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",isbn:"978-1-80356-777-8",printIsbn:"978-1-80356-776-1",pdfIsbn:"978-1-80356-778-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"84908e027f884ec3fcbaea42eb69b698",bookSignature:"Dr. Hayri Baytan Ozmen",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11524.jpg",keywords:"Computational Intelligence, Fuzzy Clustering, Fuzzy Sets Theory, Genetic Algorithm, Neural Network, Artificial Intelligence, Decision Making, Control Theory, Computer-Aided Diagnosis, Fuzzy Optimization, Pattern Recognition, Feature Extraction",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 1st 2022",dateEndSecondStepPublish:"April 29th 2022",dateEndThirdStepPublish:"June 28th 2022",dateEndFourthStepPublish:"September 16th 2022",dateEndFifthStepPublish:"November 15th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Researcher with more than sixty-five research papers published in international journals and has been involved in more than ten national and international research projects. He is the editor-in-chief of an international journal on materials and structural engineering.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"198122",title:"Dr.",name:"Hayri Baytan",middleName:null,surname:"Ozmen",slug:"hayri-baytan-ozmen",fullName:"Hayri Baytan Ozmen",profilePictureURL:"https://mts.intechopen.com/storage/users/198122/images/system/198122.png",biography:"Dr. Hayri Baytan Ozmen is currently an associate professor in the Department of Civil Engineering, Usak University, Turkey. He graduated from the Civil Engineering Department of the Middle East Technical University, Turkey, in 2001. He received his PhD in the same field from Pamukkale University in 2011. His research interests includes reinforced concrete structures, earthquake engineering, seismic evaluation, and retrofit. He has more than sixty-five research papers published in international journals and conferences and has conducted and been involved in more than ten national and international research projects. He performed seismic evaluation or design of seismic retrofit systems for more than 150 RC buildings and provided consultancy for structural engineering studies. He is the editor in chief of an international journal on materials and structural engineering.",institutionString:"Usak University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Usak University",institutionURL:null,country:{name:"Turkey"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"347259",firstName:"Karmen",lastName:"Daleta",middleName:null,title:"Ms.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"karmen@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"10198",title:"Response Surface Methodology in Engineering Science",subtitle:null,isOpenForSubmission:!1,hash:"1942bec30d40572f519327ca7a6d7aae",slug:"response-surface-methodology-in-engineering-science",bookSignature:"Palanikumar Kayaroganam",coverURL:"https://cdn.intechopen.com/books/images_new/10198.jpg",editedByType:"Edited by",editors:[{id:"321730",title:"Prof.",name:"Palanikumar",surname:"Kayaroganam",slug:"palanikumar-kayaroganam",fullName:"Palanikumar Kayaroganam"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"117",title:"Artificial Neural Networks",subtitle:"Methodological Advances and Biomedical Applications",isOpenForSubmission:!1,hash:null,slug:"artificial-neural-networks-methodological-advances-and-biomedical-applications",bookSignature:"Kenji Suzuki",coverURL:"https://cdn.intechopen.com/books/images_new/117.jpg",editedByType:"Edited by",editors:[{id:"3095",title:"Prof.",name:"Kenji",surname:"Suzuki",slug:"kenji-suzuki",fullName:"Kenji Suzuki"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3828",title:"Application of Nanotechnology in Drug Delivery",subtitle:null,isOpenForSubmission:!1,hash:"51a27e7adbfafcfedb6e9683f209cba4",slug:"application-of-nanotechnology-in-drug-delivery",bookSignature:"Ali Demir Sezer",coverURL:"https://cdn.intechopen.com/books/images_new/3828.jpg",editedByType:"Edited by",editors:[{id:"62389",title:"PhD.",name:"Ali Demir",surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"872",title:"Organic Pollutants Ten Years After the Stockholm Convention",subtitle:"Environmental and Analytical Update",isOpenForSubmission:!1,hash:"f01dc7077e1d23f3d8f5454985cafa0a",slug:"organic-pollutants-ten-years-after-the-stockholm-convention-environmental-and-analytical-update",bookSignature:"Tomasz Puzyn and Aleksandra Mostrag-Szlichtyng",coverURL:"https://cdn.intechopen.com/books/images_new/872.jpg",editedByType:"Edited by",editors:[{id:"84887",title:"Dr.",name:"Tomasz",surname:"Puzyn",slug:"tomasz-puzyn",fullName:"Tomasz Puzyn"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"43307",title:"Antibody-Based and and Cellular Therapies of Type 1 Diabetes",doi:"10.5772/53495",slug:"antibody-based-and-and-cellular-therapies-of-type-1-diabetes",body:'Type 1 diabetes (T1D) is an insulin-dependent diabetes because of insufficient insulin production by the pancreatic islet β cells. Although the pathogenic mechanism of T1D is not yet completely clear, the current view of T1D pathogenesis is that under certain genetic background, exogenous and/or endogenous factors trigger autoimmunity against islet β cells in the pancreas causing β cell damage and subsequent insufficiency of insulin production [1, 2]. About two decades ago, it was first demonstrated that T cells specific to β cell antigens were activated and participated in the pathogenesis of T1D [3, 4]. A great deal of work following these reports in both animal models and humans has provided convincing data further supporting T1D is a T cell-mediated autoimmune disease. On the other hand, the evidence showing that majority of T1D patients have high titers of autoantibodies against islet β cells [5, 6] suggests that self-reactive B cells must also be involved in the autoimmune process. The role of B cells in the pathogenesis of T1D was further supported by the recent research and clinical data demonstrating B cell depletion by anti-CD20 antibodies delayed the disease process.
The clinical presentation of T1D is preceded by a period of time of active autoimmune response occurring in the pancreatic islets. When overt diabetes occurs, approximately 95% of islets are destroyed. Therefore, tremendous efforts have been pulled in halting or slowing down autoimmune process for the purpose of preventing T1D. Several clinical trials in T1D prevention have been put forward. However, there is, thus far, no effective approach to the prevention of human T1D despite that many have shown promising results in T1D animal models. Further effort is needed to discover new ways to prevent T1D. Importantly, from a practical point of view, reversing overt diabetes is much needed. In this chapter, we will focus on recent research in immune intervention of disease process in T1D including modulation of T cells, B cells by antibodies as well as cellular therapies such as autologous hematopoietic stem cell transplantation (ASCT), treatment with mesenchymal stem cells (MSC) and cord blood transplantation.
In this section, we will discuss antibody-based therapy in T1D including therapies using anti-CD20 and anti-CD3 antibodies as well as anti-thymocyte globulin.
B cells are immune cells that produce antibodies when stimulated by exogenous or endogenous antigens. Several autoimmune diseases are associated with self-reactive B cells such as systemic lupus erythematosus and idiopathic thrombocytopenia. Reports have shown that depletion of B cells ameliorates such autoimmune conditions [7-9]. CD20 is highly expressed on the surface of mature B cells and is the B cell-specific marker. Thus, anti-CD20 antibody has been employed for the
It is generally believed that the effect of anti-CD20 therapy results from the depletion of B cells by the anti-CD20 antibodies
Complement activation by binding the Fc fragment of the antibody leads to cell lysis, or named complement-dependent cytoxicity (CDC). Complement-dependent cell lysis is controlled by the degree of complement activation and regulated by a series of complement inhibitory proteins, such as CD35, the complement receptor type 1; CD46, the membrane cofactor protein; CD55, the decay accelerating factor; and CD59, the membrane inhibitor of reactive lysis. It appears that the ability of CD20 to move into lipid rafts is needed for CDC to occur [11]. Some protein kinase pathways are also involved in regulating CDC activity, e.g. the activation of PKC, PKA and MEK is associated with B cell resistance to CDC [12]. Furthermore, complement activation has other effects besides cell lysis, such as depositing C3, C3b and additional CD3b breakdown products on the cell surface [13].
ADCC effect in anti-CD20 therapy represents killing of target cells (B cells) by the effector cells that are activated by binding the Fc fragment of anti-CD20 antibody bound on B cells. Members of the Fcγ receptor family are expressed on monocytes, macrophages and granulocytes, and include the activating high-affinity FcγRI (CD64) and low-affinity FcγRIIIA (CD16), as well as the inhibitory low affinity FcγRIIB (CD32). FcγRIIB is believed to be a key regulator on B lymphocytes [13-15]. ADCC was recently demonstrated as an important
Although the major role of anti-CD20 therapy is cell and complement-mediated cell lysis, there is evidence that anti-CD20 antibody mediates B cell death through inducing B cells to undergo apoptosis [16]. Anti-CD20 antibody, such as Rituximab induces B cell apoptosis through activation of caspase-3 [17], whereas the FAS ligand/FAS death pathway does not seem necessary. Therefore, the mitochondrial-dependent pathway is likely the death pathway induced by anti-CD20. The role of bcl-2-dependent pathways remains unclear.
Most research on the mechanisms of action of anti-CD20 therapy was conducted in B cell lymphoma to study how anti-CD20 therapy kills lymphoma tumor cells but not normal B cells. Anti-CD20 antibody therapy may work differently when used to modulate normal mature B cells. Although the existing evidence shows that anti-CD20 therapy induces regulatory T cells or regulatory B cells in autoimmune settings [18-20], the mechanisms of action of anti-CD20 in modulating normal mature B cells are not fully understood and need to be further addressed. The insight into the mechanisms of action of anti-CD20 therapy in autoimmune settings is of great importance in guiding anti-CD20 therapy in autoimmune diseases.
NOD (nonobese diabetes) mouse is an animal model of human T1D. In this strain of mice, diabetes starts to occur usually around 10 weeks of age. Tremendous measures have been tested for T1D prevention in NOD mice including anti-CD20 therapy. Hu reported for the first time that anti-CD20 therapy not only prevented but also reversed T1D in humanized NOD mice (Hu-NOD, CD20 transgenic mice). Furthermore, anti-CD20 therapy-modulated B cells can transfer diabetes-protective effect when co-transferred with diabetogenic spleen cells in NOD-scid mice, suggesting post anti-CD20 depletion the reconstituted B cells might acquire tolerogenic, or regulatory capacity. Additionally, the authors discovered that anti-CD20 therapy significantly induces CD4+CD25+Foxp3+ regulatory T cells [21]. It has been shown that NOD mice deficient for B cells from the birth fail to develop autoimmune diabetes [22]. Xiu, et al [23] directly tested how depletion of B cells influenced T1D pathogenesis in wild-type NOD mice with an intact immune system. NOD female mice at early and late pre-clinical stages of disease were treated with mouse anti-mouse CD20 mAbs. Short-term anti-CD20 mAb treatment in 5-week old NOD female mice reduced B cell numbers by 95%, decreased subsequent insulitis, and prevented diabetes in >60% of littermates. The treatment in 15-week old NOD mice was unable to prevent T1D but significantly delayed the process. In contrast to the study described previously, this study failed to show any changes in T cells and regulatory T cells [22]. The results of anti-CD20 therapy in the above T1D animal models are encouraging. Further clinical studies are needed to determine whether anti-CD20 therapy has the same efficacy in human T1D.
A randomized, double blind clinical study testing the effect of Rituximab on new-onset T1D was conducted by the T1D TrialNet Anti-CD20 study group. The results were published in New England Journal of Medicine 2009 [10]. In this well-designed clinical study, 87 patients aged 8 to 40 years who had newly diagnosed T1D were assigned to either receive infusions of 375 mg/m2 Rituximab (57 cases) or placebo (30 cases) on days 1, 8, 15, 22. The primary outcome assessed 1 year after the first infusion, was geometric mean area under the curve (AUC) for the serum C-peptide level during the first 2 hours of a mixed-meal tolerance test. The results showed that at 1 year post treatment, the mean AUC for the level of C peptide was significantly higher in the Rituximab group than in the placebo group. The levels of glycated hemoglobin and requirement of insulin were significantly reduced in Rituximab group as compared to placebo group. Peripheral blood B lymphocytes were quickly depleted in the Rituximab group, and slowly recovered with time. By the end of 1 year observation, the levels of B lymphocytes increased to 69% of baseline. It is noted that the rate of C-peptide loss did not accelerate with recovery of B cells between 6 months and 1 year. Patients in Rituximab group had more incidences of adverse events, displaying mostly grade 1 or grade 2 after the first infusion. The reactions appeared to be minimal with subsequent infusions. No increased frequency of infection or neutropenia with Rituximab was reported. In this study, the authors observed significant reduction of serum IgM but not IgG suggesting Rituximab may selectively deplete sub-populations of B cells. Based on the results of one-year follow-up, anti-CD20 therapy is a promising approach for T1D treatment. Whether repeating the course of anti-CD20 therapy is needed and whether this treatment leads to long-term protection need to be further investigated.
A follow-up study on the patients enrolled in the clinical study described above attempted to address how Rituximab infusion influences the levels of autoantibodies against islet antigens. Autoantibodies to insulin (IAAs), GAD65 (GADAs), insulinoma-associated protein 2 (IA2As), and ZnT8 (ZnT8As) were measured with radioimmunoassays. The results showed that Rituximab markedly suppressed IAAs compared with the placebo injection but had a much smaller effect on GADAs, IA2As and ZnT8As. A total of 40% (19 of 48) of Rituximab-treated patients who were IAA positive became IAA negative versus 0 patient out of 29 placebo-treated patients. In the subgroup (n=6) treated within 50 days of diabetes, IAAs were markedly suppressed by Rituximab treatment in all patients for 1 year and for four patients as long as 3 years despite of continuing insulin therapy. Independent of Rituximab treatment, the mean level of IAAs at study entry was markedly lower for patients who maintained C-peptide levels during the first year of follow up in both Rituximab-treated and placebo groups [24]. The results described above suggest that anti-CD20 therapy differentially suppresses anti-islet autoantibodies. Further studies are needed to investigate whether autoreactive B cell clones against islet antigens are differentially depleted.
As mentioned earlier, mouse studies have demonstrated that anti-CD20 therapy alters T cells. It is of interest to know how Rituximab infusion affects T cell responses in human T1D. This was explored in a follow-up study on patients in the above-described clinical trial Surprisingly, it is noted that Rituximab treatment leads to enhanced proliferative responses of T cells to diabetes-associated islet-specific autoantigens, which are positively correlated with C-peptide levels [25]. It is still unclear why B cell depletion enhances T cell proliferation. It is likely to be related to the refill of immune system post B cell depletion by T cells through homeostatic proliferation. Further studies are needed to characterize those T cells phenotypically and functionally to determine whether those autoreactive T cells are beneficial or harmful for controlling autoimmunity.
Drug resistance is the major reason of failure in the treatment of B cell lymphoma by Rituximab [26, 27]. It had been unknown whether anti-CD20 therapy in autoimmune diseases, such as T1D can also lead to drug resistance until a recent report indicating a potential mechanism for the ineffectiveness of anti-CD20 therapy in T1D [28]. This animal study showed that anti-CD20 efficiently depleted follicular but not marginal zone B cells. Interestingly, the islet infiltrated B cells lost their CD20 expression, which might explain the ineffectiveness of anti-CD20 therapy in late stage of T1D in NOD mice. Gradual recovery of the antibodies against islet antigens further suggests that autoimmune B cells are unable to be completely wiped out by anti-CD20 therapy. New drugs targeting the islet-infiltrated CD20neg B cells, such as anti-CD19 antibodies may be needed to further improve the efficacy of immunotherapy targeting B cells.
One of the most concerned issues regarding anti-CD20 therapy is the potential infection arisen by B cell depletion [29]. Anti-CD20 therapy indeed leads to hypoimmunoglobulinemia [30-32]. However, there is no significant increase in the incidence of infection during anti-CD20 therapy, which is consistent with a recent report demonstrating that anti-CD20 therapy does not deplete memory B cells specific to the antigens previously encountered [33, 34]. Another biggest concern of anti-CD20 therapy is anaphylaxis to anti-CD20 antibodies [35] because the current clinically employed anti-CD20 antibodies like Rituximab are made from animals. Humanized anti-CD20 antibodies are being developed, and are expected to overcome this severe adverse effect.
Given that T1D is a T cell-mediated autoimmune disease, T cell depletion therapy is expected to be a promising approach in T1D therapy. Much attention to anti-CD3 therapy has been drawn to the researchers and clinicians in the field of T1D. Over the years of basic and clinical studies, enormous progress has been made in terms of mechanism of action and the optimization of anti-CD3 therapy. Several clinical trials in new onset T1D are under way. In the following section, we will discuss T1D anti-CD3 therapy including mechanism of action, animal studies, clinical studies, adverse effects as well as issues to be resolved, etc.
As what has been described in anti-CD20 therapy, anti-CD3 therapy works eventually through non-selective depletion of T cells including CD4+ and CD8+ T cells. Currently, it is believed that the mechanism of action of anti-CD3 therapy is largely beyond T cell depletion. In this section, we will discuss how anti-CD3 therapy works to preserve islet β cells.
It is known that in the initial stage of anti-CD3 therapy, all T cells including CD4+ and CD8+ T cells are activated as evidenced by the expression of CD69. Activation-induced cell death (AICD) is a major mechanism regulating central tolerance during T cell development in thymus. Yu et al reported that anti-CD3 triggered AICD in activated T cells
In 2003, an elegant study by Belghith, et al [38] reported that anti-CD3 treatment induced TGF-β-producing T cells which was indispensable for the anti-CD3-induced immune tolerance. A later study further confirmed this finding and demonstrated that anti-CD3 therapy induced regulatory T cells through TGF-β released from phagocytes phagocytosing apoptotic T cells induced by anti-CD3 therapy
Another form of immune tolerance is T cell anergy. To dissect the mechanism of action of anti-CD3 therapy, it is interesting to know whether anti-CD3 therapy induces T cell anergy i
There are currently two T1D animal models that spontaneously develop diabetes under genetic susceptibility, NOD mice and diabetes-prone biobreeding (BB) rat. Although these two T1D animal models have some similarities to human T1D, there are many differences between animal and human in terms of disease progression. Nevertheless, studies on animal models will definitely provide very useful information for the immunopathogenesis, prevention and treatment of T1D. Several clinical trials are based on promising results in animal models including anti-CD3 therapy in new onset diabetes.
Anti-CD3 therapy for T1D was first tested in NOD mice. Chatenoud, et al [46] reported that anti-CD3 treatment of adult NOD mice significantly inhibits the autoimmune process. Short-term low-dose anti-CD3 treatment (5 μg/day i.v. for 5 consecutive days) prevented the occurrence of an accelerated form of the disease induced by cyclophosphamide. When this regimen was administered in adult NOD females with newly diagnosed diabetes, 64-80% of treated mice obtained a complete remission of overt diabetes showing permanent normoglycemia. It was noted that this remission was durable (>4 months) and was not associated the disappearance of insulitis. Anti-CD3 treated mice failed to reject syngeneic islet graft but maintained normal response to allogeneic skin grafts, whereas control untreated diabetic NOD females rejected both, suggesting that anti-CD3 therapy reverses diabetes through inducing islet antigen-specific immune tolerance. This study also suggests that diabetes-reversing effect can be obtained by transient targeting of the CD3/T-cell receptor without massive T-cell debulking. As described earlier, this effect may be associated with diabetes-protecting regulatory T cells induced by anti-CD3 therapy.
To improve the effectiveness of anti-CD3 therapy, a strategy of combination with islet antigens has been proposed to more effectively restore self-tolerance to islet antigens. Bresson, et al [47] reported that anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes in comparison to monotherapy with anti-CD3 or antigen alone. Further studies demonstrated the expansion of CD25+Foxp3+ and insulin antigen-specific regulatory T cells producing IL-10, TGF-β and IL-4. When adoptively transferred, these cells could transfer immune tolerance to immunocompetent recent-onset diabetic recipients and suppressed autoaggressive CD8+ responsive T cells. This strategy would act more site-specifically thereby reducing the risk for systemic side effects. The same group employed a mathematical disease model, and revealed that preexisting autoantibodies predict efficacy of oral insulin in combination with anti-CD3 antibodies to cure autoimmune diabetes [48]. This study shows that NOD mice with higher pretreatment levels of serum insulin-associated antigens (IAAs) responded with a much higher likelihood to combination therapy but not anti-CD3 monotherapy, indicating that IAAs may be a good biomarker to predict a better capability of the mice in inducing insulin-specific regulatory T cells after oral insulin immunization. Ablamunits, et al [49] reported recently that co-administration of anti-CD3 and IL-1 receptor antagonist had synergistic effect on T1D reversal, which showed that the combinatorial therapy led to persistent remission from islet inflammation. Whether the resolution of islet inflammation leads to regeneration of islet β cells was not addressed in this report.
The outcomes from animal studies have provided very useful information for developing anti-CD3-based therapeutic strategies for human T1D. Although the results of anti-CD3 therapy in human T1D are mixed, the preservation of β cell function in the current clinical trial suggests that anti-CD3 therapy is a viable regimen for human T1D.
The results of the first clinical trial using anti-CD3 therapy for human T1D were reported in New England Journal of Medicine in 2002. Herold, et al [50] studied the effects of a nonactivating humanized mnonclonal antibody against CD3 (hOKT3gamma1 (Ala-Ala) on the loss of insulin production in patients with recently diagnosed T1D. Within 6 weeks after diagnosis, 24 patients were randomly assigned to receive either a single 14-day course of anti-CD3 treatment, or no antibody and, were followed for one year. The results showed that anti-CD3 treatment maintained or improved insulin production after one year in 9 of the 12 patients in the treatment group whereas only 2 of the 12 controls had a sustained response. The treatment effect on insulin response lasted for at least 12 months after diagnosis. Glycated hemoglobin level and insulin dose requiement were reduced in the anti-CD3 treatment group. No severe adverse effect was observed, and the most common side effects were fever, rash, and anemia. Clinical responses were associated with a change of CD4+ T cells to CD8+ T cells ratios at 30 and 90 days after treatment with the responders showing reduced CD4/CD8 ratios. This study provides initial encouraging results. Longer period of follow-up would be needed to establish the long-term effectiveness of this therapy.
A clinical study was conducted using the similar protocol in the above-mentioned study but with different doses at different injection times during the treatment course. The results demonstrated significant improvement in C-peptide response to a mixed meal. The improved C-peptide responses were accompanied by reduced HbA1c and insulin requirements. These results indicate that treatment with anti-CD3 antibody, hOKT3γ1 (Ala-Ala), Teplizumab results in improved C-peptide responses and clinical parameters in T1D for at least 2 years in the absence of continued immunosuppressive medications. In this study, because of severe adverse effect of the increased dose of Teplizumab, the patient enrollment was stopped after 10 patients enrolled [51]. Among these patients, four drug-treated patients were followed up for 5 years. Results showed that C-peptide responses were maintained. During this study, it was found that increased dose of anti-CD3 antibodies caused severe adverse effects without gaining improved therapeutic effect [52]. Thus, the dosing may need to be further modified to gain the best benefit for the patients.
Recently, the results of a randomized and double blind clinical trial (clinicaltrial.gov, number NCT00385697) conducted by multi-centers from different countries on anti-CD3 therapy in treating new onset T1D was reported in Lancet journal [53]. In this 2-year trial, patients aged 8-35 years who had been diagnosed with T1D for 12 weeks or fewer were enrolled and treated at 83 clinical centers in North America, Europe, Israel and India. Participants received one of the three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose, or placebo). Patients and study staff remain masked through to study closure. 763 patients were screened, of whom 516 were randomized to receive 14-day full-dose teplizumab (n=209), 14-day low dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n-99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analysis. The primary outcome did not differ between groups at 1 year. Nonetheless, 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0.03). All groups had similar incidences of adverse effects. The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] versus 20/99 [20%] in the placebo group). This study suggests that future studies of immunotherapeutic intervention with Teplizumab might have increased success in prevention of a decline in β-cell function and provision of glycemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children.
From the results of the above clinical trials, anti-CD3 therapy is a promising regimen for human new onset T1D. However, its efficacy needs to be further improved. For this purpose, combinatorial therapy is a rational approach [54, 55]. As described above, recent animal studies demonstrated that anti-CD3 therapy combined with islet β cell antigens induced islet antigen-specific immune tolerance and significantly improved the effectiveness of anti-CD3 therapy in NOD mice. Anti-CD3 antibody combined with IL-1 receptor antagonist was tested in NOD mice and showed significant improvement of therapeutic efficacy. International multi-center clinical trials have tested the agents, anti-CD3, GAD, diapep227, insulin immunization and IL-1 receptor antagonist, anakinra, separately. There is, thus far, no clinical trial testing the efficacy of combinatorial therapy of the above-mentioned agents in treating T1D. Therefore, a phase 1 clinical trial may be needed in this respect.
Simson, et al reported that ATG treatment (500 μg/mouse) at day 1 and day 3 attenuated T1D development. It was noted that this T1D protection only presented when NOD mice were at disease onset or in the late pre-diabetic phase (12 weeks of age). It was demonstrated that when provided at 12 weeks of age, ATG reversed pancreatic insulitis, improved metabolic responses to glucose challenge, and rapidly increased frequency of antigen-presenting cells in spleen and pancreatic lymph nodes. It was also found that ATG therapy dramatically increased the frequency and functional activity of CD4+CD25+ regulatory T cells. Adoptive transfer/cotransfer studies of T1D support that ATG therapy induces a stable and transferable immunomodulatory repertoire
Our unpublished data show that ATG therapy preferentially depletes naïve T cells, and memory T cells are relatively preserved. In addition, ATG therapy largely spares CD4+CD25+ regulatory T cells. Of interest, ATG therapy does not deplete antigen-specific T cells but alters T cell responses to the previously experienced antigens, showing increased levels of Th2 and IL-10-producing Tr1 cells, which might contribute to ATG therapy-induced T1D protection. In addition, post-ATG therapy CD4+CD25+ regulatory T cells display memory-like T cells phenotypically, suggesting that those regulatory T cells might play an important role in ATG therapy-induced long-lasting T1D protective effect.
Based on the animal studies described above, a couple of clinical trials using ATG, or ATG combined with G-CSF in human T1D are ongoing (www.clinicaltrials.gov/NCT0116157, www.clinicaltrials.gov/NCT00515099). The assessment of the effectiveness of ATG therapy in human T1D await the outcomes from these clinical trials.
T1D is characterized by the autoimmune destruction of insulin-producing β cells with loss of insulin secretion. Patients with T1D have absolute requirement of insulin for survival. While insulin is effective in lowering blood glucose, hypoglycemia, even life-threatening hypoglycemia, is almost unavoidable with insulin treatment, as exogenous insulin cannot exactly mimic the profile of physiological insulin secretion. Other limitations of insulin therapy include inconvenience of daily life, physical pain and high economic costs caused by recurrent insulin injections.
Therefore, other strategies have been explored to preserve or restore β cell function in the hope that endogenous insulin secretion will achieve better glycaemic control while reducing episodes of severe hypoglycemia. As discussed above, immunotherapy, in particular the use of immunomodulatory drugs has pulled much efforts. Both experimental and clinical data demonstrate that some agents like anti-CD20 and anti-CD3 antibodies are effective in delaying the process of β cell autoimmune destruction. However, no drugs have demonstrated to prevent or reverse human T1D successfully in long-term.
More recently, many efforts have been focused on the use of stem cells as a potential therapeutic strategy for T1D. So far, accumulating data from both experimental and clinical trials have suggested that stem cell-based cellular therapy could be a promising approach for T1D treatment.
The use of bone marrow transplantation (BMT) as a potential treatment for T1D was first proposed in animal study in 1985 [58], showing that allogenic bone marrow transplantation could prevent insulitis and overt diabetes in NOD mice. This concept was further substantiated by later animal study [59].
The first clinical trial to use hematopoietic stem cell transplantation in T1D patients was reported in 2003 [60]. The objective of the study was to stop autoimmune destruction of β cells with immunosuppressive drugs and to “re-set”the impaired immunologic system with a reconstituted one using autologous HSCs in the expectations of preserving residual β cell mass and facilitating endogenous mechanisms of β cell regeneration. With the above considerations, 15 newly diagnosed T1D patients were enrolled. All received high-dose immunosuppression followed by autologous hematopoietic stem cell transplantation (AHST) within 6 weeks of diagnosis. During a 7- to 36-month follow-up (mean 18.8 months), 14 patients became insulin-free. β cell function was improved as evidenced by the increase in C-peptide levels. No significant adverse effects were observed. The mechanism concerning the beneficial effects of HST is proposed to be associated with the generation of a more tolerant immune system, which blocks the autoimmune destruction of residual β cells. This hypothesis appears to be consistent with a recent clinical observation showing that intra-pancreatic autologous bone marrow infusion has no beneficial effects on long-standing T1D patients with absence of β cell function [61].
To date, it is unclear whether the beneficial effects of HST can be sustained because of the lack of long-term follow-up study. Second, it is not known whether the beneficial effects of HST are due to immune reconstitution
Bone marrow is a rich source of stem cells, but its application is hampered by the limited availability of bone marrow donors and the invasive procedure for cell collection. Human umbilical cord blood (HUCB) is another source of stem cells. Compared to bone marrow, HUCB has some major advantages such as easy availability, absence of risk to the donor, low risk of graft-vs-host disease and tumorigenicity, high capacity for expansion [62]. UCB has been used successfully in transplantation for diseases like acute anemia, and sickle cell anemia [63]. There have been both animal and clinical studies evaluating the use of UCB cells as a potential therapy for T1D. The rationale is based on experimental studies.
Mesenchymal stem cells (MSCs) were originally identified by Friedenstein et al. in 1976 [71] in the bone marrow as a fibroblast-like cell population capable of generating osteogenic precursors. MSCs from the bone marrow (BM) are a heterogeneous, stromal population of multipotent non-hematopoietic progenitor cells capable of differentiating into multiple mesenchymal lineages including bone, fat and cartilage. In addition to bone marrow, MSCs have been found to be present in other tissues such as adipose tissue, umbilical cord blood, synovial membrane, skeletal muscle, dermis, deciduous teeth, pericytes, trabecular bone, articular cartilage, umbilical cord, placenta, liver and spleen. It is now known that MSCs are able to differentiate into mesodermal and non-mesodermal cell lineages, including osteocytes, adipocytes, chondrocytes, myocytes, cardiomyocytes, fibroblasts, myofibroblasts, epithelial cells, and neurons [72].
In addition to their pluripotency to differentiate, MSCs have high immunomodulatory capacity. The immunomodulatory property of MSCs are associated with their inhibitory effects on the proliferation and differentiation of both T cells and B cells, as well as dendritic cell (DC) [73]. Moreover, MSCs can modulate immune response through stimulating the production of CD8+ Treg (regulatory T cells) [74]. MSCs are known to secrete a variety of trophic mediators such as growth factors and cytokines (M-CSF, IL-6, IL-11, IL-15, SCF, VEGF) that are involved in the regulation of immune response and hematopoieses. This could be a major mechanism underlying the immunomodulatory action of MSCs. Recently, MSCs have been used in clinical trials for the treatment of acute graft-versus-host disease (GVHD) following allogeneic HSC transplantation [75,76], and for autoimmune diseases such as multiple sclerosis and Crohn disease [77,78]. Another striking characteristic of MSCs is the ability to differentiate into insulin-producing cells (IPCs).
By now, the use of MSCs for treatment of diabetes have been explored in two animal studies. In a model of murine STZ-induced diabetes, co-administration of BM cells with syngeneic or semi-allogeneic MSCs normalized blood glucose and serum insulin levels. The beneficial effect of this treatment does not seem due to the reconstitution of the damaged islet cells from the transplant since no donor-derived β cells were found in the recovered animals. Instead, the benefits may be due to the immunosuppressive effect of MSCs on the β cell-specific T cell response since MSCs injection caused the disappearance of beta-cell-specific T lymphocytes from diabetic pancreas, which may allow the regeneration of recipient-derived pancreatic insulin-secreting cells [80]. In another study [81], the mechanism underlying the beneficial effects of MSCs on blood glucose was investigated in a diabetic rat model induced by high-fat diet/streptozotocin (STZ) administration. Autologous MSCs were administered either 1 or 3 weeks after STZ injection. Infusion of MSCs during the early phase not only promoted β cell function but also ameliorated insulin resistance, whereas infusion in the late phase merely ameliorated insulin resistance. The improved insulin sensitivity induced by MSCs infusion is associated with an increase of GLUT4 expression and an elevation of phosphorylated insulin receptor substrate 1 (IRS-1) and Akt (protein kinase B) in insulin target tissues.
Taken together, these
In conclusion, both anti-lymphocyte antibody-based and cellular therapies are promising in stopping ongoing autoimmunity against islet antigens and likely leading to a hopeful restoration of self-tolerance. The regimens combining anti-lymphocyte antibodies, islet antigens and cellular therapies could maximize the preventive and/or therapeutic efficacy for T1D.
This work was supported by Natural Science Foundation of China (Grant number 81172854 to CQX), and NIH 1R21DK080216-01A2 to CQX
SARS-CoV-2 is a relatively large virus with single-stranded RNA genome, belongs to beta coronaviruses that affects the lower respiratory system to cause viral pneumonia. The gastrointestinal system, kidney, heart, liver, and central nervous system may also be attacked leading to multiple organ failure. It is surrounded by an envelope composed of a lipid bilayer and envelope proteins [1].
The COVID-19 viral infection is mediated by three main stages: the first one involves host cell entry through endocytosis and transportation proteins; the second stage initiates viral RNA translation to polyprotein, which is subjected to cleavage by the main viral proteinases Mpro and Papain-like proteases PLpro to produce the effector proteins; in the final stage, the negative-strand viral RNA is translocated to the Golgi apparatus to produce new virions, and the newly produced virus are released by exocytosis [1].
The viral entry was found to be mediated by endocytic pathways, which is initiated by the binding of spike protein (S protein), a protein found on the envelope of the virus, to a receptor protein located on the host cell surface membrane, known as angiotensin-converting enzyme 2 (ACE2). The S protein is cleaved into S1 and S2 by a human cell-derived protease that is assumed to be Furin. S1 then binds to its receptor, ACE2. The other fragment, S2, is cleaved by TMPRSS2, a serine protease. Thus, ACE2 and TMPRSS2 are essential in airway cells for SARS-CoV-2 infection [2].
Also the viral entry was found to be facilitated through endocytosis [3], especially clathrin-mediated endocytosis (CME) helps in translocation of ACE-2/virus complex to endosome where the virus is uncoated by the action of acidic proteases such as cathepsins, which are cysteine proteases in host cells involved in facilitating viral entry of several viruses such as SARS-COV and MERS-COV [4]. It’s worthy to note that cathepsins are also involved in S protein cleavage [5, 6].
After uncoating, the viral RNA expression and replication require subcellular localization of viral and cellular proteins from cytoplasm to the nucleus. The viral infection induces the translocation and expression of group of suprafamily protein in the host cells called karyopherin, Importins (IMP) α/β heterodimer. These proteins are reported to be utilized by the virus not only for translocation purposes, but also for disruption of self-antiviral defenses in response to interferon via intervening with the nuclear import of signal transducer and activator of transcription proteins (STAT). Chromosome Region Maintenance-1 (CRM1) is one of those proteins that contribute significantly in nuclear export of viral protein and RNA in wide range of viruses [7].
The SARS-Cov-2 genome has a large replicase gene, which contains nonstructural proteins (NSPs), structural proteins, and accessory genes. The replicase gene encodes two open reading frames (ORFs) after frameshifting, translated into two large polyproteins pp1a and pp1ab, then processed by two viral proteases: papain-like protease (PLpro, encoded within Nsp3) and Mpro aslo called 3C-like protease (3CLpro, encoded by Nsp5) to produce 16 viral Nsps that their function has been linked to RNA replication. PLpro is believed to play important role to protect the virus from immune response by inactivating ubiquitin-dependent cellular responses to viral infection and blocking of cytokine production [8, 9].
After cell invasion, a full-length negative-strand RNA template is synthesized by nonstructural protein 12 (Nsp12) RNA-dependent RNA polymerase (RdRp) to produce more viral genomic RNA [10].
Another important nonstructural protein is RNA helicase, which has main role in the replication of viruses by catalyze unwinding of double-stranded RNA. It is structurally conserved among different types of viruses, thereby making it an excellent target for development of broad-spectrum antiviral agents [11, 12].
In this stage, the viral RNA is translocated to endoplasmic reticulum (ER) where it is translated to transmembrane structural proteins (S, HE, M, and E) and some membrane-associated accessory proteins, except for the N protein, which is translated by free ribosomes in the cytoplasm [13]. These structural proteins play the main role in virion morphogenesis and the structural components recruitment to the proper assembly site. Then they are released from the cell by exocytosis by the help of several host factors [14].
However, in the COVID-19 pandemic, an integrated approach encompassing prophylaxis, diagnosis, and treatment must be adopted worldwide.
Among the top priorities for regulating and monitoring COVID-19 are:
An appropriate prophylactic procedure (vaccination).
Accurate diagnostic battery.
An unambiguous therapeutic regimen.
WHO stated that “vaccine must supply a quite convenient beneficial environment for dealing with jeopardy; with high performance, only passing with mild effects and with no danger effects.” The vaccine should be appropriate for lactating, gravid women and for all ages and has many production sources dwell in high-, middle-, and low-income countries [15]. There is a race among several pharmaceutical companies to provide a treatment for COVID-19. Unfortunately, this completion had led to a big controversy, which was refuted by WHO issued on 20 November 2020 “there is a conditional recommendation against the use of remdesivir since there isn’t enough evidence to support its use.” Moreover, WHO has issued a conditional recommendation against the use of remdesivir in hospitalized patients, regardless of disease severity, as there is currently no evidence that remdesivir improves survival and other outcomes in these patients (https://www.who.int/news-room/feature-stories/detail/who-recommends-against-the-use-of-remdesivir-in-covid-19-patients).
However, by the end of 2020 (exactly December 2020), Pfizer/BioNTech was able to get an Emergency Use Listing approval (EUL) for vaccine against COVID-19. Currently and as reported by on January 20th, 2022, nine vaccines were granted EUL status [16, 17].
The Pfizer/BioNTech Comirnaty vaccine, 31 December 2020.
The SII/COVISHIELD and AstraZeneca/AZD1222 vaccines, 16 February 2021.
The Janssen/Ad26.COV 2.S vaccine developed by Johnson & Johnson, 12 March 2021.
The Moderna COVID-19 vaccine (mRNA 1273), 30 April 2021.
The Sinopharm COVID-19 vaccine, 7 May 2021.
The Sinovac-CoronaVac vaccine, 1 June 2021.
The Bharat Biotech BBV152 COVAXIN vaccine, 3 November 2021.
The Covovax (NVX-CoV2373) vaccine, 17 December 2021.
The Nuvaxovid (NVX-CoV2373) vaccine, 20 December 2021
The clinical laboratory is an important and essential tool for the diagnosis, follow-up, and evolution, as well as in the prognosis of any pathology that is active or not. In the COVID-19 pandemic, several biomarkers’ involvement as indicators of the disease’s current state has been reported, while others have proved to be useful prognostic markers. Some of these characteristics are as follows [18].
General laboratory findings in SARS-CoV-2 infection sometimes indicate leukocytosis or leukopenia, with marked lymphopenia in the disease’s first stages. Besides, the neutrophilia presence has been related to an unfavorable prognosis [19].
Thrombocytopenia, lymphopenia, thrombocytopenia, D-dimer, elevated C-reactive protein (CRP) (happened repeatedly in critical cases), and leukopenia are not distinctive laboratory factors [20].
COVID-19 patients who have diabetes mellitus of type 2 (T2DM) expressed minimized levels of lymphocytes, body mass index (BMI), albumin, and uric acid (UA), and increased CRP levels. The reduced levels of albumin, UA, and BMI may be related to nutritional consumption and oxidative stress response. The increased CRP levels and decreased lymphocyte counts may be related to the infection [21].
Medical imaging, such as Computed Tomography (CT) and X-ray, plays a significant function in the combat against the pandemic. So, the current AI methods can be used to help medical specialists and strengthen imaging tools. Also, AI could also increase work performance by effective detection of CT and X-ray diseases. The Computer-Aided Diagnosis (CAD) models enable physicians to take correct clinical choices on disease diagnosis, monitoring, and prognosis [22]. Many radiological characteristics are used to categorize the disease and help in discovering the treatment, such as the following:
The most direct method to identify the degree of disease is imaging, as it is effective and accurate. Consolidation and diffuse lesions are features of severe pneumonia. Doubled ground-glass opacity, unification, and interlobular septal thick ply in the right and left lungs are the popular chest CT discoveries for COVID-19, which are particularly spread under the pleura. The serious part of the pandemic diagnosis and examination is computed tomography [23].
A sensitive examination method is called spiral CT. It can be used for diagnosis in the early stages and estimation of development. This method has diagnostic allergy and precision preferable to the disclosure of nucleic acid [24]. During the first week of the illness, appearance and blended predominance with opacity in the lower lung are quite dubious of COVID-19. However, few illness cases may have a normal chest outcome despite positive testing for COVID-19 [25].
The proportion of infected cases with mild COVID-19 symptoms was relatively high-rise. Misdiagnosis in some cases can result from checking for COVID-19 with only chest CT, which would result in a possibility of contagion risk. It was not appropriate as a separate screening device. Visual, quantitative interpretation depended on CT images with great diagnostic capability and good matchmaking. It can help in clinical classification; it is predictable to strictly evaluate the severe COVID-19 cases and combining with the clinical information to guide the clinical treatment [26].
Therapeutic interferences can be categorized into four main classes: general treatment, antiviral treatments, particular medications, and other medications.
The effectiveness and safety of COVID-19 have been tested using several drugs, such as chloroquine, remdesivir, favipiravir, and hydroxychloroquine. Some of them had presented antiviral impacts against COVID-19 but no conclusive evidences [27].
Although the serious disease has been related to hyperinflammation induced by COVID-19, the immune responses of acute COVID-19 stay ambiguous. Some researchers comprehensively analyzed circumferential immune troubles in blood for 42 recovered and infected by COVID-19. The activation of various immune strains is recognized, including oligoclonal plasmablast expansion, trafficking receptor modulation on granulocytes, innate lymphocytes, and T cell activation, which separated acute COVID-19 patients or moderate-severe patients from healthy donors or COVID-19-recovered. One of the predictive biomarkers is the ratio between neutrophil and lymphocyte of organ failure and disease gravity. Results appeared wide innate and adaptive leukocyte annoyances that characterize dysregulated have an infection in extreme COVID-19 disease, and medication examination is required. There were no efficacious antiviral medications, even common drugs with strong effect as abidol, ritonavir/lopinavir showed no exceptional impact on clinical progression, virus clearance, or deaths [28].
The meta-analysis of corticosteroid treatment and available observational studies suggested maximized death rates and subaltern contagion rates in influenza, maximized viremia, weakened antibody response, and weakened infection riddance MERS-CoV and SARS-CoV, and corticosteroid treatment complications in recovered patients [29]. Therefore, in the medication of COVID-19, corticosteroids should not be supported or even applied for acute patients.
The plasma of convalescent for severe influenza infection and SARS-CoV medication was proposed to minimize the mortality rate and days number in hospital, particularly after symptom appearance and administered plasma early [30].
As for inoculation, if any cross-reactive epitopes were recognized among COVID-19 and SARS-CoV, the preceding vaccine of SARS-CoV might be reused to expedite the COVID-19 vaccine progression. It is recommended for prophylaxis, streptococcus pneumonia, and influenza vaccination, especially in the elderly [31].
Drug repurposing is also a quick tool that creates a shortcut to find a safe and effective therapy for this exciting pandemic. It depends on the fact that their safety profile, side effects, posology, and drug interactions are well known [27]. Currently, several FDA-approved drugs are tested for their potential to treat COVID-19 infection such as lopinavir, chloroquine, azithromycin, hydroxychloroquine, favipiravir, umifenovir, ribavirin, remdesivir, and darunavir have been tested in many COVID-19 clinical experiments for hopeful use under emergency protocol. Unfortunately, none of these tested drugs showed a conclusive results and satisfactory outcomes among treated patients. Therefore, several studies used in silico tools for prediction of the ability of drugs to interact with molecular targets important for viral replications.
In that aspect, the liver research laboratory (FAB-Lab, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt) has applied several approaches for not only improving the pharmacological effect of easily accessible natural products, but also identifying new applications for them. Drug repositioning or repurposing may reveal a new approach to rediscover new uses for clinically approved existing old drugs [32].This book revealed the theory, applications, and/or hazardous outcomes on drug discovery in different disciplines in medicine; e.g. dermatology [33, 34], cancer [35, 36, 37], and neurological disorders [38].
A hopeful mechanism to cure COVID-19 patients is the reusing of trusted antiviral treatments in opposition to COVID-19. Viral loads are reduced by employing the antiviral treatments that have risen lung allocations, which is helpful to COVID-19 cases. There are a number of antiviral medications such as [39]:hr
Some results depended on molecular docking and network direct pharmacology action on COVID-19, for examples:
Kaempferol, aloe-emodin, quercetin, luteolin, forsythoside E, rutin, and hyperoside in Lianhua Qinwen might be the buoyant components in hindering COVID-19 by computer-assisted treatment design (CADD) of virtual checking and network pharmacology analysis through JAK-STAT signaling pathway [40, 41, 42]
Patchouli alcohol, saikosaponin ergosterol, 23-acetate alisol B, shionone, B (Bupleuri Radix) could act straight on the COVID-19 3CL pro to restrain infection multiplication. On differentiate, shionone (Asteris Radix et Rhizoma), tussilagone, patchouli alcohol, asarinin, ephedrine hydrochloride, and ergosterol might work on steward cells ACE2 to restrain the attack [43, 44, 45, 46]
Licorice glycoside E, (2R)-7-hydroxy-2-(4-hydroxyphenyl) chroman-4-ketone, robinin, naringenin, quercetin, kaempferol, irisolidone, and isorhamnetin from Huoxiang Zhengqi as 3CL pro restraints, which may block COVID-19 repetition by focusing on E2F1 and PIK3CG by PI3K-Akt signaling path [44]. Rosmarinic acid could block virus repetition through the PI3K-Akt signal path [47].
Quercetin, Kaempferol, luteolin, baicalein, glyasperin C, licochalcone B, and oroxylin A were suggested to tie with organizing different signals paths and ACE2, as BCL2, PTGS2, Kaposi sarcoma-related herpesvirus contagion, CASP3, hepatitis C, Epstein-Barr virus infection, measles, and human cytomegalovirus contagion.
Baicalein, kaempferol, luteolin, rhubarb wogonin, and quercetin had a great partiality with COVID-19 3CL hydrolase [48].
As previously explained, nonstructural proteins of COVID-19 and several factors and receptors in host cells are essential for viral entry and replication, which means that both should be considered in the process of the development of effective antiviral agents as depicted in Figure 1. In this section, we will address known natural products inhibitors to the key targets controlling viral entry and replication.
Different approaches for targeting viral entry and replication of the COVID-19. (1) Inhibition of S protein binding to ACE2, (2) disruption of endocytic pathways, (3) inhibition of nuclear translocation of viral RNA and protein by host cell mediators, (4) inhibition of the proteolysis of viral polyprotein to the nonstructural proteins (Nsp), (5) inhibition of transcription and replication of viral RNA.
Targeting host lipids is an intriguing antiviral strategy. Coronaviruses are a class of viruses with a lipid envelope that requires a plasma membrane fusion process mediated by endocytosis, a mechanism that involves certain cholesterol-rich microdomains and its ACE2 receptor [49] and mediates the early stages of internalization of coronaviruses [50].
Macromolecules such as methyl-β-cyclodextrin have been used to inhibit attachment of coronaviruses to host cells. These nontoxic macromolecules mimic attack sites for the enveloped virus, competing with host cell attack sites. It could also decrease ACE2 expression in the cell membrane, thereby reducing the infectivity of coronaviruses, such as SARS-CoV-2 [51].
Natural compounds including phytosterols and triterpenes (Figure 2) can exert the same action. For example, betulinic acid also has the same lipophilic properties as cholesterol, so it may therefore compete with cholesterol, replacing it in plasma membranes, or it may bind to the virus instead of raft cholesterol, acting as a soluble competitor [52].
Chemical structures of the most common phytosterols. They are considered as potential inhibitors of SARS-CoV-2 lipid-dependent attachment to host cells, a possible approach for decreasing its infectivity.
TMPRSS2, a human cell surface serine protease, results in membrane fusion. ACE2 and TMPRSS2 are essential in airway cells for SARS-CoV-2 infection [53]. ACE2 inhibition should not be tracked as a treatment strategy as ACE inhibitors upregulate the expression of ACE receptors providing more binding sites for SARS-CoV-2. On the other hand, blocking TMPRSS2 is accessible and will prevent the fusion of the envelope of the virus with host cell surface membranes. Nafamostat, an existing safe drug used for pancreatitis, may inhibit SARS-CoV-2 entry by inhibiting TMPRSS2 activity.
In this context, several reported serine protease inhibitors from nature could be repurposed to target TMPRSS2.
Potent serine protease inhibitors have been reported from filamentous marine cyanobacteria. Most of these molecules are 3-amino-6 hydroxy-piperidone (AHP-containing cyclic depsipeptides). The AHP moiety is crucial for serine protease inhibitory activity, and any structural or conformational variations to this unit will affect activity (Figure 3) [54].
Serine protease inhibitors isolated from marine cyanobacteria. Potential blockers for the requisite viral entry process (inhibition of the S protein-initiated membrane fusion by inhibiting TMPRSS2 activity).
It’s now well established that endocytosis is the nick bottle for COVID-19 entry to the host cells, thus inhibiting this pathway could reduce the infectivity of the virus dramatically. This could be achieved by increasing of the endosomal and lysosomal pH using lysosomotropism agents, which disrupt the proteolytic action of host cell proteases, which work optimally in acidic pH and prevent the cleavage of the S Protein of the virus [55]. While chloroquine (CQ) and its derivative are developed originally for treatment of malaria, but since they demonstrated potent activity by direct acting on the virus and by preventing its endocytosis, they were repurposed for treatment of several viral infection and currently used widely used in therapeutic protocol for treatment of COVID-19 [56]. Bafilomycin A1, a vacuolar-type H+−ATPase inhibitor, lies in the same category and could explain the use of azithromycin, a structurally related macrolide antibiotic for treatment of COVID-19 patients [57].
Inhibition of cysteine proteases such as cathepsins could be an important approach due to their role in viral entry, and luckily the incorporation of these protein in the pathogenesis of several diseases such as cancer, metabolic conditions, and Alzheimer’s has led to the discovery and development of several inhibitors that could be repurposed for treatment of COVID-19 infection. E-64, a compound isolated from the fungus
As addressed earlier, CME is one of the main mechanisms for viral entry; hence, its inhibition could be a reliable method for control of the infection. Ouabain and bufalin cardiotonic steroids, which are used for treatment of cardiovascular diseases, have demonstrated antiviral activity against MERS-CoV infection at nanomolar concentrations by affecting the CME pathway [59]. This is consistent with recent report by Jeon et al., where ouabain, lanatoside C, and digitoxin were able to reduce viral viability of COVID-19 in micromolar concentrations [60].
Bolinaquinone, a sesquiterpenoid derivative with quinone ring, isolated from marine
Like other viruses, COVID-19 uses the replication machinery of the host cell for transcription and replication of Viral RNA; this means that viral materials such as nonstructural proteins and negative-strand RNA should be relocated to the nucleus and endoplasmic reticulum.
Interestingly, ivermectin, an antiparasitic FDA-approved drug, has been reported to inhibit nuclear transport in host cells such as (IMP) α/β1 heterodimer preventing the translocation of viral DNA integrase in HIV-1 and other viruses. Recently, ivermectin has shown potent antiviral activity against COVID-19 [63]. In fact, such effect was linked to the broad-spectrum antiviral activity of this molecule [64].
Finally, leptomycin B (LMB), a compound isolated from
Chemical structure of compounds that inhibit endocytic pathway and translocation mechanisms.
We have addressed the role of host cells factor and protein inhibition in controlling viral infection. So, we will focus mainly on some important targets of the virus itself. The proteolysis of polypeptide to the 16 NSp is a rate-limiting step in viral replication; thus, it is obvious that targeting viral proteases could achieve significant antiviral activity.
Mpro is one of the best characterized drug targets among coronaviruses. This enzyme is essential for processing the translated polyproteins from the viral RNA. The Mpro works at not less than 11 cleavage sites on the large polyprotein 1ab (replicase 1ab, ~790 kDa); the recognition sequence at most sites is Leu-Gln↓(Ser,Ala,Gly).
The viral replication could be blocked by Mpro inhibitors [65, 66, 67]. There are no human proteases with a similar cleavage specificity. Therefore, these inhibitors are not supposed to be toxic. Peptidomimetic alpha keto-amides were reported to be potential Mpro inhibitors [68]. The natural α-keto amides such as eurystatin A and B, complestatin, and aplidine display prolyl endopeptidase inhibitor, HIV replication inhibitor, and antitumor activity, respectively [68]. Also, theaflavin-3,3′-digallate was reported as natural protease inhibitor in SARS-CoV [9]. Other flavonoids are reported to strongly block Mpro activity such as pectolinarin, rhoifolin, herbacetin [69].
PLpro has dual function, beside its role in release of other nonstructural protein, it neutralizes the immune response by the host cell due its deubiquitinating activity, so its inhibition will not only stop the replication cascade but will help the immune system to regain the ability to recognize and destroy the virus [70, 71]. Hirsutenone, a diarylheptanoid from
Chemical structure of natural compounds that inhibit viral proteases (Mpro and PLpro).
After the transcription of viral RNA to the required structural protein, the hijack of the host cell continues to make many replicas of the viral RNA that will be packed and released. The new virus, RNA helicase was found to be crucial to viral genome replication, which explains why it is a potential target for antiviral drug development. Scutellarin inhibits 90% of SARS-COV RNA helicase activity at 10 μM probably by binding to the ADP active site, myricetin showed the same activity but with much lower extent [75]. Interestingly, ivermectin has shown the ability to inhibit RNA helicase of flavivirus [76], taking in consideration that helicase are structurally conservative among most of the viruses. Ivermectin might also be able to exert the same activity in COVID-19, which in fact may explain the potent antiviral activity addressed previously. Figure 6 shows the chemical structure of the natural helicase inhibitor.
Chemical structure of the natural helicase inhibitors.
One of the hallmarks of late-phase COVID-19 infection is uncontrolled intense release of proinflammatory mediators, which is known as cytokines storm. Different types of viruses tend to activate mitogen-activated protein kinase (MAPKs) cascades, which control proliferation and inflammation in order to stimulate the replication process of the virus RNA. Since the upregulation of MAPKs was linked to several inflammatory and autoimmune diseases, it can lead to multiorgan failure and potentially death.
Clinically, in some patients, it has been reported that their immune response to the SARS-CoV-2 virus results in the increase of cytokines IL-6 and IL-10 [77].
Both hydroxychloroquine and chloroquine have immunomodulatory effects and can suppress the increase of immune factors. Bearing this in mind, it is possible that early treatment with either of the drugs may help prevent the progression of the disease to a critical, life-threatening state. In critically ill SARS-CoV-2-infected patients, the use of corticosteroids may be harmful. While the use of immunosuppressants (e.g., tocilizumab) is not ideal either as it can suppress the immune system and lead to an increased risk of infection. In this setting, hydroxychloroquine may be an ideal drug to treat SARS-CoV-2 infection as it can inhibit the virus via its antiviral effects and help mediate the cytokine storm via its immunomodulatory effects [78].
Fortunately, natural products could serve as the perfect solution in such case as they would not only work as antiviral agents but also could help to downregulate proinflammatory gene and protein expression via affecting a plethora of MAPKs and transcriptional factors. LPS-induced expression of proinflammatory cytokine could be considered as an excellent model for screening, since LPS also activates the inflammatory mediators through several pathways.
For example, diarylheptanoids, flavonoids, and triterpenes, which possess antiviral activity as mentioned earlier, were able to suppress the gene expression of TNF-alpha, IL-1β, IL-6 in different types of cells such as macrophages and HepG2 induced by LPS by modulating multiple intracellular signaling pathways in macrophages and prevent LPS-induced IL-6 production by reducing the mRNA stability via inhibiting ERK1/2 activation. This could be achieved by natural compounds such as flavokawain A, curcumin, quercetin curculigoside, syringic acid or vanillic acid, licochalcone A, chrysin, apigenin, and luteolin at transcriptional level [78, 79]. In brief, the anti-inflammatory effect of natural products is so prominent to be summarized in this chapter, and they can contribute significantly at reducing the mortality rates associated with COVID-19 complications (Figure 7).
Chemical structures for the potential natural immunomodulators for cytokine storm associated with COVID-19 infection.
Therapeutics: AI and ML in treatment discovery development and/or drug repurposing for COVID-19 based on:
EHR data and clinical guidelines
Interaction of human-AI in robotic surgery
Pharmacogenomics for directing the management of medications
AI may contribute to the advancement of resources to support doctors and ultimately enhance medical outcomes. Fuzzy logic can be used in decision support systems to replicate patient decision-making processes [80, 81, 82]. Admittedly, machine learning applied is to clinical data that are regularly collected will produce new knowledge and potentially new perspectives that clinicians lack.
Drug repurposing is hoped to offer a way to establish COVID-19 avoidance and cure policies. For instance, the researchers built a DL approach to classifying current and mercantile medicines for “drug-repurposing,” i.e., identifying a quick treatment using existing medicines that can be introduced to patients immediately. The idea that recently created treatment typically needs years to succeed is reviewed before getting to the public motivates research. Although the results are not accepted clinically, new approaches to combat COVID-19 disease are already opening up [83]. In silico medicine is suggested in [84] using the deep generative model to explore drugs (identifying new medicines). This analysis may be used for simulations and computer modeling to obtain compounds for COVID-19 coronavirus by new molecular entities.
IBM reported that it is now offering an analysis service based on the cloud using the COVID-19 dataset that has been educated [85]. Besides, IBM has implemented its proposed drug discovery AI technology, in which 3000 novel COVID-19 molecules have been produced [86]. In the year 2020, a systematic analysis was developed by Zeng et al. [87] to find drugs for COVID-19. With the support of active Amazon Web Services (AWS), a DL-based model was developed, and 41 data on drug types were validated. As for performance metrics, true-positive rate (TPR), false-positive rate (FPR), etc., have been presented, and the approach suggested by the author is explicit that DL serves as an important instrument for exploring therapeutics.
Earlier, our research team had presented the usefulness of AI and ML in diagnosis of several diseases [88, 89, 90]. However, COVID-19 diagnosis was based on AI.
Multiomics and clinical data
Records of Electronic Health (HER) data and expert knowledge
Nour et al. [91] have developed a DL model for COVID-19 detection, as CNN is applied as a feature extractor. For performance assessment, chest X-ray images dataset is taken into account. For feeding ML methods such as K-nearest neighbour (KNN), Decision Tree (DT), and
Pereira et al. [92] proposed a new model for forecasting the dynamics of COVID-19 that have cases that have happened in other countries or places with similar emission patterns. For all subregions and accessible countries, they implemented a grouping algorithm.
Big data in the administration of hospitals, epidemiology, insurance, medication interactions and complications, outcomes reviews based on quality, epidemic tracking.
Speech datasets include breath sounds and cough, which can be utilized for COVID-19 diagnoses and its prediction for illness seriousness. Machine learning, statistical techniques, and big data may be used to the datasets for prediction functions about the disease. Various open-source datasets for COVID-19 included mobility, diagnosis, contagion assessment, NPI analysis, statistic relationships, and sentiment analysis.
COVID-19 causes a gigantic load to the healthcare system, particularly in patients with preexisting conditions comorbidities. A comprehensive study is presented about COVID-19 symptoms, clinical classification (mild, moderate, severe, critical cases), and the risk indicators for COVID-19 infection with comorbidities.
Natural products (NPs) have been used for centuries for treatments of different maladies and inspired scientists to develop safer and more effective drugs. The COVID-19 is complex clinical condition that comprises inflammatory components. Although selective inhibitor could be developed for inhibiting critical molecular target in the life of cycle, compounds with multitargeting activity may be more favorable to reduce the possibility of mutation development. Optimum drug should be able to modulate host cell and viral-related mechanisms. This is where natural products could play important role since their ability to bind effectively to targets with completely different homology. Nevertheless, the anti-inflammatory attribute of NPs is another advantage that should be considered during choosing therapeutic protocol. Finally, the observed antiviral activity of different phytochemicals should initiate repurposing campaign of untested NPs to identify new antiviral compounds, which could be exploited to design more effective drugs with optimum pharmacokinetic properties. This study presents briefly the value of AI and ML as powerful tools in healthcare, clinical, drug industry, diagnosis, decision-making, and improvement of the selection criteria for the most appropriate protocol for the treatment of COVID-19.
The author would like to thank Ms. Rowida Omar (Department of Pharmacognosy, Faculty of Pharmacy, Delta University, Gamsa, Egypt) and Mr. Abdullah A. Elgazar (Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University, Egypt) for their great efforts in providing valuable materials of the first draft and Mrs. Zahraa Tarek (Computer Science Department, Faculty of Computer and Information, Mansoura University, Egypt) for providing materials on artificial intelligence section.
The authors declare no conflict of interest.
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To achieve this, a battery of instruments was applied to 945 Compulsory Secondary Education students from Basque Country (425 boys and 520 girls) of medium socio-cultural level and aged between 12 and 17 (Mage = 14.50, SD = 1.82). The study tests a structural model for analyzing the effects of resilience and subjective well-being on school engagement and perceived performance. The findings provide evidence in favor of the influence of resilience and subjective well-being as decisive psychological variables in the prediction of school engagement and perceived performance. Finally, the results of this study highlight the need to foster education of resilience and subjective well-being to improve academic achievement among adolescent students.",book:{id:"6225",slug:"health-and-academic-achievement",title:"Health and Academic Achievement",fullTitle:"Health and Academic Achievement"},signatures:"Arantzazu Rodríguez-Fernández, Estibaliz Ramos-Díaz and Inge\nAxpe-Saez",authors:[{id:"90485",title:"Dr.",name:"Arantzazu",middleName:null,surname:"Rodriguez-Fernández",slug:"arantzazu-rodriguez-fernandez",fullName:"Arantzazu Rodriguez-Fernández"},{id:"205183",title:"Dr.",name:"Estibaliz",middleName:null,surname:"Ramos-Díaz",slug:"estibaliz-ramos-diaz",fullName:"Estibaliz Ramos-Díaz"},{id:"223442",title:"Prof.",name:"Inge",middleName:null,surname:"Axpe-Saez",slug:"inge-axpe-saez",fullName:"Inge Axpe-Saez"}]},{id:"62994",doi:"10.5772/intechopen.76431",title:"Health, Academic Achievement and School-Based Interventions",slug:"health-academic-achievement-and-school-based-interventions",totalDownloads:2473,totalCrossrefCites:6,totalDimensionsCites:9,abstract:"There is a statistically significant relationship between health and academic achievement. Research evidence shows that children who are healthy are at a low risk for school problems than students who are unhealthy. Students with good health tend to perform better in school than those with poor health. Problems that emanate from poor health include a higher probability of school failure, poor levels of concentration, grade retention and dropout. However, health is a complex and elusive concept and its definition is often shrouded by assumptions and limitations. Therefore, the relationship between health and student achievement is often complex. The concept of health has been evolving over time, cutting across multiple disciplines. Of late, there has been a focus on achieving not only health but total well-being. Schools have been challenged to promote student health by providing favourable environments, policies, support services and information-based interventions. Schools should develop integrated health interventions because of their proven effectiveness in promoting healthy lifestyles among students. This chapter critically examines the concept of health and establishes the connection between health and achievement. The chapter also proposes health interventions that are effective in influencing academic achievement.",book:{id:"6225",slug:"health-and-academic-achievement",title:"Health and Academic Achievement",fullTitle:"Health and Academic Achievement"},signatures:"Thomas Matingwina",authors:[{id:"227293",title:"Ph.D.",name:"Thomas",middleName:null,surname:"Matingwina",slug:"thomas-matingwina",fullName:"Thomas Matingwina"}]},{id:"58183",doi:"10.5772/intechopen.71842",title:"Influence of Drugs on Cognitive Functions",slug:"influence-of-drugs-on-cognitive-functions",totalDownloads:2149,totalCrossrefCites:5,totalDimensionsCites:7,abstract:"Disorders related to the misuse of certain drugs represent not only a worldwide public health problem, but also an economic and social issue. Adolescents and children represent the most vulnerable population for drug consumption and addiction. At this early stage in life, a crucial phase of the neurodevelopmental process, substance abuse can induce brain plasticity mechanisms that may produce long-lasting changes in neural circuitry and ultimately behavior. One of the consequences of these changes is the impairment of cognitive functions, with academic negative impact in the acquisition of new knowledge. In this chapter, we will describe the effects of illicit substances of abuse, both stimulants and depressants as well as prescription drug misuse and its influence of on learning and memory processes. Recent evidence on the new so-called smart drugs is also discussed.",book:{id:"6225",slug:"health-and-academic-achievement",title:"Health and Academic Achievement",fullTitle:"Health and Academic Achievement"},signatures:"Claudia Juárez-Portilla, Tania Molina-Jiménez, Jean-Pascal Morin,\nGabriel Roldán-Roldán and Rossana Citlali Zepeda",authors:[{id:"219266",title:"Dr.",name:"Rossana C",middleName:null,surname:"Zepeda",slug:"rossana-c-zepeda",fullName:"Rossana C Zepeda"},{id:"219492",title:"Dr.",name:"Claudia",middleName:null,surname:"Juárez-Portilla",slug:"claudia-juarez-portilla",fullName:"Claudia Juárez-Portilla"},{id:"219493",title:"Dr.",name:"Tania",middleName:null,surname:"Molina-Jiménez",slug:"tania-molina-jimenez",fullName:"Tania Molina-Jiménez"},{id:"219494",title:"Dr.",name:"Gabriel",middleName:null,surname:"Roldán-Roldán",slug:"gabriel-roldan-roldan",fullName:"Gabriel Roldán-Roldán"},{id:"220789",title:"Dr.",name:"Jean-Pascal",middleName:null,surname:"Morin",slug:"jean-pascal-morin",fullName:"Jean-Pascal Morin"}]},{id:"63876",doi:"10.5772/intechopen.79938",title:"The Importance of Mindfulness in the Achievement of Optimal Functioning: Conceptualization for Research Development",slug:"the-importance-of-mindfulness-in-the-achievement-of-optimal-functioning-conceptualization-for-resear",totalDownloads:928,totalCrossrefCites:0,totalDimensionsCites:7,abstract:"The concept of ‘optimal functioning’ has emerged as a major line of research development in educational psychology. Optimal functioning, which reflects the paradigm of positive psychology, is concerned with a person’s achievement of maximization in his/her functioning, whether it is mental, cognitive, emotional, or social. This inquiry places strong emphasis on importance of flourishing, happiness, and the proactivity of human endeavors. An important question then for consideration, from this testament, is how researchers optimize the achievement of optimal functioning. We have recently made progress by focusing on empirical research development and methodological conceptualizations into the study of optimization. Our conceptualizations, collectively, contend that there are psychological, educational, and psychosocial variables that operate as sources of ‘energization’, which then stimulate the buoyancy of motivation, personal resolve, effective functioning, strength, and effort expenditure. Energization, in its totality, from our postulation, may then arouse, intensify, and sustain a person’s internal state of functioning. Our cross-institutional, cross-cultural research collaboration (e.g., Australia, Malaysia, and Taiwan), to date, has considered one notably construct that could serve as a source of internal energization for the achievement of functioning: mindfulness. We strongly believe that the totality of mindfulness, positive in nature, could play a central role in the psychological processes of human agency.",book:{id:"7698",slug:"educational-psychology-between-certitudes-and-uncertainties",title:"Educational Psychology",fullTitle:"Educational Psychology - Between Certitudes and Uncertainties"},signatures:"Huy P. Phan, Hui-Wen Wang, Jen-Hwa Shih, Sheng-Ying Shi, Ruey-Yih Lin and Bing H. 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The incorporation of factors, such as drug use and bullying, promotes the impairment of executive functions. Resorting to strategies, such as exercising, environmental enrichment, and changes in the diet, constitutes an excellent aid in the promotion of academic achievement. In this chapter, we discuss the impact of stress on cognitive executive functions associated with academic achievement and also suggest strategies to reduce the impact of stressing factors.",book:{id:"6225",slug:"health-and-academic-achievement",title:"Health and Academic Achievement",fullTitle:"Health and Academic Achievement"},signatures:"Tamara Cibrian-Llanderal, Montserrat Melgarejo-Gutierrez and\nDaniel Hernandez-Baltazar",authors:[{id:"209886",title:"Dr.",name:"Tamara",middleName:null,surname:"Cibrian-Llanderal",slug:"tamara-cibrian-llanderal",fullName:"Tamara Cibrian-Llanderal"},{id:"210172",title:"Dr.",name:"Montserrat",middleName:null,surname:"Melgarejo-Gutierrez",slug:"montserrat-melgarejo-gutierrez",fullName:"Montserrat Melgarejo-Gutierrez"},{id:"210173",title:"Dr.",name:"Daniel",middleName:null,surname:"Hernandez-Baltazar",slug:"daniel-hernandez-baltazar",fullName:"Daniel Hernandez-Baltazar"}]}],mostDownloadedChaptersLast30Days:[{id:"70837",title:"Identifying and Remediating Dyslexia in Kindergarten and the Foundation Year",slug:"identifying-and-remediating-dyslexia-in-kindergarten-and-the-foundation-year",totalDownloads:929,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Dyslexia is a learning disability found across the ability range. It is an unexpected failure to learn to read and spell despite conventional classroom instruction. It is usually identified at about 7 years of age or beyond when the dyslexic fails to learn to read. The incidence varies in different countries in different languages and with teaching methods. This research presents a new method for the identification of dyslexia by the Reception or Kindergarten teacher as part of everyday teaching. The method uses a child’s freeform writing and a checklist that identifies a critical borderline point that must be reached if the child is to become literate. In order to overcome any difficulty, a specific intervention was identified and a training technique was introduced in a Reception Year cohort (N = 175 children). It was based upon previous research that found dyslexia was caused by a unique deficit that prevented them from developing early phonological awareness in the normal course of learning. The intervention strategy also enabled disadvantaged learners to catch up with more advantaged peers and close the 11-month learning gap found in the national statistics. Their Key stage 1 school SATs showed 30% uplift 3 years later.",book:{id:"9451",slug:"learning-disabilities-neurological-bases-clinical-features-and-strategies-of-intervention",title:"Learning Disabilities",fullTitle:"Learning Disabilities - Neurological Bases, Clinical Features and Strategies of Intervention"},signatures:"Diane Montgomery",authors:[{id:"85131",title:"Prof.",name:"Diane",middleName:null,surname:"Montgomery",slug:"diane-montgomery",fullName:"Diane Montgomery"}]},{id:"58763",title:"Stress in Nursing University Students and Mental Health",slug:"stress-in-nursing-university-students-and-mental-health",totalDownloads:2425,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Stress is a physiological response that impacts the cognitive, emotional, behavioral, and social components. It also involves the adaptation of the organism, the coping resources, and the environment. In young people, stress can be triggered by social interactions or school requirements. This chapter is a narrative review analyzing scientific bibliography from the main databases (NIH, Scielo, Redalyc) that explored the main stressors and their effects on nursing students. These stressors include the care of patients, assignments and workloads, academic evaluations, and negative or hostile social interactions. Data include the deleterious effects of stress in nursing students as anxiety, depression, inhibiting learning, and burnout, which negatively impact their academic development and health. Finally, some interventions to reduce the impact of stress are discussed. Conclusion: Stress responses in nursing students vary in duration and intensity during their academic training; final effects depend on the coping mechanisms, individual resources, and hospital environment. The effects of stress on nursing students impact on academic performance but could also trigger several psychiatric disorders as depression or anxiety, as well as other associated problems such as sleep disorders, alcohol, and psychoactive drug consumption, which in the short and long term may affect the patient care.",book:{id:"6225",slug:"health-and-academic-achievement",title:"Health and Academic Achievement",fullTitle:"Health and Academic Achievement"},signatures:"Frank Pulido-Criollo, Jonathan Cueto-Escobedo and Gabriel Guillén-\nRuiz",authors:[{id:"175891",title:"MSc.",name:"Frank",middleName:null,surname:"Pulido-Criollo",slug:"frank-pulido-criollo",fullName:"Frank Pulido-Criollo"},{id:"199455",title:"Dr.",name:"Jonathan",middleName:null,surname:"Cueto-Escobedo",slug:"jonathan-cueto-escobedo",fullName:"Jonathan Cueto-Escobedo"},{id:"218681",title:"Dr.",name:"Gabriel",middleName:null,surname:"Guillén-Ruiz",slug:"gabriel-guillen-ruiz",fullName:"Gabriel Guillén-Ruiz"}]},{id:"62994",title:"Health, Academic Achievement and School-Based Interventions",slug:"health-academic-achievement-and-school-based-interventions",totalDownloads:2473,totalCrossrefCites:6,totalDimensionsCites:9,abstract:"There is a statistically significant relationship between health and academic achievement. Research evidence shows that children who are healthy are at a low risk for school problems than students who are unhealthy. Students with good health tend to perform better in school than those with poor health. Problems that emanate from poor health include a higher probability of school failure, poor levels of concentration, grade retention and dropout. However, health is a complex and elusive concept and its definition is often shrouded by assumptions and limitations. Therefore, the relationship between health and student achievement is often complex. The concept of health has been evolving over time, cutting across multiple disciplines. Of late, there has been a focus on achieving not only health but total well-being. Schools have been challenged to promote student health by providing favourable environments, policies, support services and information-based interventions. Schools should develop integrated health interventions because of their proven effectiveness in promoting healthy lifestyles among students. This chapter critically examines the concept of health and establishes the connection between health and achievement. The chapter also proposes health interventions that are effective in influencing academic achievement.",book:{id:"6225",slug:"health-and-academic-achievement",title:"Health and Academic Achievement",fullTitle:"Health and Academic Achievement"},signatures:"Thomas Matingwina",authors:[{id:"227293",title:"Ph.D.",name:"Thomas",middleName:null,surname:"Matingwina",slug:"thomas-matingwina",fullName:"Thomas Matingwina"}]},{id:"60102",title:"Bullying in School",slug:"bullying-in-school",totalDownloads:3861,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Bullying in school is a significant problem worldwide and is one of the most common antisocial behaviors among adolescents and children. Despite implementing anti-bullying prevention programs in almost every school within the United States, Europe, and some initiatives in low-income countries, yet bullying is more pervasive problems in schools than any other problems. This chapter provides a review of research and evidence on school bullying: understanding the definition of bullying in school, and the size of the problem, the consequences of bullying, academic correlations, who is at risk, students’ perceptions of bullying and the evidence school-based programs to reduce and prevent bullying.",book:{id:"6225",slug:"health-and-academic-achievement",title:"Health and Academic Achievement",fullTitle:"Health and Academic Achievement"},signatures:"Nahla Mansour Al-Ali and Khulood K. Shattnawi",authors:[{id:"228887",title:"Associate Prof.",name:"Nahla",middleName:null,surname:"Al Ali",slug:"nahla-al-ali",fullName:"Nahla Al Ali"},{id:"238157",title:"Dr.",name:"Khulood",middleName:null,surname:"Shattnawi",slug:"khulood-shattnawi",fullName:"Khulood Shattnawi"}]},{id:"58183",title:"Influence of Drugs on Cognitive Functions",slug:"influence-of-drugs-on-cognitive-functions",totalDownloads:2149,totalCrossrefCites:5,totalDimensionsCites:7,abstract:"Disorders related to the misuse of certain drugs represent not only a worldwide public health problem, but also an economic and social issue. Adolescents and children represent the most vulnerable population for drug consumption and addiction. At this early stage in life, a crucial phase of the neurodevelopmental process, substance abuse can induce brain plasticity mechanisms that may produce long-lasting changes in neural circuitry and ultimately behavior. One of the consequences of these changes is the impairment of cognitive functions, with academic negative impact in the acquisition of new knowledge. In this chapter, we will describe the effects of illicit substances of abuse, both stimulants and depressants as well as prescription drug misuse and its influence of on learning and memory processes. Recent evidence on the new so-called smart drugs is also discussed.",book:{id:"6225",slug:"health-and-academic-achievement",title:"Health and Academic Achievement",fullTitle:"Health and Academic Achievement"},signatures:"Claudia Juárez-Portilla, Tania Molina-Jiménez, Jean-Pascal Morin,\nGabriel Roldán-Roldán and Rossana Citlali Zepeda",authors:[{id:"219266",title:"Dr.",name:"Rossana C",middleName:null,surname:"Zepeda",slug:"rossana-c-zepeda",fullName:"Rossana C Zepeda"},{id:"219492",title:"Dr.",name:"Claudia",middleName:null,surname:"Juárez-Portilla",slug:"claudia-juarez-portilla",fullName:"Claudia Juárez-Portilla"},{id:"219493",title:"Dr.",name:"Tania",middleName:null,surname:"Molina-Jiménez",slug:"tania-molina-jimenez",fullName:"Tania Molina-Jiménez"},{id:"219494",title:"Dr.",name:"Gabriel",middleName:null,surname:"Roldán-Roldán",slug:"gabriel-roldan-roldan",fullName:"Gabriel Roldán-Roldán"},{id:"220789",title:"Dr.",name:"Jean-Pascal",middleName:null,surname:"Morin",slug:"jean-pascal-morin",fullName:"Jean-Pascal Morin"}]}],onlineFirstChaptersFilter:{topicId:"266",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:99,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:288,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188",scope:"This series will provide a comprehensive overview of recent research trends in various Infectious Diseases (as per the most recent Baltimore classification). Topics will include general overviews of infections, immunopathology, diagnosis, treatment, epidemiology, etiology, and current clinical recommendations for managing infectious diseases. 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He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},editorTwo:null,editorThree:null},subseries:{paginationCount:0,paginationItems:[]},overviewPageOFChapters:{paginationCount:0,paginationItems:[]},overviewPagePublishedBooks:{paginationCount:0,paginationItems:[]},openForSubmissionBooks:{},onlineFirstChapters:{paginationCount:18,paginationItems:[{id:"81778",title:"Influence of Mechanical Properties of Biomaterials on the Reconstruction of Biomedical Parts via Additive Manufacturing Techniques: An Overview",doi:"10.5772/intechopen.104465",signatures:"Babatunde Olamide Omiyale, Akeem Abiodun Rasheed, Robinson Omoboyode Akinnusi and Temitope Olumide Olugbade",slug:"influence-of-mechanical-properties-of-biomaterials-on-the-reconstruction-of-biomedical-parts-via-add",totalDownloads:0,totalCrossrefCites:null,totalDimensionsCites:null,authors:null,book:{title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering - Annual Volume 2022",coverURL:"https://cdn.intechopen.com/books/images_new/11405.jpg",subseries:{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering"}}},{id:"81751",title:"NanoBioSensors: From Electrochemical Sensors Improvement to Theranostic Applications",doi:"10.5772/intechopen.102552",signatures:"Anielle C.A. 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His research interest focuses on computational chemistry and molecular modeling of diverse systems of pharmacological, food, and alternative energy interests by resorting to DFT and Conceptual DFT. He has authored a coauthored more than 255 peer-reviewed papers, 32 book chapters, and 2 edited books. He has delivered speeches at many international and domestic conferences. He serves as a reviewer for more than eighty international journals, books, and research proposals as well as an editor for special issues of renowned scientific journals.",institutionString:"Centro de Investigación en Materiales Avanzados",institution:{name:"Centro de Investigación en Materiales Avanzados",country:{name:"Mexico"}}},{id:"76477",title:"Prof.",name:"Mirza",middleName:null,surname:"Hasanuzzaman",slug:"mirza-hasanuzzaman",fullName:"Mirza Hasanuzzaman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/76477/images/system/76477.png",biography:"Dr. Mirza Hasanuzzaman is a Professor of Agronomy at Sher-e-Bangla Agricultural University, Bangladesh. He received his Ph.D. in Plant Stress Physiology and Antioxidant Metabolism from Ehime University, Japan, with a scholarship from the Japanese Government (MEXT). Later, he completed his postdoctoral research at the Center of Molecular Biosciences, University of the Ryukyus, Japan, as a recipient of the Japan Society for the Promotion of Science (JSPS) postdoctoral fellowship. He was also the recipient of the Australian Government Endeavour Research Fellowship for postdoctoral research as an adjunct senior researcher at the University of Tasmania, Australia. Dr. Hasanuzzaman’s current work is focused on the physiological and molecular mechanisms of environmental stress tolerance. Dr. Hasanuzzaman has published more than 150 articles in peer-reviewed journals. He has edited ten books and written more than forty book chapters on important aspects of plant physiology, plant stress tolerance, and crop production. According to Scopus, Dr. Hasanuzzaman’s publications have received more than 10,500 citations with an h-index of 53. He has been named a Highly Cited Researcher by Clarivate. He is an editor and reviewer for more than fifty peer-reviewed international journals and was a recipient of the “Publons Peer Review Award” in 2017, 2018, and 2019. He has been honored by different authorities for his outstanding performance in various fields like research and education, and he has received the World Academy of Science Young Scientist Award (2014) and the University Grants Commission (UGC) Award 2018. He is a fellow of the Bangladesh Academy of Sciences (BAS) and the Royal Society of Biology.",institutionString:"Sher-e-Bangla Agricultural University",institution:{name:"Sher-e-Bangla Agricultural University",country:{name:"Bangladesh"}}},{id:"187859",title:"Prof.",name:"Kusal",middleName:"K.",surname:"Das",slug:"kusal-das",fullName:"Kusal Das",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBDeQAO/Profile_Picture_1623411145568",biography:"Kusal K. Das is a Distinguished Chair Professor of Physiology, Shri B. M. Patil Medical College and Director, Centre for Advanced Medical Research (CAMR), BLDE (Deemed to be University), Vijayapur, Karnataka, India. Dr. Das did his M.S. and Ph.D. in Human Physiology from the University of Calcutta, Kolkata. His area of research is focused on understanding of molecular mechanisms of heavy metal activated low oxygen sensing pathways in vascular pathophysiology. He has invented a new method of estimation of serum vitamin E. His expertise in critical experimental protocols on vascular functions in experimental animals was well documented by his quality of publications. He was a Visiting Professor of Medicine at University of Leeds, United Kingdom (2014-2016) and Tulane University, New Orleans, USA (2017). For his immense contribution in medical research Ministry of Science and Technology, Government of India conferred him 'G.P. Chatterjee Memorial Research Prize-2019” and he is also the recipient of 'Dr.Raja Ramanna State Scientist Award 2015” by Government of Karnataka. He is a Fellow of the Royal Society of Biology (FRSB), London and Honorary Fellow of Karnataka Science and Technology Academy, Department of Science and Technology, Government of Karnataka.",institutionString:"BLDE (Deemed to be University), India",institution:null},{id:"243660",title:"Dr.",name:"Mallanagouda Shivanagouda",middleName:null,surname:"Biradar",slug:"mallanagouda-shivanagouda-biradar",fullName:"Mallanagouda Shivanagouda Biradar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243660/images/system/243660.jpeg",biography:"M. S. Biradar is Vice Chancellor and Professor of Medicine of\nBLDE (Deemed to be University), Vijayapura, Karnataka, India.\nHe obtained his MD with a gold medal in General Medicine and\nhas devoted himself to medical teaching, research, and administrations. He has also immensely contributed to medical research\non vascular medicine, which is reflected by his numerous publications including books and book chapters. Professor Biradar was\nalso Visiting Professor at Tulane University School of Medicine, New Orleans, USA.",institutionString:"BLDE (Deemed to be University)",institution:{name:"BLDE University",country:{name:"India"}}},{id:"289796",title:"Dr.",name:"Swastika",middleName:null,surname:"Das",slug:"swastika-das",fullName:"Swastika Das",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/289796/images/system/289796.jpeg",biography:"Swastika N. Das is Professor of Chemistry at the V. P. Dr. P. G.\nHalakatti College of Engineering and Technology, BLDE (Deemed\nto be University), Vijayapura, Karnataka, India. She obtained an\nMSc, MPhil, and PhD in Chemistry from Sambalpur University,\nOdisha, India. Her areas of research interest are medicinal chemistry, chemical kinetics, and free radical chemistry. She is a member\nof the investigators who invented a new modified method of estimation of serum vitamin E. She has authored numerous publications including book\nchapters and is a mentor of doctoral curriculum at her university.",institutionString:"BLDEA’s V.P.Dr.P.G.Halakatti College of Engineering & Technology",institution:{name:"BLDE University",country:{name:"India"}}},{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248459/images/system/248459.png",biography:"Akikazu Takada was born in Japan, 1935. After graduation from\nKeio University School of Medicine and finishing his post-graduate studies, he worked at Roswell Park Memorial Institute NY,\nUSA. He then took a professorship at Hamamatsu University\nSchool of Medicine. In thrombosis studies, he found the SK\npotentiator that enhances plasminogen activation by streptokinase. He is very much interested in simultaneous measurements\nof fatty acids, amino acids, and tryptophan degradation products. By using fatty\nacid analyses, he indicated that plasma levels of trans-fatty acids of old men were\nfar higher in the US than Japanese men. . He also showed that eicosapentaenoic acid\n(EPA) and docosahexaenoic acid (DHA) levels are higher, and arachidonic acid\nlevels are lower in Japanese than US people. By using simultaneous LC/MS analyses\nof plasma levels of tryptophan metabolites, he recently found that plasma levels of\nserotonin, kynurenine, or 5-HIAA were higher in patients of mono- and bipolar\ndepression, which are significantly different from observations reported before. In\nview of recent reports that plasma tryptophan metabolites are mainly produced by\nmicrobiota. He is now working on the relationships between microbiota and depression or autism.",institutionString:"Hamamatsu University School of Medicine",institution:{name:"Hamamatsu University School of Medicine",country:{name:"Japan"}}},{id:"137240",title:"Prof.",name:"Mohammed",middleName:null,surname:"Khalid",slug:"mohammed-khalid",fullName:"Mohammed Khalid",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/137240/images/system/137240.png",biography:"Mohammed Khalid received his B.S. degree in chemistry in 2000 and Ph.D. degree in physical chemistry in 2007 from the University of Khartoum, Sudan. He moved to School of Chemistry, Faculty of Science, University of Sydney, Australia in 2009 and joined Dr. Ron Clarke as a postdoctoral fellow where he worked on the interaction of ATP with the phosphoenzyme of the Na+/K+-ATPase and dual mechanisms of allosteric acceleration of the Na+/K+-ATPase by ATP; then he went back to Department of Chemistry, University of Khartoum as an assistant professor, and in 2014 he was promoted as an associate professor. In 2011, he joined the staff of Department of Chemistry at Taif University, Saudi Arabia, where he is currently an assistant professor. His research interests include the following: P-Type ATPase enzyme kinetics and mechanisms, kinetics and mechanisms of redox reactions, autocatalytic reactions, computational enzyme kinetics, allosteric acceleration of P-type ATPases by ATP, exploring of allosteric sites of ATPases, and interaction of ATP with ATPases located in cell membranes.",institutionString:"Taif University",institution:{name:"Taif University",country:{name:"Saudi Arabia"}}},{id:"63810",title:"Prof.",name:"Jorge",middleName:null,surname:"Morales-Montor",slug:"jorge-morales-montor",fullName:"Jorge Morales-Montor",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/63810/images/system/63810.png",biography:"Dr. Jorge Morales-Montor was recognized with the Lola and Igo Flisser PUIS Award for best graduate thesis at the national level in the field of parasitology. He received a fellowship from the Fogarty Foundation to perform postdoctoral research stay at the University of Georgia. He has 153 journal articles to his credit. He has also edited several books and published more than fifty-five book chapters. He is a member of the Mexican Academy of Sciences, Latin American Academy of Sciences, and the National Academy of Medicine. He has received more than thirty-five awards and has supervised numerous bachelor’s, master’s, and Ph.D. students. Dr. Morales-Montor is the past president of the Mexican Society of Parasitology.",institutionString:"National Autonomous University of Mexico",institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"217215",title:"Dr.",name:"Palash",middleName:null,surname:"Mandal",slug:"palash-mandal",fullName:"Palash Mandal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217215/images/system/217215.jpeg",biography:null,institutionString:"Charusat University",institution:null},{id:"49739",title:"Dr.",name:"Leszek",middleName:null,surname:"Szablewski",slug:"leszek-szablewski",fullName:"Leszek Szablewski",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49739/images/system/49739.jpg",biography:"Leszek Szablewski is a professor of medical sciences. He received his M.S. in the Faculty of Biology from the University of Warsaw and his PhD degree from the Institute of Experimental Biology Polish Academy of Sciences. He habilitated in the Medical University of Warsaw, and he obtained his degree of Professor from the President of Poland. Professor Szablewski is the Head of Chair and Department of General Biology and Parasitology, Medical University of Warsaw. Professor Szablewski has published over 80 peer-reviewed papers in journals such as Journal of Alzheimer’s Disease, Biochim. Biophys. Acta Reviews of Cancer, Biol. Chem., J. Biomed. Sci., and Diabetes/Metabol. Res. Rev, Endocrine. He is the author of two books and four book chapters. He has edited four books, written 15 scripts for students, is the ad hoc reviewer of over 30 peer-reviewed journals, and editorial member of peer-reviewed journals. Prof. Szablewski’s research focuses on cell physiology, genetics, and pathophysiology. He works on the damage caused by lack of glucose homeostasis and changes in the expression and/or function of glucose transporters due to various diseases. He has given lectures, seminars, and exercises for students at the Medical University.",institutionString:"Medical University of Warsaw",institution:{name:"Medical University of Warsaw",country:{name:"Poland"}}},{id:"173123",title:"Dr.",name:"Maitham",middleName:null,surname:"Khajah",slug:"maitham-khajah",fullName:"Maitham Khajah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/173123/images/system/173123.jpeg",biography:"Dr. Maitham A. Khajah received his degree in Pharmacy from Faculty of Pharmacy, Kuwait University, in 2003 and obtained his PhD degree in December 2009 from the University of Calgary, Canada (Gastrointestinal Science and Immunology). Since January 2010 he has been assistant professor in Kuwait University, Faculty of Pharmacy, Department of Pharmacology and Therapeutics. His research interest are molecular targets for the treatment of inflammatory bowel disease (IBD) and the mechanisms responsible for immune cell chemotaxis. He cosupervised many students for the MSc Molecular Biology Program, College of Graduate Studies, Kuwait University. Ever since joining Kuwait University in 2010, he got various grants as PI and Co-I. He was awarded the Best Young Researcher Award by Kuwait University, Research Sector, for the Year 2013–2014. He was a member in the organizing committee for three conferences organized by Kuwait University, Faculty of Pharmacy, as cochair and a member in the scientific committee (the 3rd, 4th, and 5th Kuwait International Pharmacy Conference).",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"195136",title:"Dr.",name:"Aya",middleName:null,surname:"Adel",slug:"aya-adel",fullName:"Aya Adel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/195136/images/system/195136.jpg",biography:"Dr. Adel works as an Assistant Lecturer in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. Dr. Adel is especially interested in joint attention and its impairment in autism spectrum disorder",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"94911",title:"Dr.",name:"Boulenouar",middleName:null,surname:"Mesraoua",slug:"boulenouar-mesraoua",fullName:"Boulenouar Mesraoua",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94911/images/system/94911.png",biography:"Dr Boulenouar Mesraoua is the Associate Professor of Clinical Neurology at Weill Cornell Medical College-Qatar and a Consultant Neurologist at Hamad Medical Corporation at the Neuroscience Department; He graduated as a Medical Doctor from the University of Oran, Algeria; he then moved to Belgium, the City of Liege, for a Residency in Internal Medicine and Neurology at Liege University; after getting the Belgian Board of Neurology (with high marks), he went to the National Hospital for Nervous Diseases, Queen Square, London, United Kingdom for a fellowship in Clinical Neurophysiology, under Pr Willison ; Dr Mesraoua had also further training in Epilepsy and Continuous EEG Monitoring for two years (from 2001-2003) in the Neurophysiology department of Zurich University, Switzerland, under late Pr Hans Gregor Wieser ,an internationally known epileptologist expert. \n\nDr B. Mesraoua is the Director of the Neurology Fellowship Program at the Neurology Section and an active member of the newly created Comprehensive Epilepsy Program at Hamad General Hospital, Doha, Qatar; he is also Assistant Director of the Residency Program at the Qatar Medical School. \nDr B. Mesraoua's main interests are Epilepsy, Multiple Sclerosis, and Clinical Neurology; He is the Chairman and the Organizer of the well known Qatar Epilepsy Symposium, he is running yearly for the past 14 years and which is considered a landmark in the Gulf region; He has also started last year , together with other epileptologists from Qatar, the region and elsewhere, a yearly International Epilepsy School Course, which was attended by many neurologists from the Area.\n\nInternationally, Dr Mesraoua is an active and elected member of the Commission on Eastern Mediterranean Region (EMR ) , a regional branch of the International League Against Epilepsy (ILAE), where he represents the Middle East and North Africa(MENA ) and where he holds the position of chief of the Epilepsy Epidemiology Section; Dr Mesraoua is a member of the American Academy of Neurology, the Europeen Academy of Neurology and the American Epilepsy Society.\n\nDr Mesraoua's main objectives are to encourage frequent gathering of the epileptologists/neurologists from the MENA region and the rest of the world, promote Epilepsy Teaching in the MENA Region, and encourage multicenter studies involving neurologists and epileptologists in the MENA region, particularly epilepsy epidemiological studies. \n\nDr. Mesraoua is the recipient of two research Grants, as the Lead Principal Investigator (750.000 USD and 250.000 USD) from the Qatar National Research Fund (QNRF) and the Hamad Hospital Internal Research Grant (IRGC), on the following topics : “Continuous EEG Monitoring in the ICU “ and on “Alpha-lactoalbumin , proof of concept in the treatment of epilepsy” .Dr Mesraoua is a reviewer for the journal \"seizures\" (Europeen Epilepsy Journal ) as well as dove journals ; Dr Mesraoua is the author and co-author of many peer reviewed publications and four book chapters in the field of Epilepsy and Clinical Neurology",institutionString:"Weill Cornell Medical College in Qatar",institution:{name:"Weill Cornell Medical College in Qatar",country:{name:"Qatar"}}},{id:"282429",title:"Prof.",name:"Covanis",middleName:null,surname:"Athanasios",slug:"covanis-athanasios",fullName:"Covanis Athanasios",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/282429/images/system/282429.jpg",biography:null,institutionString:"Neurology-Neurophysiology Department of the Children Hospital Agia Sophia",institution:null},{id:"190980",title:"Prof.",name:"Marwa",middleName:null,surname:"Mahmoud Saleh",slug:"marwa-mahmoud-saleh",fullName:"Marwa Mahmoud Saleh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/190980/images/system/190980.jpg",biography:"Professor Marwa Mahmoud Saleh is a doctor of medicine and currently works in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. She got her doctoral degree in 1991 and her doctoral thesis was accomplished in the University of Iowa, United States. Her publications covered a multitude of topics as videokymography, cochlear implants, stuttering, and dysphagia. She has lectured Egyptian phonology for many years. Her recent research interest is joint attention in autism.",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259190/images/system/259190.png",biography:"Dr. Naqvi is a radioanalytical chemist and is working as an associate professor of analytical chemistry in the Department of Chemistry, Government College University, Faisalabad, Pakistan. Advance separation techniques, nuclear analytical techniques and radiopharmaceutical analysis are the main courses that he is teaching to graduate and post-graduate students. In the research area, he is focusing on the development of organic- and biomolecule-based radiopharmaceuticals for diagnosis and therapy of infectious and cancerous diseases. Under the supervision of Dr. Naqvi, three students have completed their Ph.D. degrees and 41 students have completed their MS degrees. He has completed three research projects and is currently working on 2 projects entitled “Radiolabeling of fluoroquinolone derivatives for the diagnosis of deep-seated bacterial infections” and “Radiolabeled minigastrin peptides for diagnosis and therapy of NETs”. He has published about 100 research articles in international reputed journals and 7 book chapters. Pakistan Institute of Nuclear Science & Technology (PINSTECH) Islamabad, Punjab Institute of Nuclear Medicine (PINM), Faisalabad and Institute of Nuclear Medicine and Radiology (INOR) Abbottabad are the main collaborating institutes.",institutionString:"Government College University",institution:{name:"Government College University, Faisalabad",country:{name:"Pakistan"}}},{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. Fifteen of his students have been appointed as full professors in Egypt, Cuba, and Hungary.",institutionString:"University of Pécs",institution:{name:"University of Pecs",country:{name:"Hungary"}}},{id:"277367",title:"M.Sc.",name:"Daniel",middleName:"Martin",surname:"Márquez López",slug:"daniel-marquez-lopez",fullName:"Daniel Márquez López",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/277367/images/7909_n.jpg",biography:"Msc Daniel Martin Márquez López has a bachelor degree in Industrial Chemical Engineering, a Master of science degree in the same área and he is a PhD candidate for the Instituto Politécnico Nacional. His Works are realted to the Green chemistry field, biolubricants, biodiesel, transesterification reactions for biodiesel production and the manipulation of oils for therapeutic purposes.",institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/196544/images/system/196544.jpg",biography:"Angel Catalá studied chemistry at Universidad Nacional de La Plata, Argentina, where he received a Ph.D. in Chemistry (Biological Branch) in 1965. From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",institution:{name:"National University of La Plata",country:{name:"Argentina"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",slug:"francisco-javier-martin-romero",fullName:"Francisco Javier Martin-Romero",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",biography:"Francisco Javier Martín-Romero (Javier) is a Professor of Biochemistry and Molecular Biology at the University of Extremadura, Spain. He is also a group leader at the Biomarkers Institute of Molecular Pathology. Javier received his Ph.D. in 1998 in Biochemistry and Biophysics. At the National Cancer Institute (National Institute of Health, Bethesda, MD) he worked as a research associate on the molecular biology of selenium and its role in health and disease. After postdoctoral collaborations with Carlos Gutierrez-Merino (University of Extremadura, Spain) and Dario Alessi (University of Dundee, UK), he established his own laboratory in 2008. The interest of Javier's lab is the study of cell signaling with a special focus on Ca2+ signaling, and how Ca2+ transport modulates the cytoskeleton, migration, differentiation, cell death, etc. He is especially interested in the study of Ca2+ channels, and the role of STIM1 in the initiation of pathological events.",institutionString:null,institution:{name:"University of Extremadura",country:{name:"Spain"}}},{id:"217323",title:"Prof.",name:"Guang-Jer",middleName:null,surname:"Wu",slug:"guang-jer-wu",fullName:"Guang-Jer Wu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217323/images/8027_n.jpg",biography:null,institutionString:null,institution:null},{id:"148546",title:"Dr.",name:"Norma Francenia",middleName:null,surname:"Santos-Sánchez",slug:"norma-francenia-santos-sanchez",fullName:"Norma Francenia Santos-Sánchez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/148546/images/4640_n.jpg",biography:null,institutionString:null,institution:null},{id:"272889",title:"Dr.",name:"Narendra",middleName:null,surname:"Maddu",slug:"narendra-maddu",fullName:"Narendra Maddu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272889/images/10758_n.jpg",biography:null,institutionString:null,institution:null},{id:"242491",title:"Prof.",name:"Angelica",middleName:null,surname:"Rueda",slug:"angelica-rueda",fullName:"Angelica Rueda",position:"Investigador Cinvestav 3B",profilePictureURL:"https://mts.intechopen.com/storage/users/242491/images/6765_n.jpg",biography:null,institutionString:null,institution:null},{id:"88631",title:"Dr.",name:"Ivan",middleName:null,surname:"Petyaev",slug:"ivan-petyaev",fullName:"Ivan Petyaev",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Lycotec (United Kingdom)",country:{name:"United Kingdom"}}},{id:"423869",title:"Ms.",name:"Smita",middleName:null,surname:"Rai",slug:"smita-rai",fullName:"Smita Rai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424024",title:"Prof.",name:"Swati",middleName:null,surname:"Sharma",slug:"swati-sharma",fullName:"Swati Sharma",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"439112",title:"MSc.",name:"Touseef",middleName:null,surname:"Fatima",slug:"touseef-fatima",fullName:"Touseef Fatima",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424836",title:"Dr.",name:"Orsolya",middleName:null,surname:"Borsai",slug:"orsolya-borsai",fullName:"Orsolya Borsai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca",country:{name:"Romania"}}},{id:"422262",title:"Ph.D.",name:"Paola Andrea",middleName:null,surname:"Palmeros-Suárez",slug:"paola-andrea-palmeros-suarez",fullName:"Paola Andrea Palmeros-Suárez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Guadalajara",country:{name:"Mexico"}}}]}},subseries:{item:{id:"25",type:"subseries",title:"Evolutionary Computation",keywords:"Genetic Algorithms, Genetic Programming, Evolutionary Programming, Evolution Strategies, Hybrid Algorithms, Bioinspired Metaheuristics, Ant Colony Optimization, Evolutionary Learning, Hyperparameter Optimization",scope:"Evolutionary computing is a paradigm that has grown dramatically in recent years. This group of bio-inspired metaheuristics solves multiple optimization problems by applying the metaphor of natural selection. It so far has solved problems such as resource allocation, routing, schedule planning, and engineering design. Moreover, in the field of machine learning, evolutionary computation has carved out a significant niche both in the generation of learning models and in the automatic design and optimization of hyperparameters in deep learning models. This collection aims to include quality volumes on various topics related to evolutionary algorithms and, alternatively, other metaheuristics of interest inspired by nature. For example, some of the issues of interest could be the following: Advances in evolutionary computation (Genetic algorithms, Genetic programming, Bio-inspired metaheuristics, Hybrid metaheuristics, Parallel ECs); Applications of evolutionary algorithms (Machine learning and Data Mining with EAs, Search-Based Software Engineering, Scheduling, and Planning Applications, Smart Transport Applications, Applications to Games, Image Analysis, Signal Processing and Pattern Recognition, Applications to Sustainability).",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11421,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,series:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403"},editorialBoard:[{id:"111683",title:"Prof.",name:"Elmer P.",middleName:"P.",surname:"Dadios",slug:"elmer-p.-dadios",fullName:"Elmer P. 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