Therapeutic agents or vaccine candidates targeting virus or immunity with promisor potential to use during ZIKV infection in pregnant women.
\r\n\tEnvironmental applications will deal with water, and wastewater treatments, characterization of different sorbents, and waste removers, contaminants detection in water, and waste management.
\r\n\tIndustrial applications will focus on the analysis of paint, paper, pharmaceutical, and sugar industries and the applicability of infrared spectroscopy in these fields.
\r\n\tDrug analysis, food and dietary supplements testing and analysis, and natural products analysis will be discussed as parts of the pharmaceutical applications of infrared spectroscopy.
\r\n\r\n\tIn addition, the book will limp to the important applications of infrared spectroscopy in chemical and biological analyses. While the topics mentioned herein ( including the basics of IR, as well as the environmental and the industrial applications, food, and drug analysis) will be the major topics of this book, other applications and topics related to infrared spectroscopy are also invited.
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Moreover, ZIKV was also classified as sexually transmitted disease (STD), since viral RNA and infectious particles were detectable in reproductive organs and others described some cases related to sexual transmission [2, 3]. Although the major concern about ZIKV infection is the intrauterine transmission [4, 5, 6].
Innate immunity during pregnancy still needs attention when some infection compromises pregnancy success. Recently, the world testified a huge public health problem during Zika virus (ZIKV) outbreak in Latin American countries [7, 8, 9], in which poor outcomes were observed firstly in Brazilian newborns from mothers infected on early pregnancy phase (1st -2nd trimester) [7, 8]. Consequences of viral infections on newborns are irreversible and public health and social costs are immensurable [10], making World Health Organization consider Zika infection a public health emergency in 2016 February [11].
Due to its neurotropic features, the infection caused by ZIKV has been evidenced [12, 13, 14], which show a correlation between clinical manifestations based on its tropism by brain neuronal cells of fetuses and neonates born from infected pregnant women, with a strong association to neurological damage, including microcephaly and other fetal neurological disorders, collectively named as Congenital Zika Syndrome (CZS) or Zika Associated with Birth Defect (ZABD) [15, 16, 17, 18].
The immune system is composed of a set of flexible mechanisms that are fundamental to maintain homeostasis, allowing many interactions and coexistence between different populations of microorganisms and the host. The imbalance of homeostasis can be caused by a microorganism because of its pathogenic behavior. With the establishment of an active infection and consequent immune response, inflammatory mediators, produced initially, collaborate to activate cellular populations of the innate immunity, promoting antiviral and cytotoxic responses, for example. At first, these effector responses would influence the viremia resolution with the re-establishment of homeostasis. However, the loss or dysfunction of this immune response can generate a harmful environment that triggers an uncontrolled damage inflammation and consequent cell death due to a direct cytopathic effect caused by the microorganism [19].
Some studies were conducted to understand the mechanisms involved in vertical transmission. During pregnancy, the transfer of ZIKV to the placenta occurs after an infection of decidua, the placenta maternal region, since studies have shown that decidua cells are permissive to ZIKV infection and remain permissive throughout pregnancy [20, 21]. From the infection of the decidua, there are two routes by which ZIKV reaches the fetus: infection of syncytiotrophoblasts (SBTs) through capillaries containing maternal blood or infection of Extravilous Trophoblast (EVTs) by cell-to-cell propagation [4]. In vitro studies have shown that ZIKV can infect first-trimester cytotrophoblasts CTBs and EVTs [4, 20, 21]. On the other hand, STBs are high producers of type III interferon and remain relatively resistant to viral infection throughout pregnancy, therefore, the main route hypothesis for transplacental transmission of ZIKV is that of the spread of decidua to EVTs [21, 22]. Additionally, infection of placental macrophages, the Hofbauer cells by ZIKV may contribute to both intrauterine transmission and immunomodulation [23, 24]. Further, transplacental transfer of ZIKV is more likely to occur in the pro-inflammatory environment and tolerant to placental immunity in the first trimester.
Histopathological and immunological studies in placentas have shown that infections by ZIKV lead to an increase in important inflammation markers such as TNF, CCL5, and altered vascular permeability such as metalloproteinases [25]. In addition, in vitro experiments demonstrate that trophoblastic cells become progressively more resistant to infection by ZIKV during pregnancy, partly through the secretion of IFNs [26]. In this context, a lot of efforts were raised to provide funds to deeply investigate how to avoid another spread of Zika virus infection, as well as drugs tests and vaccine development based on viral proteins, DNA vaccines, Virus Like Particles (VLP), chimeric viruses, among other strategies [27, 28, 29, 30]. Therefore, there are few studies to investigate the pregnancy immunity and how the immune interface mother-to-child could contribute to infection spread with drastic consequences to fetus [21, 31, 32, 33, 34]. To our knowledge, the imbalance of normal pregnancy immunity is already cause of metabolic disorders and the poor outcome is related to abortion [35, 36, 37]. Then, a viral infection can make this picture worst and tragic [8, 13, 15, 38, 39].
Like other Flaviviruses, ZIKV life cycle modulates machinery and functions of target immune host cells, making essential virus-cells interactions for pathogenesis development. Moreover, while several human and animal models’ studies have argued and proved ZIKV neurotropism, there are still many answers regarding viral pathogenesis in mother and its influence the fetal neural system and persistence, and clinical outcome. In this chapter we will put together the information about innate immunity during gestation, highlighting three parts probably involved with clinical outcome: 1) interferon type III; 2) innate regulatory cells; and 3) cell death pathways modulation. Additionally, we will focus on discussing how the dynamic responses of innate immune system during pregnancy and its effects in newborns, could be modulated by ZIKV, as well as how efforts on development of new/old drugs and vaccines could be effective to help pregnancy success.
The success of pregnancy is dependent on a coordinated balance between the “invading” fetal trophoblast and a receptive maternal decidua in the placenta, maintaining a dynamic and responsive immune system. The longest period of the pregnancy, fetal growth, demands a symbiotic and tolerogenic environment, but congenital viral infections can disrupt this equilibrium. In order to avoid infection severity placenta actively modulates the immunologic profile of the maternal-fetal interface [40, 41]. In this context, recent studies demonstrated that placenta responds to ZIKV infection by production of the newest interferon group type III interferons [21, 42, 43].
Type III interferon (IFN-λ 1–4) comprising a group of cytokines with action pathways under strengthen discovery [44, 45, 46], basically acting with shared inflammatory regulation and antiviral properties [47]. IFN-λs receptor was identified as a complex composed of two subunits: IFN-λR1 and IL-10R2, which is also a receptor subunit of the regulatory cytokines IL10, IL22, and IL26 [48]. In contrast with the classical pro-inflammatory type I interferons which receptors are expressed in almost all cell types, the IFNLR1/IL10RB complex is expressed primarily in cells of epithelial origin and few immune cells conferring selective IFN-λ responsiveness to them: neutrophils [49], myeloid dendritic cells (DCs) [50, 51] and plasmacytoid dendritic cells (pDC) [52]. Because of the restricted cell types producing IFN-λs, this cytokine acts locally as an immunologic barrier in organs with suppressing innate pro-inflammatory responses and limiting host damaging effects associated with inflammation [53]. Moreover, IFN-λs utilize mechanisms to suppress viral infections which induce a strong antiviral state following receptor binding with non-translational and translational processes [49, 54].
Between the different inflammatory regulation actions already described for IFN-λs, the suppression of neutrophil gains prominence because they are the immune cells that present higher expression.
of IFN-λR1 at the steady-state [55, 56, 57]. Neutrophils contribute to various stages of the reproductive process since conception and implantation, ensuring fetal wellbeing during pregnancy and finally contributing to parturition and postpartum maternal health. On the other hand, aberrant neutrophil activity is associated with severe pregnancy-related disorders such as pre-eclampsia, recurrent fetal loss or gestational diabetes mellitus [58, 59, 60]. In murine models, it was demonstrated that neutrophil exposed to IFN-λ can induce antiviral interferon-stimulated genes (ISGs); and IFN-λ (but not IFN-β) specifically activated a translation-independent signaling pathway that diminished the production of reactive oxygen species and degranulation in neutrophils, which might permit a controlled development of the inflammatory process [49].
Studies utilizing a cellular model of collagen-induced arthritis demonstrated that IFN-λ2 was protective and could stop the progression of the disease, diminishing infiltration of neutrophils to the inflamed joints as well as the production of IL-1β upon treatment with pegylated recombinant IFN-λ2 [57].
IFN-λ is strongly associated with DCs activity inducing an effector adaptive immunity response [63, 64]. Studies with a mice model of influenza A virus infection demonstrated that IFN-λ directed acts in the migration and function of CD103(+) dendritic cells, also regulating DC IL-10 network [65]. Migratory CD103(+) DCs derived from skin, lung, and intestine, efficiently present exogenous antigens in their corresponding draining lymph nodes to specific CD8(+) T cells through a mechanism known as cross-presentation, demonstrating the IFN-λ importance for the development of specific CD8+ T cell responses [65, 66]. Moreover, IFN-λ contributes to the formation of tolerogenic DCs cell, contributing to control inflammatory responses and homeostasis by fostering the conversion of naive T cells into induced Foxp3(+) regulatory T cells [66]. In vitro studies demonstrated that IFN- λ directs DCs to a regulatory phenotype with diminished capacity to stimulate T cell proliferation in a PD-1/PD-L1 dependent manner with contribution from the imbalanced cytokine milieu, such as low IL-12 and IL-2 and/or high IL-10 production [50]. Another study using mixed lymphocyte cultures demonstrated that IFN- λ -treated DCs specifically induced IL-2-dependent proliferation of a CD4(+) CD25(+) Foxp3(+) T-cell subset with contact-dependent suppressive activity on T-cell proliferation initiated by fully mature DCs [51].
Plasmacytoid dendritic cells (pDC) are rare cells found in peripheral blood and lymphoid tissues, considered to be “professional” type I IFN-producing cells and produce 10- to 100-fold more IFN-α than other cell types in response to enveloped viruses. However, in vitro IFN-λ treatment of pDC resulted in increased virus-induced expression of both IFN-α and IFN-λ, indicating that pDC are high producers of IFN-λ1 and -λ2 in response to viral stimulation and the consequences of this high IFN-λ production by pDC should be further explored [52].
In human congenital ZIKV infections, it was demonstrated that ZIKV infection leads to a typical inflammatory response in the placenta, including the expression of anti-viral Type I interferon genes (
Summary of Interferon lambda (IFN-λ) function during normal pregnancy (A), Healthy Congenital Zika infection (B), and Zika-Associated Birth Defects (C). (A) In normal pregnancy, trophoblasts exhibit a constitutive IFN-λ production, contributing to the general tolerogenic environment demanded by pregnancy (A1); Considering the peripheral blood tissue IFN-λ Interact with: (A2) neutrophils leading to a decrease in ROS and IL1β, and (A3) migratory CD103+Dendritic cells (DC) that present low levels of PD1, IL2 and IL12 together with high IL10. These CD103+DC foster the conversion of naive T cells into induced Foxp3(+) regulatory T cells (Treg) (A4). In the placenta, the constitutive IFN-λ is accompanied by decreased type I IFN pathway: low expression of IFIT5, IFNA, and IFNB, and high expression of type I IFN the negative regulator ISG15 (A5). In the lack of viral infection, the interferon regulatory factors IRF7 and IRF9 present low expression levels (A7). (B) In healthy congenital Zika infections, the placenta expresses high levels of IFN-λ to protect the fetus from congenital defects (B1). In this low damage antiviral response, high levels of IFN-λ elicits the production of ISGs and the decrease of ROS and IL1β by circulating neutrophils (B2), meanwhile the CD103+ DC presents an accented regulatory profile (B3), with induction of high specific anti-ZIKV response by Treg (B4) and TCD8+ cells (B5). In the placental level type, I interferon pathway shows a slight increase, together with the enhance of IRF7 and IRF9, forming a balanced antiviral response. (C) In Congenital Zika Syndrome (CZS) the lack of IFN-λ contributes to a damaging outcome (C1). Diminished levels of IFN-λ could not control the neutrophil activity, culminating in augmented ROS and IL1β (C2), and presence of aberrant activation forms as well as degranulation, migration, and NETosis (C3). Without IFN-λ the Dendritic Cells (DC) present a prό-inflammatory profile, with augmented PD1, IL2, and IL12 and diminished IL10 (C4). The placenta shows an exacerbated type I interferon response, which together with low IFN-λ levels (C5), leads to an imbalanced damaging antiviral response. Grey arrows represent the production or expression levels (up = high, down = low). Double arrows represent a high magnitude of production or expression. Red dashed arrows represent the direction of function/induction events that have been known and those suggested. Figure created using Biorender software (
Immunity during pregnancy is very important to be explored since successful pregnancy requires that immunoregulatory mechanisms are triggered to suppress activated fetal-specific T cells lymphocytes [36, 37]. Maternal immune cells can recognize paternal antigens on fetus. Thus, it has been very well described that dysfunction of immune cells during pregnancy can lead to immunologic fetal rejection by mother, in which the consequences are related to abortion, preterm delivery, or other severe complications [35, 36, 37].
Then, maternal-fetal tolerance involves the regulation of mother’s immune system to tolerate the semi allogeneic fetus expressing paternal antigens without immune rejection. Even though, some studies showed that regulatory T cells are the main cells which plays an important role in suppressing activated T cells during gestation; since then innate immunity system is poorly investigated [69, 70, 71].
Considering infections during pregnancy, it is also important to know that changes on maternal immune responses are required to induce limited immunosuppression without loss of host defense, in which a balance between activated and immunosuppressed cells needs to be regular [35].
Myeloid-derived suppressor cells (MDSC) are a heterogeneous mixture of immature myeloid cells, been part of innate immune cells, having a crucial role in immunomodulatory mechanisms during pregnancy [36, 72, 73]. There are two subtypes of MDSC, a monocytic and granulocytic. Phenotype is characterized by expression of CD33 and CD11b in humans, CD14 by monocytic MDSC and CD15 by granulocytic MDSC cells but lacks the maturation marker HLA-DR. But both subtypes share the characteristic of immune-suppressive function inhibiting activated NK and T cell expansion [73, 74].
Normally, immature myeloid cells as MDSC are scarcely found in peripheral blood, and their maturation includes macrophages, dendritic cells, and granulocytes formation. Nevertheless, the MDSC are also recognized by their role in some pathological conditions, like cancer, sepsis, stress, autoimmune disorders and infectious diseases [38, 75, 76].
Several studies have been reported that a decrease of MDSC during pregnancy may lead to poor outcomes, as miscarriage [77]. Also, it has been shown that progesterone levels increase MDSC during pregnancy in mice, as well as high levels of TNF and IL-1β, pro-inflammatory cytokines [38, 78].
In murine models, it was demonstrated that MDSC can produce TGF-β and IL-10, as immunosuppressive cytokines, similarly to regulatory T cells. Adding to that, MDSC can suppress T cell activation and function by arginase-1 (Arg-1) secretion, as well as nitric oxide synthase and indoleamine 2,3 dioxygenase aimed to deplete nutrients for T cell proliferation, as I-arginine (I-Arg). According to Ismail 2018, arginine is also involved in replication, and virulence of several agents, as viruses and bacteria. Then, it is suggested that an accumulation of MDSC in placenta could influence an increase of arginase activity, and it would serve for a dual purpose, inhibiting the adaptive immune system whilst also providing potential protection against infection by arginine auxotrophic pathogens [79].
Nitric oxide (NO) has been related to embryo successful implantation during early pregnancy, but excessive NO production by decidual macrophages seems to be harmful and was linked with early pregnancy loss [37, 80, 81]. Another study suggests that in early pregnancy in decidua CD33+ cells express nitric oxide synthase, playing an important role to maintained pregnancy during this phase, while in later pregnancy CD33+ cells lose the expression of this enzyme [35, 37].
Kostlin-Gille
Regarding Zika virus, there are few studies showing the presence of MDSC on women blood and during pregnancy, and considering the facts, it will be very important to know any relationship of their presence with congenital syndrome, as observed in 2016, Brazil [82, 83]. A study with 10 non-pregnant women with Zika infection showed that frequencies of circulating MDSC did not change over time [84]. Another study with pregnant monkeys infected with Zika virus showed that an imbalance on blood frequencies of MDSC and activated CD8 T cells in the acute phase may lead to poor outcome to the fetus. Adding to that, the high frequency of MDSC on placenta from pregnant monkeys showed a positive effect on pregnancy outcome, even more if a drug antiviral treatment was used [85].
Furthermore, it is worth to note that immune signature, sometimes is the key factor to explain some diseases progressions. Despite Dengue viruses is more related to signals and symptoms with Zika virus infection [86, 87], some similarities with hepatitis C virus (HCV) were also noted, and mechanisms of immune evasion have been described, as inhibition of interferon pathway, allowing virus life cycle for a long-term period, up to 100 days [88, 89]. To note, ZIKV infection is also classified as an immune-mediated viral disease, like Dengue and other viruses [86, 87, 90]. Disease progression in HCV patients to chronic infection has been associated to an increase of MDSC phenotype in peripheral blood mediated by viral proteins [38]. Wang et al., 2017 examined Japanese encephalitis virus (JEV) infection leading acute encephalopathy depending on suppression of adaptive immune response, especially T follicular helper cells, mediated by enhanced MDSC populations, such as an involvement of MDSC on splenic B cells reduction, and in lower levels of total IgM JEV-specific neutralizing antibodies in mice models [39]. Burrack et al., also suggests that MDSC has an important suppressive T cells activity and may contribute to reduce the immune-mediated disease during Chikungunya infection [90].
Otherwise, the immunosuppressive activity triggered by RNA viruses, MDSC has been associated with metabolic regulation of immunopathology induced by DNA viruses, like hepatitis B virus (HBV) [91]. Pallett et al., 2015 showed that frequencies of MDSC on liver from HBV patients without liver damage, monitored by levels of liver transaminase enzymes, were higher in comparison with patients with liver damage, showing a protective effect for patients with immune-mediated viral disease, as hepatitis B [91].
In the new coronavirus pandemic (COVID-19), the MDSC have been reported to play an important role in the early phase of symptoms, increasing their frequency on blood in the first days of signals and symptoms, and it was related to poor outcome in severe acute respiratory syndrome in hospitalized patients. Pregnancy is a risk factor for COVID-19 severity, given the Brazilian high mortality rate of 12.7% in June 2020 withing pregnant, which may be associated with the change of the immunity [92, 93, 94].
Although few studies involving MDSC frequencies on blood during Zika infection were published yet, those cell type needs to be investigated, even though in animal models for medical science breakthroughs. The technique to characterize this cell phenotype is simpler than to characterize regulatory T cells, once the procedure does not require intracellular staining [95].
If those MDSC are crucial to maintaining a healthy pregnancy, any adverse effects, as Zika virus infection could trigger an imbalance between MDSC and T cells. This dysfunction may induce a deactivation of functional MDSC on blood and placenta with failure to attempt to eliminate viral infection. In addition, T cell function during ZIKV infection is known to be delayed throughout interferences on interferon pathway, as described above. Then, this scenario may contribute to immune evasion of ZIKV, in which viral replication on maternal-fetal environment is unavoidable, inducing poor outcomes during pregnancy: fetal death, congenital syndrome, abortion, neurological disorders, etc. (Figure 2).
Myeloid-derived suppressor cell (MDSC) activation and regulation triggered by normal pregnancy and by Zika virus infection. Summary of MDSC functionality during normal pregnancy (A) and during acute phase of Zika virus infection (B) as suggested by others into an innate immunity dysregulation observed in abnormal pregnancies on monkeys [
It has been described that a protective response by innate immune cells to viruses is triggered by several distinct mechanisms including apoptosis, necrosis, paraptosis, pyroptosis, autophagy cell death, and others. Each one is depending on several aspects of infection, including where the microorganism was detected, susceptible target-cells, through signaling systems discharging the death signal, and its intensity. During the innate immune response to infections, programmed cell death may occur as a direct pathogenic mechanism of viral spread and escape from the immune system or represents an appropriate host response to limit pathogen replication. Apoptosis of lymphocytes and monocytes also plays an important role in the control of inflammatory responses, as well as in the development of maternal-fetal tolerance [96, 97, 98, 99].
Type 1 programmed cell death, also known as apoptosis, is defined by internucleosomal DNA fragmentation, marked irreversible apoptotic characteristic indicating chromatin condensation, degradation of cytoskeleton and nuclear proteins, protein crosslinking, apoptotic bodies’ formation baring ligands for receptors of phagocytic cells and, finally, the uptake by these phagocytes [97, 98, 99]. Type 2, or autophagic cell death, presents unique characteristics organelles formation including autophagosomes and autophagolysosomes in the dying cell, sources of self-degradation, and recycling [100].
Two pathways can regulate the apoptosis program in different aspects: extrinsic and intrinsic. Extrinsic pathway is activated by a transduction signal through death receptors, in which TNF, Fas ligand, or TRAIL bind to their respective receptors, such as TNF receptor family: TNFR1, Fas (CD95/APO-1) and TRAIL-R1/2. A complex signal mediated by this binding leads to an enzymatic cascade of cell degradation, and at this point caspase-3 is activated promoting DNA damage [101]. Intrinsic pathway involves intracellular mitochondria, which its membrane is the local for many Bcl-2 family members and their activity in inducing / inhibiting the mitochondrial apoptosis program implies in those proteins lead to membrane collapse as well as a transition from mitochondrial permeability promoting apoptosis process [96, 101, 102, 103, 104, 105].
Taking together, type 2, or autophagic cell death, consists of a conserved catabolic process that contributes to degradation and recycling of many intracellular substances, through lysosome activity. In this sense, many studies have shown its importance in immune responses, including degradation of microbes, direct viral peptides MHC class I presentation [106] and even altering T-cell signaling and tolerance [107, 108]. At first, autophagy is necessary to keep the cell alive under stress conditions that precede their demise. Such kind of cell death could be achieved by several mechanisms, including prolonged hypoxia or digestion of vital factors, regulatory molecules or essential organelles. In a stress situation, caused by virus, an infected cell can induce intracellular signals of autophagy, inhibiting cell proliferation, arresting cell cycle and eventually leading to cell death [106, 107, 108, 109, 110, 111].
In the acute ZIKV infection during pregnancy, macrophages and dendritic cells are involved in inflammatory cytokines production, in which CARD9 expression, an important regulator of caspase activity playing an important role in cell apoptosis regulation, is elevated allowing that pattern recognition receptors (PRR) induce pro-inflammatory cytokines cascade, as the first step on CZS, as suggested [67]. According to Quicke et al., Hofbauer cells infected with ZIKV in placenta induces IFN type I activation, reactive oxygen species production, as well as pro-inflammatory cytokines, but with minimal cell death, showing a scape of innate immune response [23]. Recently, Cao et al., showed that ZIKV could activate and increase an autophagic process in pregnant mice, suggesting an imbalance of trophoblastic cells in placenta, and relation with fetal loss [112]. Corroborating, Ribeiro et al. using a human model of placenta explants for in vitro infection demonstrated tissue injury as consequence of the association between fetal pro-inflammatory responses mediated by IL-1β, IL-6 and TNF and extrinsic caspase 3 dependent apoptosis (TNF-TNFR pathway). Together data suggest that ZIKV infection corroborates to placenta innate immune and hormonal dysfunction, increasing loss barrier integrity [42]Thus, this inflammatory status could trigger cell death and barrier loss, allowing ZIKV cross placenta and infect fetuses’ neural stem cells (Figure 3) [23, 113, 114, 115]. Interesting, autophagosomes are present in neural stem cells and it could facilitate ZIKV replication [116], although inflammation generated as well as the cytopathic effect itself culminate in extensive caspase-dependent neuronal cell death.
Programmed cell death activation during normal pregnancy and abnormal pregnancy induced by Zika virus. Normal pregnancy equilibrium is driven by regulation of number of innate immune cells in placenta leading by programmed cell death. In this situation, caspase activity starts on CARD9 expression with cytokines production by Hofbauer cells (1.A), which oxide nitric (NO) regulates trophoblasts autophagy (2.A, 3.A). Products of Hofbauer cells activity in the surveillance in placental parenchyma contributing to extrinsic (Fas/Fas-L) and intrinsic pathway (BCL2/BAX) activation in fetus brain with low expression of pro-inflammatory cytokines, regulating number of neural stem cells and microglia by apoptosis (4.A), maintaining the healthy pregnancy. Acute ZIKV infection during pregnancy suggests that macrophages and DCs are involved in pro-inflammatory cytokines production, in which CARD9 is upregulated, increasing caspase activity, allowing pro-inflammatory cytokines and reactive species cascade (1.B, 2.B), exacerbating autophagy in placenta (3.B). Taking together this innate immune dysfunction, fetus brain is affected by high activation of apoptosis pathway (4.B), provoking a cascade of cell death with an abrupt reduction of neural cells, causing severe damage [
Corroborating, Lum et al. has shown that ZIKV mainly infects fetal microglia and induces high levels of pro-inflammatory cytokines that could be harmful to the fetus [117]. In addition, the analysis of in vitro culture, fetal brain histology and
Thus, once in fetus central nervous system, ZIKV may contribute to extrinsic (Fas/Fas-L) and intrinsic (Bcl-2) pathways activation for programmed cell death, reducing number of neuronal cells. Thus, the risk of congenital syndrome is eminent, mainly in the first trimester, as well documented (Figure 3) [67, 118, 119, 120, 121, 122, 123]. Some studies with fetuses’ autopsies and infants with microcephaly have been demonstrated a broad spectrum of microscopic neuropathological abnormalities and brain damage, with direct virus cytopathic effects in neural glial cells. In this way, these data support the strong association with apoptotic cell death and microcalcifications [13, 23, 124].
In general, pregnancy is a challenge for prevention and control infectious diseases regard to a safe drug or vaccine development to do not disturb the innate/adaptive immunity homeostasis, however, there were no drugs approved for ZIKV infection treatment [28, 29, 30]. Here, drugs and vaccines candidates tested in animal models or in newborns will be described with details (Table 1).
Therapy | classification | Mechanism of action | Immune effect | Pregnancy safety | References |
---|---|---|---|---|---|
Peg Interferon-λ2 | Not approved | Antiviral immunobiological | Enhance IFNL-λ pathway activity | Yes/Mice models | Jagger et al., 2017 [26] |
Sofosbuvir | Category B/Approved for hepatitis C treatment | Direct-acting antiviral drugs | Not explored | Yes/Mice models | Mesci et al., 2018 [136] |
NITD008 | Not approved | Direct-acting antiviral drugs | Not explored | Yes/Mice models | Watanabe et al., 2019 [27] |
Hydroxycloroquine | Category C/Approved for malaria and autoimmune diseases therapy | Cell membrane interaction to induce cell death | Reduction of autophagy activity | Yes/Pregnant women | Cao et al., 2017 [112] |
rVSV vaccine | Not approved | Recombinant viral vector vaccine | Increases in CD8+/CD44high/IFN-γ + T cell populations on spleen | Yes/Mice models | Betancourt et al., 2017 [147] |
VRC5283 | Clinical trial phase II (VRC-ZKADNA090–00-VP) | DNA plasmid vaccine | Induce antigen-specific antibody production/ induce of CD8+ T cells response | Yes/Mice models | Richner et al.,2017 [155] |
mRNA-LNP vaccine | Clinical trial phase I (NCT03014089) | mRNA vaccine | Induce antigen-specific antibody production/ induce of CD8+ T cells response/Minimizes ADE | Yes/Mice models | Richner et al.,2017 [156] |
Therapeutic agents or vaccine candidates targeting virus or immunity with promisor potential to use during ZIKV infection in pregnant women.
Type III interferon has been emerging as an efficient and low damaging therapeutic agent not only directed for the virus but also for fungal and bacterial infections, as well as cancer, autoimmune, and vascular diseases [54]. The more restricted expression of IFNLR1 likely contributes to the improved safety profile of IFN-λl in clinical studies compared to type I IFN. Pegylated IFN-λ1 have already been tested in phase 2b clinical trial to chronic hepatitis C treatment and hepatitis B, associated with improved rates of virologic response with fewer extrahepatic adverse events compared to pegylated IFN-α [125]. Even though it was deemed less effective than alternative treatments for these infections, pegylated- IFN- λ can be potential candidate ready for deployment if new indications are identified [126]. There are other viral targets for IFN- λ therapy been tested in murine models: norovirus [127], and influenza virus [128], and west nile virus – last one is another member of Flaviviridae family. It is noteworthy the effect of IFN-λ on infection with west nile virus, an encephalitic flavivirus: Treatment of IFNLR1 knockout mice with pegylated IFN-λ2 resulted in decreased blood–brain barrier permeability, reducing west nile virus infection in the brain without affecting viremia, and improved survival against lethal virus challenge [129].
The effectiveness and low damage treatments for other correlated viral infections, combined with the protagonist of IFN-λs as immunoregulatory and antiviral agent in ZIKV raise the idea of IFN-λs as ZIKV therapy, and some groups already achieve exciting good results. Concerning ZIKV infections, Jagger, et al., (2017) suggest that IFN-λ2 treatment could be a safe solution to minimize Congenital Zika Syndrome severe outcomes. Using a type III interferon-deficient mouse model, authors showed that these animals had an increase of ZIKV replication in the placenta under ZIKV infection, and treatment of pregnant mice with IFN-λ2 reduced ZIKV viremia [26]. Considering the vaginal epithelium as the first line of defense against sexually transmitted ZIKV, treatment of primary human vaginal and cervical epithelial cells lineages with IFN-λ induces host defense transcriptional signatures with augmented expression of ISGs (IFI44L, OASL, OAS1, and MX1) and inhibition of ZIKV replication. Female mice submitted to treatment with IFN-λ and intravaginal ZIKV transmission showed low levels of virus replication in the female reproductive tract with a hormonal stage-dependent role [130].
Some studies were driving to evaluate effects of independent direct-acting antiviral drugs on Zika virus infection (Table 1), as sofosbuvir, an FDA-approved nucleotide analog inhibitor of the hepatitis C (HCV) RNA-dependent RNA polymerase (RdRp) [131, 132]. In vitro and
There are few studies investigating innate immunity during antiviral therapy, especially when its concern to Flaviviridae family [38, 135, 138, 139]. Scarce literature revealed knowledge about antiviral therapy immune effects only during hepatitis C infection [138, 139]. Antiviral drugs, as pegylated interferon (PEG-IFN), ribavirin, and direct-acting antiviral agents (DAA) have been related with a reduction of innate regulatory cells, as MDSC, in peripheral blood from hepatitis C chronic patients, in which T cells were increased and immune function was reestablished [138, 139]. Nevertheless, all those drugs are aimed to interrupt viral replication and any dysregulation of immune cells during pregnancy is not safe, then those drugs are not recommended to be used during gestational period [140]. Besides no immune response evaluation was related to DAA therapy, it has been known that small molecules with specific activity should not induce any immune alterations in maternal-fetal immunity [140].
Safety and effectiveness of sofosbuvir on Zika virus infection should be addressed to immune response evaluation, which is poorly explored, even more in pregnant animal models. More studies and investments are needed for non-clinical and clinical studies, to get safety therapeutic protocols aimed to pregnant women with Zika virus or other flavivirus infection.
Genetic manipulation has been proven to be a promising tool for vaccine and therapy development. Considering the type 2 of programmed death, autophagy is activated by ZIKV in placental parenchyma and is involved in poor outcome during pregnancy, this cell death pathway has been a target for therapies [112, 141, 142, 143].
Recently, a study showed the role of an autophagy gene (Atg16I1) during ZIKV infection in pregnant mice model, in which inducing a deficiency in this gene limited ZIKV vertical transmission, as well fetal damage, improving placental and fetal outcomes [112]. In addition, an antiviral compound approved to be used by pregnant women for malaria and autoimmune diseases [141], hydroxychloroquine (HCQ), has been used to dampen autophagic activity
Based on the knowledge of ZIKV infection that can trigger a caspase-3 activation contributing to cell death of neural progenitor cells during pregnancy, it is an extremely relevant approaches targeting cell death pathways for antiviral treatments even though for therapeutic vaccines.
Recombinant viral vectors have been highlighted as therapeutic alternatives to prevent and treat infectious disease [144, 145], considering its specificity and the adverse effects of antiviral drugs and some vaccines [140, 146]. Betancourt et al., 2017 showed that a recombinant viral vector from vesicular stomatitis virus (rVSV) anti-ZIKV vaccine increased IFN-γ production by splenic CD8+ T cells as well as high neutralizing anti-ZIKV antibody titers from pregnant mice. This study also demonstrates that neonatal mouse from vaccinated dams was partially protected against neurological manifestations of ZIKV infection following wild-type virus challenge [147]. This rVSV using pre membrane and envelope region together obtained from a ZIKV strain as reference had the potential to protect from ZIKV infection during prenatal and neonatal development, likely through the transmission of maternal IgG. Despite rVSV vaccine induces IFN-γ production in pregnant mice, this vaccine needs to be evaluated for other types of interferon, mainly its effects on placental tissues .
mRNA vaccines as well as DNA-based vaccines represent a versatile vaccine platform and an alternative to conventional vaccine approaches because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration [148]. Recent technological advances have allowed mRNA vaccines to demonstrate encouraging results in both animal and human models. Regarding prophylactic mRNA vaccines, a number of reports have demonstrated the potency and versatility of mRNA to elicited protective immunity against a variety of infectious agents in animal models against, including influenza virus, Ebola virus, Zika virus, Human Immunodeficiency virus 1 (HIV-1), herpes simplex virus, cytomegalovirus, hepatitis C and respiratory syncytial virus [149, 150, 151]. It has been noted that approximately ten mRNA vaccines programs have entered clinical trials [152].
The importance of mRNA-based vaccines and therapies is emphasized when mRNA-based biopharmaceuticals are entering the market with guidance of new biopharmaceutical companies. Modern Therapeutics, an mRNA therapy company evaluated various mRNA vaccine technologies to identify immunogenic and scalable candidates. The pipeline of this company shows different investigative stages mRNA vaccines of the following vaccines Respiratory Syncytial virus (RSV), Cytomegalovirus (CMV), human metapneumovirus (hMPV) + Parainfluenza virus Type 3 (PIV3), Influenza A subtypes H10N8, and H7N9, Zika, and Chikungunya. Curevac is the first biopharmaceutical company that developed the first prophylactic mRNA vaccine in the clinics, recently they showed that RNActive® vaccines induced long-lived and protective immunity to influenza A virus infections in various animal models [153].
Thus, big pharmaceutic companies, such as Merck & Co., have been invested in Modern Therapeutics aiming to expand the field of mRNA vaccine (https://www.modernatx.com/). Indeed, nucleic acid vaccine platform has been presented to combat the emergence of acute viral diseases, mainly to rapidly contain emerging outbreaks before they spread out of control. In this context, two vaccines were developed to combat the ZIKV outbreak (1) DNA plasmid vaccine encoding the prM-E genes of ZIKV and (VRC5283) (2) mRNA vaccine (mRNA-LNP), both vaccines mediate protection from ZIKV infection in mouse models. The DNA plasmid vaccine is in phase 2 human clinical trials (VRC-ZKADNA090–00-VP) and vaccine mRNA-LNP is in phase 1 clinical trial (NCT03014089) [154, 155, 156].
Considering that vaccine trials might not be performed in pregnant women and have not yet tested vaccines against ZIKV vertical transmission, there is a need for establishing the efficacy of ZIKV vaccines against mother-to-child transmission in animal models. In order to address those questions, it has been shown that vaccination with DNA plasmid encoding Zika virus prM-E and a lipid-encapsulated mRNA vaccine-elicited antigen-specific antibody and CD8+ T cell responses in mice, being able to generate a high level of protection against vertical transmission. Moreover, the mRNA-LNP vaccine not only inhibited vertical transmission but also ensured that fetuses are protected therefore, reinforcing its potential as promising vaccine for pregnant women [155]. Since there are few studies in the field of ZIKV vaccine candidates that evaluated vertical transmission, intrinsic maternal factors as well as fetal health, nucleic acid vaccines are pointed as a great opportunity to contain ZIKV infection.
Considering the normal pregnancy, the innate immunity balance is conduct by downregulation of effector T cells and NK cells leading by innate regulatory cells (MDSC) and upregulation of pro-inflammatory cytokines. This innate immune modulation that occurs mainly at the placenta, includes interferon pathway and cell death modulation as shown in Figure 4A. Gestation has its own difficulties to successful outcomes regarding maternal immune tolerance. Zika virus infection becomes classified as disease-causing birth defects, developing an abnormal pregnancy, as consequence of immune dysregulation (Figure 4B). Thus, antiviral therapy is the key to control this immune imbalance showing positive effects in innate immunity on pregnant mice models. It has been known that efforts through vaccines development targeting pregnant women will be the solution for ZIKV prevention, as well as for other arboviral infections, to maintain immune homeostasis and generate healthy babies. Finally, this chapter brings some new thoughts that help for targeted improvements in medical science considering Zika infection on pregnancy, and innate immune system linked to therapies previewing the prevention and control.
Summary of innate immunity functionality during normal pregnancy and in Zika virus infection focus on interferon III, myeloid-derived suppressor cells, and programmed cell death activities. During pregnancy, initial signal is dependent on nidation process and placenta formation leading by trophoblasts expansion and activation. Following this process, innate cells, such as neutrophils, DCs, and cytokines are activated (1.A, 2.A) with IL10 and TGF-beta production in periphery, allowing immunosuppressive functionality triggered by regulatory cells (MDSC and Treg) (3.A). This condition facilitates suppression of effector cells (NK and lymphocytes) in peripheral blood and in placenta triggered by MDSC (4.A), whereas Hofbauer cells maintain reactive species (NO) balanced (5.A) as well as the IFN-λ downregulation, IFN type I upregulation, and trophoblast autophagy (6.A), contributing to the cross-linking in the fetus-maternal interface. Adding to that, programmed cell death contributes to control the accelerated growth of neural cells in fetus brain (7.A), corroborating with a successful pregnancy. Zika virus has been related to abnormal pregnancy, leading to massive innate immune alteration, causing severe brain damage to fetus. Given that, when the virus is in the blood, there is a gross activation of innate cells, elevation of cytokines and chemokines (1.B, 2.B), and suppressive activity by regulatory cells is compromised (3.B), generating early activation of NK and T cells in blood (4.B) and macrophages in placenta (5.B). Virus invasion in placenta through Hofbauer and trophoblast cells results in high autophagy activity with interferon type I gene highly expressed combined with super downregulation of interferon type III (6.B). This imbalance also contributes to fetal brain damage, orchestra by high activation of apoptosis pathway, avoiding neural cells growing progress. Thus, Zika provides severe damage to fetus, in which drugs, vaccines and immunotherapies have been designed suggesting a modulation of three important keys of innate immunity to control virus replication and spread into fetus-maternal interface: interferon type III expression, MDSC frequency, and autophagy process (highlighted with red rectangles) to avoid severe fetus brain damage, allowing a healthy pregnancy. This figure was made based on the information from
The authors would like to thank Directory of Technological Development from Immunobiological Technology Institute, Biomanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil for founding support.
Authors to declare no conflicts of interest.
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The growing interest for using bio-polymers from renewable resources, such as wood/forest, corn, and cereals have spurred significant R&D developments toward the use of bio-polymers in green wood adhesives. The scope of the present chapter is to summarize, in short, some of the most recent scientific literature regarding the development of green adhesives.",book:{id:"6256",slug:"applied-adhesive-bonding-in-science-and-technology",title:"Applied Adhesive Bonding in Science and Technology",fullTitle:"Applied Adhesive Bonding in Science and Technology"},signatures:"Emelie Norström, Deniz Demircan, Linda Fogelström, Farideh\nKhabbaz and Eva Malmström",authors:[{id:"214119",title:"Prof.",name:"Eva",middleName:null,surname:"Malmström",slug:"eva-malmstrom",fullName:"Eva Malmström"},{id:"214120",title:"MSc.",name:"Emelie",middleName:null,surname:"Norström",slug:"emelie-norstrom",fullName:"Emelie Norström"},{id:"214121",title:"Dr.",name:"Linda",middleName:null,surname:"Fogelström",slug:"linda-fogelstrom",fullName:"Linda Fogelström"},{id:"214122",title:"Dr.",name:"Farideh",middleName:null,surname:"Khabbaz",slug:"farideh-khabbaz",fullName:"Farideh Khabbaz"},{id:"221508",title:"Dr.",name:"Deniz",middleName:null,surname:"Demircan",slug:"deniz-demircan",fullName:"Deniz Demircan"}]},{id:"39762",doi:"10.5772/48339",title:"Application of Finite Element Analysis in Implant Dentistry",slug:"application-of-finite-element-analysis-in-implant-dentistry",totalDownloads:5842,totalCrossrefCites:6,totalDimensionsCites:22,abstract:null,book:{id:"3050",slug:"finite-element-analysis-new-trends-and-developments",title:"Finite Element Analysis",fullTitle:"Finite Element Analysis - New Trends and Developments"},signatures:"B. Alper Gultekin, Pinar Gultekin and Serdar Yalcin",authors:[{id:"142533",title:"Dr.",name:"Alper",middleName:null,surname:"Gultekin",slug:"alper-gultekin",fullName:"Alper Gultekin"},{id:"145578",title:"Dr.",name:"Pınar",middleName:null,surname:"Gültekin",slug:"pinar-gultekin",fullName:"Pınar Gültekin"},{id:"145579",title:"Prof.",name:"Serdar",middleName:null,surname:"Yalçın",slug:"serdar-yalcin",fullName:"Serdar Yalçın"}]},{id:"39767",doi:"10.5772/50038",title:"Finite Element Analysis in Dental Medicine",slug:"finite-element-analysis-in-dental-medicine",totalDownloads:3517,totalCrossrefCites:9,totalDimensionsCites:11,abstract:null,book:{id:"3050",slug:"finite-element-analysis-new-trends-and-developments",title:"Finite Element Analysis",fullTitle:"Finite Element Analysis - New Trends and Developments"},signatures:"Josipa Borcic and Alen Braut",authors:[{id:"146157",title:"PhD.",name:"Josipa",middleName:null,surname:"Borcic",slug:"josipa-borcic",fullName:"Josipa Borcic"},{id:"150367",title:"Dr.",name:"Alen",middleName:null,surname:"Braut",slug:"alen-braut",fullName:"Alen Braut"}]},{id:"39753",doi:"10.5772/50374",title:"Finite Element Analysis of Machining Thin-Wall Parts: Error Prediction and Stability Analysis",slug:"finite-element-analysis-of-machining-thin-wall-parts-error-prediction-and-stability-analysis",totalDownloads:3399,totalCrossrefCites:7,totalDimensionsCites:10,abstract:null,book:{id:"2915",slug:"finite-element-analysis-applications-in-mechanical-engineering",title:"Finite Element Analysis",fullTitle:"Finite Element Analysis - Applications in Mechanical Engineering"},signatures:"YongAn Huang, Xiaoming Zhang and Youlun Xiong",authors:[{id:"126210",title:"Prof.",name:"Youlun",middleName:null,surname:"Xiong",slug:"youlun-xiong",fullName:"Youlun Xiong"},{id:"147553",title:"Prof.",name:"YongAn",middleName:null,surname:"Huang",slug:"yongan-huang",fullName:"YongAn Huang"},{id:"149622",title:"Prof.",name:"Xiaoming",middleName:null,surname:"Zhang",slug:"xiaoming-zhang",fullName:"Xiaoming Zhang"}]},{id:"57763",doi:"10.5772/intechopen.71854",title:"Adhesives: Applications and Recent Advances",slug:"adhesives-applications-and-recent-advances",totalDownloads:2348,totalCrossrefCites:8,totalDimensionsCites:10,abstract:"Adhesives can be defined as social substances capable to join permanently to surfaces, by an adhesive process. This process involves two dissimilar bodies being held in intimate contact such that mechanical force or work can be transferred across the interface. Since their early discovery by the Egyptians—3300 years ago—intensive research efforts have been made with the purpose of obtaining high-quality, biocompatible adhesives. Bitumen, tree pitches and beeswax—used in ancient and mediaeval times—were replaced by rubber cements and natural and synthetic components; nowadays, the focus is being mostly on eco-friendly adhesives. Starting with a brief history of adhesive use, this chapter then proceeds to cover the main industrial, biomedical and pharmaceutical applications of adhesives. Additionally, we focus on the new generation of adhesives, based on modern technologies such as nanotechnology, derivatised polymers, and biomimetic adhesives. The limited raw materials and the negative impact of synthetic adhesives on both human health and environment impose that further research is conducted with regard to renewable materials, in order to obtain environmentally safe bioadhesives that best fit their applicability domains.",book:{id:"6256",slug:"applied-adhesive-bonding-in-science-and-technology",title:"Applied Adhesive Bonding in Science and Technology",fullTitle:"Applied Adhesive Bonding in Science and Technology"},signatures:"Elena Dinte and Bianca Sylvester",authors:[{id:"202938",title:"BSc.",name:"Bianca",middleName:null,surname:"Sylvester",slug:"bianca-sylvester",fullName:"Bianca Sylvester"},{id:"218165",title:"Associate Prof.",name:"Elena",middleName:null,surname:"Dinte",slug:"elena-dinte",fullName:"Elena Dinte"}]}],mostDownloadedChaptersLast30Days:[{id:"39751",title:"Nonlinear Large Deflection Analysis of Stiffened Plates",slug:"nonlinear-large-deflection-analysis-of-stiffened-plates",totalDownloads:7325,totalCrossrefCites:0,totalDimensionsCites:2,abstract:null,book:{id:"2915",slug:"finite-element-analysis-applications-in-mechanical-engineering",title:"Finite Element Analysis",fullTitle:"Finite Element Analysis - Applications in Mechanical Engineering"},signatures:"Khosrow Ghavami and Mohammad Reza Khedmati",authors:[{id:"142986",title:"Prof.",name:"Khosrow",middleName:null,surname:"Ghavami",slug:"khosrow-ghavami",fullName:"Khosrow Ghavami"},{id:"143767",title:"Dr.",name:"Mohammad Reza",middleName:null,surname:"Khedmati",slug:"mohammad-reza-khedmati",fullName:"Mohammad Reza Khedmati"}]},{id:"39743",title:"Optimization and Improvement of Throwing Performance in Baseball Pitching Machine Using Finite Element Analysis",slug:"optimization-and-improvement-of-throwing-performance-in-baseball-pitching-machine-using-finite-eleme",totalDownloads:4855,totalCrossrefCites:1,totalDimensionsCites:1,abstract:null,book:{id:"2915",slug:"finite-element-analysis-applications-in-mechanical-engineering",title:"Finite Element Analysis",fullTitle:"Finite Element Analysis - Applications in Mechanical Engineering"},signatures:"Shinobu Sakai and Hitoshi Nakayama",authors:[{id:"141256",title:"Dr.",name:"Shinobu",middleName:null,surname:"Sakai",slug:"shinobu-sakai",fullName:"Shinobu Sakai"},{id:"143643",title:"Mr.",name:"Hitoshi",middleName:null,surname:"Nakayama",slug:"hitoshi-nakayama",fullName:"Hitoshi Nakayama"}]},{id:"57763",title:"Adhesives: Applications and Recent Advances",slug:"adhesives-applications-and-recent-advances",totalDownloads:2350,totalCrossrefCites:8,totalDimensionsCites:10,abstract:"Adhesives can be defined as social substances capable to join permanently to surfaces, by an adhesive process. This process involves two dissimilar bodies being held in intimate contact such that mechanical force or work can be transferred across the interface. Since their early discovery by the Egyptians—3300 years ago—intensive research efforts have been made with the purpose of obtaining high-quality, biocompatible adhesives. Bitumen, tree pitches and beeswax—used in ancient and mediaeval times—were replaced by rubber cements and natural and synthetic components; nowadays, the focus is being mostly on eco-friendly adhesives. Starting with a brief history of adhesive use, this chapter then proceeds to cover the main industrial, biomedical and pharmaceutical applications of adhesives. Additionally, we focus on the new generation of adhesives, based on modern technologies such as nanotechnology, derivatised polymers, and biomimetic adhesives. The limited raw materials and the negative impact of synthetic adhesives on both human health and environment impose that further research is conducted with regard to renewable materials, in order to obtain environmentally safe bioadhesives that best fit their applicability domains.",book:{id:"6256",slug:"applied-adhesive-bonding-in-science-and-technology",title:"Applied Adhesive Bonding in Science and Technology",fullTitle:"Applied Adhesive Bonding in Science and Technology"},signatures:"Elena Dinte and Bianca Sylvester",authors:[{id:"202938",title:"BSc.",name:"Bianca",middleName:null,surname:"Sylvester",slug:"bianca-sylvester",fullName:"Bianca Sylvester"},{id:"218165",title:"Associate Prof.",name:"Elena",middleName:null,surname:"Dinte",slug:"elena-dinte",fullName:"Elena Dinte"}]},{id:"71845",title:"Strengthening of High-Alloy Steel through Innovative Heat Treatment Routes",slug:"strengthening-of-high-alloy-steel-through-innovative-heat-treatment-routes",totalDownloads:750,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Heat treatment route is an important route for the development of high-strength alloy steel. Many heat treatment processes are applied depending on alloy compositions and desired mechanical properties. There are various high-strength alloy steels, namely, austenitic stainless steel (16–26 wt%Cr, 0.07–0.15 wt%C, 8–10 wt%Ni, rest Fe), where the heat treatment adopted is the low-temperature plasma nitriding so as to achieve a strength in a range of 800–1000 MPa. In twinning-induced plasticity (TWIP) steel (>20 wt%Mn, <1 wt%C, <3 wt%Si, <3 wt%Al, rest Fe), high-temperature thermomechanical heat treatment provides a strength greater than 1000 MPa. High-speed steel (18 wt%W, 4 wt%Cr, 1 wt%V, 0.7 wt%C, 5–8 wt%Co, rest Fe) suits best for high-speed machining purpose, owing to secondary hardening. Besides, high-temperature annealing is performed with majorly ferritic structure to achieve a maximum bending strength of 4700 MPa. Furthermore, in Hadfield steel (11–14 wt%Mn, 1–1.4 wt%C), a fully austenitic phase is obtained with a strength level of 1000 MPa. High-alloy tool steel (5 wt%Mo, 6 wt%W, 4 wt%Cr, 0.3 wt%Si, 1 wt%V, rest Fe) is provided with austenitizing, quenching, and tempering treatment to achieve a maximum hardness of 1200–1400 HV.",book:{id:"9208",slug:"welding-modern-topics",title:"Welding",fullTitle:"Welding - Modern Topics"},signatures:"Nicky Kisku",authors:[{id:"315275",title:"Ph.D.",name:"Nicky",middleName:null,surname:"Kisku",slug:"nicky-kisku",fullName:"Nicky Kisku"}]},{id:"39774",title:"Finite Element Analysis of Stationary Magnetic Field",slug:"finite-element-analysis-of-stationary-magnetic-field",totalDownloads:11365,totalCrossrefCites:3,totalDimensionsCites:6,abstract:null,book:{id:"3050",slug:"finite-element-analysis-new-trends-and-developments",title:"Finite Element Analysis",fullTitle:"Finite Element Analysis - New Trends and Developments"},signatures:"Elena Otilia Virjoghe, Diana Enescu, Mihail-Florin Stan and Marcel Ionel",authors:[{id:"143217",title:"Dr.",name:"Diana",middleName:null,surname:"Enescu",slug:"diana-enescu",fullName:"Diana Enescu"},{id:"146305",title:"PhD.",name:"Elena Otilia",middleName:null,surname:"Virjoghe",slug:"elena-otilia-virjoghe",fullName:"Elena Otilia Virjoghe"},{id:"155183",title:"Dr.",name:"Marcel",middleName:null,surname:"Ionel",slug:"marcel-ionel",fullName:"Marcel Ionel"},{id:"155184",title:"Dr.",name:"Mihail-Florin",middleName:null,surname:"Stan",slug:"mihail-florin-stan",fullName:"Mihail-Florin Stan"}]}],onlineFirstChaptersFilter:{topicId:"818",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters: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:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"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:5,paginationItems:[{id:"19",title:"Animal Science",coverUrl:"https://cdn.intechopen.com/series_topics/covers/19.jpg",editor:{id:"259298",title:"Dr.",name:"Edward",middleName:null,surname:"Narayan",slug:"edward-narayan",fullName:"Edward Narayan",profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",biography:"Dr. Edward Narayan graduated with Ph.D. degree in Biology from the University of the South Pacific and pioneered non-invasive reproductive and stress endocrinology tools for amphibians - the novel development and validation of non-invasive enzyme immunoassays for the evaluation of reproductive hormonal cycle and stress hormone responses to environmental stressors. \nDr. Narayan leads the Stress Lab (Comparative Physiology and Endocrinology) at the University of Queensland. A dynamic career research platform which is based on the thematic areas of comparative vertebrate physiology, stress endocrinology, reproductive endocrinology, animal health and welfare, and conservation biology. \nEdward has supervised 40 research students and published over 60 peer reviewed research.",institutionString:null,institution:{name:"University of Queensland",institutionURL:null,country:{name:"Australia"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",institutionString:null,institution:{name:"Universidade Paulista",institutionURL:null,country:{name:"Brazil"}}},{id:"191123",title:"Dr.",name:"Juan José",middleName:null,surname:"Valdez-Alarcón",slug:"juan-jose-valdez-alarcon",fullName:"Juan José Valdez-Alarcón",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBfcQAG/Profile_Picture_1631354558068",institutionString:"Universidad Michoacana de San Nicolás de Hidalgo",institution:{name:"Universidad Michoacana de San Nicolás de Hidalgo",institutionURL:null,country:{name:"Mexico"}}},{id:"161556",title:"Dr.",name:"Maria Dos Anjos",middleName:null,surname:"Pires",slug:"maria-dos-anjos-pires",fullName:"Maria Dos Anjos Pires",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS8q2QAC/Profile_Picture_1633432838418",institutionString:null,institution:{name:"University of Trás-os-Montes and Alto Douro",institutionURL:null,country:{name:"Portugal"}}},{id:"209839",title:"Dr.",name:"Marina",middleName:null,surname:"Spinu",slug:"marina-spinu",fullName:"Marina Spinu",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLXpQAO/Profile_Picture_1630044895475",institutionString:null,institution:{name:"University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca",institutionURL:null,country:{name:"Romania"}}},{id:"92185",title:"Dr.",name:"Sara",middleName:null,surname:"Savic",slug:"sara-savic",fullName:"Sara Savic",profilePictureURL:"https://mts.intechopen.com/storage/users/92185/images/system/92185.jfif",institutionString:'Scientific Veterinary Institute "Novi Sad"',institution:{name:'Scientific Veterinary Institute "Novi Sad"',institutionURL:null,country:{name:"Serbia"}}}]},{id:"20",title:"Animal Nutrition",coverUrl:"https://cdn.intechopen.com/series_topics/covers/20.jpg",editor:{id:"175967",title:"Dr.",name:"Manuel",middleName:null,surname:"Gonzalez Ronquillo",slug:"manuel-gonzalez-ronquillo",fullName:"Manuel Gonzalez Ronquillo",profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",biography:"Dr. Manuel González Ronquillo obtained his doctorate degree from the University of Zaragoza, Spain, in 2001. He is a research professor at the Faculty of Veterinary Medicine and Animal Husbandry, Autonomous University of the State of Mexico. He is also a level-2 researcher. He received a Fulbright-Garcia Robles fellowship for a postdoctoral stay at the US Dairy Forage Research Center, Madison, Wisconsin, USA in 2008–2009. He received grants from Alianza del Pacifico for a stay at the University of Magallanes, Chile, in 2014, and from Consejo Nacional de Ciencia y Tecnología (CONACyT) to work in the Food and Agriculture Organization’s Animal Production and Health Division (AGA), Rome, Italy, in 2014–2015. He has collaborated with researchers from different countries and published ninety-eight journal articles. 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That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356823",title:"MSc.",name:"Seonghee",middleName:null,surname:"Min",slug:"seonghee-min",fullName:"Seonghee Min",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Daegu University",country:{name:"Korea, South"}}},{id:"353307",title:"Prof.",name:"Yoosoo",middleName:null,surname:"Oh",slug:"yoosoo-oh",fullName:"Yoosoo Oh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Yoosoo Oh received his Bachelor's degree in the Department of Electronics and Engineering from Kyungpook National University in 2002. He obtained his Master’s degree in the Department of Information and Communications from Gwangju Institute of Science and Technology (GIST) in 2003. In 2010, he received his Ph.D. degree in the School of Information and Mechatronics from GIST. In the meantime, he was an executed team leader at Culture Technology Institute, GIST, 2010-2012. In 2011, he worked at Lancaster University, the UK as a visiting scholar. In September 2012, he joined Daegu University, where he is currently an associate professor in the School of ICT Conver, Daegu University. Also, he served as the Board of Directors of KSIIS since 2019, and HCI Korea since 2016. From 2017~2019, he worked as a center director of the Mixed Reality Convergence Research Center at Daegu University. From 2015-2017, He worked as a director in the Enterprise Supporting Office of LINC Project Group, Daegu University. His research interests include Activity Fusion & Reasoning, Machine Learning, Context-aware Middleware, Human-Computer Interaction, etc.",institutionString:null,institution:{name:"Daegu Gyeongbuk Institute of Science and Technology",country:{name:"Korea, South"}}},{id:"262719",title:"Dr.",name:"Esma",middleName:null,surname:"Ergüner Özkoç",slug:"esma-erguner-ozkoc",fullName:"Esma Ergüner Özkoç",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Başkent University",country:{name:"Turkey"}}},{id:"346530",title:"Dr.",name:"Ibrahim",middleName:null,surname:"Kaya",slug:"ibrahim-kaya",fullName:"Ibrahim Kaya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"419199",title:"Dr.",name:"Qun",middleName:null,surname:"Yang",slug:"qun-yang",fullName:"Qun Yang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Auckland",country:{name:"New Zealand"}}},{id:"351158",title:"Prof.",name:"David W.",middleName:null,surname:"Anderson",slug:"david-w.-anderson",fullName:"David W. Anderson",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Calgary",country:{name:"Canada"}}}]}},subseries:{item:{id:"8",type:"subseries",title:"Bioinspired Technology and Biomechanics",keywords:"Bioinspired Systems, Biomechanics, Assistive Technology, Rehabilitation",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11404,editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",slug:"adriano-andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",biography:"Dr. Adriano de Oliveira Andrade graduated in Electrical Engineering at the Federal University of Goiás (Brazil) in 1997. He received his MSc and PhD in Biomedical Engineering respectively from the Federal University of Uberlândia (UFU, Brazil) in 2000 and from the University of Reading (UK) in 2005. He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. His research interests include Biomedical Signal Processing and Modelling, Assistive Technology, Rehabilitation Engineering, Neuroengineering and Parkinson's Disease.",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,series:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343"},editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",slug:"hitoshi-tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",slug:"marcus-vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",slug:"ramana-vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},onlineFirstChapters:{paginationCount:17,paginationItems:[{id:"81647",title:"Diabetes and Epigenetics",doi:"10.5772/intechopen.104653",signatures:"Rasha A. 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