Genetic and physical testing used in genetic programs of common dog breeds.
\r\n\tThis volume presents the multifaceted aspects and should allow readers at all levels an entry into the exiting world of Chlamydomonas research.
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Diabetus mellitus (DM) is an important public health issue, with a constantly growing prevalence from 4.7% in 1980 to 8.5% in 2014 [1]. In 2019, 463 million adults between 20 and 79 years had DM [2]. Diabetic retinopathy (DR) is one of the most frequent microvascular complications of diabetes. Most type 1 DM (T1DM) patients develop DR only after 5 years or even more from the onset of DM, but after 20- year history of disease, 99% present a form of DR [3]. On the contrary, for type 2 DM (T2DM) patients, DR may be present even from the diagnosis, while after 20 years of T2DM, 60% of the patients develop DR [3]. Currently, DR staging is performed depending on the presence of clinical ocular biomarkers, such as microaneurysms, hemorrhages, soft or hard exudates, macular oedema and new vessels. The treatment for DR targets especially the severe non-proliferative diabetic retinopathy (NPDR) or proliferative diabetic retinopathy (PDR) stage and diabetic macular oedema (DME). The therapeutic options are intravitreal injections with anti-VEGF agents, corticosteroids injections, retinal laser or surgery such as pars plana vitrectomy (PPV). A large body of evidence supports the role of inflammation in the development and progression of DR. There is evidence that low-grade subclinical inflammation is responsible for many of the characteristic vascular lesions of DR [4]. In this review we provide an overview of several local inflammatory biomarkers of DR laboratory and retinal imaging together with anti-inflammatory therapeutic options.
Inflammation is defined as the body’s mechanism of self-defense against pathogens. In this complex process, mediators such as pro-inflammatory cytokines, chemokines and adhesion molecules are involved. They initiate the interaction between the endothelium and leukocytes and consequently induce the migration of leukocytes towards the injured or infected tissue [5]. Although acute inflammation is considered beneficial, a chronic and dysregulated one produces harmful effects, being known to be involved in diseases such as rheumatoid arthritis, multiple sclerosis and atherosclerosis [5].
Lutty et al. were the first who reported an increased neutrophil number per square millimeter in both retinal and choroidal vessels in DR patients [6]. Moreover, they continued the study of neutrophils in diabetic monkeys and found an association between the accumulation of neutrophils and capillary closure [7]. Further studies found evidence that capillary occlusion and intraretinal neovascularization are associated with the attachment of neutrophils and monocytes [8], while the level of leukocytes adherence to the retinal vasculature, known as leukostasis, is associated with the progression of DR [9]. Recent findings implicate that an increase of ICAM-1 and integrins at the level of endothelial cells and leukocytes is responsible for the increase in leukostasis, while ICAM-1 blocking and CD18 deletion decreases the leukostasis induced by DM [10, 11]. Microglial cell is a resident macrophage distributed throughout the retina, which releases inflammatory cytokines such as TNF-α after being activated [12].
There are several processes in DR pathogenesis in which inflammation is involved:
vessel leakage: retinal endothelial permeability is induced by TNF-α, but is successfully prevented by PKCζ inhibitor [13]. After TNF-α was blocked with Etanercept, a soluble TNF-α receptor, the activation of NF-κB was inhibited and blood retinal barrier (BRB) breakdown was prevented [14]. Similarly, VEGF is directly involved in the breakdown of inner BRB, being proved that after blocking ICAM-1, the leukostasis is reduced but also VEGF induced vascular leakage is blocked [15].
vessel closure: IL-1β and TNF-α increase caspase 3 activity and induce endothelial cell apoptosis [16, 17].
pathological neovascularization: New vessels’ formation is induced by leukocytes by interfering in the releasing of pro-angiogenic factors, such as VEGF, angiopoietin 1, basic fibroblast growth factor, transforming growth factor and platelet derived factor. All these agents promote recruitment of endothelial progenitor cells and enhance the migration, proliferation and survival of the pre-existing endothelial cells [17].
retinal neuronal death: TNF-α, IL-1β, reactive oxygen species (ROS) and excessive nitric oxide (NO) released by leukocytes during inflammation are involved in retinal neuronal cell death [5].
DM causes increased systemic and local production of numerous inflammatory molecules involved in DR onset and development.
A biomarker has been defined as “a biological molecule found in blood, or other bodily fluids, or tissue which represents a sign of a normal or abnormal process of a condition or disease” [18]. Due to the rapid advancement in engineering, methodology and equipment, researchers are able to generate large amounts of data analyzing only small amounts of samples, using mass spectrometry techniques. In DR studies, several kinds of samples were used, such as tear, cornea, aqueous humor (AH), lens, vitreous humor (VH), retina and serum [19]. Although VH is in direct contact with the retina, it requires a highly invasive procedure, whereas the tears can be collected using non-invasive methods but interact indirectly with the retina [19].
The tears are composed of an aqueous solution of water, lipids, proteins and salt. The major proteins are lactoferrin, lysozyme, serum albumin, secretory immunoglobin A, lipocalin and lipophilin [20]. One study identified 1526 proteins using protemics approaches, most of them being shown to respond to insults such as cataract surgery or diseases like DM [21, 22]. Mainly because it contains proteins in high concentration (about 8 μg/μl) and it is easy to collect, tears have been a fluid of interest for many studies [21]. Herber et al. was one of the first to demonstrate that DM patients’ tear composition is different from control subjects [23]. Azzaralo et al. found increased levels of lactotransferin, also known as lactoferrin, a glycoprotein with immunomodulatory, anti-microbial and anti-tumor effects [24]. Increased levels of monocyte chemoattractant protein-1 (MCP-1) were also identified in DM with or without DR. A previous study demonstrated elevated Interleukin-1 receptor anatagonist (IL-1ra) levels, which represent an anti-inflammatory factor inhibiting pro-inflammatory activity of IL-1beta [25]. A positive correlation between IL-6 levels and DR stage was found. IL-6 is involved in synthesis and the release of acute phase reactants and matrix metalloproteinase 9 (MMP-9), decreased tear production, having also a role in the release of IL-1β [26]. TNF-α is a cytokine able to induce the disruption of BRB by loosening the tight junctions between endothelial cells and between RPE cells, with a role in the leukocytes adhesion to the endothelium [13]. TNF-α level was increased in patients with PDR (13.5 pg./mL) compared to NPDR (2.8 pg./mL) [27]. The tear sample can be obtained using two techniques: the direct one using aspiration with the help of a micropipette or a microcapillary tube placed in the inferior fornix, or the indirect one, with the help of a Schirmer test strip or cellulose sponge.
Aqueous humor (AH) is produced by the ciliary body epithelium and represents the fluid in the anterior chamber of the eye. It is involved in the removal of metabolic wastes, in ocular immunity, it supplies oxygen and nutrients, and has a role in refraction. AH is composed of water, electrolytes and proteins, which although are present in relatively low concentrations compared to blood serum, are vital in the maintenance of anterior segment homeostasis. AH is not in direct contact with the retina but proteins released from it can enter AH either through disrupted BRB, cilio-retinal circulation or through diffusion from the VH and the VH-AH barrier [28]. Proteomic analysis studying AH from patients with DR compared to subjects without DM, found several proteins associated with PDR like apolipoprotein A-I (APOA1), apolipoprotein A-II (APOA2), apolipoprotein A-IV (APOA4), and α-1-acid glycoprotein 1 (ORM1) [29] as well as selenoprotein P (SELENOP), and cystathionine β-synthase (CBS) [28].
IL-23 levels were increased in PDR patients, and IL-17 was also higher in NPDR and PDR compared to control subjects as shown by Wang et al. in 625 patients with T2DM [30]. IL-17 is a powerful pro-inflammatory cytokine capable of mobilizing neutrophils and inducing the secretion of IL-6 and IL-8 prostagladin E2 [30]. Regarding IL-23, it stimulates Th17 cells to secrete IL-17, which further increases the cycle of inflammation.
Concerning IL-10, the cytokine with immunosuppresive properties, capable of attenuating the antigen-presenting ability of APC, studies found contradictory results: decreased concentrations in DR compared to NPDR by Cheung et al. and Zhang et al., contrary to Hu et al. who reported increased levels [30]. It was also suggested that IL-10 levels could be correlated with central subfield thickness (CST), one study reporting higher IL-10 concentration in PDR (224,79 pg./mL) that in the control group (160/14 pg./mL) [31]. TGF-beta is involved in the differentiation of activated CD4+Th0 cells into Treg cells, but it is also involved in promoting differentiation of CD4+Th0 cells into Th17 cells in combination with IL-23 [32]. Zhang et al. found elevated and stable TGF-beta levels in DM compared to control [30].
Myonectin inhibits the inflammatory response triggered by lipopolysaccharide in macrophages and in myonectin-knockout mices, in which the proinflammatory gene expression was identified. Previous studies demonstrated decreased myonectin concentrations in AH belonging to T2DM especially with PDR but also in NPDR compared to control subjects [33, 34]. In refractory DME, IL-2, IL-8, PIGF and VEGF were found elevated but only IL-8 was correlated with responsiveness, exhibiting higher levels in the refractory group [31]. This result is supported by Jeon et al., who observed that after injecting triamcinolone intravitreally to patients unresponsive to IVB, the effect was positive while the efficacy was associated with IL-8 levels in the AH [35].
IL-6, another proinflammatory cytokine was found elevated in PDR and DME patients. Additionally, it induces VEGF expression, being involved in the breakdown of BRB and thus being involved in the pathogenesis of earlier stages of NPDR [36]. IL-6 is considered as a driving force because it changes the overall cytokine profile in the AH of DM patients. Moreover, the level of VEGF in AH was strongly correlated with VEGF level from the VH [37].
IFN-α is a known angiogenic inhibitor, with a protective role against retinal damage in diabetes. Cheung et al. found reduced IFN-α levels in DM patients compared to control subjects [38].
MCP-1 level in AH is believed to be a predictor for a worse visual acuity outcome of PDR patients after vitrectomy, while there was no significant correlation between VEGF levels and BCVA, as noted by Lei et al. [39]. MCP-1 stimulates the recruitment and activation of monocytes and macrophages which further leads to higher microvascular permeability or ischemia from vessel occlusions. A few studies have investigated the effect of intravitreal triamcinolone [40] or dexamethasone implant [41] on the intraocular inflammatory cytokines and concluded that both drugs could significantly decrease the level of MCP-1 in the AH.
Samples from AH are collected through a paracenthesis from patients undergoing cataract surgery, trabeculectomy or from post-mortem eyes. The volume collected ranges from 100 to 150 μL. The samples from living patients are more useful since the profile from post-mortem eye is different due to the accumulation of metabolic waste [26].
The vitreous humor is the gelatinous component of the posterior segment of the eye that gives its spherical shape. In addition to its role in structural support, the transparent nature of the vitreous body aids in light transmission to the retina. Because of its avascular nature, much of the proteins found in VH are derived from the retina itself [28]. Several proteins in the VH have been identified as biomarkers for different stages of DR, like components of the acute phase response, coagulation pathway, complement system and other inflammatory pathways (e.g., VEGF, amyloid-β A4 protein, metalloproteinase inhibitor 1, kininogen-1) [19].
Pigment epithelium-derived factor (PEDF) is a negative regulator of inflammatory processes, with lower levels in VH from DR patients compared to NDR. This finding suggest that beside an increase in proinflammatory cytokines, there is also a decrease in the anti-inflammatory ones [42]. Clusterin, a protein involved in the regulation of complement cascade, was found decreased in DR patients [43]. One of its function consists in an anti-inflammatory protection for the BRB [44]. Kallikrein, a known central component of pro-inflammatory kallikrein-kinin system, was found elevated in the VH from DR patients [45].
Anti-VEGF agents such as bevacizumab did not have a significant effect on VH inflammatory proteins as shown by Loukovaara et al. [46], as opposed to Zou et al. who studied VH proteome from patients treated with anti-VEGF agent ranibizumab and found decreased VEGF levels as well as a decrease in complement activation protein, acute inflammatory response and platelet degranulation [47]. Similarly, photocoagulation reduced the levels of pro-inflammatory protein osteopontin (SPP1), as shown by Wei et al. [48].
When exposed to intravitreal injection of IL-1β, retinal capillary endothelial cells degenerate [49], while co-administration of IL-1β, together with high concentrations of glucose, disrupt the RPE cells [50]. Increased levels of IL-1β were found in the VH collected from diabetic patients compared to control [51], underlining its role it the DR-related inflammatory processes.
IL-8, responsible for activating neutrophils and T Lymphocytes, together with IL-6, a chemokine responsible for increased endothelial cell permeability by rearranging actin filaments and changing the shape of endothelial cells, were both found elevated in VH of PDR patients [52]. Their origin does not seem to be the serum, since higher levels were found in the vitreous, suggesting that macrophages, RPE cells, glial cells or monocytes from the vitreous of PDR patients, could produce citokines [53]. IL-10, another anti-inflammatory cytokine, with the ability of deactivating macrophages, was not found to be increased in PDR patients, the author of the study suggesting the lack of a counter balanced by the anti-inflammatory cytokines [54].
MCP-1, with its known role in promoting leukocyte recruitment and inducer of angiogenesis and fibrosis, was found elevated in DR VH, with levels being higher than in the serum [55]. Hyperglycemia seems to increase the formation of MCP-1 from RPE cells, retinal vascular endothelial cells and Muller’s cells [56]. This finding further encouraged that MCP-1 gene polymorphism to be proposed as a potential risk factor for DR [57].
Stromal cell-derived factor-1 (SDF-1) is upregulated in damaged tissues and as a response, it mobilizes progenitor cells to promote repair [58]. Together with VEGF, it promotes endothelial progenitor cells from the bone marrow to the ischemic retina [59]. Butler et al. found increased SDF-1 concentrations in VH from DME or PDR patients, and moreover the increase was correlated with disease severity [60].
Extracellular High-Mobility Group Box-1 Protein (HMGB1) as a proinflammatory cytokine, leads to overexpression of TNF-α, MCP-1, ICAM-1, through activation of NF-β [61]. In addition, El-Asrar reported elevated levels of HMGB1 in VH belonging to PDR patients. They further reported that HMGB1 and its receptor for advanced glycation products (RAGE) are expressed by vascular endothelial cells and stromal cells in PDR fibrovascular epiretinal membranes [61].
Tumor Necrosis Factor-
ICAM-1 levels in PDR were found increased, especially in active PDR compared to inactive PDR [61]. ICAM-1 was highly expressed in retinal and choroidal blood vessels, as well as in fibrovascular membranes, and its expression seems to correlate with the number of migrated neutrophils in the retina and choroid [6]. When ICAM-1 blocking was obtained, the leukostasis, endothelial cell death and also the vascular leakage in the retinal vessels was diminished.
When retinal capillary endothelial cells were exposed to high concentration of glucose, TNF-α or IL-1β, they produce the membrane-bound form of vascular adhesion protein-1(VAP1) and release the soluble vascular adhesion protein 1 (sVAP-1) [63]. Its role consists in leukostasis and leukocyte entrapment. High levels of sVAP-1 were found in the serum and VH of patients with PDR [64].
Samples from VH are collected through vitreous taps from patients that underwent PPV or after intravitreal injections. Simo et al. raised the problem of confounding factors that could lead to misinterpretation of result. Vitreous hemorrhage could induce a massive influx of serum proteins. Similarly, the disruption of BRB also leads to increased protein levels in VH. The first problem could be solved by rejecting samples with hemoglobin >5 mg/mL, while the second one, by correcting the intravitreal concentration of peptide under study for total vitreal proteins or calculating the vitreous/plasma ratio [56].
These lesions are found under the name of hyperreflective foci, dots or spots. Hyperreflective retinal foci (HRF) have been first described in wet AMD but they were also noted in retinal vein occlusion, MacTel type 2, central serous retinopathy, retinitis pigmentosa, Stargardt disease and Best disease. Different pathogenetic origins were hypothesized: initially they were considered precursor of hard exudates or lipid-laden macrophages [65], representing subclinical features of lipoprotein extravasation that were not observed on clinical examination, fundus photography, or fluorescein angiography, due to their small size [66]. In contrast to the previous studies, Lee et al. proposed that HRF represent activated microglial cells since they determined the presence of increased soluble CD14 in the AH. Soluble CD14 seems to be released by activated microglial cells [67, 68]. Other theories assumed that HRF represent debris of photoreceptors or RPE hyperplasia [65, 66].
HRF are initially present in the inner retinal layers, where resting retinal microglia are normally located and after they are activated, they subsequently migrate to the outer retinal layers [66, 69]. Another argument that HRF are in fact microglia is that both are primarily found in the inner retina in DR without edema and show an extended distribution into the outer retina in DME [68]. By contrast, Bolz et al. described that HRF are distributed throughout all retinal layers in eyes with different types of diabetic macular edema (DME), diffuse or cystoid [70]. Uji et al. reported the presence of HRF in the outer retina in 53.7% cases while in the inner retina in 99.1% cases in eyes with DME [71]. Uji et al. further suggested an origin from degenerated photoreceptors or macrophages engulfing the former, since HRF were found in the outer retina closely associated with disrupted external limiting membrane or IS/OS line [71].
HRF appears on OCT as small discrete, well-circumscribed, dot-shaped hyperreflective intraretinal lesions (Figure 1) [69]. Their size is less than 30 μm, and as opposed to hard exudates they do not induce back-shadowing, while their reflectivity is similar to retinal nerve fiber layer and equal or greater than the retinal pigment epithelium (RPE) band [67, 72].
Spectral domain OCT linear scan in the macula of a diabetic patient with PDR. The yellow arrows indicate HRF while red arrows indicate hard exudates.
As opposed to HRF, hard exudates are thought to form from microaneurysms, which is the major source of leakage in focal edema [68]. Other theories even suggested that HRF can occur even before DR development, representing a neurodegenerative process [69]. Both the presence and number of HRF was increased in diabetics versus control subjects, especially in those with signs of DR, but interestingly, none of the patients had signs of DME, hard exudates nor subclinical signs of DME on OCT examinations [68].
The size and also the number of HRF seem to decrease after treatment with anti-VEGF or corticosteroids [71]. The decreased microglial activity following anti-VEGF therapy could contribute to the reduced loads of inflammatory cytokines, which further translates into decreased number of HRS and reduced CMT [68]. Moreover, HRS was the first feature to disappear or reduce after anti-VEGF therapy [66]. One study revealed that an initial presence of larger number of HRF responded better to dexamethasone implants than anti-VEGF therapy but a higher number of HRF is associated with early recurrence of DME after steroid implant [67].
One study found that eyes with HRF in the outer retinal layers presented a greater disruption in EZ (IS/OS) lines at baseline but they improved more than the eyes without the foci at 12 months. Taking into account this result, the authors further suggested that greater VA improvement could be partially explained by foveal photoreceptor restoration in eyes with HRF in the outer retinal layers [65].
Hypoalbuminemia lowers the intravascular osmotic pressure and together with increased hydrostatic pressure can cause retention of fluid in the subretinal space. The role of subretinal fluid (SRF) in final visual and anatomical outcomes is still unclear. There is a number of studies which have shown that the presence of SRF is associated with good anatomical and functional gains. Contrary to this, there are other studies which have reported the association between the presence of SRF with poor visual gains [73]. Results from RESTORE study [74] and post hoc analysis from RISE/RIDE study [75] proved the protective role of SRF. These studies revealed the correlation between the presence of baseline SRF with better visual gains at the end of 1 year. These studies also showed a positive impact from SRF in response to ranibizumab therapy. Eyes with SRF seem to have increased IL-6 levels, which signifies active inflammation in these eyes, suggesting that inflammation has an important role in the development of this phenotype of DME [76]. Sonoda et al. found that eyes with subretinal detachment (SRD) presented increased intravitreal levels of IL-6, IL-8 and VEGF [77]. Discontinuation of the external limiting membrane in the SRD type of DME induces cellular damage, which further attracts scavenger cells to the retina, producing IL-6 (Figure 2) [78]. The migration of activated microglia in the outer segments of the retinal layer could support the production of IL-6 and subsequently the accumulation of SRF. The SRD type of DME is associated with an increased number of HRF and significant functional impairment of the macula [78]. The presence of numerous HRF is also associated with poorer glycemic control in patients without significant DME [79]. The levels of ICAM 1 are associated with the height of SRF, indicating that increased vascular permeability by inflammatory mediators results in SRF [80]. An important finding was that DME eyes with SRF respond significantly better to dexamethasone implants and the authors consequently supported the use of dexamethasone implants in patients with DME with SRF [81]. Interestingly, a recent study assessing the change of parameters in DME with SRD after treatment, reported that intravitreal injection of steroid like dexamethasone implant showed greater decrease in number of RHF compared to anti-VEGF agent such as ranibizumab [82].
Spectral domain OCT linear scan in the macula of a diabetic patient with PDR. The small arrow indicates sub-foveal detachment. In the magnified segment of the image, the tall arrows indicate intact external limiting membrane (ELM) while the curly brackets indicate a discontinuous ELM.
The analysis of the choroid could be an important tool in the assessment of progressing DR. Choroidal parameters such as luminal area (LA), stromal area (SA) and total choroidal area (TCA) were found decreased in diabetic patients compared to control by a recent study [83]. Hyperreflective choroidal foci (HCF) is a recently described entity in DR. It is postulated that HCF represent HRF migrated from the retina, into the choroidal layers, which was permitted by ELM and EZ disruption (Figure 3). The hypothesis that HCF are actually migrated HRF, is supported by the study of Roy and al. where all 59 eyes with HCF had HRF as well and there was no eye which had HCF in the absence of HRF on SD-OCT [84]. Presence of HCF could be used as a biomarker of disease severity in eyes with DR [84]. HCF were found to be present significantly more in PDR eyes than NPDR eyes [67].
Spectral domain OCT linear scan in the macula of a diabetic patient with PDR. Right upper image: White-on-black OCT scan. Right lower image: Black-on-white OCT scan. The white arrows head indicate hyperreflective choroidal foci. The white and black arrow highlights a group of hyperreflective retinal foci.
Inner BRB is affected by elevated levels of VEGF leading to increased vascular permeability, which will result in a decreased osmotic gradient, extracellular fluid accumulation, and cyst formation [67]. VEGF is also responsible for the depletion of the occludin in RPE which will further disrupt the tight junction in the outer BRB [85]. Damian and al. found decreased RPE thickness in almost all quadrants in the PDR-DMO group as opposed to NPDR-DMO group, where the quadrants number was lower [86]. This finding was explained by a disruption of the RPE-photoreceptors complex due to ischemia and level of inflammation that varies according to the stage of DR. Cysts larger than >200 μm in the outer nuclear layer (ONL) are seen in advanced stages of DME and may cause irreversible damage to visual functions. Due to their location, they damage photoreceptor cells and disrupt inner segment–outer segment (IS/OS) junction (Figure 4). Regarding their content, there is paucity of information in the literature. Liang and al. hypothesize that fibrin and other inflammatory cells may fill these spaces [87]. Treatment with anti-VEGF therapy leads to a decrease in the number and size of ONL cysts by decreasing the permeability of the inner BRB. This was associated with improvement in BCVA and microperimetric retinal sensitivity. Hyperreflective signals within the cyst are associated with severe disruption of the BRB [67].
Spectral domain OCT linear scan in the macula of a diabetic patient with PDR. The white arrows indicate intraretinal cystoid spaces.
Fundus autofluorescence (FAF) is a rapid, noninvasive imaging technique that may give new insights into the evaluation of DME. Short wavelength FAF derives its signal mainly from lipofuscin in the RPE. Long wavelength autofluorescence or near-infrared (NIR) FAF derives its signal from melanin which is present in RPE and choroid. Melanin accumulates in the apical parts of the RPE cells and is thought to protect the RPE. In DR, local ocular inflammation and oxidative stress lead to increased amount of lipofuscin and decreased amount of lutein and zeaxanthin in the macula. This is responsible for increased FAF signal in subjects with DME. In addition, activation of microglia in DM could cause oxidation of proteins and lipids. Histologic studies have found lipofuscin to accumulate in microglia [67].
Over the years, significant effort has been made to develop new strategies for the treatment of DR by targeting inflammation. Clinical and pre-clinical trials have tested a variety of anti-inflammatory therapeutics.
Intravitreal injection of crystalline cortisone was first reported in 2001 by Jonas et al. [88]. Their mechanism of action consist in repressing pro-inflammatory transcription factors. Several routes of administration were tried but the oral steroids were avoided because of the high risk of DM exacerbation and systemic complications [89]. Tamura et al. found that intravitreal injection of dexamethasone suppresses the leukostasis, the up-regulation of ICAM-1 and also prevents retinal vascular leakage [90]. Since it seems to target different pathways than those targeted by anti-VEGF agents, corticosteroids may improve DME [91]. Especially DME with SRD, no HRF and a continuous ellipsoid zone at the fovea seems to have a better response to injectable dexamethasone implant, as shown by previous studies [92], explained by the increased concentrations of inflammatory cytokines and IL-6 found in the AH and VH of eyes with SRD. In a similar manner, intravitreal triamcinolone has proved to be effective in the resolution of cyst in the CME type of DME [93]. The source of intraretinal cyst is the liquefaction and necrosis of Müller cells which subsequently induces the production of prostaglandins and inflammatory cytokines. The better outcome of steroid might be explained by the reduction of Müller cells’ swelling [94]. One study found better results for intravitreal injection of triamcinolone than with anti-VEGF therapy in reducing macular thickness and improving BCVA in patients with SRD but the authors requested cautious interpretation of the results because of the short follow-up (24 weeks) and the increased risk of associated long-term complications like cataract and elevated intraocular pressure [95].
Their anti-inflammatory activity is characterized by inhibiting the production of the two isoforms of cyclooxygenase enzyme-mediated eicosanoid (COX): COX-1 and COX-2. While COX-1 is involved in homeostatic processes, COX-2 produces pro-inflammatory Prostaglandins (PGE), like PGE2 and PGF2α [96]. In the retina of diabetic animal models, increased expression of COX-2 and PGE2 was found, and it seems that COX-2 has a pivotal role in DR pathogenesis since the inhibition of COX-2 but not COX-1 reduced the levels of PGE2 [97]. Retinal inflammatory reactions such as ICAM-1 expression and leukostasis were blocked after COX-2 inhibition [98]. Aspirin, sodium salicylate and sulfasalazine prevented capillary cell apoptosis and vessel degeneration while COX-2 inhibitors reduced vessel degeneration, vascular leakage and capillary cell apoptosis [99, 100, 101]. Moreover, retinal microaneurysm development was decreased by high doses of aspirin (900 mg/day), as shown by the Early Treatment DR study and the Dipyridamole Aspirin Microangiopathy of Diabetes Study [102, 103]. While COX-2 inhibitors have the potential to increase the incidence of strokes and heart attacks, their use in clinical trial being discouraged [104], local COX-2 inhibitors have shown reduction of DR sigs similar to systemic COX-2 [105].
It is a small-molecule antagonist of leukocyte function-associated antigen (LFA)-1 a cell surface adhesion molecule of the β2 (CD18) family of integrin receptors expressed on leukocytes, and intercellular adhesion molecule (ICAM)-1, expressed by endothelial cells. SAR 1118 inhibits the binding of LFA-1, to ICAM1–1, being capable of preventing leukocytes adhesion to endothelial cells in vivo [106]. Rao et al. found that SAR 1118 eye drops significantly reduced BRB breakdown and leukostasis in a dose dependent manner [106].
Both drugs block TNF-α induced inflammation. High dose of etanercept reduced leukocyte adhesion and suppressed BRB breakdown, reduced ICAM-1 expression but it did not reduced the expression of CD11a, CD11b and CD18, and neither changed the retinal vascular endothelial growth factor levels [14]. After Infliximab administration, BCVA improved and CMT decreased [107]. But caution should be taken since intravitreal use of TNF-α inhibitors has proved to induce intraocular inflammation [56].
Integrin alpha 4 (CD49d), in complex with integrin beta1, forms very late antigen-4 (VLA-4), which interacts with vascular cell adhesion molecule-1, being involved in leukocyte adhesion. Iliaki et al. showed that injection of an anti-alpha 4 integrin/CD49d neutralizing antibody reduced the diabetes induced upregulation of NF- kappaB activation, VEGF, and TNF-alpha protein levels and significantly reduced diabetes-induced leukocyte adhesion and vascular leakage [108].
Another key mediator in inflammation is oxidative stress. Vitamin C attenuated the development of acellular capillaries [109] and vitamin E reversed some changes in the retinal vessels of diabetic patients [110].
The receptor for advanced glycation end products (AGEs) has been implicated in the pathogenesis of diabetic complications. When soluble RAGE, a competitor of cellular RAGE for its ligands was administered, neuronal dysfunction and reduced development of capillary lesions was proved by Barile et al. in mouse diabetic models [111].
NAPDH oxidase activity blocking by apocynin reduces oxidative stress. Previous studies showed that by blocking NADPH oxidase, oxidative stress, retinal inflammation, vessel leakage as well as neovascularization are prevented [5].
The RAS system is involved in different DR pathways, such as oxidative stress and AGEs. Captopril proved to inhibit capillary degeneration in early stages of DR, while Losartan (an AT1R blocker) and Enalapril (angiotensin converting enzyme inhibitor) reduced the progression of DR by 70% and 65% respectively [112]. Retinal adherent leukocyte was significantly suppressed by telmisartan or valsartan [113].
Plasma kallikrein is involved in both VEGF-mediated and VEGF-independent mechanisms of DME. In a Phase 1B study, KVD001, a novel intravitreous plasma kallikrein selective competitive inhibitor was administered in DME eyes [114]. The authors of the previous study reported that KVD001 was safe and well tolerated while a significant number of eyes experienced a reduction of CRT (central retinal thickness) and BCVA improvement. Another recent Phase 2A study evaluated patients who received either a sham, a high dose or a low dose of 4 intravitreal injections of KVD001 at monthly intervals [115]. There were no statistical differences between the number of gained letters, neither regarding the central subfield thickness (CST) nor the diabetic retinopathy severity scale (DRSS) but only 32.5% of patients from the 6 μg dose group experienced a reduction in vision compared to 54.5% of patients from the sham group (p = 0.042) [116]. THR-149 is a reversible peptide inhibitor of plasma kallikrein, by inhibiting the release of bradykinin in the vitreous. Since it is VEGF-independent, anti-VEGF nonresponding patients could benefit from its effect. A Phase 1 study in which 12 patients were followed, proved THR-149 is safe and well tolerated while BCVA improved since day 1 and maintained until month 3 [117].
In accordance with the presented studies, multiple local laboratory and imaging biomarkers are involved in the onset and progression of DR, which could support and improve the screening, treatment and follow-up of these patients.
The encouraging positive effects of several tested drugs on BCVA but also on anatomical outcomes are likely to provide a background for further research.
The authors declare no conflict of interest.
In recent years, genetic studies on dog genomics have multiplied worldwide. Currently, there are over 50 international laboratories which are involved in canine genome projects and several applications will be available in the near future from these studies. These new findings will improve our understanding of the selection process of the dogs and provide useful information for the study and control of genetic diseases.
\nThe single-control characters are influenced by genes located in a locus on one of the pairs of the chromosomes (78 in the dog) and have a binomial distribution. For example, the hair length in dogs is coded by two genes present at an autosomal locus. Short-haired animals have genotype LL (dominant homozygotes), while, long-haired animals have genotype ll (recessive homozygotes). From their mating originates short-haired animals with genotype Ll (heterozygotes), indistinguishable from short-haired parents. Even those characters that express different degrees of dominance, different from the Mendelian inheritance, are considered simple characters (e.g. incomplete or partial dominance). The simple characters are not influenced by the environment and, therefore, to each genotype corresponds a certain phenotype (P = G, where P = phenotype and G = genotype). The study of simple characters includes also multiple alleles (several alleles present in a population), pleitropy, association or linkage and incomplete penetrance. For characters with simple inheritance, it is easier to make selection than for multiple control characters. The multiple control characters are also called quantitative or polygenic characters. These characters are influenced by many genes distributed on several loci and they are influenced by environmental factors. The strong artificial selection exercised by man during the domestication process and during the creation of the different breeds has led to the setting of several characters. Color inheritance illustrates the case of separate loci that control the expression of the phenotype. The coat of dogs consists of two parts: top coat (protective function) and undercoat (heat-insulating function). Some breeds have no undercoat (e.g. Yorkshire). The color of the coat depends on the characteristics of the pigments contained in the medullary and cortical layers of the hair [1]. According to Willis [1], it is possible to explain all the colors by means of two chemical pigments: hemoglobin and melanin. More specifically, melanin is differentiated into eumelanin (black-brown) and pheomelanin (yellow-reddish). The synthesis of pigments in the hair of mammals depends on the interaction between the Agouti protein and the Melanocortin 1 receptor [2]. The coat colors in the dog are linked to the presence/absence of two types of melanin and their possible combinations. It is important to underline that melanin do not show a precise time of formation and they develop during the different phases of the fetal development and after birth [1]. The knowledge of the genetic inheritance of the morphological traits is very important in order to establish suitable selection objectives in the different breeds.
\nMeasurement of F coefficient (consanguinity) in a population can be considered as a measure of the increase in the proportion of homozygous individuals following an inbreeding mating (between relatives) [3]. The coefficient of consanguinity F can be calculated with the following methods: 1) pedigree 2) run of homozigosity (ROH); 3) genomic kinship matrix; 4) SNP genotyping [4, 5]. Inbreeding can occur in small closed populations due to mating between related animals. In a closed population, the decrease in the fraction of heterozygotes from one generation to the next may be referred to as ΔF. This value varies in relation to the size of the population: ΔF = 1 / 2Ne where Ne is the effective number or effective size of the population. In a population, Ne depends on the number of males (Nm), and on the number of females (Nf), in the following relationship:
\nThe inbreeding coefficient, at a given t generation, can be calculated as a function of ΔF and t as:
\nwhich shows the decrease (ΔF) of heterozygotes that occurs at each generation following inbreeding [6]. Lewis
The general actions to be taken in a program for the genetic improvement within a breed should include: 1) genomic identification and characterization of individuals, highlighting their potential in terms of their contribution to maintaining biodiversity, aptitude and use 2) monitoring of demographic parameters and assessment of the risk of reduced genetic variability 3) characterization and evaluation of the intra-breed genetic variability for proper management activities. Modern molecular techniques can be helpful for the improvement of management strategies, even for small breeds and for qualitative traits. The current hypothesis is to add molecular data to classical schemes (assisted selection) to improve their accuracy. The first step in planning an improvement program consists of: 1) a clear definition of the objectives 2) identification of the traits to be recorded 3) evaluation of the gene effect of the characters to be selected 4) estimate of the effect of the environment (epigenetic effect) on the characters to be selected. In \nTable 1\n are reported the genetic and physical testing used in genetic programs of several dog breeds [11].
\nBreed | \nDNA test | \nPhysical test | \n
---|---|---|
\n | \nFanconi | \nEye assessment | \n
\n | \n | Hip score | \n
\n | Progressive Retinal Atrophy | \nThyroid | \n
\n | \n | Heart assessment | \n
\n | Hemolytic anaemia | \n\n |
\n | Pyruvate kinase deficiency | \n\n |
\n | DNA inbreeding coefficient Factor | \n\n |
\n | DNA identification Thyroid | \n\n |
\n | \nNeuronal Ceroid Lipofuscinosis | \nElbow score | \n
\n | Trapped Neutrophil Syndrome | \nHip score | \n
\n | Collie Eye Anomaly | \nEye assessment | \n
\n | Multi-Drug Resistance Gene 1 | \nGeneral vet check | \n
\n | Imerslund-Grasbeck Syndrome | \nChiropractor vet check | \n
\n | Degenerative Myelopathy | \nCollie collaps | \n
\n | Parentage (Orivet) | \nHearing test | \n
\n | Glaucoma | \n\n |
\n | \nDegenerative Myelopathy | \nHip score | \n
\n | Ivermectin Sensitivity | \nElbow score | \n
\n | Long stock coat gene | \n\n |
\n | Canine Renal Dysplasia | \n\n |
\n | Dwarfism | \n\n |
\n | Haemophilia | \n\n |
\n | \n\n | \n |
\n | Ichthyosis | \nHip score | \n
\n | Progressive Retinal Atrophy 1 | \nEye assessment | \n
\n | Progressive Retinal Atrophy 2 | \nHeart assessment | \n
\n | Progressive Rod Cone Degeneration | \nElbow score | \n
\n | \n | Dentition assesment | \n
Genetic and physical testing used in genetic programs of common dog breeds.
In general, genetic diseases result from a mutation in a gene. In most cases, the mutations are traits that follow a simple Mendelian inheritance model (autosomal recessive, autosomal dominant or sex chromosome-linked character). Other hereditary diseases can be more complex and show reduced penetrance or multiple loci (multigenic disease). Genetic disorders can result from new mutations, but in most cases they result from old mutations passed on from one generation to the next. Mutated alleles can persist within a population for many reasons: 1. they can confer particular advantages in the state of heterozygotes; 2. the symptomatological signs can appear late 3. the mutation can be a recessive trait and therefore the defective allele can be spread in the population by healthy carriers. Without a mutation screening program, the carrier status can become evident only after the production of sick offspring.
\nThe canine genome contains approximately 19,000 genes spread over 39 pairs of chromosomes (38 homologous chromosomes and 2 sex chromosomes). To date, nearly 400 hereditary diseases have been recognized in dogs. However, the precise ways in which these diseases are inherited are known for only about a third of them. In most cases, they are linked to autosomal recessive mutations. Bellumori
The candidate gene approach consists in selecting a particular gene considered as the most likely site of a mutation. The main criteria for selecting a gene as a candidate are the following: 1) genes are selected because they are defective in similar animal species (usually humans or mice) 2) genes are selected based on their function. The analysis of the candidate gene consists in sequencing the entire gene and comparing two groups (healthy
The method of linkage analysis is based on completely different assumptions from the candidate gene approach. The main difference is that no assumptions are made about which gene is responsible for the disease, nor, more generally, the chromosomal tract involved. In this method, the whole genome is potentially subjected to analysis, without directing attention to any particular region. The search for the causal mutation takes place through the use of genetic markers whose chromosomal position is known. The more such markers are physically close to the mutation site, the more likely they will be co-inherited together with the mutation from one parental generation to the next. In a very simplified way, linkage analysis evaluates whether any of the variants of the markers appear in the population is associated with the presence of the disease. The ideal markers, and normally used to perform this type of study, are microsatellites, considered as practically ideal genetic markers because they are abundantly scattered throughout the genome and generally highly polymorphic. The number of microsatellites used to perform a linkage analysis is not fixed but generally the higher it is, the higher the probability that the study has success. This assumption derives from the fact that not directing attention towards specific genes and particular chromosomal portion, genome screening it must be as large as possible, i.e. it must contain the highest possible number of markers in order to understand the whole genome (so-called genome-wide screening). Generally, to perform a linkage study within a family tree informative are employed between 200 and 300 microsatellites using pedigrees with at least a hundred animals. For a given area of the genome, the probability of a recombination event occurring between a marker and a disease gene is directly proportional to their distance. The probability of occurrence of this event is expressed as a recombination fraction (θ). If θ is equal to 0.5, the marker and the disease gene are not linked and are therefore independently segregated. In other words, the probability that the marker and gene are inherited, associated or separated is identical. Conversely, if the marker and disease gene are linked together, the θ is less than 0.5. The lod score (Z) is the parameter which is used to estimate the linkage between 2 genetic loci. Z is the logarithm of the ratio between the probability that the 2 loci are linked (θ <0.5) and the probability that the 2 loci are randomly recombined (θ = 0.5). Traditionally the linkage is accepted if the lod score is at least 3. Linkage analysis leads to the identification of a chromosomal region where the locus of the disease is probably located. The analysis must continue with the so-called refinement, that is, a further linkage analysis. Only later, the analysis proceeds through a gene candidate approach. All the genes of the region are identified and a sequence analysis is performed.
\nAnimal mtDNA is a cycular molecule ranging from 14,000 to 26,000 bp. The mtDNA codes for 13 proteins. Mitochondria contain most of the genes that code for cell energy production and electron transfer (NADH deydrogenase subunits, cytochrome oxidase subunits, ATPase 6 and 8, cytochrome b, rRNAr, RNA, 12S and 16S) [14, 15]. The choice of the sequence to be used for the genetic analysis depends on the phylogenetic hypothesis to be tested: D loop, sequences that evolve rapidly; cytocrome b, sequences that evolve moderately; Cytocrome oxidase I, sequences that evolve slowly. The mitochondrial control region (CR) sequence is the most popular marker. The mtDNA is uniparental (maternal line), characterized by a high evolution rate (5–10 times higher than nuclear genes) and the lack of introns and recombinations. The mtDNA is used to clarify the direction of hybridization and the incidence of introgression. In the case of hybridization, erroneous inferences can be obtained only using the evolutionary history of the females. In phylogeographic studies, information from various loci of the nuclear genome are also included [16, 17, 18]. The use of both parents allows a better analysis of the population structure.
\nNuclear microsatellites (one to six in tandem repeated nucleotides) are used in population genetics for the description of the population structure and kinship identification [19]. The reason for the wide use of microsatellites is due to the fact that are co-dominant, multi-allelic, highly reproducible and with a high resolution. The information per locus is about 10 times more informative than SNP markers. The most common repeats are di, tri and tetra-nucleotides. Microsatellite loci with a di-nucleotide motif are generally used, since they are easier to isolate and high density (on average every 30–50 kb) [20]. Microsatellites are also known as SSR (Simple Sequence Repeats) or STRs (Short Tandem Repeats). The maximum length is about 200 bp. Microsatellites are distributed throughout the genome with greater prevalence in non-coding regions. They are neutral in terms of selection. The typical problems encountered in the genotyping analysis are: homoplasy (condition of equality in the type and number of microsatellite repeats between two alleles) [21]; stutters (in the form of allelic pre-peaks); null alleles (NA) (possible mutations in the pairing site of the primers can prevent the pairing to the target sequence, causing the non-amplification of some alleles. The genetic analysis of microsatellites produce the following data: the distribution of allele frequencies for each microsatellite locus, the percentage of expected (HE) and observed (HO) heterozygosity, the estimates of the Fst values; Nei distances; conformity to the Hardy–Weinberg equilibrium (HWE) of the allele frequencies for each locus.
\nStarting in the 2000s, the analysis of SNPs led to the beginning of a new era in molecular genetics. The direct study of the genome using SNPs markers allows to integrate the genealogical information and to obtain high levels of accuracy in the estimation of the main genetic parameters of the population. The development of new sequencing techniques has made it possible to study the consequences of gene flow using a larger number of markers. At the beginning, the Sanger’s technology was used to sequence the genomes of different animal species. This sequencing technique produces reads (>700 bp) with a very low error (<0.01%) and high cost (>600 US $ per Gb). This technique was subsequently improved through the use of the Celera assembler with a significant reduction in time and costs. New generation sequencing technologies (Next Generation Sequencing - NGS), also known as High Throughput Sequencing (HTS) technologies, have evolved rapidly offering an ever greater number of sequenced bases at a lower cost. In 2006, the first second-generation NGS technologies (Second-Generation Sequencing - SGS) appeared. Illumina (MiSeq, HiSeq and NovaSeq) is the most popular platform, due to its high performance and low cost. This technology is based on the fragmentation of DNA, amplification in multiple reactions in parallel, obtaining short reads, between 100 and 300 bp. Depending on the library, it is possible to sequence only one end of the fragment, single reads (single end) or both ends. The distance between the read pairs is called insert size (mate pair (2–5 kb); paired end (<1 kb)). Since 2013, the third-generation NGS techniques emerged, also known as the Single Molecule Sequencing (SMS) method. Single molecule sequencing produces long reads with higher costs (>2000 US$ per Gb). These techniques do not require the library amplification step and they are capable of directly sequencing a single DNA molecule, without applying any enzymatic or hybridization process. The main platforms of the third generation are Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT). These platforms produce longer reads than the previous ones (5–50 kb) but have a much higher error rate. The Pacbio platform routinely generates reads with an N50 > 1 Mb and it has recently reduced the error rate with a new technique (circular consensus sequencing) and the production of high fidelity reads of 15 Kb. The most popular softwares used for the bio-informatic analysis are Canu; Marvel and Mecat Flye. Then, results obtained are cleaned with some software such as Racon; Nanopolish and Pilon. \nFigure 1\n shows an example of workflow using long reads.
\nExample of NGS bioinformatic analysis (long read sequencing).
After identifying the putative protein coding regions (CDSs), UCEs (Ultra Conserved Elements), it is possible to infer the correct reading pattern (Open Reading Frames, ORF) and translate the nucleotide sequences into amino acids [22]. In this way, we will obtain the set of predicted proteins encoded by the study genome. BLAST (nucleotide, protein, translated, genomes), HMMER or InterProScan databases can be used to functionally annotate these proteins. InterProScan provides the information on functional processes (GO terms) and metabolic pathways (KEGG). Once the functional and structural annotation has been obtained, the analysis of the functional elements of interest such as polymorphic positions or genes with differential expression can be performed. \nFigure 2\n shows an example of workflow for the genomic annotation analysis.
\nExample of NGS annotation analysis.
Orthmcm, Orthofinder; EggNog sofwares can be used for the homology analysis. Several studies, in recent years, have shown that the best way to understand complex systems (for example diseases) is to combine different omic data together. \nFigure 3\n shows a detailed analysis using omic data (genomic, transcrptomics, proteomics and metabolomics).
\nExample of OMICs analysis (genomics,transcrptomics, proteomics and metabolomics).
Several new techniques have been developed in the last decade. The most popular is the restriction-site-associated DNA sequencing (RAD-Seq) [23] and the genotyping by sequencing method (GBS) [24]. The main advantage of RRGS methods is that it reduces the cost of analysis with an high coverage compared to the traditional sequencing methods. The
In the recent years, the availability of massive genomic data obtained from the last generation sequencing techniques allowed the efficient identification of a large number of SNPs [26]. The GWAS is a method of investigation that allows to examine the entire genome by analyzing the single nucleotide polymorphism of genomic markers (SNPs) with the use of high density SNP arrays [27] (the last versions Illumina Canine HD SNP 170 K have hundreds of thousands of SNPs distributed throughout the genome). The study identified the genetic structure of the populations present in Italy and the selection signatures. Reduction of genotyping costs is achieved using inference methods such as the imputation. Imputation techniques allow to transfer information from DNA from high density bead chips to low density ones.
\nThe genome-wide association studies (GWAS) have been proposed as an effective approach for the identification of many causative mutations and genetic factors that constitute the main traits. Unlike linkage studies, which consider the phenomenon of inheritance of chromosomal regions linked to the presence of a trait within a family, association studies consider instead the difference between the frequency of SNPs affecting the trait of interest. Association studies may be conducted through two approaches: direct and indirect. A direct association study is to catalog and test one by one all the possible causal mutations. However, the direct approach presents some practical problems. This strategy involves genome-wide identification of all genes (up to 19,000 genes) as well as of all SNPs. For these reasons, the use of the direct method is limited to a few cases and it has almost always replaced with the application of the indirect method. The indirect strategy avoids the need to catalog all mutations that could potentially give predisposition to a given trait and instead relies on the association between a giver phenotype and markers located near a strategic locus. These associations are obtained from studies of linkage disequilibrium (LD) between marker loci. The indirect strategy, then employs a dense map of polymorphic markers to explore the genome in a systematic way. The choice of markers differentiates further the indirect approach in two different strategies. In the first, markers are chosen very close to exon regions of known genes. The second employs markers located in large regions, virtually anywhere in the genome, thus considering the chromosomes in their entirety, including intronic regions. The choice of the marker falls on bi-allelic SNPs because of their high frequency in the animal genomes, for the low rate of mutation and for the ease with which it can be analyzed. Linkage means the presence of genes in closed loci on the same chromosome. LD is a combination of alleles at two or more loci that occurs more often than it does happen by chance. Two markers are in LD when they occur together in the same individual more frequently than would be expected by chance. The presence of a LD thus indicates co-segregation of two markers. In generally, the LD between two SNPs decreases with the physical distance and the extent of LD varies strongly among the regions of the genome. LD analysis is a valuable tool for fine mapping. Doherty [28] conducted an GWAS analysis using 9700 SNPs on 72,000 dogs (63 breeds). Eight SNPs were significantly correlated with the live weight and five SNPs with cancer mortality. Plassais [29] analyzed the genomes (WGS) of 722 dogs and used the Illumina canine HD SNP BeadArray to identify over 91 million SNPs. In this way the main SNPs coding for body weight and main morphological characters were identified. In \nTable 2\n is reported an example of SNP genotyping using a SNP chip array in dogs [30].
\nGenomic analysis | \n
---|
Illumina CanineHD SNP chip (San Diego, CA) | \n
Genotype SNP calls using Illumina’s Genome Studio | \n
Selection of samples with a | \n
SNPs with Gentrain scores | \n
Minor allele frequency | \n
\n | \n
\n | \n
\n | \n
\n | \n
\n | \n
\n | \n
\n | \n
SNP genotyping using a SNP chip array in dogs.
The domestic dog is thought to be the most recent species of the canine family, within which three phylogenetic groups, or clades, are distinguished: the domestic dog belongs to the same clade as the gray wolf, coyote and jackals [31]. It is thought that the dog appeared about 40,000 years ago, and that the first steps in its domestication took place in East Asia [32]. Most of the domestic breeds we know today, however, are the result of human selection over the past two or three centuries. Many of the most popular modern breeds were created in Europe in the 19th century. Some of the breeds were already present in the ancient world as the greyhound and the dog of the pharaohs. Studies conducted at the genomic level have highlighted a stratification of genetic variability within dog breeds. The recent sequencing methods and the use of SNP arrays allow the screening of the whole genome for the presence of signatures of selection. Sequencing data are aligned to the reference genome to identify selective sweeps. The presence of genes with a large number of outliers indicates a positive or negative effect of selection. A genome scan approach can be used to distinguish genome-wide processes (expected to mainly reflect demographic histories) from processes at individual loci. Genome scans may suffer from inflated numbers of false positives under hierarchical spatial structure coupled with isolation by-distance dynamics. In the case of positive selection, there is an increase in the fitness of the population due to a new (or rare) mutation. In the case of hard sweeps, there is an increase in the frequency of some variants and in the linkage disequilibrium. Kim et al. [33] compared 127 dogs (sport-hunting vs. terrier) for sporting characteristics. Results of the study showed the main SNPs (cardio-circulatory, muscular and neuronal systems) and selection signature that are involved in the sport-hunting breeds. In \nTable 3\n is reported an example of GWAS and selective sweep analysis in dogs
Dataset of 268 dogs representing 130 breeds | \n
---|
\n | \n
\n | \n
Samples with ≥10x coverage, selecting two males and two females | \n
\n | \n
\n | \n
\n | \n
Vcftools60 | \n
\n | \n
\n | \n
\n | \n
Example of GWAS and selective sweep analysis in dogs.
The canine genome project was launched in the early 1990s. After some preliminary results, in 2003, a fist sequence of the dog’s genome was obtained from a female boxer which is now the reference sequence for the dog [34]. The availability of a high quality canine genome has revolutionized the way in which geneticists operate. The first version of the boxer’s genome, carried out with a coverage of 7.5x, covered nearly 99 percent of the animal’s genome. The genome sequence provided a first description of the organization, number of genes and the presence of repeated elements. To some surprise, they found a high presence of short interspersed nuclear elements (SINEs) throughout the genome, sometimes located in locations from which they could affect gene expression. For example, the insertion of a SINE into the gene encoding the hypocretin receptor (a neuropeptide hormone found in the hypothalamus) causes narcolepsy in the Doberman. Similarly, the insertion of a SINE element into the silv gene, which is known to be linked to the pigmentation process, is responsible for a particular mottled color called merle. The 2003 sequence comprises approximately 2.4 billion of bases and revealed the existence of approximately 19,000 genes. For about 75% of genes, the homology (resulting from shared ancestral material) between the dog, man and mouse is very high. The study also found that many genes have no gaps in their sequence, which is beneficial if you would like to study the correlation between a given gene and a disease. During its evolution, the dog’s genome has accumulated more than two million of SNPs. These markers are proving crucial in understanding the role of genetic variability within one breed and in different breeds. SNPs, analyzed by means of DNA microarrays or bead arrays, can make an important contribution to GWAS (association studies) aimed at identifying the genes responsible for complex traits in dogs. A microarray with around 170,000 SNPs is currently available. By comparing data from dogs with a certain disease with healthy individuals, it is possible to quickly identify the genes responsible for the disease. Dog breeds differ not only in the overall body size but also in leg length, head shape and many other morphological characteristics. In the dog, the phenotypic variability of several traits is very high compared to the other living terrestrial mammals. The first molecular study on the genetic aspects of dog morphology was conducted at the University of Utah [35, 36]. Called Georgie Project (in memory of a dog), the study focused on the Portuguese water dog breed, ideal for this type of study because it comes from a small number of ancestors. In the project, DNA samples of more than a thousand dogs were collected. A completed genome scan using 500 microsatellite markers was carried out. For these animals, in addition to the genealogical and medical data, more than 90 anatomical measurements were obtained from a series of five radiographs taken on each animal during the first phase of the study. Based on the analysis of these data, four primary main components (CP) have been identified (\nFigure 4\n).
\nExample of PCA (principal component analysis) of genotypic data (autosomal) of three dog populations.
The analysis of the genome scans and principal components (CPs) revealed 44 putative QTLs (quantitative trait loci associated with a particular quantitative trait) on 22 chromosomes. QTLs are identified by means of a complicated statistical analysis and identify the genome regions that contribute to the expression of a certain trait. Of particular interest is the gene CFA15 on chromosome 15 which showed a strong association with the body size. Although, it is only one of seven loci thought to affect the body size, it was chosen as the starting point. To find the gene CFA15, several SNPs were identified and then the resulting set of genome-wide markers were genotyped. The distribution of these markers showed a single peak near the insulin-like growth factor-1 (IGF 1) gene, which codes for insulin-like growth factor which is known to code for the body size in humans and mice. IGF 1 was analyzed in detail, discovering that there are only two specific combinations of alleles (called haplotypes) and one of them is present in 96% of the population. The haplotype associated with the small size was called B, while the one associated with the largest size was called I. Homozygous dogs for the haplotype B showed a smaller average body size while, dogs homozygous for I were larger. Heterozygous dogs showed an intermediate size. The Georgie Project is important for the number of genes discovered. In addition to the genes related to the head shape, body size, leg length and many other traits, additional genes were discovered that control the sexual dimorphism [37, 38]. This dimorphism is observed in almost all mammals but its mechanisms it is not yet fully known. Indeed, it was found a gene on chromosome 15 which interacts with other genes to make males larger and females smaller. On average, females of the Portuguese water dog breed are 15% smaller than the males.
\nIn the past fifteen years, tremendous progress has been made in dog genomics [39, 40, 41]. Several genetic aspects of cancer, heart disease, hip dysplasia, vision and hearing problems in dogs have been investigated and studied in detail. Genome-wide associative studies have made possible to identify several genes associated with diseases, morphological and behavioral traits. The Dog10K project will produce 10,000 new dog genomes (20x) within five years [42]. The mapping of disease-associated genes will hopefully lead to the production of new genetic tests and improve the management of running breeding programs, which in turn will produce healthier and longer-living dogs. It will be easier to select for specific physical traits such as the size or coat color. Finally, perhaps we will be able to identity which genes are responsible for the typical behaviors of each breed.
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Antioxidant compounds act through several chemical mechanisms: hydrogen atom transfer (HAT), single electron transfer (SET), and the ability to chelate transition metals. The importance of antioxidant mechanisms is to understand the biological meaning of antioxidants, their possible uses, their production by organic synthesis or biotechnological methods, or for the standardization of the determination of antioxidant activity. In general, antioxidant molecules can react either by multiple mechanisms or by a predominant mechanism. The chemical structure of the antioxidant substance allows understanding of the antioxidant reaction mechanism. This chapter reviews the in vitro antioxidant reaction mechanisms of organic compounds polyphenols, carotenoids, and vitamins C against free radicals (FR) and prooxidant compounds under diverse conditions, as well as the most commonly used methods to evaluate the antioxidant activity of these compounds according to the mechanism involved in the reaction with free radicals and the methods of in vitro antioxidant evaluation that are used frequently depending on the reaction mechanism of the antioxidant.",book:{id:"8008",slug:"antioxidants",title:"Antioxidants",fullTitle:"Antioxidants"},signatures:"Norma Francenia Santos-Sánchez, Raúl Salas-Coronado, Claudia Villanueva-Cañongo and Beatriz Hernández-Carlos",authors:[{id:"143354",title:"Dr.",name:"Raúl",middleName:null,surname:"Salas-Coronado",slug:"raul-salas-coronado",fullName:"Raúl Salas-Coronado"},{id:"148546",title:"Dr.",name:"Norma Francenia",middleName:null,surname:"Santos-Sánchez",slug:"norma-francenia-santos-sanchez",fullName:"Norma Francenia Santos-Sánchez"},{id:"193718",title:"Dr.",name:"Beatriz",middleName:null,surname:"Hernández-Carlos",slug:"beatriz-hernandez-carlos",fullName:"Beatriz Hernández-Carlos"},{id:"278133",title:"Dr.",name:"Claudia",middleName:null,surname:"Villanueva-Cañongo",slug:"claudia-villanueva-canongo",fullName:"Claudia Villanueva-Cañongo"}]},{id:"65331",doi:"10.5772/intechopen.83731",title:"Flavonoids and Phenolic Acids as Potential Natural Antioxidants",slug:"flavonoids-and-phenolic-acids-as-potential-natural-antioxidants",totalDownloads:2726,totalCrossrefCites:34,totalDimensionsCites:75,abstract:"For centuries, aromatic herbs and spices have been added to different foods to improve the flavor and organoleptic properties. The use of aromatic plants and spices in phytotherapy is mostly related to different activities of their essential oils, such as antimicrobial, spasmolytic, carminative, hepatoprotective, antiviral, and anticarcinogenic activities. Furthermore, many studies point to strong antioxidant activities of aromatic plants and their essential oils. Knowing that phenolic compounds are the most responsible for the antioxidant activity, the amount of total phenolic contents and content of flavonoids have also been determined. In order to examine the antioxidant properties of five different extracts of Laurus nobilis L. leaves, various assays which measure free radical scavenging ability were carried out: 1,1-diphenyl-2-picrylhydrazyl, hydroxyl, superoxide anion, nitric oxide and hydroxyl radical scavenger capacity test, and lipid peroxidation assay. In all of the tests, only the EtOAc extract showed a potent antioxidant effect.",book:{id:"8008",slug:"antioxidants",title:"Antioxidants",fullTitle:"Antioxidants"},signatures:"Biljana Kaurinovic and Djendji Vastag",authors:[{id:"142369",title:"Prof.",name:"Biljana",middleName:null,surname:"Kaurinovic",slug:"biljana-kaurinovic",fullName:"Biljana Kaurinovic"},{id:"286918",title:"Prof.",name:"Djendji",middleName:null,surname:"Vastag",slug:"djendji-vastag",fullName:"Djendji Vastag"}]},{id:"44805",doi:"10.5772/56424",title:"Discovery, Development, and Regulation of Natural Products",slug:"discovery-development-and-regulation-of-natural-products",totalDownloads:8291,totalCrossrefCites:15,totalDimensionsCites:34,abstract:null,book:{id:"3320",slug:"using-old-solutions-to-new-problems-natural-drug-discovery-in-the-21st-century",title:"Using Old Solutions to New Problems",fullTitle:"Using Old Solutions to New Problems - Natural Drug Discovery in the 21st Century"},signatures:"Juergen Krause and Gailene Tobin",authors:[{id:"162495",title:"Dr.",name:"Juergen",middleName:null,surname:"Krause",slug:"juergen-krause",fullName:"Juergen Krause"}]},{id:"48052",doi:"10.5772/59468",title:"Intranasal Drug Administration — An Attractive Delivery Route for Some Drugs",slug:"intranasal-drug-administration-an-attractive-delivery-route-for-some-drugs",totalDownloads:4702,totalCrossrefCites:10,totalDimensionsCites:30,abstract:null,book:{id:"4539",slug:"drug-discovery-and-development-from-molecules-to-medicine",title:"Drug Discovery and Development",fullTitle:"Drug Discovery and Development - From Molecules to Medicine"},signatures:"Degenhard Marx, Gerallt Williams and Matthias Birkhoff",authors:[{id:"71452",title:"Dr.",name:"Degenhard",middleName:null,surname:"Marx",slug:"degenhard-marx",fullName:"Degenhard Marx"},{id:"72854",title:"Mr.",name:"Matthias",middleName:null,surname:"Birkhoff",slug:"matthias-birkhoff",fullName:"Matthias Birkhoff"},{id:"172384",title:"Dr.",name:"Gerallt",middleName:null,surname:"Williams",slug:"gerallt-williams",fullName:"Gerallt Williams"}]},{id:"41155",doi:"10.5772/52508",title:"Data Analysis Approaches in High Throughput Screening",slug:"data-analysis-approaches-in-high-throughput-screening",totalDownloads:6487,totalCrossrefCites:5,totalDimensionsCites:21,abstract:null,book:{id:"3086",slug:"drug-discovery",title:"Drug Discovery",fullTitle:"Drug Discovery"},signatures:"Asli N. Goktug, Sergio C. Chai and Taosheng Chen",authors:[{id:"71406",title:"Dr.",name:"Taosheng",middleName:null,surname:"Chen",slug:"taosheng-chen",fullName:"Taosheng Chen"},{id:"120804",title:"Dr.",name:"Sergio",middleName:"C.",surname:"Chai",slug:"sergio-chai",fullName:"Sergio Chai"},{id:"165635",title:"M.Sc.",name:"Asli",middleName:"Nur",surname:"Goktug",slug:"asli-goktug",fullName:"Asli Goktug"}]}],mostDownloadedChaptersLast30Days:[{id:"66259",title:"Antioxidant Compounds and Their Antioxidant Mechanism",slug:"antioxidant-compounds-and-their-antioxidant-mechanism",totalDownloads:7491,totalCrossrefCites:53,totalDimensionsCites:135,abstract:"An antioxidant is a substance that at low concentrations delays or prevents oxidation of a substrate. Antioxidant compounds act through several chemical mechanisms: hydrogen atom transfer (HAT), single electron transfer (SET), and the ability to chelate transition metals. The importance of antioxidant mechanisms is to understand the biological meaning of antioxidants, their possible uses, their production by organic synthesis or biotechnological methods, or for the standardization of the determination of antioxidant activity. In general, antioxidant molecules can react either by multiple mechanisms or by a predominant mechanism. The chemical structure of the antioxidant substance allows understanding of the antioxidant reaction mechanism. This chapter reviews the in vitro antioxidant reaction mechanisms of organic compounds polyphenols, carotenoids, and vitamins C against free radicals (FR) and prooxidant compounds under diverse conditions, as well as the most commonly used methods to evaluate the antioxidant activity of these compounds according to the mechanism involved in the reaction with free radicals and the methods of in vitro antioxidant evaluation that are used frequently depending on the reaction mechanism of the antioxidant.",book:{id:"8008",slug:"antioxidants",title:"Antioxidants",fullTitle:"Antioxidants"},signatures:"Norma Francenia Santos-Sánchez, Raúl Salas-Coronado, Claudia Villanueva-Cañongo and Beatriz Hernández-Carlos",authors:[{id:"143354",title:"Dr.",name:"Raúl",middleName:null,surname:"Salas-Coronado",slug:"raul-salas-coronado",fullName:"Raúl Salas-Coronado"},{id:"148546",title:"Dr.",name:"Norma Francenia",middleName:null,surname:"Santos-Sánchez",slug:"norma-francenia-santos-sanchez",fullName:"Norma Francenia Santos-Sánchez"},{id:"193718",title:"Dr.",name:"Beatriz",middleName:null,surname:"Hernández-Carlos",slug:"beatriz-hernandez-carlos",fullName:"Beatriz Hernández-Carlos"},{id:"278133",title:"Dr.",name:"Claudia",middleName:null,surname:"Villanueva-Cañongo",slug:"claudia-villanueva-canongo",fullName:"Claudia Villanueva-Cañongo"}]},{id:"67588",title:"Preformulation Studies: An Integral Part of Formulation Design",slug:"preformulation-studies-an-integral-part-of-formulation-design",totalDownloads:4059,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"When a promising new chemical entity is synthesized, it needs transformation to appropriate formulation in order to show a better and desirable action at appropriate site. Preformulation study is a phase which is initiated once the new molecule is seeded. In a broader way, it deals with studies of physical, chemical, analytical, and pharmaceutical properties related to molecule and provides idea about suitable modification in molecule to show a better performance. Study of these parameters and suitable molecular modification can be linked to generation of effective, safer, stable, and reliable pharmaceutical formulation. Therefore, preformulation study is an approach for generation of pharmaceutical formulation which utilizes knowledge and area application of toxicology, biochemistry, medicinal chemistry, and analytical chemistry. The highlighted chapter is framed with a vision to provide an in-depth knowledge about pharmaceutical formulation development.",book:{id:"8331",slug:"pharmaceutical-formulation-design-recent-practices",title:"Pharmaceutical Formulation Design",fullTitle:"Pharmaceutical Formulation Design - Recent Practices"},signatures:"Pinak Patel",authors:null},{id:"37165",title:"Modern Medicine and Pharmaceutics",slug:"modern-medicine-and-pharmaceutics",totalDownloads:4471,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"1519",slug:"promising-pharmaceuticals",title:"Promising Pharmaceuticals",fullTitle:"Promising Pharmaceuticals"},signatures:"Purusotam Basnet",authors:[{id:"98426",title:"Prof.",name:"Purusotam",middleName:null,surname:"Basnet",slug:"purusotam-basnet",fullName:"Purusotam Basnet"}]},{id:"37170",title:"Good Manufacturing Practices (GMP) for Medicinal Products",slug:"good-manufacturing-practices-gmp-for-medicinal-products",totalDownloads:32651,totalCrossrefCites:1,totalDimensionsCites:1,abstract:null,book:{id:"1519",slug:"promising-pharmaceuticals",title:"Promising Pharmaceuticals",fullTitle:"Promising Pharmaceuticals"},signatures:"Jaya Bir Karmacharya",authors:[{id:"155087",title:"Mr.",name:"Jaya",middleName:"Bir",surname:"Karmacharya",slug:"jaya-karmacharya",fullName:"Jaya Karmacharya"}]},{id:"66222",title:"Bioavailability and Bioequivalence Studies",slug:"bioavailability-and-bioequivalence-studies",totalDownloads:3351,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"In vivo bioavailability studies are performed for new drug to establish essential pharmacokinetic parameters including rate of absorption, extent of absorption, rates of excretion and metabolism and elimination half-life after a single and multiple dose administration. These essential pharmacokinetic parameters are useful in establishing dosage regimens. Bioequivalence used to assess the expected in vivo biological equivalence of two proprietary preparations of drug products. If two drugs are bioequivalent, it means that they are expected to be same for all intents and purposes. In determining bioequivalence between two drugs such as a reference drug or brand and potential to be test drug or marketed generic drug. Pharmacokinetic studies are conducted whereby each of the drugs is administered in a cross over study to healthy volunteer’s subjects. Plasma is obtained at regular intervals and assayed for parent drug or metabolite concentration to compare the two drugs. For comparison purpose of two formulations, the plasma concentration data are used to assess key pharmacokinetic parameters. If 90% confidence interval for the ratio of the geometric least square means of peak plasma concentration, area under curve of test and reference drugs are within 80–125%, then bioequivalence will be established.",book:{id:"8331",slug:"pharmaceutical-formulation-design-recent-practices",title:"Pharmaceutical Formulation Design",fullTitle:"Pharmaceutical Formulation Design - Recent Practices"},signatures:"Divvela Hema Nagadurga",authors:null}],onlineFirstChaptersFilter:{topicId:"217",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,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:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,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:"June 29th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:32,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:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. 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