the most well-known Mendelian disorders, IPEX is characterized by a loss of immunological tolerance caused by a lack of functioning Tregs and was discovered to be associated with the mutations in Foxp3 [7, 8]. In the absence of Tregs, activated CD4+ T cells instigate multi-organ damage resulting in type 1 diabetes (T1D), enteropathy, eczema, hypothyroidism, and other autoimmune disorders.
Moreover, studies on Tregs depletion by cytotoxic T-lymphocyte antigen (CTLA)-4 Ab (e.g., ipilimumab) in tumor patients have shown a strong correlation between the induction of tumor regression and autoimmunity [9]. Ipilimumab acts not only on effector T cells (Teffs) but also on Tregs because the latter ones in both mouse systems and humans can be directly targeted by ipilimumab due to the constitutive expression of CTLA-4 on their cell surface [10, 11]. Except for a decreased frequency of circulating CD25+CD4+ Tregs can be observed upon ipilimumab, CTLA-4 blockade renders Teffs resistant to the inhibitory activity of Tregs, rather than modulating the immunosuppressive effects of Tregs on T cells and NK cells [12]. It is indicated that loss of Tregs has a close relationship with the development of autoimmune diseases from another perspective.
Our body’s immune system has evolved to perform self-tolerance to resist the autoimmune reactions directed against our own cells via sophisticated mechanisms. On the T cell level, self-tolerance is executed by deletion of T cells with self-reactive T cell receptor (TCR) in the thymus (central tolerance) or maintained by specialized cells, including Tregs, outside of the thymus (peripheral tolerance). The importance of Tregs for the maintenance of immune tolerance has also been illustrated to have a close relationship with the expression of the Foxp3 gene, both in humans and mice [13, 14]. Foxp3, together with other transcription factors and coactivators/corepressors, represses the transcription of IL-2 in Tregs, rendering them highly dependent on exogenous IL-2 (mainly produced by activated non-Tregs) for their maintenance and function. Tregs constitutively express the high-affinity IL-2 receptor (α chain), which serves as a sink for IL-2 that controls the expansion of Teffs. The development of autoimmune/inflammatory disease can be promoted if disrupting this IL-2-mediated feedback loop at any step. Further, manipulation of this feedback loop is instrumental in tuning the intensity of Tregs-mediated suppression, hence the strength of a variety of immune responses [15]. Foxp3 also activates the genes encoding Tregs-associated molecules, including CD25, CTLA-4, and Glucocorticoid induces tumor necrosis factor receptor (GITR) and confers suppressive activity to Tregs, which directly suppress non-Tregs or modulate the function of antigen-presenting cells (APCs) to activate non-Tregs [16].
The Tregs-mediated immune suppression may be related to three mechanisms, including secretion of immunosuppressive cytokines [17], cell-contact-dependent suppression [18], and functional modification or killing of APCs [19]. More than one mechanism may operate for controlling the particular immune response in a synergistic and sequential manner.
IL-10 and TGF-β may act as the main immunosuppressive cytokines contributing to control the autoimmune disorders or inflammatory diseases secreted by Tregs [17]. IL-10 indirectly prevents antigen-specific T cell activation, which is associated with downregulation of the antigen presentation and accessory cell functions of monocytes, macrophages, and dendritic cells (DCs), as well as inhibits T-cell expansion by directly inhibiting IL-2 production by these cells. The pivotal function of TGF-β is to maintain tolerance via the regulation of lymphocyte proliferation, differentiation, and survival. TGF-β can block the proliferation of T lymphocytes by suppressing the expression of IL-2 (via Smad3 signaling pathway), cyclins (including cyclin D2 and cyclin E), cyclin-dependent kinase (CDK)-4, and c-myc. TGF-β also can inhibit the differentiation of Th1 and Th2 cells by blocking the T-bet/STAT4 and GATA-3/NFAT signaling transduction pathway, and down-regulating the differentiation of cytotoxic T lymphocyte (CTL) via regulating the expression of c-myc and T-bet [20]. TGF-β can also induce the expression of Foxp3 and the generation of Tregs. In addition, nTregs can also predominantly produce IL-35, a new member of the IL-12 family, to perform the suppressive function [21]. IL-35 is a novel Epstein-Barr-virus-induced gene (Ebi) 3-IL-12α heterodimeric cytokine, and Ebi3, which encodes IL-27 β, is a downstream target of Foxp3. Ebi3−/− and IL12α−/− Tregs have significantly reduced regulatory activity
Antigen-activated Tregs, which are highly mobile, are swiftly recruited to APCs (especially DCs), upon being stimulated by the specific antigen. The recruitment of Tregs to APCs is in chemokines or adhesion molecules depended on manner. Once the Tregs aggregate around the APCs, they will outcompete antigen-specific naïve T cells regarding interaction with DCs, mainly because of the high expression of adhesion molecules on Tregs, such as lymphocyte function-associated antigen (LFA)-1 [22].
Tregs can modulate the function of APCs. Activated Tregs promote the downregulation of CD80 and CD86 on APCs or stimulate DCs to form the enzyme indoleamine 2, 3-dioxygenase both by a CTLA-4-dependent mechanism [23, 24]. Indoleamine 2, 3-dioxygenase is capable of catabolizing the essential amino acid tryptophan to kynurenines, which are toxic to T cells. Alternatively, Tregs can induce the apoptosis of responder T cells or APCs by secreting granzyme/perforin or immunosuppressive cytokines (such as IL-10), or through the delivery of a negative signal (possible including intracellular cyclic AMP) to inactivate the responder T cells [19]. The upregulation of intracellular cyclic AMP will lead to the inhibition of T cell proliferation and IL-2 production, as well as the generation of pericellular adenosine catalyzed by CD39 and CD73 by Tregs.
Type 1 diabetes (T1D) is a typical kind of autoimmune disease affecting millions of people worldwide with a steadily rising incidence, and islet infiltrating self-reactive T cells mediated β-cell destruction is considered to be primary pathogenesis of this disease. The initiation of the autoimmune process is related to the recognition of self-antigens by the autoreactive subsets of CD4+ T-helper lymphocytes, which can preferentially produce the Th1 cytokine spectrum after activation. The presence of autoreactive CD8+ cytotoxic T lymphocytes is necessary for the further development of T1D as well. It has been demonstrated that CD4+CD25+FoxP3+ Tregs also play an indispensable role in the development of T1D by preventing destructive autoimmunity [25]. Although the application of immunosuppressive reagents is one of the available therapies, it can have severe side effects. Optimal immune-based therapies for T1D should restore self-tolerance without inducing chronic immunosuppression. Thus, efforts to repair or replace Tregs in T1D probably can reverse autoimmune response and protect the remaining insulin-producing β cells. There is a large body of evidence to suggest that Foxp3+ Tregs function is altered in patients with T1D, though the overall frequency of Foxp3+ Tregs may be unaltered in these individuals [26, 27]. Data from the non-obese diabetic (NOD) mouse model of autoimmune diabetes and human with T1D suggest that increasing resistance of Teffs to Tregs regulation may be the primary cause for reduced suppression, and it can be explained by the inability of Teffs to provide an environment conducive to Tregs fitness and function, including the reduced IL-2 production or downregulation of the IL-2 signaling pathway by Teffs [28, 29].
Apart from their canonical function of immune suppression, it is now well accepted that Tregs can likewise be induced in the periphery in an antigen-specific manner and take residence in tissues to play important roles in maintaining tissue homeostasis. So, antigen-specific induction of disease-relevant Tregs will offer the opportunity to treat or prevent the T1D for a long-standing goal. It has been demonstrated that in the peripheral blood of children who are at risk to develop T1D, the proportion of insulin-specific Tregs reduced during the onset of islet autoimmunity, while the higher reduction was related to a rapid progression to clinically overt T1D [30]. This finding suggested that inducing these insulin-specific Tregs may delay the progression to clinically symptomatic T1D. Nevertheless, very little is known about pancreas residing Tregs, and all studies conducted so far on these tissue-specific Tregs focused solely on NOD mice with ongoing insulitis. A recent study found that a combinatorial regimen involving the anti-CD3, cyclophosphamide (CyP), and IAC (IL-2/JES6–1) antibody complex can promote the engraftment of antigen-specific donor Tregs through ablating host conditioning and control islet autoimmunity without long-term immunosuppression [31].
Rheumatoid arthritis (RA) is one kind of common systemic inflammatory autoimmune disease, and its typical clinical symptoms are musculoskeletal pain, joint swelling, and stiffness, which can seriously damage body function and reduce the quality of life of patients. Patients with RA are more likely to develop osteoporosis, infection, cardiovascular diseases, respiratory diseases, cancer, and other diseases than the general population. Similar to other autoimmune diseases, Tregs also play a vital role in the pathogenetic process in RA. When the number and/or function of Tregs are decreased or inhibited, autoantigen or ligand death receptors (DRs) related immune cascade can be amplified, and the levels of various cytokines, such as IL-2, will be rapidly increased, leading to the activation of macrophages in the synovium of bones and joints to produce many inflammatory cytokines including IL-1, IL-6, and IL-8 [32, 33]. These inflammatory reactions destroy articular cartilage and eventually lead to joint deformities.
However, contradictory results on the number (increased [34], unchanged [35], or decreased [36]) and functional characteristics (enhancement [32] or attenuation [33]) of Tregs in the peripheral blood of patients with RA have been reported in different studies, and this discrepancy can be explained by the ongoing difficulties in the recognition of Tregs. In most studies, the high-level expression of Foxp3, CD25, and low-level expression of CD127 (the α-chain of the IL-7 receptor) are used to define Tregs, and the CD3+CD4+CD25highCD127low phenotype is most commonly isolated from Tregs population. However, Foxp3 requires intracellular staining and the expression levels in Tregs in the resting state and activated state are different, and conventional T cells (Tconvs) also express a low levels of Foxp3 and CD25 upon TCR stimulation and low levels of CD127 [37]. Thus, some other supplementary cell surface markers, such as CD62 ligand, integrin Ea (CD103), GITR (TNFRSF18), CTLA-4 (CD152), CD45RO, and neuropilin, have been also used to identify Tregs in clinical practice [38]. CD45RA and CD45RO can be used to distinguish immature Tregs (CD45RA+Foxp3low) from activated memory Tregs (CD45RA−Foxp3high) cells [39]. A more stringent method to define Tregs has revealed the number of Tregs decreased in peripheral blood and increased in synovial fluid by performing a meta-analysis [40].
However, although the Tregs isolated from RA patients can show normal inhibitory activity
Autoimmune hepatitis (AIH) is a severe hepatopathy that occurs globally in all ethnicities and affects children and adults of all ages. It is with a female predominance and characterized by hypergammaglobulinemia, interface hepatitis on histology, and seropositivity for disease-defining autoantibodies. In AIH, the autoimmune reaction resulting in liver injury initiates with the presentation of liver autoantigen by APCs to an uncommitted T lymphocyte. Following antigen encounter, Th0 becomes activated and differentiates into Th1, Th2, and Th17. Th1 cells secrete interferon (IFN)-γ and IL-2, which can lead to the activation of macrophages and upregulation of major histocompatibility complex (MHC) class I and II by hepatocytes [46]. Th2 lymphocytes secrete IL-4 and IL-10, which can promote the B cell activation and maturation into plasma cells. Plasma cells then produce autoantibodies and mediate cell cytotoxicity in turn [47]. Activation of Th17 cells, which can secrete IL-17 proinflammatory cytokines, has been associated with the induction of pro-fibrotic events [48]. The autoimmune attack will continue perpetrating and favoring the progression of tissue damage if these events are not opposed by effective immunoregulation.
It has been demonstrated that the impairment of Tregs plays an important role in the initiation and progression of AIH. A numerical and functional defect in CD4+CD25+/highFoxp3+ cells was reported in patients with AIH compared with the healthy subjects [49]. Before immunosuppressive treatment is instituted, Tregs isolated from AIH patients are also impaired in their ability to expand, and unable to regulate CD4+ and CD8+ T cells proliferation and modify CD4+ and CD8+ T cells cytokine profile as in the case of healthy controls [50, 51].
This deficiency of Tregs in AIH patients might be linked to increased expression of the cell surface marker CD127 [52] and defects in the expression of the ectonucleotidase CD39 [53]. CD127 is also known as the α-chain of the IL-7 receptor (IL-7Rα), while CD39+ Tregs decrease in frequency in AIH patients leading to the failure to control the production of IL-17 by Th17. So, Tregs in AIH subjects are more prone to acquire features of effectors than their counterparts when exposed to a proinflammatory challenge, which suggests the defective immunoregulation of Tregs in AIH might have some relationship with the increased conversion of Tregs into effector lymphocytes [53]. A recent study confirmed that impaired CD39 levels derive from alterations of aryl hydrocarbon receptor (AhR) signaling [54]. AhR is a mediator of toxin responses and adaptive immunity. Upon binding to endogenous or exogenous ligands, AhR undergoes activation, which will bring about the upregulation of CD39.
However, aberrantly high levels of aryl hydrocarbon receptor repressor and estrogen receptor alpha (Erα) can be detected in AIH. AhR binds Erα with higher affinity than aryl hydrocarbon receptor nuclear translocator (ARNT), the classical AhR binding partner. These non-conventional binding give rise to impaired CD39 upregulation.
Impaired Tregs function in AIH is also linked to defective levels of Galectin-9 (Gal-9). Gal-9, a member of the galectin family, is one kind of β galactoside binding protein expressed on Tregs. It can bind to the mucin domain 3 (Tim-3) on CD4+CD25− Teffs. Upon Gal-9 binding to Tim-3, apoptosis in CD4+CD25− Teffs will be induced. Thus, reduced expression of Gal-9 in Tregs in AIH contributes to the less suppressing ability of Tregs and rendering CD4+CD25− Teffs less prone to the control of Tregs [55].
In addition, defective Tregs function in AIH is linked with reduced ability to produce IL-10 as well. It is resulting from poor response to IL-2 as reflected by impaired ability to upregulate the phosphor signal transducer and activator of transcription 5 (pSTAT-5) [56].
Inflammatory bowel disease (IBD) is a chronic, inflammatory, and autoimmune disorder. The types of IBD include ulcerative colitis (UC) and Crohn’s disease. The etiology of IBD is possibly linked to the dissonance of the host immune system, genetic variability as well as an environmental factor, and the pathogenesis of this disorder has not been fully elucidated [57]. In recent years, it has been found that the abnormal intestinal mucosal immune system plays a crucial role in the occurrence, development, and prognosis of IBD, involving the imbalance in Th17 and Tregs [58]. The differentiation of Th17 cells goes through three stages—initiated by IL-6 and TGF-β, expanded by IL-21, and IL-23 maintains the stable maturation of Th17 cells during the later stage of differentiation [59]. Except for protecting the intestinal mucosa via keeping the balance of the immune microenvironment, Th17 cells also can exacerbate the intestinal inflammatory response through secreting proinflammatory cytokines, such as IL-17. Compared with the healthy controls, Th17 cells infiltrate the intestinal mucosa of IBD patients and the amount of IL-17 increases [60]. Tregs and Th17 cells are related through differentiation and share a common signal pathway mediated by TGF-β. In the UC mouse model, Th17 cells in the peripheral blood of mice increased, yet Tregs decreased [61]. Therefore, Tregs deficiency may be the central link in the pathogenesis of IBD and the regulation of Th17/Tregs balance is prospective to be a new target for the treatment of IBD. The immunological factors affecting the Th17/Tregs balance in IBD consist of both TCR and costimulatory signals and cytokines. IL-2 inducible T cell kinase (ITK), a critical regulator of intracellular signaling downstream of the TCR, positively regulates the differentiation of Th17 and negatively regulates the differentiation of Tregs [62]. The T cell costimulatory molecule OX40 and its cognate ligand OX40L collectively play an essential role in keeping the growth of Th17 and Tregs, that is, activation of OX40 enhanced Th17 function while blocking OX40L decreased Tregs proliferation [63].
While organ transplantation is one of the greatest achievements in modern medicine, rejection is still the major barrier to successful transplantation. The immune response to an allograft is an ongoing dialog between the innate and adaptive immune systems. One of the reasons that transplantation induces such a dynamic immune response is the high precursor frequency of T cells capable of responding to mismatched MHC molecules. Although immunosuppression regimens are effectively able to control the acute rejection and decrease graft loss in the first year after transplantation, it is difficult to get a durable effect on long-term graft survival with these modern regimens, owing to a combination of drug toxicities, the emergence of chronic alloimmune responses and the serious complications, such as chronic infections or malignancies. Studies on experimental transplant models have suggested a role for Tregs in protecting allografts by suppressing both autoimmune and alloimmune responses [64, 65]. Further, Tregs-based therapies do not require harsh conditioning and have a risk of graft-versus-host disease.
The first step in the adaptive immune response to a transplant in a solid organ transplantation recipient is T-cell recognition of alloantigen or allorecognition. Graft-specific Tconvs, which are capable of direct recognition of alloantigen, are present at a very high frequency so that they can respond to the transplant without first clonally expanding in lymph nodes. When graft-specific Tconvs are recruited to the graft, they will lead to inflammation and tissue damage. Increasing graft-specific Tregs combined with the reduction of graft-specific Tconvs allow the former one to dominate in the graft and prevent recruitment and activation of the later one. Moreover, once entering the draining lymph node, inflammatory APCs can activate more graft-specific Tconvs, while tolerogenic APCs are able to expand graft-specific Tregs and prevent the expansion of graft-specific Tconvs to maintain tolerance [66].
Moreover, Tregs with direct alloantigen specificity, which are also present at high frequency, play important role in the induction of tolerance, whereas Tregs with indirect alloantigen specificity are important for the maintenance of tolerance [67]. Tregs control transplant rejection by first migrating to the organ to prevent graft damage and then retreating to draining lymph nodes to maintain tolerance [65]. During an active alloimmune response, Tregs with both direct and indirect specificities expand and infiltrate the organs, but the homeostatic function of Tregs is insufficient to prevent rejection from occurring due to the potency of alloimmune responses until the organs have suffered substantial damage [67]. That is because Teffs arrive at the graft site first and expand in number before the arrival of Tregs so that the grafts are dominated by Teffs [64], and at the peak of alloimmune responses, a high antigen load, vigorous co-stimulation, and high concentrations of cytokines, such as IL-1 and IL-6, override Tregs suppression so that effective immune functions can be carried out to induce rejection quickly. Thus, prevention of rejection and establishment of tolerance by Tregs require attenuation of Teffs responses and inflammation control.
Currently, allogeneic hematopoietic cells transplantation (HCT) or bone marrow transplantation (BMT) in humans is widely used in the treatment of tumors of the hematopoietic and immune systems, including leukemia, lymphoma, and myeloma. However, they are usually complicated by serious and potentially lethal side effects, such as immunodeficiency and graft-versus-host disease (GVHD). GVHD represents a dysregulated immune response and has been assessed across both major and minor histocompatibility barriers, and the pace of these reactions is much more accelerated across major histocompatibility barriers. The onset and course of GVHD depend on the degree of major and minor MHC disparity and the T-cell dose. It has been demonstrated by using animal models that T cells rapidly migrate to nodal sites, spleen, and mesenteric lymph nodes and begin to dramatically expand by 3–4 days following adoptive transfer, and within 7–10 days, they infiltrate the major sites of GVHD pathophysiology, such as lymph nodes, spleen, gastric intestinal tract (GI tract), liver, and skin [68]. Depletion of CD4+CD25+ T cells from the donor graft accelerated the GVHD course and increased lethality, which provided evidence for the role of Tregs in mediating GVHD [69]. Tregs also expand dramatically upon adoptive transfer and traffic to nodal sites to promote immune reconstitution and suppress GVHD across both major and minor histocompatibility barriers, while interestingly allowing for the maintenance of graft-versus-tumor (GVT) responses [70, 71, 72]. Tregs proliferate in the same way as Tconvs with similar kinetics and tend to fade out over time. Upon the adoptive transfer, the dramatic expansion of Tconvs can be detected, whereas when the same numbers of Tregs were adopted along with the Tconvs, this dramatic proliferation of Tconvs is significantly reduced, yet the homing and activation of Tconvs are not impacted [73]. It is indicated that the adopted Tconvs are still able to be activated and home to specific sites within the body, yet this drastic T-cell expansion required for GVHD is diminished. Thus, clinical strategies to enhance the function of Tregs hold great promise to improve outcomes following allogeneic HCT and BMT.
The ability of Tregs to maintain self-tolerance means they are critical for the control and prevention of autoimmune diseases. Currently, a large body of data in the literature has provided evidence on the possible Tregs therapy for various immune-mediated diseases. Restoring immune homeostasis and tolerance through the promotion, activation, or delivery of Tregs has emerged as a focus for therapies aimed at curing or controlling autoimmune diseases. A variety of Tregs-based therapies are being explored in the treatment and prevention of autoimmune diseases, such as
Polyclonal Tregs therapy uses autologous
However, the therapeutic effect of this clinical trial correlated with increased Tregs post-infusion, and only persisted for a short time. The subsequent trials confirmed the limited persistence of expanded Tregs even after a second infusion [83], and obtaining sufficient cell numbers can be challenging in many disease scenarios [84], although polyclonal Tregs therapy is generally considered safe and efficacious. Perhaps the use of other Tregs-promoting therapies in combination with polyclonal Tregs therapy would prolong the suppressive effect and increase the number of Tregs with improved patient outcomes.
As mentioned earlier, it has been widely accepted that IL-2 plays a critical role mainly in Tregs fitness and homeostasis, thus low-dose IL-2 therapy alone has the effect of expanding
Furthermore, an advantage of low-dose IL-2 therapy is that recombinant human IL-2 is already available as a therapeutic drug called Aldesleukin or Proleukin for the treatment of malignant melanoma and renal cell carcinoma in the clinic [87].
HSPs are highly conserved proteins present in all kingdoms of organisms, and expressed under stress conditions to protect the cells from injuries. They are classified into five families according to their molecular weight, including HSPH, HSPC, HSPA, HSPD, and DNAJ. Intracellular HSPs play an essential role in physiological processes, involving of folding of nascent and stress-accumulated protein-substrate assembly and preventing the aggregation of these proteins, transporting across membranes and degrading other proteins. While extracellular or receptor-bound HSPs mediate immunological functions and immunomodulatory activity, including the induction, proliferation, suppressive function, and cytokine production of Tregs [88]. In patients with juvenile idiopathic arthritis (JIA), DNAJ was found to improve the suppressive function of Tregs in culture and stimulate T cells for the production of IL-10, and high serum levels of DNAJ correspond with a milder course of the disease, indicating epitopes derived from human DNAJ can induce differentiation and/or stimulate cell proliferation of Tregs [89]. Acting as co-stimulators of human Tregs, HSPD can enhance the suppression and proliferation of Tregs via binding of Toll-like receptor (TLR) 2 on the Tregs surface to inhibit target T cell proliferation, IFN-γ and tumor necrosis factor (TNF)-α secretion, as well as upregulate the expression of IL-10 [90]. HSPD can enhance the differentiation of cord blood mononuclear cell (CBMC) into CD4+IL-10+Foxp3+ Tregs as well [91]. HSPA can stimulate the suppressive activity of Tregs, increase the production of IL-10, and downregulate the production of inflammatory cytokines via the TLR4-signaling pathway, which may be important for Foxp3 induction [92]. Animal studies have shown that oral, nasal, intraperitoneal, or intradermal administration of HSPA significantly inhibits the development of the autoimmune arthritic model, which suggested that suppression of autoimmune response in experimental animals was mediated by increased expansion of Tregs specific for HSPA, and the secretion of anti-inflammatory IL-10 [93, 94, 95]. Moreover, HSPC can promote Tregs-dependent suppression as well [96]. HSP gp96, the endoplasmic reticulum form of HSPC, is required for Tregs maintenance and function, as loss of GP96 resulted in instability of the Tregs lineage and impairment of suppressive functions
Tregs constitutively express the transcription factor Foxp3, which is critical for their immunosuppressive function. Several studies have provided evidence that ectopic expression of Foxp3 can confer a suppressive phenotype to naïve or memory CD4+ T cells, so it is probably a way to circumvent the requirement of a large number of polyclonal Tregs for therapy [99]. Lentiviral delivery of the Foxp3 gene into IPEX patient-derived CD4+ T cells can acquire the characteristic features, such as decreased proliferation, hyporesponsiveness, reduced cytokine release, and suppressive activity, which are able to mirror the Tregs population from healthy donors, and these induced Tregs were demonstrated to be stable in inflammatory conditions not only
Cell permeable form of Foxp3 is another approach to enforce Tregs differentiation. This protein form can link to the protein transduction domain (PTD) from the HIV transactivator of transcription and allow Foxp3 to be delivered to the cytoplasm and nucleus, which has been shown to induce a Tregs phenotype in both human and mouse T cells [104]. However, a major limitation of this approach is the high cost for human patients.
While the initially limited success of polyclonal Tregs is encouraging, the amounts of cells needed for infusions are quite large and the risk of nonspecific immunosuppression should be considered. Tregs developed in the thymus (i.e., nTregs) harbor a TCR repertoire that is skewed toward self-antigens, while Tregs induced in the periphery in an antigen-specific manner (i.e., pTregs) can be characterized with a TCR repertoire different from their nTregs counterparts [105]. So, it is a good strategy to induce disease-relevant antigen-specific Tregs with the goal to interfere with the unwanted immune reactions in allergies and autoimmunity and to restore the self-tolerance, and it has been verified through considerate research in humans or mice [106, 107]. Compared with the polyclonal Tregs therapy, growing evidence from animal models indicates that antigen-specific Tregs may be more efficient in controlling pathological immune responses in a disease-specific manner. It is possible because infused Tregs migrating toward the tissues of cognate antigen exposure will lead to more effective and localized control of inflammation, along with risk reduction of broad immunosuppression and its related adverse events [108, 109]. Moreover, the enhanced migration ability of antigen-specific Tregs to target tissues can probably lead to a lower administration number of Tregs than the polyclonal approach, and facilitate the obtainment of Tregs via standard
Tregs therapy can be enhanced by the introduction of an autoantigen-specific TCR (TCR-Tregs), which have the ability to redirect their response toward the desired autoantigen specificity. Tregs can be
Compared to polyclonal Tregs, fewer antigen-specific Tregs may be needed to alleviate autoimmune disease; however, the challenge of the identification of an appropriate, high-affinity, autoantigen-specific TCR for transduction onto Tregs still remains, due to some autoimmune diseases being with poorly defined dominant epitopes. It is hard to isolate and identify antigen-specific Tregs due to both the great diversity in TCRs and very low count of them naturally circulating in the peripheral blood. The majority of antigen-specific Tregs were generated using TCRs isolated from Tconvs, which would influence the stability, avidity, and migration to specific parts of the engineered Tregs, for the reason that the intrinsic affinity and specificity of TCRs isolated from Tregs are distinct from Tconvs. Moreover, there are some other limitations of this approach, such as the requirement for MHC restriction and the risk of mispairing with endogenous TCR.
Single-cell sequencing is required for TCR identification since each T cell clone expresses a different TCR sequence from the others, and the successful sequencing of both the α and β chain TCR is required to successfully identify one TCR [115]. In a recent study, single-cell TCR analyses of islet Tregs revealed their specificity for insulin and other islet derived antigen, and these antigen-specific Tregs were reported to be efficient in protecting NOD mice from diabetes [116].
Although Tregs engineered with TCRs (TCR-Tregs) seem to be promising, they are still MHC-restricted and their modular application in individual patients is constrained. Engineer with genes encoding chimeric antigen receptors (CARs), which typically consist of a single-chain variable fragment (scFv) for binding to a monoclonal antibody, an extracellular hinge, a transmembrane region, and intracellular signaling domains, is an MHC-independent strategy of generating antigen specificity for Tregs [117]. In animal models, CAR-Tregs have shown great potential for treating different diseases, especially allograft rejection and various autoimmune diseases.
HLA-A mismatching is often associated with poor outcomes after transplantation, so, HLA-A is a potential target antigen to generate antigen-specific Tregs for inducing transplantation tolerance. One kind of HLA-A2-specific CAR (A2-CAR) Tregs was created in a peptide-independent manner, and not only can maintain high expression of canonical Tregs markers, including Foxp3, CD25, Helios, CTLA-4, and a high degree of demethylation of the Treg-specific demethylated region (TSDR) of the FOXP3 locus but also can enable stronger antigen-specific activation than did an endogenous TCR [118]. Further, CAR-stimulated Tregs had a higher surface expression of CTLA-4, latency-associated peptide (LAP), and the inactive precursor of TGF-β than TCR-Tregs. Unlike TCR-Tregs, CARs could also stimulate IL-2-independent Tregs proliferation in the short term [118]. Thus, CAR-Tregs may be superior to TCR-Tregs.
CAR Tregs isolated from transgenic BALB/c mice with a CAR specific for 2,4,6-trinitrophenol (TNP), an antigen commonly used in a mouse model of colitis, were reported to capable of suppressing the proliferation of Teffs
Different approaches that involve boosting Tregs have been tested in several disease settings so for. Polyclonal Tregs and antigen-specific Tregs therapy have demonstrated their efficacy in immunotherapy in various clinical trials or preclinical models (Table 1).
Approach | Technique | Indication | Stage of study | Study ID or references |
---|---|---|---|---|
Polyclonal Tregs therapy | Autologous polyclonally expanded Tregs | T1D | Clinical trials phase 1 (completed) | NCT01210664 |
Polyclonal Tregs therapy | GVHD | Clinical trials phase I (active) | NCT01795573 | |
Polyclonal Tregs therapy | Autologous polyclonally expanded Tregs | Kidney transplant | Clinical trials phase I/II (Active) | NCT02129881 |
Polyclonal Tregs therapy | Donor alloantigen reactive Tregs | Liver transplant | Clinical trials phase I (recruiting) | NCT02188719 |
Polyclonal Tregs therapy | Autologous polyclonal expanded nTregs | AIH | Clinical trials phase I/II (unknown) | NCT02704338 |
Antigen-specific Tregs therapy | CD4+CD25+ T cells from TCR-transgenic BDC2.5 mice expanded | T1D | Preclinical studies (NOD model) | [122] |
Antigen-specific Tregs therapy | CD4+ T cells transduced with Foxp3 and a TCR of a CIA-associated T cell clone | RA | Preclinical studies (DBA1 mice) | [123] |
Antigen-specific Tregs therapy | CD4+CD25+ T cells from TCR-transgenic Tg4 mice expanded | MS | Preclinical studies (B10.Pl mice) | [124] |
Antigen-specific Tregs therapy | CAR-engineered CD4+CD25+ Tregs specific for CEA | Colitis | Preclinical studies (CEABAC mice) | [111] |
Antigen-specific Tregs therapy | CAR-engineered human CD4+CD25+ Tregs specific for HLA-A2 | Skin transplantation | Preclinical studies (CEABAC mice) | [125] |
Antigen-specific Tregs therapy | TGF-β-induced iTregs generated from CD4+ T cells of TxA23 mice | Autoimmune gastritis | Preclinical studies (BALB/c mice) | [126] |
Antigen-specific Tregs therapy | TGF-β-induced OVA-specific iTregs generated from CD4+ T cells of OT-II mice | GVHD | Preclinical studies (C57Bl/6 mice) | [127] |
Clinical trials or preclinical models with polyclonal Tregs or antigen-specific Tregs in different diseases.
To sum up, Tregs are crucial in maintaining tolerance. Hence, Tregs immunotherapy is an attractive therapeutic option in autoimmune diseases and organ transplantations. However, there are still many challenges and bottlenecks in implementing Tregs therapy.
At first, the cellular variability of Tregs is wide. It is important to characterize the phenotype and suppressor function of each subtype of Tregs present in the periphery or the thymus. The success of Tregs therapy depends initially on the isolation and characterization of cells, while current research does not use a universally applicable standard for Tregs identification. This gap in identification leads to conflicting and doubtful research results. Meanwhile, one of the drawbacks of this cell therapy is the time delay to administer Tregs from taking peripheral blood to obtaining sufficient numbers of cells, and antigen-specific Tregs technology may presumably need administration of lower Tregs numbers than polyclonal approachesSecondly, to improve the efficacy of Tregs immunotherapy, it is necessary that Tregs can migrate, survive, and function in the specific target tissue. The plasticity of polyclonal or CAR-Tregs in an inflamed microenvironment is still an unknown factor. The inflamed microenvironment enriched with pro-inflammatory cytokines can either lead to a reduction in the potency of Tregs or resistance of Teffs to Tregs suppression, or even converting Tregs into pathogenic Teffs. There are also questions to be addressed regarding the long-term proliferative potential and survival of polyclonal or antigen-specific Tregs in the tissue microenvironment, which is enriched with cytokines, metabolites, low oxygen levels, and microbial peptides.
Thirdly, the application of CAR-Tregs is an exciting option in both transplantation and autoimmune diseases, when the antigen is known. Nevertheless, before CAR-Tregs can be put into practice in the clinic, there are still obstacles required to be overcome, because antibodies specific for self- or alloantigen must be characterized to construct antigen-specific CAR-Tregs. For the reason that autoimmune diseases always have a large autoantigenic repertoire of T or B cells, or spreading epitope, it will be not adequate to focus Tregs therapy on one specific epitope for an autoantigen. Although CAR-Tregs own a greater affinity to the cognate antigen than TCR-Tregs, the former requires the target cells to have at least 100 target autoantigens for successful recognition and Tregs stimulation. Moreover, it has not been confirmed yet whether CAR-Tregs would also lead to adverse reactions, such as cytokine storm and neuronal cytotoxicity, as the treatments with anti-tumor CAR-T cells.
Besides, it is still a hard nut to crack to access the localization of infused Tregs to the exact target site, and exhaustion of Tregs may limit their efficacy in immunosuppression. Meanwhile, the choice of immunosuppression in patients with Tregs therapy is crucial, for example, rapamycin has been shown to enhance Tregs frequency. To achieve efficacious and successful Tregs therapy, it is necessary to continue on immunosuppression that is favorable to Tregs survival and proliferation.
Therefore, more work is required to administer Tregs therapy effectively and safely to restore tolerance in transplantations and autoimmune diseases.
Tregs have proved to be a major breakthrough as an exciting immunotherapy option in the last two decades. Early phase clinical trials demonstrated safety, feasibility, and early efficacy with Tregs therapy in both autoimmune diseases and organ transplantation. The development of antigen-specific Tregs and CAR-Tregs would lead to exciting new frontiers in the cell therapy field as these cells are more efficacious and lesser numbers are required due to their target tissue homing affinity. It is crucial to obtain tissue biopsies following Tregs infusion to access the localization of infused cells. Optimizing the manufacturing processes and culture media will support infused Tregs survival in future clinical trials. In addition, improving our understanding on the patient’s omics profile with new technology will also allow us to put the personalized Tregs immunotherapy into effect.
In a word, although challenges still remain, the prospect of Tregs immunotherapy is exciting if the cell therapy community can maintain the collaboration closely. The immunosuppression-free period for patients with autoimmune disease and transplantation is in front of us.
IntechOpen will act in accordance with its published Refund Policy if requests for refunds are made.
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He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:null},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"357085",title:"Mr.",name:"P. 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Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356823",title:"MSc.",name:"Seonghee",middleName:null,surname:"Min",slug:"seonghee-min",fullName:"Seonghee Min",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Daegu University",country:{name:"Korea, South"}}},{id:"353307",title:"Prof.",name:"Yoosoo",middleName:null,surname:"Oh",slug:"yoosoo-oh",fullName:"Yoosoo Oh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Yoosoo Oh received his Bachelor's degree in the Department of Electronics and Engineering from Kyungpook National University in 2002. He obtained his Master’s degree in the Department of Information and Communications from Gwangju Institute of Science and Technology (GIST) in 2003. In 2010, he received his Ph.D. degree in the School of Information and Mechatronics from GIST. In the meantime, he was an executed team leader at Culture Technology Institute, GIST, 2010-2012. In 2011, he worked at Lancaster University, the UK as a visiting scholar. In September 2012, he joined Daegu University, where he is currently an associate professor in the School of ICT Conver, Daegu University. Also, he served as the Board of Directors of KSIIS since 2019, and HCI Korea since 2016. From 2017~2019, he worked as a center director of the Mixed Reality Convergence Research Center at Daegu University. From 2015-2017, He worked as a director in the Enterprise Supporting Office of LINC Project Group, Daegu University. His research interests include Activity Fusion & Reasoning, Machine Learning, Context-aware Middleware, Human-Computer Interaction, etc.",institutionString:null,institution:{name:"Daegu Gyeongbuk Institute of Science and Technology",country:{name:"Korea, South"}}},{id:"262719",title:"Dr.",name:"Esma",middleName:null,surname:"Ergüner Özkoç",slug:"esma-erguner-ozkoc",fullName:"Esma Ergüner Özkoç",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Başkent University",country:{name:"Turkey"}}},{id:"346530",title:"Dr.",name:"Ibrahim",middleName:null,surname:"Kaya",slug:"ibrahim-kaya",fullName:"Ibrahim Kaya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"419199",title:"Dr.",name:"Qun",middleName:null,surname:"Yang",slug:"qun-yang",fullName:"Qun Yang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Auckland",country:{name:"New Zealand"}}},{id:"351158",title:"Prof.",name:"David W.",middleName:null,surname:"Anderson",slug:"david-w.-anderson",fullName:"David W. 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The following concerns will be addressed in this Cell Physiology subject, which will consider all organ systems (e.g., brain, heart, lung, liver; gut, kidney, eye) and their interactions: (1) Neurodevelopment and Neurodevelopmental Disease (2) Free Radicals (3) Tumor Metastasis (4) Antioxidants (5) Essential Fatty Acids (6) Melatonin and (7) Lipid Peroxidation Products and Aging Physiology.
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He is Member ofthe National Research Council (CONICET), Argentina, and Argentine Society foBiochemistry and Molecular Biology (SAIB). His laboratory has been interested for manyears in the lipid peroxidation of biological membranes from various tissues and different species. Professor Catalá has directed twelve doctoral theses, publishedover 100 papers in peer reviewed journals, several chapters in books andtwelve edited books. Angel Catalá received awards at the 40th InternationaConference Biochemistry of Lipids 1999: Dijon (France). W inner of the Bimbo PanAmerican Nutrition, Food Science and Technology Award 2006 and 2012, South AmericaHuman Nutrition, Professional Category. 2006 award in pharmacology, Bernardo\r\nHoussay, in recognition of his meritorious works of research. Angel Catalá belongto the Editorial Board of Journal of lipids, International Review of Biophysical ChemistryFrontiers in Membrane Physiology and Biophysics, World Journal oExperimental Medicine and Biochemistry Research International, W orld Journal oBiological Chemistry, Oxidative Medicine and Cellular Longevity, Diabetes and thePancreas, International Journal of Chronic Diseases & Therapy, International Journal oNutrition, Co-Editor of The Open Biology Journal.",institutionString:null,institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}},editorTwo:null,editorThree:null,series:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261"},editorialBoard:[{id:"186048",title:"Prof.",name:"Ines",middleName:null,surname:"Drenjančević",slug:"ines-drenjancevic",fullName:"Ines Drenjančević",profilePictureURL:"https://mts.intechopen.com/storage/users/186048/images/5818_n.jpg",institutionString:null,institution:{name:"University of 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In Southeast Asia, for example, Talaromyces marneffei is an important pathogenic thermally dimorphic fungus that causes systemic mycosis. Widespread fungal infections with complicated and variable clinical manifestations, such as Candida auris infection resistant to several antifungal medicines, Covid-19 associated with Trichoderma, and terbinafine resistant dermatophytosis in India, are among the most serious disorders. \r\nInappropriate local or systemic use of glucocorticoids, as well as their immunosuppressive effects, may lead to changes in fungal infection spectrum and clinical characteristics. Hematogenous candidiasis is a worrisome issue that affects people all over the world, particularly ICU patients. CARD9 deficiency and fungal infection have been major issues in recent years. Invasive aspergillosis is associated with a significant death rate. Special attention should be given to endemic fungal infections, identification of important clinical fungal infections advanced in yeasts, filamentous fungal infections, skin mycobiome and fungal genomes, and immunity to fungal infections.\r\nIn addition, endemic fungal diseases or uncommon fungal infections caused by Mucor irregularis, dermatophytosis, Malassezia, cryptococcosis, chromoblastomycosis, coccidiosis, blastomycosis, histoplasmosis, sporotrichosis, and other fungi, should be monitored. \r\nThis topic includes the research progress on the etiology and pathogenesis of fungal infections, new methods of isolation and identification, rapid detection, drug sensitivity testing, new antifungal drugs, schemes and case series reports. 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Many parasitic diseases are classified as neglected tropical diseases because they have received minimal funding over recent years and, in many cases, are under-reported despite the critical role they play in morbidity and mortality among human and animal hosts. The current topic, Parasitic Infectious Diseases, in the Infectious Diseases Series aims to publish studies on the systematics, epidemiology, molecular biology, genomics, pathogenesis, genetics, and clinical significance of parasitic diseases from blood borne to intestinal parasites as well as zoonotic parasites. We hope to cover all aspects of parasitic diseases to provide current and relevant research data on these very important diseases. In the current atmosphere of the Coronavirus pandemic, communities around the world, particularly those in different underdeveloped areas, are faced with the growing challenges of the high burden of parasitic diseases. At the same time, they are faced with the Covid-19 pandemic leading to what some authors have called potential syndemics that might worsen the outcome of such infections. Therefore, it is important to conduct studies that examine parasitic infections in the context of the coronavirus pandemic for the benefit of all communities to help foster more informed decisions for the betterment of human and animal health.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",keywords:"Blood Borne Parasites, Intestinal Parasites, Protozoa, Helminths, Arthropods, Water Born Parasites, Epidemiology, Molecular Biology, Systematics, Genomics, Proteomics, Ecology"},{id:"6",title:"Viral Infectious Diseases",scope:"The Viral Infectious Diseases Book Series aims to provide a comprehensive overview of recent research trends and discoveries in various viral infectious diseases emerging around the globe. The emergence of any viral disease is hard to anticipate, which often contributes to death. A viral disease can be defined as an infectious disease that has recently appeared within a population or exists in nature with the rapid expansion of incident or geographic range. This series will focus on various crucial factors related to emerging viral infectious diseases, including epidemiology, pathogenesis, host immune response, clinical manifestations, diagnosis, treatment, and clinical recommendations for managing viral infectious diseases, highlighting the recent issues with future directions for effective therapeutic strategies.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",keywords:"Novel Viruses, Virus Transmission, Virus Evolution, Molecular Virology, Control and Prevention, Virus-host Interaction"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:null},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/175698",hash:"",query:{},params:{id:"175698"},fullPath:"/profiles/175698",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)}()