Primary CMS male sterility systems utilized in hybrid rice production.
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The use of hybrid greatly increased rice production worldwide due to the improved yields, better tolerance to pest, diseases and environmental stress compared to inbred varieties. The discovery of cytoplasmic male sterility was the major milestone to the development of hybrid rice [1]. Further discovery of two line male sterility made hybrid breeding more efficient and further increased the probability in finding the best performing hybrid combinations [2].
\nTwo different male sterility systems are available for hybrid seed production (Figure 1). The first is a cytoplasmic male sterility (CMS) which is a three-line system that uses a male sterile line, a restorer line and a maintainer line. The male sterility is more stable albeit more complicated to breed and maintain [3]. The second is the two-line male sterility system that uses a genetic male sterile which is controlled by temperature, photoperiod or both. The use of this system is increasing due to the ease in breeding, finding more heterotic combinations, and in seed multiplication of parental male sterile lines. However, hybrid seed production may be catastrophic if there are severe changes in environmental conditions [4]. Both systems proved effective in hybrid rice production which increased yields by up to 20% therefore, increased farm profitability and has contributed significantly in addressing global food security.
\nComparison of two-line and three-line hybrid rice breeding system. A: two line hybrid system; S—genetic male sterile, R—restorer/pollen fertile, F1—hybrid. B: three line hybrid system A—CMS line, B—maintainer line, R—restorer line with restorer gene, F1—hybrid.
Heterosis in hybrid rice minimize the impact of reduced yields brought by diseases compared to the inbred counterpart. However, due to narrow genetic diversity of the male sterile parent, they became vulnerable to pathogens and pests resulting to the loss of its yield potential [5]. This makes it difficult for growers to recover the high cost of seed and F1 production. It became apparent that discovering new sources of male sterility to increase genetic diversity and further introgression of resistance genes are necessary to secure the yield gain in hybrid rice [6].
\nThis chapter focuses on the discovery of rice male sterility, genetics, mechanisms and procedures in multiplication and handling of male sterile rice for hybrid rice breeding.
\nDevelopment and cultivation of hybrid rice started in China with the initial work of rice breeder Yuan Longping. As early as 1964, Yuan Longping have tested different male sterile lines however, no stable sterility exists and the group started resorting to making distant hybridization by crossing wild rice with cultivated rice. In 1970, a wild-abortive type cytoplasmic male sterile rice CMS-WA were discovered which eventually leads to the release of the first hybrid rice in 1976. By 1980’s, hybrid rice accounts to about 55% of the total rice planting area in China [7, 8]. More CMS types were discovered that further expand the diversity in hybrid rice three-line system. These were developed by direct crossing or backcross breeding from two different species, subspecies or different cultivars [9]. The major type of CMS systems with their cytoplasm and nucleus sources are shown in Table 1.
\nMS type | \nMale sterility source | \n|
---|---|---|
Cytoplasm | \nNucleus | \n|
CMS-BT | \nChinsurah Boro II ( | \nLiming ( | \n
CMS-HL | \nHong lian ( | \nLiantanzao ( | \n
CMS-CW | \nChinese wild W1 ( | \nReimei ( | \n
CMS-WA | \nWild abortive ( | \nErjiunan ( | \n
CMS-LD | \nBurmese “Lead rice” ( | \nFujisaka 5 ( | \n
Primary CMS male sterility systems utilized in hybrid rice production.
There were more than 60 types of CMS systems discovered in China alone but most of them may only be classified in three types CMS-BT (Boro II), CMS-WA (wild abortive), and CMS-HL (Honglian) [10, 11]. The three major types produces pollen that lack starch or are starch deficient while CMS-LD and CMS-CW produces morphologically normal pollen grains but were unable to fully germinate [12]. In CMS-WA, pollen abortion occur at a uninucleate stage primarily during microspore development [13]. The result is an irregularly shaped and lightly stained pollen when treated with 1% iodine potassium iodide solution (I2KI). The genotype of sporophytic tissues determines pollen abortion. In CMS-BT, pollen abortion occurs at trinucleate stage with pollen lightly stained due to deficiency of starch and spherical in shape rather than irregular [14]. In CMS-HL, pollen abortion appears at binucleate stage and the pollen is spherical in shape but without starch. Restoration to fertility in all CMS type except CMS-WA are all gametophytic therefore producing half of the pollen fertile in the F1 generation (Figure 2).
\nA schematic presentation of the five well-studied rice CMS types. Abbreviations for cytoplasm sources are RWA for wild-abortive
Sterility in CMS is controlled by the interaction of genes in the cytoplasm and the nucleus. The sterility factor S is located in the mitochondrial DNA while the
Schematic diagram of CMS three line system. Rfrf = nuclear gene homozygote recessive, RfRf = nuclear gene homozygote dominant, Rfrf = nuclear gene heterozygous, N = cytoplasmic factor (fertile), s = cytoplasmic factor (sterile).
CMS-BT genes were the first to be identified that has the mitochondrial open reading frame
A total of six restorer of fertility genes (
Diversification of both CMS maintainers and restorer lines are very important to guarantee the continued progress of finding the best hybrid combinations. Extensive evaluation of lines and backcross breeding were employed to improve the lines and adapt to a particular environment [21]. Furthermore, new maintainers and restorers were developed from the original donors. A new CMS source was discovered in Dongxiang wild rice by continuous backcrossing to the
Although the CMS three-line system greatly increased yields in hybrid rice, there are difficulties and limitations on its use. One of the difficulties is the need to simultaneously develop maintainer lines (B lines) by subsequent nucleus substitution of the original CMS line with the B lines through repeated backcrossing. Furthermore, there are also limited choices available for restorer lines (R lines) with only about 5% of the current existing lines can be used that carries the restorer gene [7]. The discovery of genetic male sterility or photoperiod and/or thermosensitive male sterile lines addresses these problems. These lines responds to photoperiod, temperature or a combination of both which cause the plant to be fertile or sterile depending on the critical daylength or temperature [23]. With the two-line system using genetic male sterile, there is no need to develop a maintainer line and any fertile line can be used as a restorer. This greatly reduce the time and resources in making hybrid combination and parental seed production. Moreover, it broadens the available choices of restorers that can generate more combinations which in turn increases the probability of finding the best hybrids [4].
\nExtensive studies suggest that genetic male sterile lines can be broadly classified into three categories; photoperiod genetic male sterile (PGMS), thermosensitive genetic male sterile (TGMS), and photoperiod and thermosensitive genetic male sterile (PTGMS) [15, 24, 25]. The first reported genetic male sterile came from spontaneous mutant in a japonica cultivar Nongken 58 discovered in Hubei China and were later called as Nongken 58S [2]. Further studies after its discovery revealed that the male sterility is regulated mainly by photoperiod and thus referred to as photoperiod genetic male sterile (PGMS). Nongken 58S showed complete pollen sterility when grown under long day conditions (>14 h), fertility was restored when subjected to <10 h of light under controlled environment [26].
\nA thermosensitive type of male sterility was discovered in a spontaneous mutant AnnongS-1 (Ans-1) in 1997. The pollen remained sterile at both long and short day when exposed to 33°C and reverts back to fertile when the temperature reached 24°C [27]. Additional lines exhibiting thermosensitivity were also discovered in Zhu1S, Hengnong 1S and Guangzhang 63S where the fertility rates vary at different controlled temperatures regardless of daylength [28, 29, 30].
\nThe third classification of genetic male sterility affects both photoperiod and temperature. Pei’ai 64S is a line derived from the original male sterile mutant Nongken 58S with genetic backgrounds such as
Numerous genetic studies concluded that genetic male sterility can be controlled by single, two genes or multiple genes depending on the genetic background and the environment. The original Nongken 58S when crossed to conventional
Studies conducted under US conditions on
Male sterile line 2009S grown in the greenhouse (A) and in the field (C). 2008S male sterile line grown in the greenhouse (B) and in the field (D). Both lines exhibited 100% sterility when grown at H. Rouse Caffey Rice Research Station in Crowley, Louisiana USA under high temperature and long day conditions.
Another male sterile line 2009S currently used by the LSU Agcenter for their hybrid rice breeding program shows a single gene recessive inheritance (Figure 4). Field trials carried out in Crowley Louisiana over 2 years (2013–2014) in two F2 and four BC1F2 populations showed consistent results both in seed and pollen fertilities [25, 41]. A comparison of the pollen sterility frequency distribution is presented in Figure 5 for 2008S and 2009S F2 populations.
\nPollen sterility distribution of F2 plants in populations of 2008S/CL131 and 2009S/10HB020 male sterile lines planted in 2013 at H. Rouse Caffey Rice Research Station, Crowley LA USA.
Several candidate genes were identified in controlling male sterility in PGMS lines. More recent studies using Nongken 58S discovered that the gene in LOC_Os12g36030 which was previously mapped as pms3 and is also allelic to p/tms12-1 located on chromosome 12 regulates photoperiod genetic male sterility. The single nucleotide polymorphism (SNP) mutation located in non-coding region increased the methylation on the promoter which in turn reduced transcription of LOC_Os12g36030.The reduced transcription caused the pre-programmed cell death in developing anthers causing pollen sterility [42, 43].
\nA second study conducted in PTGMS line Pei’ai 64S revealed that the gene LOC_Os07g12130 previously mapped as pms1(t) encodes a protein containing Myb-like DNA binding domain that affect the transcription of a protein responsible for the photo-thermosensitive response. RT-PCR results showed that mRNA levels of LOC_Os07g12130 changes at different photoperiod and temperature conditions [31]. However, the gene is yet to be cloned and further study needs to be conducted. De Guzman [4] sequenced both locus in male sterile line 2008S and found both SNPs present. When QTLs were analyzed in two segregating populations using both single marker analysis and interval mapping, each locus and their interaction gives significant effects [25].
\nFor lines exhibiting thermosensitivity, candidate genes associated with TGMS lines were mapped on chromosome 2. QTL mapping using bulk segregant analysis approach (BSA) identified the ptgms2-1 locus [30]. Further analysis showed LOC_Os02g12290 encode a ribonuclease Z gene that when the SNP is present, it created a premature stop codon rendering the RNase ZS1 defective. The mechanism described that when the mutant male sterile is exposed under high temperature (28°C), it induced the accumulation of mRNA ribosomal protein UbL40 in microspore mother cell that were not processed by the defective RNase ZS1 enzyme consequently causing pollen degeneration. At lower temperatures (23°C), UBL40 mRNAs levels remained low allowing production of normal pollen. This mutation was reported in TGMS varieties Guangzhang 63S, Ans-1 and Zhu1S [28]. Zhang [44] discovered that the locus tms5, ptgms2-1 and tms9 were allelic and were all mapped to chromosome 2 that contains the similar ribonuclease Z gene. De Guzman [25] sequenced the locus LOC_Os02g12290 in line 2009S and discovered the same SNP present in TGMS lines. Inheritance studies on F2 and BC1F2 showed similar segregation ratios. SNP marker were developed using CEL1 nuclease to identify association of the marker to the trait and showed that the markers were able to predict 95–100% of male sterile lines in F2 and BC1F2 population [41].
\nSince PTGMS and TGMS have different responses to temperature and photoperiod, methods in seed multiplication and breeding varies including selection of specific location and time of planting. On PTGMS lines, weak and strong photoperiodic responses were reported [45]. In strong photoperiodic response such as in long daylength, the critical sterility inducing temperature (CST) is low (21°C) and at short daylength high (25–26°C).
\nFor a PTGMS lines with weak photoperiodism, the (CST) is about 22°C under short daylength. In China, Chen [45] suggested that seed production of this type should be bred during autumn in Guangdong and Guangxi, and in winter in Hainan province. Cold water irrigation treatment has been used extensively in lines with both weak and strong photoperiod. This solved the problem of low yields in multiplication of PTGMS lines such as Pei’-ai 64 s with low CST [46].
\nFor TGMS lines, there is no weak or strong photoperiodism, thus timing and selection of location is important for seed production of male steriles and hybrids. On most TGMS lines, the ideal CST is about 22.5°C. Seed production are also treated with continuous cold water irrigation to increase seed yield during the winter [46].
\nIn the US, RiceTec of Alvin Texas successfully used both ptgms and tgms lines however, seed production locations are unknown and specific methods of seed multiplications of male sterile lines are undisclosed.
\nIn Louisiana USA, the LSU AgCenter initiated the hybrid rice breeding program in 2009 using ptgms and cytoplasmic male sterile lines obtained via a Material Transfer Agreement with the Guangxi Academy of Agricultural Sciences, Nanning, China. Test crosses made from these lines showed equal or superior grain and head rice yield compared to the current RiceTec commercial varieties. However, high chalk, lodging, and late maturities were observed that warrant the development of male sterile with improved agronomic traits and are suitable to the southern US conditions [47]. The breeding cycle starts with crosses of adapted lines to male sterile lines to produce F1’s. Seeds from hybrids then harvested and spaced planted. Single plant selections of male sterile lines were performed by looking at sterile pollen stained with 1% I2KI under the microscope during early heading. Plants suitable for generation advance were selected with the following characteristics: 98–100% pollen sterile, 60–80 cm in height, short flag leaf, intermediate tillering and with compact growth habit. Selected plants were uprooted, placed in one gallon pots and transferred in the greenhouse. The plants were ratooned by cutting ~9–10 cm from the soil line. The ratoons are allowed to grow up to early booting stage where the majority of the shoots have the measurement distance of about of 1–3 cm between the flag leaf collar to the leaf node or at about the early booting stage (meiotic division of pollen mother cell). Plants are then subsequently treated in a growth chamber with temperatures 22°C during the night and 28°C during the day at 11 h daylength for 10 d. After treatment, plants are then transferred to the greenhouse for 30–35 days for the seed to mature (Figure 6). Seed multiplication were carried out in Puerto Rico agricultural experiment station planted during October to November [48, 49].
\nMethods of selection and production of male sterile lines in LSU Agcenter hybrid rice breeding program.
Introgression of disease resistance traits in hybrid rice becomes a necessity largely due to the narrow genetic diversity of both CMS and genetic male sterile sources. A study showed leading hybrids from China that was introduced in Africa were out yielded by inbred checks due to non-adaptability and susceptibility to diseases and pests [50]. There were also reported insect and disease incidence in China that are more frequent in hybrid rice than on inbred varieties [5]. Research institutes such as the International Rice Research Institute (IRRI) was aware of these issues and has continued to develop new CMS, maintainer, restorers and genetic male steriles in diverse background. Current improvement on hybrid rice focuses on incorporation of resistance gene identified from inbred and wild sources. For instance, blast resistance genes have been introgressed in maintainer, restorer and S lines through hybridization, backcross and marker assisted selection (MAS) [6]. In the early 2000, varieties with multiple bacterial panicle blight resistance were released in Indonesia and China. These varieties were developed using MAS and produced significant yield gain demonstrated in farmer’s field [51].
\nCMS and genetic male sterility revolutionize rice production due to its contribution to the development of hybrid rice. Elucidation of physiological and molecular mechanism leads to the establishment of the process involved in breeding male sterile and hybrids. The increase in yield and tolerance to biotic and abiotic stress are largely due to the effect of heterosis. However, the narrow genetic diversity presents a challenge as very few sources of male sterility are used. Improving parental lines by incorporation of genes with resistance to biotic and abiotic conditions are essential to secure the yield advantage of hybrids over inbreds. Different methods can be used to add genetic diversity to the hybrids. Mutation, MAS and interspecific hybridization are a proven approach to incorporate targeted traits as well as discovering new genes from wild relatives. Genomic selection as well as gene editing will likely play a significant role in future improvement of rice hybrids.
\nThis work was supported by Southeast Missouri State University and the Missouri Rice Research and Merchandising Council. The authors also wish to thank the assistance of the LSU Agcenter H. Rouse Caffey Rice Research Station for research related to two line hybrids.
\nThe authors declare that they have no conflict of interests.
Chronic spontaneous urticarial (CSU) with or without angioedema, is a condition which lasts more than 6 weeks, without an apparent trigger. It results from a pathogenic over-activation of dermal mast cells and basophils, followed by their degranulation and the release of pro-inflammatory mediators (mainly histamine) inducing the appearance of transient itchy wheals, and occasionally episodes of angioedema. The prevalence of CSU is estimated to be between 0.5-1percent in the general population, with an incidence of 0.10 to 1.50 per 1000 person-years. It predominantly affects female, with symptom onset occurring mainly between 20 and 40 years [1]. Earlier studies reported on CSU lasting over one year in more than 70% of cases and continuing to exist in 14% of them after five years. CSU duration was associated with the presence of angioedema and disease severity. In a recent study, younger CSU patients (22 ± 16 years) tended to have a significantly longer course, were in 16% of patients, CSU symptoms lasted over ten years [2, 3]. In addition to its prolonged duration, CSU severely affects quality of life and is associated with comorbidities such as lack of sleep, impairments in work productivity, and depression/anxiety. In one study about 50% of patients with CSU were diagnosed with one or more psychosomatic disorders, the most frequent of which was anxiety, followed by depressive and somatoform disorders [4, 5]. The prevalence of rheumatoid arthritis, systemic lupus erythematosus, thyroiditis and vitiligo were found to be significantly increased in CSU patients [6]. Patients without any evidence of comorbidities at the time of their CSU diagnosis had an increased risk of developing mast cell-mediated diseases including atopic diseases [7]. Many studies have focused on the importance of clinical and laboratory biomarkers for the assessment of CSU severity and the evaluation of treatment efficacy. Clinical manifestations such as asthma and thyroid disease were associated with higher disease severity and duration [8]. Laboratory markers, namely, C-reactive protein (CRP), autologous serum skin test (ASST), basophil activation test (BAT, D-dimer levels and total serum IgE are all potential blood biomarkers that are useful for CSU management [9]. Many CSU patients continue to suffer from symptoms of pruritus, urticaria, and angioedema despite the acceptable up dosing of second-generation antihistamines (up to fourfold) [10]. Recurrent short courses of steroids were also reported to have only a short-term beneficial effect in severe CSU patients. Current treatments are considerably effective in achieving good response and favorable remission, however, many CSU patients are still refractory to these available treatments. This is why, it is extremely important to identify and understand underlying disease mechanisms, in order to achieve better therapeutic outcomes. In addition to a brief summary covering the pathogenesis of CSU, and the currently used therapies, this chapter will focus on emerging new therapies, some of which are being studied in on-going clinical trials, and others that are being assessed as potential candidates for treatment.
At the very beginning (four decades ago), CSU was considered to be a T-cell mediated disorder, supported by the finding of rich CD4+ T-cell infiltration in the skin of CSU patients [11]. The involvement of activated T-cells in peripheral blood of CSU patients, namely the increased expression of CD40 ligand on T-cells similarly to what we find on activated T-cells from patients suffering from active systemic lupus erythematosus and other autoimmune diseases was also reported [12]. In concert with this, there are studies showing an increased switch of Th1 to Th17 in the peripheral blood of CSU patients in correlation with CSU disease severity, and IL-17 levels are significantly higher in the autologous serum skin test (ASST) positive than ASST negative CSU patients. Plasma levels of interferon-γ (IFN-γ), IL-2 and IL-21 were also found to be significantly higher in ASST-positive CSU subgroups, known to involve the positive regulation of the Janus-kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway [13]. In a recent study using Kunming mice (a model of CSU), a longer duration and higher intensity of pruritus was demonstrated to be in association with enhanced levels of eosinophils, inflammatory cytokine expression and activated the JAK/STAT signaling pathway. This was found to be in mice overexpressing IL-9 and IL-10, contributing to the development of CSU by signaling the JAK/STAT pathway [14]. Commensurate with this, is the later finding of antigen/disease-specific auto-reactive CD4 + T cells that target FcεRIα in most patients with CSU, with a cytokine secretion profile typical of aTh1 immune response. This is compatible with the earlier finding of IgG autoantibodies to FcεRIα on dermal mast cells and basophils, supporting the concept that CSU is an autoimmune disorder probably mediated by auto-reactive T cells. IFN-γ and autoantibody responses to FcεRIα were found to be inversely related, with IFN-γ responses being detected earlier than autoantibodies in the course of CSU. This finding of inverse relationship between auto-reactive T-cell responses and autoimmunity suggests these responses to be different stages in the pathogenesis of CSU [15]. In a very recent study we found that increased numbers of CD4 + T cells and mast cells were present in both lesional and non-lesional skin of CSU patients when compared with the healthy controls. Both types of cells were strongly positive for IL-17A and found to be in close proximity to each other [16]. With respect to the aforementioned, autoimmunity in CSU patients is reported to be found in at least 50% of cases. Two types of autoimmunity have been documented and supported by numerous reports. The first (type I) is driven by IgE auto-antibodies against thyroid antigens and/or auto-allergens, defined by the presence of anti-TPO antibodies. In parallel to this, is the finding of type IIb autoimmunity characterized by the binding of IgG auto-antibodies (recently also IgA and Ig M) to IgE and/or FcɛRIα on mast cells [17, 18, 19]. Both types are followed by the intense activation and degranulation of mast cells and the release of inflammatory mediators in the skin that are able to induce itchy wheals and angioedema. Among the many mediated agents, histamine, pro-inflammatory cytokines and chemokines are the most frequent [20]. Basophils and Eosinophils have recently been included among other cells actively involved in the pathogenesis of CSU. In this respect, peripheral blood basopenia is frequently reported in association with CSU disease severity. It has been postulated that this is a result of the migration of basophils from blood to the skin of active CSU patients. Basopenia resolves in parallel with CSU remission and therefore may become a suitable marker for follow-up [21]. Recent evidence suggests that eosinophils may also play role in the pathogenesis of CSU. Both eosinophils and eosinophil granules were displayed in lesional skin of CSU patients. This is in contrast to allergic rhinitis and asthma where peripheral blood eosinophilia is a characteristic finding, while in CSU, peripheral blood eosinopenia is observed in association with disease severity. As in the case of basopenia, depletion of active eosinophils and their shift to the skin of CSU patients is the most accepted mechanism of this phenomenon [22]. The issue of how all these cells, and mechanisms, are linked, and how they act at onset or during the persistence of CSU is extremely complex. However, current therapies, targeting free IgE, mast cells and T cells are reported to be tremendously efficient in inducing CSU remission.
The introduction of the non-sedative anti-histamines replacing the first generation (sedative) one was a giant step forward in the treatment of CSU. At a later date, H1-antihistamine up-dosing was established and shown to be safe and of better efficacy. However, even when up-dosing was increased fourfold, the rate of non-responders remained high, thereby suggesting that additional treatments were needed [23]. As early as 1991, targeting T-cells by cyclosporine A (CsA) was shown to be highly effective in severe cases of CSU [24]. Later on, we demonstrated that low doses of CsA (2–3 mg/ml) given for three months were both extremely beneficial and had a low prevalence of side-effects. In some patients, we could demonstrate a long-lasting full remission, while in others it was even curative [25]. The efficacy of CsA was established by many double-blind, randomized studies. Symptom scores significantly improved in the CsA group over with placebo. CsA was well tolerated at daily doses of 3 mg/kg. Side effects such as hypertension and increased serum creatinine were rare [26]. In addition, the efficacy and safety of CsA in CSU was evaluated by a meta-analysis of eighteen studies. A low-dose (2–3 mg/kg/d) was considered to be both beneficial and safe, and adverse events appear to be dose dependent and occur more frequently in patients that have been treated with moderate doses (4–5 mg/kg/d) [27]. In a recent study, the prediction of beneficial response to CsA treatment, was assessed using, positive ASST, plasma D-dimer levels, IL-2, IL-5 levels and total IgE level. Decreased plasma D-dimer levels, and decreased serum IL-2 and IL-5were reported to be correlated with clinical improvement after CsA treatment [28]. While cyclosporine A is still used in cases with severe CSU, the fear of side effects, mainly in those with mild hypertension or diabetes, has limited its usage, allowing omalizumab (an IgG-anti-IgE monoclonal antibody), approved for the treatment of anti-histamine-refractory CSU in 2014 to become the preferable option in treating CSU. In the European Academy of Allergology and Clinical Immunology, Global Allergy and Asthma European Network, European Dermatology Forum, and World Allergy (EAACI/GA2LEN/EDF/WAO) guidelines for the treatment of CSU, it is recommended that omalizumab should be added to off-label doses of anti-histamines when CSU is inadequately controlled [29, 30]. Cyclosporine A remains the final option for those considered to be omalizumab failures. The main mechanism through which omalizumab acts, is its ability to bind soluble IgE and the down regulation of FcεRI expression on skin mast cells. This is followed by decreased mast cell activation and degranulation. In this respect, higher levels of FcεRI expression, predict a faster response to omalizumab. In addition higher levels of total serum IgE were shown to be associated with a greater responsiveness to omalizumab [31]. While it is well accepted that a complete response to the standard dose of omalizumab (300 mg/month) is observed in about 59% of patients, 15% of treated patients still remain resistant to this dose of omalizumab [32]. In many studies, up dosing of omalizumab to 450 mg/month was shown to achieve better clinical respnses with a good safety profile [33]. Options of higher doses of cyclosporine A or the combination of omalizumab and cyclosporine A were also reported in few case reports in severe and refractory to all of the above mentioned approaches. Un-met needs and the requirement for new treatments in still refractory CSU are the subject of many on-going clinical trials in which targeting new relevant pathways is assessed.
Ligelizumab (QGE031) is a new monoclonal antibody directed against the Cε3 domain of IgE, which in preclinical and in phase I clinical studies demonstrated its 50-fold greater affinity to IgE in vitro and six- to nine-fold greater potency in vivo compared to omalizumab. This affinity difference is caused due to epitope differences between ligelizumab and omalizumab that contribute to their distinct qualitative IgE-receptor profiles. Ligelizumab was superior in its ability to suppress IgE binding to FcεRI, basophil activation, and IgE secretion by B cells [34]. It was also shown that Ligelizumab provided a longer suppression of free and cell-bound IgE [35]. Omalizumab was shown to inhibit the interaction of IgE-FcεRII (CD23) more efficiently than Omalizumb, and this finding might explain the superior anti-asthmatic effect of omalizumb, considering the role of CD23 in lung inflammation [34]. In order to further assess its efficacy in CSU, a phase IIb dose-finding trial was designed for the efficacy and safety of ligelizumab. Doses of 24 mg, 72 mg, and 240 mg every four weeks were compared to the omalizumab standard dose of 300 mg every four weeks and to placebo in 382 adult patients with CSU. Clinical beneficial effects were evaluated by using - UAS7 (Urticaria Activity Score) and HSS7 (Hives Severity Score). The percentage of patients with a complete control of their hives (HSS7:0) and a complete control of their symptoms (UAS7:0) at week 12 was significantly higher in all ligelizumab arms (24 mg, 72 mg, 240 mg) compared with omalizumab (300 mg) and the placebo. The question regarding the low complete response rates with omalizumab was attributed to the high percentage of patients with an autoimmune pattern and angioedema. Adverse events rates were similar in all groups, except for a slightly higher incidence of local reaction at the injection site of ligelizumab 240 mg compared to omalizumab [36]. Patient’s follow up in this clinical study revealed that among patients who achieved an UAS7 ≤ 6 at week 20, the beneficial therapeutic response was maintained for a median of 16, 8 and 8 weeks with ligelizumab 240 mg, 72 mg, and omalizumab, respectively. In addition, a 1-year extension phase of the above clinical study showed that in patients with UAS7 ≥ 12 who received ligelizumab 240 mg every 4 weeks (NCT02649218), the UAS7 ≤ 6 score response was maintained for a median period of 28 weeks [37]. Moreover, the treatment with ligelizumab was superior in other clinical measures when compared with omalizumab, namely, a decrease in the use of rescue medication [38] a greater and sustained efficacy in reducing angioedema at week 12 (the percentage of angioedema-free patients with ligelizumab 72 mg, 240 mg, omalizumab 300 mg, and placebo, was 87.5%, 94.9%, 76.3%, and 68.3%, respectively [39]. Several Phase III clinical trials (NCT03580356, NCT03580369, NCT03437278, NCT04210843) are currently in progress in order to further investigate the efficacy and safety of ligelizumab 72 mg and 120 mg when compared with omalizumab 300 mg and a placebo in CSU adolescent and adult patients up to 52 weeks. In Japan, in adult CSU patients who failed to response to H1-anti-histamines, are part of another phase III, open-label, and single-arm study of ligelizumab that is currently in progress (NCT03907878). It is hopeful that these studies and the extension phase study with ligelizumab will better characterize its usage in re-treatment, and self-administration, as well as its its benefit as a monotherapy.
Another new monoclonal antibody against IgE, UB-221, has up to eightfold greater affinity for free IgE in comparison with omalizumab. This new compound is currently being investigated for safety, tolerability, pharmacodynamics and pharmacokinetics in an ongoing phase I clinical trial in adult patients with CSU. The study is composed of single doses [0.2, 0.6, 2, 6, 10 mg/kg UB-221] given intravenously (IV) vs. a placebo (NCT03632291, NCT04175704) [40].
Bruton tyrosine kinase (BTK) is a tyrosine kinase which was found to play a major role in B cell development. At a later date, it was found to be expressed in various hematopoietic cells including macrophages, mast cells, and basophils. In the context of CSU pathogenesis, BTK was also found to play a major role in the FcεR activation and signaling in mast cells [41, 42]. BTK inhibitors are widely used today to treat several B cell malignancies and auto immune disorders [43]. Out of the many known BTK inhibitors, four (ibrutinib, dasatinib, AVL-292, CNX-774) are recognized to be effective suppressors of IgE-induced activation and histamine release from basophils and mast cells [44]. Ibrutinib (420 mg/day), was assessed in patients suffering from peanut/tree nut allergy and reported to suppress skin test responses to these food allergens within seven days, and without any discernable adverse events. No serious adverse events 100. Upon considering of the pivotal role of FcεRI signaling in CSU, it seems that the use of BTK inhibitors for CSU could be a potential new treatment option. LOU064 (remibrutinib), a more selective BTK inhibitor is being investigated in ongoing phase II clinical trials (NCT03926611, NCT04109313) for its efficacy and safety in adult patients with CSU. In an in-vitro study, the binding of BTK by remibrunitib was more efficient than fenebrutinib, thus it has a faster onset of action and its effects are maintained longer [45]. Another phase II study, investigating a new BTK inhibitor (fenebrutinib 200 mg orally twice a day), in adult patients suffering from CSU, has recently been completed. The results of this study indicated that at week 8, a marked improvement of the UAS7 was achieved at 200 mg twice a day compared with the placebo group [33].
Rituximab (RTX) is a well-known monoclonal antibody directed against CD20. It causes the depletion of mature and memory B cells through several mechanisms such as CDC and ADCC. For many years, it has been used to treat B cell hematological malignancies and autoimmune diseases such as- rheumatoid arthritis (RA), and pemphigus vulgaris [46]. Due to the autoimmune nature of CSU, it seems reasonable that the reduction of memory B cells and a subsequent decrease of the autoantibodies due to Rituximab, could well become a beneficial treatment option, particularly in autoimmune CSU. So far, only five patients in whom severe CSU refractory to immunosuppressive treatments, have been treated with rituximab [47, 48, 49, 50, 51]. The treatment regimen in these patients was either as used in lymphoma (375 mg/m2 weekly for 4 weeks) or as used in the RA protocol (two doses of 1000 mg with a 2-week interval). Four patients responded well to this treatment, and only one failed. However, a phase I/II open-label trial (NCT00216762) was terminated due to safety concerns. To date, there are no ongoing clinical trials on Rituximab in CSU patients. It appears that Rituximab could be reserved for future use as an alternative treatment option in patients with very severe, and treatment-resistant CSU.
CRTH2 is the prostaglandin D2 (PGD2) receptor that is secreted from mast cells upon activation and degranulation. CRTH2 is normally expressed on eosinophils, basophils, and Th2 cells. The signaling pathways following PGD2-interaction\\ligation to CRTH2 results in the stimulation and chemotaxis of basophils and eosinophils, Th2 response, and the increase in the amount of histamine released from basophils [52, 53]. In patients suffering from CSU, membrane CRTH2 expression on basophils and eosinophils, was found to be extremely low, which was presumably attributed to the internalization of CRTH2 upon PGD2 binding. These results suggested a role for PGD2 via CRTH2 ligation in CSU [54]. A particular CRTH2 gene polymorphism was demonstrated in several patients suffering from CSU, and these specific patients needed high doses of anti-histamines in order to control CSU [53]. These findings further establish a role for CRTH2 in CSU pathogenesis, suggesting the relevance of its targeting. Based on these considerations, a new oral CRTH2 antagonist, AZD1981, was generated and used for the treatment of CSU in a clinical trial. In a phase II, double-blind, placebo-controlled trial, twenty-six CSU patients were enrolled and completed the 4-week treatment period with either AZD1981 (40 mg three times daily) or a placebo. A clinical assessment of UAS7 and ISS7 scores revealed a significant reduction in these scores when compared with the baseline scores before treatment. However, the primary endpoint (a reduction in UAS7 ≥ 9.5 points when compared with the baseline) was not achieved in this study. No significant differences were observed in terms of anti-histamines use or the frequency of angioedema-attacks between the treatment and control groups. No serious adverse events were observed and the overall treatment was well tolerated [52], Regarding biological effects, the treatment with AZD1981 significantly inhibited PGD2-mediated eosinophil migration to the skin. Despite failing to meet the primary endpoint, future studies evaluating the efficacy of AZD1981 with longer treatment duration and higher doses are needed.
Spleen tyrosine kinase (SYK) is a pivotal player that regulates histamine release and the synthesis of immune mediators (e.g. leukotriene, prostaglandin) upon FcεRI activation in mast cells [55]. Nowadays, oral SYK inhibitors such as fostamatinib are used extensively in the treatment for autoimmune diseases such as immune thrombocytopenic purpura, chronic graft-versus-host disease and Rheumatoid Arthritis. A new intranasal SYK inhibitor, R112, was also proven to suppress FcεRI-related mediator release following mast cell degranulation, thereby suggesting that SYK inhibitors are extremely efficient in suppressing mast cell degranulation [56]. Based on the above data the use of SYK inhibitors to successfully treat CSU patients was not surprising. The first study to use SYK inhibitors was an in vitro study where a topical SYK inhibitor, was used in an ex vivo human skin model, GSK2646264. In this study it was shown that this inhibitor blocked the histamine release from mast cells through IgE signaling [57]. Following this study, a randomized, placebo-controlled phase I trial (NCT02424799) was conducted in order to evaluate the efficacy and safety of GSK2646264 0.5% and 1% topical cream in patients with CSU and cold urticarial. The results of this study are not available yet. In another in vitro study, the expression level of SYK was evaluated in mast cells from CSU patients. These patients were categorized according to the clinical out- come as responders and non-responders; the degree of basophil’s histamine release and the expression of SYK protein in mast cells. This study found that the SYK protein was expressed significantly higher in responders when compared with non-responders and healthy controls. It also revealed that the increased expression of SYK was correlated with the spontaneous histamine release from mast cells in these patients [58].
The IL-1 cytokine family in general and IL-1α and IL-1β, specifically have pro-inflammatory effects, which are neutralized by using the IL-1R antagonist. [59]. Several IL-1 mutations (NLRP3 genes) are collectively defined as auto-inflammatory syndromes, which cause the increased secretion of IL-1β. This is associated with a heterogeneous syndrome (NLRP3-AID (consisting of familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and chronic infantile neurological, cutaneous and articular syndrome. The urticarial-like rash is one of most common hallmarks of these syndromes [60, 61]. IL-1 inhibitors, such as canakinumab (monoclonal antibody against of IL-1β), anakinra (recombinant IL-1R antagonist), and rilonacept (IL-1α/β blocker) are very effective in reducing inflammation and the clinical spectrum of these syndromes [62]. It is worth mentioning, that the emerging knowledge regarding the use of IL-1-blocking agents in the treatment of Schnitzler’s syndrome, is characterized by the presence of urticarial rash and systemic inflammation [63, 64]. In on-going clinical trials, the effectiveness and safety of RPH-104 (a novel molecule against IL-1β), rilonacept, and canakinumab has been confirmed in Schnitzler syndrome (NCT04213274), acquired cold-contact urticaria (NCT02171416), and CSU (NCT01635127). The results of these trials have not yet been published. In few sporadic reports, anti-IL-1drugs were shown to be beneficial in CSU patients, who remained resistant to all classical therapies for CSU [65]. A new somatic mutation in NLRP3 was recently reported in two elderly patients with long-standing, refractory CSU associated with fever and increased CRP. Both of these patients improved dramatically following the usage of anakinra. As a result, it is assumed assumed that in patients with refractory urticaria and markers of systemic inflammation (a possible underlying NLRP3-related disorder), anti-IL-1 treatment requires further evaluation [66].
In the process of Th2 differentiation several cytokines are produced. The most important cytokines in this process are interleukin-4 and IL-13 [59]. Dupilumab, a new monoclonal antibody directed against the alpha subunit of IL-4 and IL-13 receptors, was recently approved for the treatment of asthma, nasal polyposis, and atopic dermatitis [67]. Increased levels of IL-4 were recently demonstrated in patients with CSU, thereby suggesting a pathogenic role of both Th1/Th2 responses and raising the option of treating CSU with Dupilumab [68]. A recent case report involving six patients with concomitant atopic dermatitis and CSU who were refractory to high dose of omalizumab (600 mg\\4 weeks) documented their successful treated with Dupilumab. In this report, it was postulated that the beneficial therapeutic effect of Dupilumab could be the result of its blocking Th2 inflammatory pathways by inhibiting IL-4 and IL-13, respective [69]. Currently, there are three ongoing, phase II/III clinical studies investigating the efficacy and safety of Dupilumab in CSU (NCT03749135, NCT04180488 (EFC16461-CUPID)) and cholinergic urticaria (NCT03749148) unresponsive to a high dosage of antihistamines and omalizumab.
Eosinophils, are considered to have a pivotal role in the pathogenesis of CSU. Many reports have demonstrated elevated numbers of eosinophils in urticarial lesions when compared with normal skin. Their contribution to CSU pathogenesis is probably achieved through interactions with mast cells, the secretion of histamine and other inflammatory mediators and the activation of the coagulation cascade [70]. The important role of interleukin-5 (IL-5) in eosinophil development and maturation, as well as in increased chemotaxis towards skin urticarial lesions has been well documented [59]. Several monoclonal antibodies were recently approved for the treatment of eosinophil related airway diseases (e.g. asthma, Churg-Strauss syndrome, nasal polyposis etc.) by targeting IL-5 (reslizumab, mepolizumab) or its receptor, IL-5R (benralizumab). These drugs were recently used in three CSU patients who were refractory to classical therapies; two patients responded well and showed a significant improvement with Reslizumab and mepolizumab [71, 72], while the other patient who suffered from symptomatic dermographism (SD) benefited from their treatment with benralizumab [73]. In a recent single-blind, repeated measures study, 12 CSU patients were treated with benralizumab (30 mg subcutaneously) every 4 weeks for 12 weeks following a single dose of a placebo. Among the nine patients who completed the study, five had complete response. Their UAS7 and CU-Q2oL scores improved significantly with benralizumab when compared with the placebo [74]. Gene-expression analysis in patients with CSU following benralizumab treatment demonstrated the normalization of SIGLEC-8 expression and IL-4/5 induced inflammation [75]. Although the results imply that eosinophils play a role in CSU, the exact mechanism of action has not yet been understood. Two clinical trials investigating the efficacy of benralizumab (NCT03183024) and mepolizumab (NCT03494881) in CSU are still in progress, and their results are not yet available. Regarding benralizumab, a phase IIb study (ARROYO Trial- D3259C00001) is set to start soon.
The Siglecs are a family of sialic-acid-binding immunoglobulin-like lectins, which are thought to promote cell–cell interactions and regulate the functions of cells in the innate and adaptive immune systems through glycan recognition. These proteins have regulatory effects on intercellular and intracellular signaling such as the inhibition of cellular proliferation/activation and the induction of apoptosis [76, 77]. Siglec-8 is highly and selectively expressed by eosinophils, but it became clear that it is also expressed by human mast cells and weakly, but consistently, by human basophils. Studies showed that the activation of Siglec-8 induces eosinophil apoptosis (in a caspase-, mitochondrial-, and reactive oxygen species–dependent way). It was also shown that activated eosinophils are especially sensitive to Siglec-8-induced death [78]. It also inhibits the release of FcεRI-mediated histamine and PGD2 from mast cells [79, 80]. In a recent phase I, randomized, placebo-controlled study conducted with more than 50 healthy volunteers, a single dose of a monoclonal anti-Siglec-8 antibody, namely- AK002 (autolimab) (0.001, 0.003, 0.01, 0.03, 0.1, 0.3, and 1 mg/kg IV), resulted in the complete depletion of circulating eosinophils within one hour from the infusion. This effect was maintained for up to 84 days only in the group who received 1 mg/kg. This result pointed to a possible administration schedule of AK002 at monthly or quarterly intervals [81]. Additionally, in another additional study it was also demonstrated that treatment with AK002 provided symptomatic and histologic improvement in patients with eosinophilic esophagitis [82]. Taking this into consideration, a phase IIa study in CSU and CIndU (cholinergic urticaria and symptomatic dermographism) patients was conducted. These patients received six doses of AK002. At week 22, following treatment, based on changes in UCT score - the response rates in CSU patients were the following, complete + partial response in 92% and 86% in omalizumab-naive (
Many new regulatory molecules are recently evaluated for their potential inhibitory effect on mast cell degranulation. Some of them are under development and are to be included in the pipe-line of clinical trials for the treatment of CSU. Among these molecules are SHIP and CD200R, which deserve our attention. It has been shown that SHIP-negative mast cells are more likely to degranulate following IgE binding [85]. The inhibitory effects of SHIP-1 occur through the hydrolysis of phosphatidylinositol 3, 4, 5-trisphosphate by limiting the entry of extracellular calcium, thereby decreasing phosphoinositide 3-kinase (PI3K)-mediated mast cell activation [86, 87, 88]. CD200R is a member of the Ig supergene family that is primarily expressed on myeloid cells. In vivo studies demonstrated that CD200R is an inhibitory receptor that is capable of regulating the activation threshold of inflammatory immune responses. Furthermore, CD200R was also shown to be expressed on mouse and human mast cells and that engagement of CD200R by agonist Abs or ligand results in a potent inhibition of mast cell degranulation and cytokine secretion responses. The proposed mechanism for that effect was possibly due to the inhibition of FcεRI activation that was observed both in vitro and in vivo. [88] Considering their regulatory functions on mast cells, the use of SHIP, CD200R antibodies, or PI3K inhibitors for the treatment of CSU is of great interest.
The emerging field of histamine H4 receptors in allergy and clinical immunology is continuously growing. H4 histamine receptor, is a member of the G protein-coupled receptor superfamily that is largely expressed in haematopoietic cells and plays an increasing role in the regulation of immune responses. H4 receptors modulate eosinophil migration and selective recruitment of mast cells that leads to an increased histamine-release and chronic inflammation. It is also involved in T cell differentiation thereby is involved in many immunomodulatory pathways. The observation that H4 is a histamine receptor on many immune cells shed light on the potential of their targeting in inflammatory disorders, such as allergy, chronic pruritus and autoimmune diseases e.g. CSU [89]. Several ongoing clinical studies currently taking place are aimed at evaluating the beneficial effect of targeting H4 receptors in patients suffering from atopic dermatitis and pruritus (JNJ-7777120, ZPL-3893787). Preliminary results have indicated a significant reduction in histamine-mediated scratch and Th2-induced inflammation in atopic dermatitis [90, 91]. These results are encouraging and indicate the need to further evaluate any potential benefits of these drugs in the treatment of CSU.
MrgX2 is a member of Mas-related genes that is primarily expressed in human dorsal root ganglia and mast cells and is activated by basic peptides. MrgX2 is a multi-ligand receptor responding to various exogenous and endogenous stimuli. As they are highly expressed on skin mast cells, MRGPRX2 triggers their degranulation and release of pro inflammatory mediators, thus promoting multicellular signaling cascades, such as itch induction and transmission in sensory neurons. The expression of MRGPRX2 by skin mast cells and the levels of the MRGPRX2 agonists (eg, substance P, major basic protein, eosinophil peroxidase) are up-regulated in the serum and skin of patients with inflammatory and pruritic skin diseases, such as CSU and atopic dermatitis. Thus, MRGPRX2 and its agonists might possibly be potential biomarkers for the progression of cutaneous inflammatory diseases and the response to treatment in the future. In addition, they may well represent promising targets for the prevention and treatment of signs and symptoms in patients with skin diseases or drug reactions [92].
Quilizumab, is another new humanized monoclonal antibody directed specifically against membrane-bound IgE. This molecule was also evaluated for its efficacy and safety for the treatment of CSU in a phase II trial. Unfortunately, following a 20-week treatment with quilizumab 450 mg or a placebo every 4 weeks, no statisticallly significant differences were observed in all clinical scores ISS7, HSS7, and UAS7 – between the two groups. Moreover, even in the minimally important difference (MID) range the quilizumab group also failed to attain significant differences. [93]. Thus, further development of quilizumab for CSU was discontinued.
The expression of thymic stromal lymphopoietin (TSLP), a promotor of Th2 response, was proven to be increased in patients with CSU, thus making the anti-TSLP monoclonal antibody, tezepelumab, a potential treatment alternative for CSU [94, 95].
The finding of increased blood levels of IL-17 in CSU patients was previously reported to be in association with CSU severity. This encouraged us to assess the status of IL-17 in the skin of CSU patients, thus, demonstrating increased IL-17 expression in CD4+ T cells and mast cells of both lesional and non-lesional skin of severe CSU patients. With this in mind, eight severe CSU patients (refractory to all approved therapies and steroid dependent) were treated with the anti-IL-17A antibody, secukinumab, demonstrating a significant improvement in CSU disease activity and were able to discontinue steroids. Future studies should be planned in order to expand this promising therapeutic approach [16, 96].
The need for new treatments evolve from the fact that 15–20% of severe CSU patients will stay unresponsive to Omalizumab and are defined as being of un-met needs. Thus, a better understanding of the complexity of CSU pathogenesis led to the development of many new treatment options. In this chapter we reviewed the known and the ongoing clinical studies of the new treatments for severe CSU. We expect that some of these strategies will be efficient and will be added to the market of the existing therapies.
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Shohel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"605",title:"Machine Learning",slug:"numerical-analysis-and-scientific-computing-machine-learning",parent:{id:"95",title:"Numerical Analysis and Scientific Computing",slug:"numerical-analysis-and-scientific-computing"},numberOfBooks:2,numberOfSeries:0,numberOfAuthorsAndEditors:73,numberOfWosCitations:88,numberOfCrossrefCitations:80,numberOfDimensionsCitations:121,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicId:"605",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"10651",title:"Machine Learning",subtitle:"Algorithms, Models and Applications",isOpenForSubmission:!1,hash:"6208156401c496e0a4ca5ff4265324cc",slug:"machine-learning-algorithms-models-and-applications",bookSignature:"Jaydip Sen",coverURL:"https://cdn.intechopen.com/books/images_new/10651.jpg",editedByType:"Edited by",editors:[{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5191",title:"Artificial Neural Networks",subtitle:"Models and Applications",isOpenForSubmission:!1,hash:"367a7a8daf581754dcd37bc588ec5cbf",slug:"artificial-neural-networks-models-and-applications",bookSignature:"Joao Luis G. Rosa",coverURL:"https://cdn.intechopen.com/books/images_new/5191.jpg",editedByType:"Edited by",editors:[{id:"151889",title:"Dr.",name:"Joao Luis Garcia",middleName:null,surname:"Rosa",slug:"joao-luis-garcia-rosa",fullName:"Joao Luis Garcia Rosa"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:2,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"50570",doi:"10.5772/63256",title:"Bayesian Regularized Neural Networks for Small n Big p Data",slug:"bayesian-regularized-neural-networks-for-small-n-big-p-data",totalDownloads:3113,totalCrossrefCites:34,totalDimensionsCites:51,abstract:"Artificial neural networks (ANN) mimic the function of the human brain and they have the capability to implement massively parallel computations for mapping, function approximation, classification, and pattern recognition processing. ANN can capture the highly nonlinear associations between inputs (predictors) and target (responses) variables and can adaptively learn the complex functional forms. Like other parametric and nonparametric methods, such as kernel regression and smoothing splines, ANNs can introduce overfitting (in particular with highly-dimensional data, such as genome wide association -GWAS-, microarray data etc.) and resulting predictions can be outside the range of the training data. Regularization (shrinkage) in ANN allows bias of parameter estimates towards what are considered to be probable. Most common techniques of regularizations techniques in ANN are the Bayesian regularization (BR) and the early stopping methods. Early stopping is effectively limiting the used weights in the network and thus imposes regularization, effectively lowering the Vapnik-Chervonenkis dimension. In Bayesian regularized ANN (BRANN), the regularization techniques involve imposing certain prior distributions on the model parameters and penalizes large weights in anticipation of achieving smoother mapping.",book:{id:"5191",slug:"artificial-neural-networks-models-and-applications",title:"Artificial Neural Networks",fullTitle:"Artificial Neural Networks - Models and Applications"},signatures:"Hayrettin Okut",authors:[{id:"179217",title:"Prof.",name:"Hayrettin",middleName:null,surname:"Okut",slug:"hayrettin-okut",fullName:"Hayrettin Okut"}]},{id:"51330",doi:"10.5772/64026",title:"Advanced Methods in Neural Networks-Based Sensitivity Analysis with their Applications in Civil Engineering",slug:"advanced-methods-in-neural-networks-based-sensitivity-analysis-with-their-applications-in-civil-engi",totalDownloads:2421,totalCrossrefCites:13,totalDimensionsCites:18,abstract:"Artificial neural networks (ANNs) are powerful tools that are used in various engineering fields. Their characteristics enable them to solve prediction, regression, and classification problems. Nevertheless, the ANN is usually thought of as a black box, in which it is difficult to determine the effect of each explicative variable (input) on the dependent variables (outputs) in any problem. To investigate such effects, sensitivity analysis is usually applied on the optimal pre-trained ANN. Existing sensitivity analysis techniques suffer from drawbacks. Their basis on a single optimal pre-trained ANN model produces instability in parameter sensitivity analysis because of the uncertainty in neural network modeling. To overcome this deficiency, two successful sensitivity analysis paradigms, the neural network committee (NNC)-based sensitivity analysis and the neural network ensemble (NNE)-based parameter sensitivity analysis, are illustrated in this chapter. An NNC is applied in a case study of geotechnical engineering involving strata movement. An NNE is implemented for sensitivity analysis of two classic problems in civil engineering: (i) the fracture failure of notched concrete beams and (ii) the lateral deformation of deep-foundation pits. Results demonstrate good ability to analyze the sensitivity of the most influential parameters, illustrating the underlying mechanisms of such engineering systems.",book:{id:"5191",slug:"artificial-neural-networks-models-and-applications",title:"Artificial Neural Networks",fullTitle:"Artificial Neural Networks - Models and Applications"},signatures:"Maosen Cao, Nizar F. Alkayem, Lixia Pan and Drahomír Novák",authors:[{id:"180549",title:"Prof.",name:"Maosen",middleName:null,surname:"Cao",slug:"maosen-cao",fullName:"Maosen Cao"},{id:"180560",title:"Dr.",name:"Lixia",middleName:null,surname:"Pan",slug:"lixia-pan",fullName:"Lixia Pan"},{id:"180562",title:"Dr.",name:"Nizar Faisal",middleName:null,surname:"Alkayem",slug:"nizar-faisal-alkayem",fullName:"Nizar Faisal Alkayem"}]},{id:"51466",doi:"10.5772/64047",title:"Generalized Regression Neural Networks with Application in Neutron Spectrometry",slug:"generalized-regression-neural-networks-with-application-in-neutron-spectrometry",totalDownloads:2454,totalCrossrefCites:3,totalDimensionsCites:8,abstract:"The aim of this research was to apply a generalized regression neural network (GRNN) to predict neutron spectrum using the rates count coming from a Bonner spheres system as the only piece of information. In the training and testing stages, a data set of 251 different types of neutron spectra, taken from the International Atomic Energy Agency compilation, were used. Fifty-one predicted spectra were analyzed at testing stage. Training and testing of GRNN were carried out in the MATLAB environment by means of a scientific and technological tool designed based on GRNN technology, which is capable of solving the neutron spectrometry problem with high performance and generalization capability. This computational tool automates the pre-processing of information, the training and testing stages, the statistical analysis, and the post-processing of the information. In this work, the performance of feed-forward backpropagation neural networks (FFBPNN) and GRNN was compared in the solution of the neutron spectrometry problem. From the results obtained, it can be observed that despite very similar results, GRNN performs better than FFBPNN because the former could be used as an alternative procedure in neutron spectrum unfolding methodologies with high performance and accuracy.",book:{id:"5191",slug:"artificial-neural-networks-models-and-applications",title:"Artificial Neural Networks",fullTitle:"Artificial Neural Networks - Models and Applications"},signatures:"Ma. del Rosario Martinez-Blanco, Víctor Hugo Castañeda-Miranda,\nGerardo Ornelas-Vargas, Héctor Alonso Guerrero-Osuna, Luis\nOctavio Solis-Sanchez, Rodrigo Castañeda-Miranda, José María\nCelaya-Padilla, Carlos Eric Galvan-Tejada, Jorge Isaac Galvan-Tejada,\nHéctor René Vega-Carrillo, Margarita Martínez-Fierro, Idalia Garza-\nVeloz and Jose Manuel Ortiz-Rodriguez",authors:[{id:"19773",title:"Dr.",name:"Jose Manuel",middleName:null,surname:"Ortiz-Rodriguez",slug:"jose-manuel-ortiz-rodriguez",fullName:"Jose Manuel Ortiz-Rodriguez"},{id:"22531",title:"Dr.",name:"Maria Del Rosario",middleName:null,surname:"Martinez-Blanco",slug:"maria-del-rosario-martinez-blanco",fullName:"Maria Del Rosario Martinez-Blanco"},{id:"82380",title:"Dr.",name:"Hector Rene",middleName:null,surname:"Vega-Carrillo",slug:"hector-rene-vega-carrillo",fullName:"Hector Rene Vega-Carrillo"},{id:"183473",title:"Dr.",name:"Luis Octavio",middleName:null,surname:"Solis-Sanchez",slug:"luis-octavio-solis-sanchez",fullName:"Luis Octavio Solis-Sanchez"},{id:"189184",title:"MSc.",name:"Victor Hugo",middleName:null,surname:"Castañeda-Miranda",slug:"victor-hugo-castaneda-miranda",fullName:"Victor Hugo Castañeda-Miranda"},{id:"189185",title:"MSc.",name:"Gerardo",middleName:null,surname:"Ornelas-Vargas",slug:"gerardo-ornelas-vargas",fullName:"Gerardo Ornelas-Vargas"},{id:"189186",title:"MSc.",name:"Hector Alonso",middleName:null,surname:"Guerrero-Osuna",slug:"hector-alonso-guerrero-osuna",fullName:"Hector Alonso Guerrero-Osuna"},{id:"189187",title:"Dr.",name:"Jose Maria",middleName:null,surname:"Celaya-Padilla",slug:"jose-maria-celaya-padilla",fullName:"Jose Maria Celaya-Padilla"},{id:"189189",title:"Dr.",name:"Idalia",middleName:null,surname:"Garza-Veloz",slug:"idalia-garza-veloz",fullName:"Idalia Garza-Veloz"},{id:"189191",title:"Dr.",name:"Rodrigo",middleName:null,surname:"Castañeda-Miranda",slug:"rodrigo-castaneda-miranda",fullName:"Rodrigo Castañeda-Miranda"},{id:"189792",title:"Dr.",name:"Jorge Isaac",middleName:null,surname:"Galvan-Tejada",slug:"jorge-isaac-galvan-tejada",fullName:"Jorge Isaac Galvan-Tejada"},{id:"189793",title:"Dr.",name:"Carlos Eric",middleName:null,surname:"Galvan-Tejada",slug:"carlos-eric-galvan-tejada",fullName:"Carlos Eric Galvan-Tejada"},{id:"190887",title:"MSc.",name:"Celina Lizeth",middleName:null,surname:"Castañeda-Miranda",slug:"celina-lizeth-castaneda-miranda",fullName:"Celina Lizeth Castañeda-Miranda"},{id:"211746",title:"Dr.",name:"Margarita de la Luz",middleName:null,surname:"Martinez-Fierro",slug:"margarita-de-la-luz-martinez-fierro",fullName:"Margarita de la Luz Martinez-Fierro"}]},{id:"50486",doi:"10.5772/63109",title:"Analyzing the Impact of Airborne Particulate Matter on Urban Contamination with the Help of Hybrid Neural Networks",slug:"analyzing-the-impact-of-airborne-particulate-matter-on-urban-contamination-with-the-help-of-hybrid-n",totalDownloads:1913,totalCrossrefCites:1,totalDimensionsCites:8,abstract:"In this study, particulate matter (PM), total suspended particulate (TSP), PM10, and PM2.5 fractions) concentrations were recorded in various cities from south of Romania to build the corresponding time series for various intervals. First, the time series of each pollutant were used as inputs in various configurations of feed-forward neural networks (FANN) to find the most suitable network architecture to the PM specificity. The outputs were evaluated using mean absolute error (MAE), mean absolute percentage error (MAPE), root mean square error (RMSE), and Pearson correlation coefficient (r) between observed series and output series. Second, each time series was decomposed using Daubechies wavelets of third order into its corresponding components. Each decomposed component of a PM time series was used as input in the optimal feed-forward neural networks (FANN) architecture established in the first step. The output of each component was re-included to form the modeled series of the original pollutant time series.",book:{id:"5191",slug:"artificial-neural-networks-models-and-applications",title:"Artificial Neural Networks",fullTitle:"Artificial Neural Networks - Models and Applications"},signatures:"Daniel Dunea and Stefania Iordache",authors:[{id:"82418",title:"Prof.",name:"Stefania Felicia",middleName:null,surname:"Iordache",slug:"stefania-felicia-iordache",fullName:"Stefania Felicia Iordache"},{id:"180202",title:"Associate Prof.",name:"Daniel",middleName:null,surname:"Dunea",slug:"daniel-dunea",fullName:"Daniel Dunea"}]},{id:"50680",doi:"10.5772/63332",title:"From Fuzzy Expert System to Artificial Neural Network: Application to Assisted Speech Therapy",slug:"from-fuzzy-expert-system-to-artificial-neural-network-application-to-assisted-speech-therapy",totalDownloads:2205,totalCrossrefCites:3,totalDimensionsCites:6,abstract:"This chapter addresses the following question: What are the advantages of extending a fuzzy expert system (FES) to an artificial neural network (ANN), within a computer‐based speech therapy system (CBST)? We briefly describe the key concepts underlying the principles behind the FES and ANN and their applications in assisted speech therapy. We explain the importance of an intelligent system in order to design an appropriate model for real‐life situations. We present data from 1‐year application of these concepts in the field of assisted speech therapy. Using an artificial intelligent system for improving speech would allow designing a training program for pronunciation, which can be individualized based on specialty needs, previous experiences, and the child's prior therapeutical progress. Neural networks add a great plus value when dealing with data that do not normally match our previous designed pattern. Using an integrated approach that combines FES and ANN allows our system to accomplish three main objectives: (1) develop a personalized therapy program; (2) gradually replace some human expert duties; (3) use “self‐learning” capabilities, a component traditionally reserved for humans. The results demonstrate the viability of the hybrid approach in the context of speech therapy that can be extended when designing similar applications.",book:{id:"5191",slug:"artificial-neural-networks-models-and-applications",title:"Artificial Neural Networks",fullTitle:"Artificial Neural Networks - Models and Applications"},signatures:"Ovidiu Schipor, Oana Geman, Iuliana Chiuchisan and Mihai Covasa",authors:[{id:"180248",title:"Dr.",name:"Oana",middleName:null,surname:"Geman",slug:"oana-geman",fullName:"Oana Geman"},{id:"181060",title:"Prof.",name:"Ovidiu-Andrei",middleName:null,surname:"Schipor",slug:"ovidiu-andrei-schipor",fullName:"Ovidiu-Andrei Schipor"},{id:"181064",title:"Dr.",name:"Iuliana",middleName:null,surname:"Chiuchisan",slug:"iuliana-chiuchisan",fullName:"Iuliana Chiuchisan"},{id:"185161",title:"Prof.",name:"Mihai",middleName:null,surname:"Covasa",slug:"mihai-covasa",fullName:"Mihai Covasa"}]}],mostDownloadedChaptersLast30Days:[{id:"50570",title:"Bayesian Regularized Neural Networks for Small n Big p Data",slug:"bayesian-regularized-neural-networks-for-small-n-big-p-data",totalDownloads:3113,totalCrossrefCites:34,totalDimensionsCites:51,abstract:"Artificial neural networks (ANN) mimic the function of the human brain and they have the capability to implement massively parallel computations for mapping, function approximation, classification, and pattern recognition processing. ANN can capture the highly nonlinear associations between inputs (predictors) and target (responses) variables and can adaptively learn the complex functional forms. Like other parametric and nonparametric methods, such as kernel regression and smoothing splines, ANNs can introduce overfitting (in particular with highly-dimensional data, such as genome wide association -GWAS-, microarray data etc.) and resulting predictions can be outside the range of the training data. Regularization (shrinkage) in ANN allows bias of parameter estimates towards what are considered to be probable. Most common techniques of regularizations techniques in ANN are the Bayesian regularization (BR) and the early stopping methods. Early stopping is effectively limiting the used weights in the network and thus imposes regularization, effectively lowering the Vapnik-Chervonenkis dimension. In Bayesian regularized ANN (BRANN), the regularization techniques involve imposing certain prior distributions on the model parameters and penalizes large weights in anticipation of achieving smoother mapping.",book:{id:"5191",slug:"artificial-neural-networks-models-and-applications",title:"Artificial Neural Networks",fullTitle:"Artificial Neural Networks - Models and Applications"},signatures:"Hayrettin Okut",authors:[{id:"179217",title:"Prof.",name:"Hayrettin",middleName:null,surname:"Okut",slug:"hayrettin-okut",fullName:"Hayrettin Okut"}]},{id:"51466",title:"Generalized Regression Neural Networks with Application in Neutron Spectrometry",slug:"generalized-regression-neural-networks-with-application-in-neutron-spectrometry",totalDownloads:2454,totalCrossrefCites:3,totalDimensionsCites:8,abstract:"The aim of this research was to apply a generalized regression neural network (GRNN) to predict neutron spectrum using the rates count coming from a Bonner spheres system as the only piece of information. In the training and testing stages, a data set of 251 different types of neutron spectra, taken from the International Atomic Energy Agency compilation, were used. Fifty-one predicted spectra were analyzed at testing stage. Training and testing of GRNN were carried out in the MATLAB environment by means of a scientific and technological tool designed based on GRNN technology, which is capable of solving the neutron spectrometry problem with high performance and generalization capability. This computational tool automates the pre-processing of information, the training and testing stages, the statistical analysis, and the post-processing of the information. In this work, the performance of feed-forward backpropagation neural networks (FFBPNN) and GRNN was compared in the solution of the neutron spectrometry problem. From the results obtained, it can be observed that despite very similar results, GRNN performs better than FFBPNN because the former could be used as an alternative procedure in neutron spectrum unfolding methodologies with high performance and accuracy.",book:{id:"5191",slug:"artificial-neural-networks-models-and-applications",title:"Artificial Neural Networks",fullTitle:"Artificial Neural Networks - Models and Applications"},signatures:"Ma. del Rosario Martinez-Blanco, Víctor Hugo Castañeda-Miranda,\nGerardo Ornelas-Vargas, Héctor Alonso Guerrero-Osuna, Luis\nOctavio Solis-Sanchez, Rodrigo Castañeda-Miranda, José María\nCelaya-Padilla, Carlos Eric Galvan-Tejada, Jorge Isaac Galvan-Tejada,\nHéctor René Vega-Carrillo, Margarita Martínez-Fierro, Idalia Garza-\nVeloz and Jose Manuel Ortiz-Rodriguez",authors:[{id:"19773",title:"Dr.",name:"Jose Manuel",middleName:null,surname:"Ortiz-Rodriguez",slug:"jose-manuel-ortiz-rodriguez",fullName:"Jose Manuel Ortiz-Rodriguez"},{id:"22531",title:"Dr.",name:"Maria Del Rosario",middleName:null,surname:"Martinez-Blanco",slug:"maria-del-rosario-martinez-blanco",fullName:"Maria Del Rosario Martinez-Blanco"},{id:"82380",title:"Dr.",name:"Hector Rene",middleName:null,surname:"Vega-Carrillo",slug:"hector-rene-vega-carrillo",fullName:"Hector Rene Vega-Carrillo"},{id:"183473",title:"Dr.",name:"Luis Octavio",middleName:null,surname:"Solis-Sanchez",slug:"luis-octavio-solis-sanchez",fullName:"Luis Octavio Solis-Sanchez"},{id:"189184",title:"MSc.",name:"Victor Hugo",middleName:null,surname:"Castañeda-Miranda",slug:"victor-hugo-castaneda-miranda",fullName:"Victor Hugo Castañeda-Miranda"},{id:"189185",title:"MSc.",name:"Gerardo",middleName:null,surname:"Ornelas-Vargas",slug:"gerardo-ornelas-vargas",fullName:"Gerardo Ornelas-Vargas"},{id:"189186",title:"MSc.",name:"Hector Alonso",middleName:null,surname:"Guerrero-Osuna",slug:"hector-alonso-guerrero-osuna",fullName:"Hector Alonso Guerrero-Osuna"},{id:"189187",title:"Dr.",name:"Jose Maria",middleName:null,surname:"Celaya-Padilla",slug:"jose-maria-celaya-padilla",fullName:"Jose Maria Celaya-Padilla"},{id:"189189",title:"Dr.",name:"Idalia",middleName:null,surname:"Garza-Veloz",slug:"idalia-garza-veloz",fullName:"Idalia Garza-Veloz"},{id:"189191",title:"Dr.",name:"Rodrigo",middleName:null,surname:"Castañeda-Miranda",slug:"rodrigo-castaneda-miranda",fullName:"Rodrigo Castañeda-Miranda"},{id:"189792",title:"Dr.",name:"Jorge Isaac",middleName:null,surname:"Galvan-Tejada",slug:"jorge-isaac-galvan-tejada",fullName:"Jorge Isaac Galvan-Tejada"},{id:"189793",title:"Dr.",name:"Carlos Eric",middleName:null,surname:"Galvan-Tejada",slug:"carlos-eric-galvan-tejada",fullName:"Carlos Eric Galvan-Tejada"},{id:"190887",title:"MSc.",name:"Celina Lizeth",middleName:null,surname:"Castañeda-Miranda",slug:"celina-lizeth-castaneda-miranda",fullName:"Celina Lizeth Castañeda-Miranda"},{id:"211746",title:"Dr.",name:"Margarita de la Luz",middleName:null,surname:"Martinez-Fierro",slug:"margarita-de-la-luz-martinez-fierro",fullName:"Margarita de la Luz Martinez-Fierro"}]},{id:"50519",title:"Neural Networks for Gas Turbine Diagnosis",slug:"neural-networks-for-gas-turbine-diagnosis",totalDownloads:2233,totalCrossrefCites:5,totalDimensionsCites:4,abstract:"The present chapter addresses the problems of gas turbine gas path diagnostics solved using artificial neural networks. As a very complex and expensive mechanical system, a gas turbine should be effectively monitored and diagnosed. Being universal and powerful approximation and classification techniques, neural networks have become widespread in gas turbine health monitoring over the past few years. Applications of such networks as a multilayer perceptron, radial basis network, probabilistic neural network, and support vector network were reported. However, there is a lack of manuals that summarize neural network applications for gas turbine diagnosis.",book:{id:"5191",slug:"artificial-neural-networks-models-and-applications",title:"Artificial Neural Networks",fullTitle:"Artificial Neural Networks - Models and Applications"},signatures:"Igor Loboda",authors:[{id:"179551",title:"Dr.",name:"Igor",middleName:null,surname:"Loboda",slug:"igor-loboda",fullName:"Igor Loboda"}]},{id:"51130",title:"Application of Neural Networks (NNs) for Fabric Defect Classification",slug:"application-of-neural-networks-nns-for-fabric-defect-classification",totalDownloads:1905,totalCrossrefCites:4,totalDimensionsCites:4,abstract:"The defect classification is as important as the defect detection in fabric inspection process. The detected defects are classified according to their types and recorded with their names during manual fabric inspection process. The material is selected as “undyed raw denim” fabric in this study. Four commonly occurring defect types, hole, warp lacking, weft lacking and soiled yarn, were classified by using artificial neural network (ANN) method. The defects were automatically classified according to their texture features. Texture feature extraction algorithm was developed to acquire the required values from the defective fabric samples. The texture features were assessed as the network input values and the defect classification is obtained as the output. The defective images were classified with an average accuracy rate of 96.3%. As the hole defect was recognized with 100% accuracy rate, the others were recognized with a rate of 95%.",book:{id:"5191",slug:"artificial-neural-networks-models-and-applications",title:"Artificial Neural Networks",fullTitle:"Artificial Neural Networks - Models and Applications"},signatures:"H. İbrahim Çelik, L. Canan Dülger and Mehmet Topalbekiroğlu",authors:[{id:"89349",title:"Prof.",name:"Lale Canan",middleName:null,surname:"Dülger",slug:"lale-canan-dulger",fullName:"Lale Canan Dülger"},{id:"178353",title:"Dr.",name:"Halil",middleName:"İbrahim",surname:"Çelik",slug:"halil-celik",fullName:"Halil Çelik"},{id:"185835",title:"Prof.",name:"Mehmet",middleName:null,surname:"Topalbekiroğlu",slug:"mehmet-topalbekiroglu",fullName:"Mehmet Topalbekiroğlu"}]},{id:"51444",title:"Neural Network Inverse Modeling for Optimization",slug:"neural-network-inverse-modeling-for-optimization",totalDownloads:2280,totalCrossrefCites:4,totalDimensionsCites:4,abstract:"In this chapter, artificial neural networks (ANNs) inverse model is applied for estimating the thermal performance () in parabolic trough concentrator (PTC). A recurrent neural network architecture is trained using the Kalman Filter learning from experimental database obtained from PTCs operations. Rim angle (φr), inlet (Tin), outlet (Tout) fluid temperatures, ambient temperature (Ta), water flow (Fw), direct solar radiation (Gb) and the wind velocity (Vw) were used as main input variables within the neural network model in order to estimate the thermal performance with an excellent agreement (R2=0.999) between the experimental and simulated values. The optimal operation conditions of parabolic trough concentrator are established using artificial neural network inverse modeling. The results, using experimental data, showed that the recurrent neural network (RNN) is an excellent tool for modeling and optimization of PTCs.",book:{id:"5191",slug:"artificial-neural-networks-models-and-applications",title:"Artificial Neural Networks",fullTitle:"Artificial Neural Networks - Models and Applications"},signatures:"Oscar May, Luis J. Ricalde, Bassam Ali, Eduardo Ordoñez López,\nEduardo Venegas-Reyes and Oscar A. Jaramillo",authors:[{id:"181162",title:"Dr.",name:"Luis Josue",middleName:null,surname:"Ricalde Castellanos",slug:"luis-josue-ricalde-castellanos",fullName:"Luis Josue Ricalde Castellanos"},{id:"185657",title:"Dr.",name:"Oscar",middleName:null,surname:"May",slug:"oscar-may",fullName:"Oscar May"}]}],onlineFirstChaptersFilter:{topicId:"605",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters: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:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"May 24th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:27,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"10",title:"Animal Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/10.jpg",isOpenForSubmission:!0,editor:{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. 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From\r\n1964 to 1974, he worked as Assistant in Biochemistry at the School of MedicineUniversidad Nacional de La Plata, Argentina. From 1974 to 1976, he was a Fellowof the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor oBiochemistry at the Universidad Nacional de La Plata, Argentina. He is Member ofthe National Research Council (CONICET), Argentina, and Argentine Society foBiochemistry and Molecular Biology (SAIB). His laboratory has been interested for manyears in the lipid peroxidation of biological membranes from various tissues and different species. Professor Catalá has directed twelve doctoral theses, publishedover 100 papers in peer reviewed journals, several chapters in books andtwelve edited books. Angel Catalá received awards at the 40th InternationaConference Biochemistry of Lipids 1999: Dijon (France). W inner of the Bimbo PanAmerican Nutrition, Food Science and Technology Award 2006 and 2012, South AmericaHuman Nutrition, Professional Category. 2006 award in pharmacology, Bernardo\r\nHoussay, in recognition of his meritorious works of research. Angel Catalá belongto the Editorial Board of Journal of lipids, International Review of Biophysical ChemistryFrontiers in Membrane Physiology and Biophysics, World Journal oExperimental Medicine and Biochemistry Research International, W orld Journal oBiological Chemistry, Oxidative Medicine and Cellular Longevity, Diabetes and thePancreas, International Journal of Chronic Diseases & Therapy, International Journal oNutrition, Co-Editor of The Open Biology Journal.",institutionString:null,institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}},editorTwo:null,editorThree:null},{id:"12",title:"Human Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/12.jpg",isOpenForSubmission:!0,editor:{id:"195829",title:"Prof.",name:"Kunihiro",middleName:null,surname:"Sakuma",slug:"kunihiro-sakuma",fullName:"Kunihiro Sakuma",profilePictureURL:"https://mts.intechopen.com/storage/users/195829/images/system/195829.jpg",biography:"Professor Kunihiro Sakuma, Ph.D., currently works in the Institute for Liberal Arts at the Tokyo Institute of Technology. He is a physiologist working in the field of skeletal muscle. He was awarded his sports science diploma in 1995 by the University of Tsukuba and began his scientific work at the Department of Physiology, Aichi Human Service Center, focusing on the molecular mechanism of congenital muscular dystrophy and normal muscle regeneration. His interest later turned to the molecular mechanism and attenuating strategy of sarcopenia (age-related muscle atrophy). His opinion is to attenuate sarcopenia by improving autophagic defects using nutrient- and pharmaceutical-based treatments.",institutionString:null,institution:{name:"Tokyo Institute of Technology",institutionURL:null,country:{name:"Japan"}}},editorTwo:null,editorThree:{id:"331519",title:"Dr.",name:"Kotomi",middleName:null,surname:"Sakai",slug:"kotomi-sakai",fullName:"Kotomi Sakai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000031QtFXQA0/Profile_Picture_1637053227318",biography:"Senior researcher Kotomi Sakai, Ph.D., MPH, works at the Research Organization of Science and Technology in Ritsumeikan University. She is a researcher in the geriatric rehabilitation and public health field. She received Ph.D. from Nihon University and MPH from St.Luke’s International University. Her main research interest is sarcopenia in older adults, especially its association with nutritional status. Additionally, to understand how to maintain and improve physical function in older adults, to conduct studies about the mechanism of sarcopenia and determine when possible interventions are needed.",institutionString:null,institution:{name:"Ritsumeikan University",institutionURL:null,country:{name:"Japan"}}}},{id:"13",title:"Plant Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/13.jpg",isOpenForSubmission:!0,editor:{id:"332229",title:"Prof.",name:"Jen-Tsung",middleName:null,surname:"Chen",slug:"jen-tsung-chen",fullName:"Jen-Tsung Chen",profilePictureURL:"https://mts.intechopen.com/storage/users/332229/images/system/332229.png",biography:"Dr. Jen-Tsung Chen is currently a professor at the National University of Kaohsiung, Taiwan. He teaches cell biology, genomics, proteomics, medicinal plant biotechnology, and plant tissue culture. Dr. Chen\\'s research interests include bioactive compounds, chromatography techniques, in vitro culture, medicinal plants, phytochemicals, and plant biotechnology. He has published more than ninety scientific papers and serves as an editorial board member for Plant Methods, Biomolecules, and International Journal of Molecular Sciences.",institutionString:"National University of Kaohsiung",institution:{name:"National University of Kaohsiung",institutionURL:null,country:{name:"Taiwan"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:43,paginationItems:[{id:"81796",title:"Apoptosis-Related Diseases and Peroxisomes",doi:"10.5772/intechopen.105052",signatures:"Meimei Wang, Yakun Liu, Ni Chen, Juan Wang and Ye Zhao",slug:"apoptosis-related-diseases-and-peroxisomes",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"The Metabolic Role of Peroxisome in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/10837.jpg",subseries:{id:"11",title:"Cell Physiology"}}},{id:"81723",title:"Peroxisomal Modulation as Therapeutic Alternative for Tackling Multiple Cancers",doi:"10.5772/intechopen.104873",signatures:"Shazia Usmani, Shadma Wahab, Abdul Hafeez, Shabana Khatoon and Syed Misbahul Hasan",slug:"peroxisomal-modulation-as-therapeutic-alternative-for-tackling-multiple-cancers",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"The Metabolic Role of Peroxisome in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/10837.jpg",subseries:{id:"11",title:"Cell Physiology"}}},{id:"81638",title:"Aging and Neuropsychiatric Disease: A General Overview of Prevalence and Trends",doi:"10.5772/intechopen.103102",signatures:"Jelena Milić",slug:"aging-and-neuropsychiatric-disease-a-general-overview-of-prevalence-and-trends",totalDownloads:14,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Senescence",coverURL:"https://cdn.intechopen.com/books/images_new/10935.jpg",subseries:{id:"11",title:"Cell Physiology"}}},{id:"81566",title:"New and Emerging Technologies for Integrative Ambulatory Autonomic Assessment and Intervention as a Catalyst in the Synergy of Remote Geocoded Biosensing, Algorithmic Networked Cloud Computing, Deep Learning, and Regenerative/Biomic Medicine: Further Real",doi:"10.5772/intechopen.104092",signatures:"Robert L. Drury",slug:"new-and-emerging-technologies-for-integrative-ambulatory-autonomic-assessment-and-intervention-as-a-",totalDownloads:9,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Autonomic Nervous System - Special Interest Topics",coverURL:"https://cdn.intechopen.com/books/images_new/10835.jpg",subseries:{id:"12",title:"Human Physiology"}}}]},overviewPagePublishedBooks:{paginationCount:11,paginationItems:[{type:"book",id:"7264",title:"Calcium and Signal Transduction",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7264.jpg",slug:"calcium-and-signal-transduction",publishedDate:"October 24th 2018",editedByType:"Edited by",bookSignature:"John N. Buchholz and Erik J. Behringer",hash:"e373a3d1123dbd45fddf75d90e3e7c38",volumeInSeries:1,fullTitle:"Calcium and Signal Transduction",editors:[{id:"89438",title:"Dr.",name:"John N.",middleName:null,surname:"Buchholz",slug:"john-n.-buchholz",fullName:"John N. Buchholz",profilePictureURL:"https://mts.intechopen.com/storage/users/89438/images/6463_n.jpg",biography:"Full Professor and Vice Chair, Division of Pharmacology, Loma Linda University, School of Medicine. He received his B.S. Degree in Biology at La Sierra University, Riverside California (1980) and a PhD in Pharmacology from Loma Linda University School of Medicine (1988). Post-Doctoral Fellow at University of California, Irvine, College of Medicine 1989-1992 with a focus on autonomic nerve function in blood vessels and the impact of aging on the function of these nerves and overall blood vessel function. Twenty years of research funding and served on NIH R01 review panels, Editor-In-Chief of Edorium Journal of Aging Research. Serves as a peer reviewer for biomedical journals. Military Reserve Officer serving with the 100 Support Command, 100 Troop Command, 40 Infantry Division, CA National Guard.",institutionString:null,institution:{name:"Loma Linda University",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"6925",title:"Endoplasmic Reticulum",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6925.jpg",slug:"endoplasmic-reticulum",publishedDate:"April 17th 2019",editedByType:"Edited by",bookSignature:"Angel Català",hash:"a9e90d2dbdbc46128dfe7dac9f87c6b4",volumeInSeries:2,fullTitle:"Endoplasmic Reticulum",editors:[{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",profilePictureURL:"https://mts.intechopen.com/storage/users/196544/images/system/196544.jpg",biography:"Angel Catalá studied chemistry at Universidad Nacional de La Plata, Argentina, where he received a Ph.D. in Chemistry (Biological Branch) in 1965. From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}}]},{type:"book",id:"6924",title:"Adenosine Triphosphate in Health and Disease",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6924.jpg",slug:"adenosine-triphosphate-in-health-and-disease",publishedDate:"April 24th 2019",editedByType:"Edited by",bookSignature:"Gyula Mozsik",hash:"04106c232a3c68fec07ba7cf00d2522d",volumeInSeries:3,fullTitle:"Adenosine Triphosphate in Health and Disease",editors:[{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. Fifteen of his students have been appointed as full professors in Egypt, Cuba, and Hungary.",institutionString:"University of Pécs",institution:{name:"University of Pecs",institutionURL:null,country:{name:"Hungary"}}}]},{type:"book",id:"8008",title:"Antioxidants",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/8008.jpg",slug:"antioxidants",publishedDate:"November 6th 2019",editedByType:"Edited by",bookSignature:"Emad Shalaby",hash:"76361b4061e830906267933c1c670027",volumeInSeries:5,fullTitle:"Antioxidants",editors:[{id:"63600",title:"Prof.",name:"Emad",middleName:null,surname:"Shalaby",slug:"emad-shalaby",fullName:"Emad Shalaby",profilePictureURL:"https://mts.intechopen.com/storage/users/63600/images/system/63600.png",biography:"Dr. Emad Shalaby is a professor of biochemistry on the Biochemistry Department Faculty of Agriculture, Cairo University. He\nreceived a short-term scholarship to carry out his post-doctoral\nstudies abroad, from Japan International Cooperation Agency\n(JICA), in coordination with the Egyptian government. Dr.\nShalaby speaks fluent English and his native Arabic. He has 77\ninternationally published research papers, has attended 15 international conferences, and has contributed to 18 international books and chapters.\nDr. Shalaby works as a reviewer on over one hundred international journals and is\non the editorial board of more than twenty-five international journals. He is a member of seven international specialized scientific societies, besides his local one, and\nhe has won seven prizes.",institutionString:"Cairo University",institution:{name:"Cairo University",institutionURL:null,country:{name:"Egypt"}}}]}]},openForSubmissionBooks:{},onlineFirstChapters:{},subseriesFiltersForOFChapters:[],publishedBooks:{},subseriesFiltersForPublishedBooks:[],publicationYearFilters:[],authors:{paginationCount:617,paginationItems:[{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/158492/images/system/158492.jpeg",biography:"Prof. Dr. Yusuf Tutar conducts his research at the Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, Turkey. He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNVJQA4/Profile_Picture_2022-03-07T13:23:04.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Associate Prof.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/15648_n.jpg",biography:"Dr. Mohd Aftab Siddiqui is currently working as Assistant Professor in the Faculty of Pharmacy, Integral University, Lucknow for the last 6 years. He has completed his Doctor in Philosophy (Pharmacology) in 2020 from Integral University, Lucknow. He completed his Bachelor in Pharmacy in 2013 and Master in Pharmacy (Pharmacology) in 2015 from Integral University, Lucknow. He is the gold medalist in Bachelor and Master degree. He qualified GPAT -2013, GPAT -2014, and GPAT 2015. His area of research is Pharmacological screening of herbal drugs/ natural products in liver and cardiac diseases. He has guided many M. Pharm. research projects. He has many national and international publications.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. degree from Integral University. Currently, he’s working as an Assistant Professor of Pharmaceutics in the Faculty of Pharmacy, Integral University. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than 32 original articles published in reputed journals, 3 edited books, 5 book chapters, and a number of scientific articles published in ‘Ingredients South Asia Magazine’ and ‘QualPharma Magazine’. He is a member of the American Association for Cancer Research, International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs that aim to provide practical solutions to current healthcare problems.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}},{id:"297507",title:"Dr.",name:"Charles",middleName:"Elias",surname:"Assmann",slug:"charles-assmann",fullName:"Charles Assmann",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297507/images/system/297507.jpg",biography:"Charles Elias Assmann is a biologist from Federal University of Santa Maria (UFSM, Brazil), who spent some time abroad at the Ludwig-Maximilians-Universität München (LMU, Germany). He has Masters Degree in Biochemistry (UFSM), and is currently a PhD student at Biochemistry at the Department of Biochemistry and Molecular Biology of the UFSM. His areas of expertise include: Biochemistry, Molecular Biology, Enzymology, Genetics and Toxicology. He is currently working on the following subjects: Aluminium toxicity, Neuroinflammation, Oxidative stress and Purinergic system. Since 2011 he has presented more than 80 abstracts in scientific proceedings of national and international meetings. Since 2014, he has published more than 20 peer reviewed papers (including 4 reviews, 3 in Portuguese) and 2 book chapters. He has also been a reviewer of international journals and ad hoc reviewer of scientific committees from Brazilian Universities.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",country:{name:"Brazil"}}},{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",biography:"Dr. Margarete Dulce Bagatini is an associate professor at the Federal University of Fronteira Sul/Brazil. She has a degree in Pharmacy and a PhD in Biological Sciences: Toxicological Biochemistry. She is a member of the UFFS Research Advisory Committee\nand a member of the Biovitta Research Institute. She is currently:\nthe leader of the research group: Biological and Clinical Studies\nin Human Pathologies, professor of postgraduate program in\nBiochemistry at UFSC and postgraduate program in Science and Food Technology at\nUFFS. She has experience in the area of pharmacy and clinical analysis, acting mainly\non the following topics: oxidative stress, the purinergic system and human pathologies, being a reviewer of several international journals and books.",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",country:{name:"Brazil"}}},{id:"226275",title:"Ph.D.",name:"Metin",middleName:null,surname:"Budak",slug:"metin-budak",fullName:"Metin Budak",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226275/images/system/226275.jfif",biography:"Metin Budak, MSc, PhD is an Assistant Professor at Trakya University, Faculty of Medicine. He has been Head of the Molecular Research Lab at Prof. Mirko Tos Ear and Hearing Research Center since 2018. His specializations are biophysics, epigenetics, genetics, and methylation mechanisms. He has published around 25 peer-reviewed papers, 2 book chapters, and 28 abstracts. He is a member of the Clinical Research Ethics Committee and Quantification and Consideration Committee of Medicine Faculty. His research area is the role of methylation during gene transcription, chromatin packages DNA within the cell and DNA repair, replication, recombination, and gene transcription. His research focuses on how the cell overcomes chromatin structure and methylation to allow access to the underlying DNA and enable normal cellular function.",institutionString:"Trakya University",institution:{name:"Trakya University",country:{name:"Turkey"}}},{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",biography:"Anca Pantea Stoian is a specialist in diabetes, nutrition, and metabolic diseases as well as health food hygiene. She also has competency in general ultrasonography.\n\nShe is an associate professor in the Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. She has been chief of the Hygiene Department, Faculty of Dentistry, at the same university since 2019. Her interests include micro and macrovascular complications in diabetes and new therapies. Her research activities focus on nutritional intervention in chronic pathology, as well as cardio-renal-metabolic risk assessment, and diabetes in cancer. She is currently engaged in developing new therapies and technological tools for screening, prevention, and patient education in diabetes. \n\nShe is a member of the European Association for the Study of Diabetes, Cardiometabolic Academy, CEDA, Romanian Society of Diabetes, Nutrition and Metabolic Diseases, Romanian Diabetes Federation, and Association for Renal Metabolic and Nutrition studies. She has authored or co-authored 160 papers in national and international peer-reviewed journals.",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",country:{name:"Romania"}}},{id:"279792",title:"Dr.",name:"João",middleName:null,surname:"Cotas",slug:"joao-cotas",fullName:"João Cotas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279792/images/system/279792.jpg",biography:"Graduate and master in Biology from the University of Coimbra.\n\nI am a research fellow at the Macroalgae Laboratory Unit, in the MARE-UC – Marine and Environmental Sciences Centre of the University of Coimbra. My principal function is the collection, extraction and purification of macroalgae compounds, chemical and bioactive characterization of the compounds and algae extracts and development of new methodologies in marine biotechnology area. \nI am associated in two projects: one consists on discovery of natural compounds for oncobiology. The other project is the about the natural compounds/products for agricultural area.\n\nPublications:\nCotas, J.; Figueirinha, A.; Pereira, L.; Batista, T. 2018. An analysis of the effects of salinity on Fucus ceranoides (Ochrophyta, Phaeophyceae), in the Mondego River (Portugal). Journal of Oceanology and Limnology. in press. DOI: 10.1007/s00343-019-8111-3",institutionString:"Faculty of Sciences and Technology of University of Coimbra",institution:null},{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279788/images/system/279788.jpg",biography:"Leonel Pereira has an undergraduate degree in Biology, a Ph.D. in Biology (specialty in Cell Biology), and a Habilitation degree in Biosciences (specialization in Biotechnology) from the Faculty of Science and Technology, University of Coimbra, Portugal, where he is currently a professor. In addition to teaching at this university, he is an integrated researcher at the Marine and Environmental Sciences Center (MARE), Portugal. His interests include marine biodiversity (algae), marine biotechnology (algae bioactive compounds), and marine ecology (environmental assessment). Since 2008, he has been the author and editor of the electronic publication MACOI – Portuguese Seaweeds Website (www.seaweeds.uc.pt). He is also a member of the editorial boards of several scientific journals. Dr. Pereira has edited or authored more than 20 books, 100 journal articles, and 45 book chapters. He has given more than 100 lectures and oral communications at various national and international scientific events. He is the coordinator of several national and international research projects. In 1998, he received the Francisco de Holanda Award (Honorable Mention) and, more recently, the Mar Rei D. Carlos award (18th edition). He is also a winner of the 2016 CHOICE Award for an outstanding academic title for his book Edible Seaweeds of the World. In 2020, Dr. Pereira received an Honorable Mention for the Impact of International Publications from the Web of Science",institutionString:"University of Coimbra",institution:{name:"University of Coimbra",country:{name:"Portugal"}}},{id:"61946",title:"Dr.",name:"Carol",middleName:null,surname:"Bernstein",slug:"carol-bernstein",fullName:"Carol Bernstein",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61946/images/system/61946.jpg",biography:"Carol Bernstein received her PhD in Genetics from the University of California (Davis). She was a faculty member at the University of Arizona College of Medicine for 43 years, retiring in 2011. Her research interests focus on DNA damage and its underlying role in sex, aging and in the early steps of initiation and progression to cancer. In her research, she had used organisms including bacteriophage T4, Neurospora crassa, Schizosaccharomyces pombe and mice, as well as human cells and tissues. She authored or co-authored more than 140 scientific publications, including articles in major peer reviewed journals, book chapters, invited reviews and one book.",institutionString:"University of Arizona",institution:{name:"University of Arizona",country:{name:"United States of America"}}},{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",slug:"ademar-serra",fullName:"Ademar Serra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/182258/images/system/182258.jpeg",biography:"Dr. Serra studied Agronomy on Universidade Federal de Mato Grosso do Sul (UFMS) (2005). He received master degree in Agronomy, Crop Science (Soil fertility and plant nutrition) (2007) by Universidade Federal da Grande Dourados (UFGD), and PhD in agronomy (Soil fertility and plant nutrition) (2011) from Universidade Federal da Grande Dourados / Escola Superior de Agricultura Luiz de Queiroz (UFGD/ESALQ-USP). Dr. Serra is currently working at Brazilian Agricultural Research Corporation (EMBRAPA). His research focus is on mineral nutrition of plants, crop science and soil science. Dr. Serra\\'s current projects are soil organic matter, soil phosphorus fractions, compositional nutrient diagnosis (CND) and isometric log ratio (ilr) transformation in compositional data analysis.",institutionString:"Brazilian Agricultural Research Corporation",institution:{name:"Brazilian Agricultural Research Corporation",country:{name:"Brazil"}}}]}},subseries:{item:{id:"12",type:"subseries",title:"Human Physiology",keywords:"Anatomy, Cells, Organs, Systems, Homeostasis, Functions",scope:"Human physiology is the scientific exploration of the various functions (physical, biochemical, and mechanical properties) of humans, their organs, and their constituent cells. The endocrine and nervous systems play important roles in maintaining homeostasis in the human body. Integration, which is the biological basis of physiology, is achieved through communication between the many overlapping functions of the human body's systems, which takes place through electrical and chemical means. Much of the basis of our knowledge of human physiology has been provided by animal experiments. Because of the close relationship between structure and function, studies in human physiology and anatomy seek to understand the mechanisms that help the human body function. The series on human physiology deals with the various mechanisms of interaction between the various organs, nerves, and cells in the human body.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/12.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11408,editor:{id:"195829",title:"Prof.",name:"Kunihiro",middleName:null,surname:"Sakuma",slug:"kunihiro-sakuma",fullName:"Kunihiro Sakuma",profilePictureURL:"https://mts.intechopen.com/storage/users/195829/images/system/195829.jpg",biography:"Professor Kunihiro Sakuma, Ph.D., currently works in the Institute for Liberal Arts at the Tokyo Institute of Technology. He is a physiologist working in the field of skeletal muscle. He was awarded his sports science diploma in 1995 by the University of Tsukuba and began his scientific work at the Department of Physiology, Aichi Human Service Center, focusing on the molecular mechanism of congenital muscular dystrophy and normal muscle regeneration. His interest later turned to the molecular mechanism and attenuating strategy of sarcopenia (age-related muscle atrophy). His opinion is to attenuate sarcopenia by improving autophagic defects using nutrient- and pharmaceutical-based treatments.",institutionString:null,institution:{name:"Tokyo Institute of Technology",institutionURL:null,country:{name:"Japan"}}},editorTwo:null,editorThree:{id:"331519",title:"Dr.",name:"Kotomi",middleName:null,surname:"Sakai",slug:"kotomi-sakai",fullName:"Kotomi Sakai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000031QtFXQA0/Profile_Picture_1637053227318",biography:"Senior researcher Kotomi Sakai, Ph.D., MPH, works at the Research Organization of Science and Technology in Ritsumeikan University. She is a researcher in the geriatric rehabilitation and public health field. She received Ph.D. from Nihon University and MPH from St.Luke’s International University. Her main research interest is sarcopenia in older adults, especially its association with nutritional status. Additionally, to understand how to maintain and improve physical function in older adults, to conduct studies about the mechanism of sarcopenia and determine when possible interventions are needed.",institutionString:null,institution:{name:"Ritsumeikan University",institutionURL:null,country:{name:"Japan"}}},series:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261"},editorialBoard:[{id:"213786",title:"Dr.",name:"Henrique P.",middleName:null,surname:"Neiva",slug:"henrique-p.-neiva",fullName:"Henrique P. Neiva",profilePictureURL:"https://mts.intechopen.com/storage/users/213786/images/system/213786.png",institutionString:null,institution:{name:"University of Beira Interior",institutionURL:null,country:{name:"Portugal"}}},{id:"39275",title:"Prof.",name:"Herbert Ryan",middleName:null,surname:"Marini",slug:"herbert-ryan-marini",fullName:"Herbert Ryan Marini",profilePictureURL:"https://mts.intechopen.com/storage/users/39275/images/9459_n.jpg",institutionString:null,institution:{name:"University of Messina",institutionURL:null,country:{name:"Italy"}}},{id:"196218",title:"Dr.",name:"Pasquale",middleName:null,surname:"Cianci",slug:"pasquale-cianci",fullName:"Pasquale Cianci",profilePictureURL:"https://mts.intechopen.com/storage/users/196218/images/system/196218.png",institutionString:null,institution:{name:"University of Foggia",institutionURL:null,country:{name:"Italy"}}}]},onlineFirstChapters:{},publishedBooks:{},testimonialsList:[{id:"18",text:"It was great publishing with IntechOpen, the process was straightforward and I had support all along.",author:{id:"71579",name:"Berend",surname:"Olivier",institutionString:"Utrecht University",profilePictureURL:"https://mts.intechopen.com/storage/users/71579/images/system/71579.png",slug:"berend-olivier",institution:{id:"253",name:"Utrecht University",country:{id:null,name:"Netherlands"}}}},{id:"27",text:"The opportunity to work with a prestigious publisher allows for the possibility to collaborate with more research groups interested in animal nutrition, leading to the development of new feeding strategies and food valuation while being more sustainable with the environment, allowing more readers to learn about the subject.",author:{id:"175967",name:"Manuel",surname:"Gonzalez Ronquillo",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",slug:"manuel-gonzalez-ronquillo",institution:{id:"6221",name:"Universidad Autónoma del Estado de México",country:{id:null,name:"Mexico"}}}},{id:"8",text:"I work with IntechOpen for a number of reasons: their professionalism, their mission in support of Open Access publishing, and the quality of their peer-reviewed publications, but also because they believe in equality.",author:{id:"202192",name:"Catrin",surname:"Rutland",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",slug:"catrin-rutland",institution:{id:"134",name:"University of Nottingham",country:{id:null,name:"United Kingdom"}}}}]},submityourwork:{pteSeriesList:[],lsSeriesList:[],hsSeriesList:[],sshSeriesList:[],subseriesList:[],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:null},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"ofsBook.detail",path:"/welcome/0400d540d2b8fb55d4cc8590e1e58844",hash:"",query:{},params:{hash:"0400d540d2b8fb55d4cc8590e1e58844"},fullPath:"/welcome/0400d540d2b8fb55d4cc8590e1e58844",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()