Examples of association between vitamin E and other active molecules.
\r\n\t
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Vitamin E can eliminate free radicals induced by endogenous and/or exogenous agents such as ultraviolet radiation, drugs and pollution agents, avoiding their deleterious effects. The antioxidant activity of vitamin E is directly linked to its ability to inhibit the lipid peroxidation in unsaturated fatty acids, incorporating itself into cell membranes, which effectively inhibits lipid peroxidation [1, 2].
The antioxidant activity of vitamin E (alpha-tocopherol) has its property due to its ability to react mainly with the peroxyl radical (HOH•) and singlet oxygen (1O2), which favors lipid peroxidation. The free radical scavenging reaction occurs through the formation of a stable, low-energy radical, tocopheroxyl, which does not have the capacity to react with the free radical-forming agent [3]. Alpha-tocopherol is the main agent capable of removing peroxyl radicals from lipid membranes, such as membranes or low-density lipoproteins (LDL) [4].
It is a classic dermatological ingredient used alone in its purified form, alpha-tocopherol or by its derivatives. However, the conversion to the purified (isolated) form is required in skin to obtain the desired effects. Topical applications are designed for treating melasma, protecting against ultraviolet radiation (UVR) and improving aging damages [5, 6], The association of vitamin E with other antioxidants increase the effects in skin [7].
Some studies suggest that a poor diet of vitamin E could be related with skin disorders. Oral supplementation of vitamin E is recommended in many skins’ therapies, such as: yellow nail syndrome, epidermolysis bullosa, cutaneous ulcers, pressure ulcers and burns, sub corneal pustular dermatosis, scleroderma, morphea, calcinosis cutis, Raynaud’s phenomenon, and inflammatory diseases. The oral supplementation of vitamin E could reduce the pigmentation in melasma and contact dermatitis lesions, too demonstrated remission of atopic dermatitis, prevention of sunburn reaction as well as the subsequent chronic skin damage [5]. Vitamin E combined with other antioxidants has shown positive results topically in the photoprotection, as well as delay the growth of the melanoma by promoting the apoptosis of tumor cells and inhibiting VEGF-mediated angiogenesis. Other results with alpha-tocopherol: improvement in periorbital fine lines, roughness, radiance, skin tone, elasticity, density, collagen production and overall appearance by clinical evaluations of skin. Topical application of tocopherol acetate significantly reduces the severity of erythema, edema and skin sensitivity associated with sunburn by UVB [8]. It is difficult to determine the
Skin products can be classified as medicines, cosmetics and cosmeceuticals, however, the teaching line between the categories is tenuous, being widely discussed by dermatologists, pharmacists and beauticians. Medicines and cosmetics are already widely discussed and accepted by world regulatory agencies; however, the term cosmeceutical is used as a marketing appeal and is not recognized as an official legal category. Skin products considered to be cosmetics are generally defined as products to clean, beautify, promote attractiveness, or change appearance, while medicines are intended for the diagnosis, cure, mitigation, treatment or prevention of diseases, which can affect the structure or any function of the skin. Regulatory agencies in different countries seek to organize the offer of products to ensure the safety for users.
Topical products that contain vitamin E can be classified as medicines or cosmetics, depending on their purpose. If the product is intended to lubricate the skin, it will be considered cosmetic and if it has therapeutic use as a healing agent, it will be a medicine. There are legal limits on the daily consumption of vitamin E as a supplement, however, for most international regulatory agencies, such as the NHS, FDA, Health Canada the limits for topical use are not described [10].
The antioxidant alpha-tocopherol acetate is the most common form of vitamin E in skin care products. In 2001, the Scientific Committee on Cosmetic and Non-Food Products for Consumers (SCCNFP) presented its opinion during the 18th Plenary Meeting. At the time, SCCNFP believed that alpha-tocopherol acetate did not pose a threat to consumer health and therefore did not propose any restrictions or use conditions [11].
The Cosmetic Ingredients Review Panel (CIR) in 2002 has assessed the safety of 14 tocopherols and tocotrienols and concluded that these ingredients are safe when used in cosmetics. The Panel further reviewed data from clinical and animal studies to determine the safety of tocopherols and tocotrienol ingredients and considered it appropriate to extrapolate existing information to conclude on the safety of all tocopherols and tocotrienols [12].
Since vitamin E can absorb ultraviolet light to produce free radicals, there is a possibility that strong exposure to sunlight after topical application may cause skin reactions. However, vitamin E concentrations between 0.1–1.0% are generally considered to be safe and effective for increasing vitamin E levels in the skin, but higher levels of α-tocopherol have been used with no apparent side effects [8]. Vitamin E as alpha-tocopherol or tocopherol acetate is used in over-the-counter products in concentrations ranging from 1.0 to 5.0% [13, 14, 15].
Vitamin E is the main fat-soluble antioxidant in the body with biological activity and it is the collective name for the eight mains naturally occurring substances such four tocopherols and four tocotrienols. The eight analogues of vitamin E share similar chemical antioxidant activity, however, they are distinguished by their individual physico-chemical and biological effects at the molecular level in humans and higher animals. Alpha tocopherol is the most active, being considered an important asset in protecting cell membranes from lipid peroxidation promoted by free radicals [13, 14, 15].
Alpha-tocopherol is practically insoluble in water and this characteristic can difficult the development of topical products with high water content. In addition, this molecule is easily oxidized by atmospheric oxygen. Vitamin E acid acetate and succinate esters are applicable for clinical use due to their high oxidation stability but require the use of surfactants to improve the water solubility. Alpha-tocopherol is solubilized by large amounts of surfactants, but the hydrolysis of acetate is the limiting step in terms of its concentration during bioavailability [15].
The antioxidant properties of vitamin E are attributed to its free aromatic hydroxyl group; thus, the esters of vitamin E need to be hydrolyzed during absorption by the skin to exhibit this activity. In the biologically inactive esterified form, vitamin E acetate is more used because of its greater stability, acting as a prodrug, being hydrolyzed in active free vitamin E (alpha-tocopherol) after penetration into the skin. The bioconversion of vitamin E into the active form can be influenced by the technology involved in the development of formulations, by the target layer of the skin and exposure to ultraviolet rays. The stratum corneum seems to have less efficiency in the bioconversion of esters of vitamin E when compared to the nucleated epidermal layers. Thus, alpha-tocopherol should provide more efficient antioxidant protection for skin surface lipids and skin barrier constituents than vitamin E esters. However, in the nucleated epidermis the bioconversion of vitamin E acetate to active free form occurs at a much higher rate. In this sense, the choice of which vitamin E molecule to be used must consider the target layer of the skin and include product development strategies so that the activity of vitamin E is fully utilized [15, 16].
Vitamin E, more specifically alpha tocopherol, is considered one of the main fat-soluble and non-enzymatic antioxidant agents of natural origin, due to its advantages in terms of the protective activity against physical and chemical damage promoted by free radicals (FR). Vitamin E is an antioxidant capable of binding to the membrane in various tissues [17, 18]. Therefore, it is involved in several oxidative mechanisms in epidermis and dermis, catalyzed by ultraviolet radiation (UVR) and pollutants (Figure 1).
Oxidative mechanisms involving vitamin E in human skin exposed to ultraviolet radiation and pollution. ROS, reactive oxygen species.
The first studies related to the damage caused by the formation of FR on the skin, promoting lipid peroxidation, date from the 1950s and 1960s. To avoid the damages, the use of natural and synthetic substances was suggested in order to prevent the formation of FR [19, 20].
Reactive oxygen species (ROS) such as superoxide (O2−•), hydroxyl radicals (OH•), peroxyl (HOH•) and singlet oxygen (1O2), can be formed by endogenous (physiological) processes such as inflammation, physical activity in excess, nutritional disorder, hereditary issues, neoplasms, and even, by processes related to exogenous sources such as UVR and pollution agents. In the skin, the main damage related to lipid peroxidation generated by FR from exogenous sources is the activation of melanogenesis and damage to collagen fibers [19, 21, 22].
The lipid peroxidation of the epidermis cells occurs through the action of the ROS, which has the ability to bind to the unsaturated bonds present in the polyunsaturated fatty acids of the cell membrane phospholipids [22, 23]. The process starts between polyunsaturated fatty acids (PUFA) and the oxygen radical, obtaining a lipid radical, which causes a rearrangement process in the presence of molecular oxygen, becoming a peroxy lipid radical. The lipid peroxyl radical is also capable of attacking unsaturated lipids, generating new radicals, such as the lipid radical as in the first stage of the reaction and the lipid hydro peroxide radical, thus promoting a cyclic reaction. Thus, it is necessary to use substances capable of interacting with cell membranes and to extinguish the free radicals formed, such as vitamin E [24, 25].
In a more detailed way, the mechanism involved in the lipid peroxidation process occurs through a chain reaction of the polyunsaturated fatty acids (PUFA) of biological membranes, which due to the large amount of unsaturation, become extremely susceptible to attack by free radicals. The process begins with the activity of the free radical like OH*, which extracts H from PUFA resulting in the radical PUFA*. After the molecular rearrangement of a conjugated diene, the molecule is susceptible to attack by O2, resulting in a peroxyl radical (PUFAOO*). PUFAOO* can extract H from the adjacent PUFA, thus propagating a chain reaction. Self-oxidation occurs continuously, which can seriously affect the functionality of the tissue [26].
The action of pollutants and UV radiation (UVR) on the skin has already been studied, but the mechanisms involved are still uncertain, knowing that the damage is initially related to the composition of the skin’s sebum and the quality of the stratum corneum, which may lead to the formation of wrinkles, hyperchromies (spots), wrinkles and accelerated extrinsic aging and dermatological diseases such as atopic dermatitis, related to lipid peroxidation [27, 28, 29].
The chronic and acute damage to the skin caused by UVR (UVB and UVA) are related to the direct absorption of rays and indirectly through photosensitization reactions. Mostly (> 95%), UVA radiation, more specifically UVAI (340–400 nm), has the major ability to penetrate the skin and it causes deeper damage. The aggression of UVA radiation targets collagen and supporting fibers, in addition to cellular DNA. The DNA damage is related to the mutagenic power of UVA radiation, which can act directly or indirectly through photosensitization reactions [30].
Studies prove the mutagenic power of UVA through direct oxidation reactions of DNA nucleic acids with ROS, which can lead to simple disruptions of the DNA strands or to disruptions in symmetrical positions in the two strands. Several studies (
As the UVR, polluting agents have harmful effects on the skin by increasing the oxidative stress and decreasing the physiological enzymatic and non-enzymatic antioxidant capacity. With the formation of FR and ROS, an interaction occurs with the lipid layer membrane, initiating the cascade reactions of lipid peroxidation and the release of pro-inflammatory mediators, which result in the accumulation of neutrophils and phagocytic cells, that also generate radicals free, thus promoting a cyclical reaction. Oxidative stress initiates a series of quite complex biological processes that result in DNA damage, activation of transcription factors such as activating protein 1 (AP1) and the nuclear factor Kappa-B (NF-KB) and even some pathways of signaling involved in cell growth and differentiation and degradation of dermal connective tissue. Pollutants are also capable of inducing functional changes in lipids, DNA, skin proteins, favoring the acceleration of skin aging, inflammatory processes and dermatological pathologies [33, 34].
Melanogenesis can be considered as the first skin defense, being directly influenced by the skin phototype and, consequently, by the amount and type of melanin present. Melanocytes are particularly vulnerable to excessive oxidative stress from ROS due to their pro-oxidant state and the melanin synthesis involves oxidation reactions and generation of superoxide anion (O2−) and hydrogen peroxide (H2O2), promoting oxidative stress. The initiation of melanin synthesis occurs by a single route, with the conversion of tyrosine to dopa by the catalytic activity of the enzyme tyrosinase, releasing O2−, which also oxidizes dopa to dopaquinone with the release of O2−. From the obtaining of dopaquinin, a specific orthoquinone, capable of reacting with nucleophilic compounds, the synthesis follows two distinct pathways, eumelanogenesis and pheomelanogenesis, which respectively produce the darkest and lightest melanin monomers (red-yellow) [35, 36].
The homeostasis of human melanocytes in the epidermis is maintained mainly through a complex paracrine network, involving growth factors and cytokines synthesized by epidermal keratinocytes and dermal fibroblasts and modulated by UV radiation. Keratinocyte-derived endothelin-1 is a potent mitogen and a melanogenic factor capable of reducing H2O2 generation and apoptosis in human UV-irradiated melanocytes [37]. The α-MSH melanocortin and adrenocorticotropic hormone (ACTH) are synthesized by keratinocytes and melanocytes and stimulate the synthesis of eumelanin, as well as the survival and proliferation of melanocytes by binding and activating the melanocortin 1 receptor (MC1R). The MC1R is a receptor located on the surface of melanocytes with the ability to bind to protein G. Studies show that the treatment of human melanocytes in culture with α-MSH, results in a decrease in the generation of H2O2, due to exposure to UV rays [35].
With the production of ROS, oxidative stress formed can interrupt melanocyte homeostasis, compromising their survival or even leading to malignant pathogens. Thus, the balance between the pro and antioxidant properties of melanin in the skin is mainly determined by the proportions of eumelanin and pheomelanin, the levels of melanin intermediates and the concentrations of reactive metals in the melanosome microenvironment. The generation of H2O2 in response to the action of UV radiation is inversely proportional to the constitutive pigmentation, suggesting a natural antioxidant effect of melanin [35, 38]. The inhibition of melanogenesis occurs in several stages, such as the inhibition of the enzyme tyrosinase that acts in several phases of the melanin production cascade, and also influences the post-transcriptional concentration of tyrosinase and other enzymes related to melanogenesis, such as tyrosinase-related protein 1 (TRP1) and DOPA chrome tautomerase (TRP2) [39].
The mechanism of action of vitamin E (Figure 2) regarding the antioxidant activity in the skin is directly related to the chemical mediation of the phenolic hydroxyl (OH) of its structure, capable of donating H to the peroxyl radical (PUFAOO*), resulting in the formation of a stable lipid species (PUFAOOH). Thus, when donating the hydroxyl H, vitamin E becomes a relatively non-reactive free radical, as the unpaired electron moves to the aromatic ring. Thus, with electronic displacement, incorporation occurs in biological membranes, being located awfully close to the polyunsaturated fatty acids of the cell membrane phospholipids, interrupting the chain reaction. Vitamin E stops the reaction by the ability to donate hydrogen from the OH group to the unsaturated lipid or to the lipid peroxyl radical (PUFOO *), forming the low-energy tocopheroxyl stable radical (VE-O *), which in turn does not present the ability to act as a free radical forming agent [40, 41]. Vitamin E also has antioxidant activity involving other lipid radicals, acting directly on the radical’s singlet oxygen and superoxide anion [19].
Mechanism of lipid peroxidation and vitamin E in cells. PUFA, polyunsaturated fatty acids; PUFA*, lipid radical; PUFAOO*, Peroxy lipid radical; OH*, oxygen radical - hydroxyl; O2, oxygen; VE-OH, Vitamin E, alpha-tocopherol; VE-O*, radical tocopheroxyl.
Studies have shown the activity of vitamin E in the modulation of damage caused by FR mediated by the action of UVR on the skin, such as lipid peroxidation, photoaging, immunosuppression and photocarcinogenesis [42]. Vitamin E is able to reduce the inflammatory reactions of the skin, attenuating the production of prostaglandin involved in the process, pro-inflammatory cytokines, cyclooxygenase-2 (COX-2) and NADPH oxidase [43, 44, 45].
In addition to its anti-inflammatory capacity, vitamin E is also able to modulate the protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3-K) signaling pathways and to reduce the increase in collagenase expression. PKC modulation may be representative in terms of cell growth control, however, the interaction between vitamin E (alpha-tocopherol) and PKC protein does not occur directly, assuming that it occurs preventively to its action at the cellular level [45, 46].
Vitamin E has the ability to significantly suppress collagen degradation by inhibiting metalloprotein 1 (MMP-1), involved in the initial process of collagen hydrolysis [44]. It can be identified in deeper layers of the skin, supposing its activity to minimize the photocarcinogenesis process, being considered as one of the main antioxidants of the human epidermis. Another characteristic of vitamin E is its use as an early and very sensitive marker for oxidative damage promoted by the environment [47, 48]. Thus, vitamin E prevents the lipoperoxidation of cell membranes and the degradation of fatty acids that are essential for the proper functioning of the body and skin [8, 49, 50].
Vitamin E can eliminate FR induced by UVA radiation, protect endogenous antioxidants from degrading processes, prevent lipid peroxidation and reduce immunosuppression caused by UVR. To increase protection against erythema and sunburn, the association of vitamins E and C is indicated, presenting potential against skin aging and skin cancer. Another activity of vitamin E on the skin is its application before sun exposure, avoiding the formation of the cyclobutane pyrimidine dimer (CPD) induced by UVB [46].
In general, exposure excessive to pollution and ultraviolet radiation promotes a greater production of free radicals, thus requiring an oral and/or topical supplementation of antioxidant substances, such as vitamin E, thus, the endogenous mechanism is not sufficient to prevent deleterious skin damage [51].
After vitamin E depletion, oral intake is the best way to replenish the stock of this antioxidant in skin. In fact, oral supplementation brings cosmetic effects after 8–12 weeks. For alpha-tocopherol alone, a photoprotection effect by reduction of human skin malondialdehyde concentration was observed [52]. The combination of vitamin E with other antioxidants is very beneficial for skin treatments. Alpha-tocopherol in combination with ascorbic acid increased UVB photoprotection in the human epidermis [53, 54]. The same combination showed a reduction in UV-induced inflammation [55]. Good outcomes for treating chloasma were seen with the same mixture during double blinded clinical trials [56]. When more antioxidants act together, strong outcomes are seen, such as reduction of UVB-induced wrinkle and increased collagen synthesis [57] and treatments of melasma [58, 59]. Despite the benefits to skin appearance, oral intake is not considered cosmetic treatment for its systemic effects.
Topical delivery also plays an important role in restock vitamin E. It is widely used in its purified forms or indirectly using vegetable seed oils [60]. It is a classical ingredient in dermatology and still used in cosmetics worldwide in a recent growth tendency. Cosmetics containing vitamin E are most valuable in the USA, UK and France. The top cosmetic claims used in labels and the categories are in Figure 3 [61].
Evolution of the most explored categories using tocopherol in cosmetics’ labels between 2016 and 2020 (A). Claims used in cosmetics’ labels containing tocopherol between 2016 and 2020(B).
The lipophilic nature of vitamin E requires an oily or alcoholic phase at the topical formulation. In cosmetics, the main drivers capable of delivering this type of molecule are serums, tonics, oils and especially emulsions. For vitamin E alone, hydro-alcoholic solution of alpha-tocopherol showed a reduction of UV-induced erythema in the epidermis [62] and the reduction on the number of epidermal sunburn cells. While O/W and W/O emulsions containing alpha-tocopherol acetate increased skin hydration and water-binding capacity in the stratum corneum [63]. Vitamin E is also used as coadjutant in other topical products to improve physical–chemical characteristics or to donate different effects. One of the most studied associations is with vitamin C, due its primary replenisher of vitamin E mechanism in skin. Vitamin C regenerates the oxidized form of vitamin E to its reduced form [64, 65]. A similar mechanism is expected using other antioxidants. Table 1 shows examples of associations of vitamin E and other molecules. The type of molecule and/or type of formulation is chosen depending on the target to address.
Vitamin E | Combined molecule | Effect | Model | Reference |
---|---|---|---|---|
Alpha-tocopherol (1%) | L-ascorbic acid (15%) | Synergic protection against erythema and sunburn cell formation | Aqueous solution applied to pig skin | [66] |
Tocopheryl acetate (1%) | L-ascorbic acid (20%) + | Improved the appearance of aging skin (Skin color, elasticity, radiance, smoothness, scaliness and wrinkles) | Commercial serum applied | [67] |
Tocopheryl acetate | Bioflavanoids from | Protected the skin from UV damage by reduction on the number of sunburn cells | Emulsion containing 5% of the mixture | [68] |
Vitamin E | A good antibacterial activity against | Dressing | [69] | |
Vitamin E 5 IU | vitamin A (10 000 IU) + vitamin D (1000 IU) + vitamin B1 (50 mg) + vitamin B2 (12.7 mg) + vitamin B6 (15 mg) + vitamin C (500 mg) + nicotinamide (100 mg) + dexpanthenol (vitamin B5) (25 mg) | Reduction of age spots and melasma | [70] | |
Vitamin E | Resveratrol + Baicalin | Improvement on the periorbital fine lines, roughness, radiance, skin tone, elasticity, density, and overall appearance | [71] | |
Vitamin E | Photostable filters (octyl methoxycinnamate, avobenzone and 4-methylbenzilidene camphor) + vitamins A (1,700,000 UI/g) and C [2% (w/w) ascorbyl tetraisopalmitate] | The formulation with filters showed better stability comparing with the vitamins alone | In mouse skin | [72] |
Vitamin E | Amniotic membrane mesenchymal stem cell | Decreased the diameter of lesions | In chronic leprosy | [73] |
Vitamin E | Ferulic acid + Vitamin C | Suggests preventing skin cancer | Topically solution in the skin of white Yorkshire pigs | [74] |
Vitamin E | Vitamin C | Prevention of inflammation due lipid peroxidation caused by | [5] | |
Alpha-tocopherol | Ferulic acid | Inhibition of melanization | [75, 76] | |
Delta-tocopherol glucoside (0.05%) | Retinaldehyde (0.05%) + glycylglycine oleamide (0.1%) | Improvement on the elastin fiber production and a protection effect of the elastin and fibrillin fiber network against UV-induced alterations | [77] |
Examples of association between vitamin E and other active molecules.
The metabolization of derivatives into the active form of vitamin E (alpha-tocopherol) occurs at a far extend in the nucleated epidermis [6]. Therefore, the conversion is highly dependent on the delivery system of cosmetic preparations into controlling skin permeation [14]. To address this issue, several innovations on cosmetic formulations have appeared during the last decade.
The use of chemical permeation enhancers (e.g. alcohol, surfactants, terpenoids) is a good strategy to change stratum corneum polarity and fluidity. Likewise, the use of devices that create micron-scale pores in skin (e.g. iontophoresis, microneedles) is also available in clinics [78]. The benefits of using those techniques is to maintain the original formulation. However, adaptations may be needed to maintain stability in the case of adding chemical agents. Another strategy is to change the formulation completely by using new delivery systems to encapsulate vitamin E.
Micro and nanoemulsions are strong candidates for its permeation capacity. Nevertheless, reduced sizes may have systemic effects, which is not allowed for cosmetics. Regulatory issues must be address in controlling the particle size. Vitamin E microemulsions (256 nm) reach dermis, however with the aid of surfactants [79]. More recently, bigels are a viable cosmetic formulation. These biphasic systems formed by hydrogels and organogels show good spreadability and emollient and moisturizing effect, besides its transdermal capacity [80]. However, bigels containing alpha-tocopherol showed no difference against regular emulsions for hyperpigmentation and inflammatory markers in in vivo tests [81]. More tests are required to evaluate the benefits and safety of new cosmetic formulations.
Many products in the cosmetic market have vitamin E in its composition. The definition of optimal dosage of vitamin E in cosmetics products depends on the derivative molecule and the type of formulation.
Studies with animals to evaluate safety is common in many countries, especially in oral products. In animal experiments, 200 mg/kg was administered orally to frogs, rabbits, cats, dogs, and monkeys, with repeated application to mice over a period of 10–61 days. In food of rats, 4.000 mg/kg of Vitamin E was added and, in these experiments, was not mutagenic, teratogenic nor carcinogenic properties [82].
The toxicity of vitamin E is very low, because in clinical studies, a daily dosage of 100–300 mg of vitamin E was considered harmless, even when their use extends over a long period of time. Double-blind studies demonstrated that large oral doses of up to 3,200 USP-Units/day led to no consistent adverse effects. They mentioned that the optimal human plasma concentration of vitamin E is between 1.0 and 1.5 mg/dl [82].
Numerous genotoxicity studies were conducted with tocopherol, tocopheryl acetate, tocopheryl phosphate (MTP), and tocopheryl succinate. The only remarkable result was tocopheryl succinate with only a weak positive in a sister chromatid exchange assay in the presence of metabolic activation [12].
Tocopherol and tocopheryl acetate are generally recognized as safe food ingredients [12]. According to Brigelius-Flohe et al. [83], vitamin E supplements for pregnancy usually contain only small doses of vitamin E, although adverse effects have not been observed at higher doses. The original report on tocopherols indicated that tocopheryl succinate, up to 75 mg/d in the diet did not have reproductive or developmental effects in rats. In relation to tocopheryl acetate, 1.6 g/kg/d, generally did not have any reproductive or developmental effects in rabbits, hamsters, rats, or mice [84]. There is no published report documenting adverse fetal effects due to use of topical vitamin products. Topical application of vitamin E can rarely cause contact dermatitis, erythema multiforme, and xanthoma [5].
Vitamin E and its derivatives are widely used in many cosmetic and dermatologic products, in general, papers with side effects such as allergic or irritant skin reactions are rare. In clinical studies, tocopherol and tocopherol acetate were found to be safe for use in topical skin formulation since irritant or sensitizing reactions were found only in very small percentages [85]. Tocopheryl acetate was not irritating to rabbit eyes in one study, but it produced weak-to-moderate conjunctival irritation in another study [86]. Positive patch test results of alfa-tocopherol are rare and need to be critically reviewed. However, the derivative (alpha-tocopheryl linoleate), demonstrated allergic popular and follicular contact dermatitis in 1000 cases, reported in Switzerland by a line cosmetic in 1992. This compound was easily oxidized under the storage condition [8]. According to Baumann and Spencer [87], 33% of the patients studied developed a contact dermatitis to the vitamin E. The ingredients considered safe to use in cosmetics were Ascorbyl tocopheryl acetate, Ascorbyl tocopheryl maleate, Dioleyl tocopheryl methylsilanol, Potassium ascorbyl tocopheryl phosphate, Sodium tocopheryl phosphate, Tocopherol, Tocophersolan, Tocopheryl acetate, Tocopheryl linoleate, Tocopheryl linoleate/oleate, Tocopheryl nicotinate, Tocopheryl phosphate, Tocopheryl succinate and Tocotrienols. remembering that the concentrations and conditions of use in the safety tests must be observed [12].
Tocopheryl acetate, 0.2 mL applied under an occlusive patch for 24 hours prior to irradiation, was not phototoxic in a study in 11 participants [84]. According to ECHA [86], animal and clinical testing concluded that tocopheryl acetate was not photoallergenic or phototoxic. The dermal LD50 of tocopheryl acetate is >3 g/kg bw in albino rats. Five animals per group were dosed with 1 or 3 g/kg bw undiluted tocopheryl acetate in vegetable oil under an occlusive patch for 24 hours. Slight erythema was observed 24 to 48 hours after exposure. Slight abrasion was observed in one low dose female, two high-dose females, and two high-dose males [86]. The acute dermal toxicity of mixed tocopheryl phosphates (MTPs) was determined in New Zeal and rabbits; the dermal LD50 was greater than 1,130 mg/kg bw MTP in female rabbits [88].
An aqueous gel containing 1,130 mg/kg bw MTP (918 mg/kg bw a-tocopherol equivalents) was applied to the clipped dorsal skin of 5 male and 5 female rabbits for 24 hours using surgical gauze. At 24 hours, slight-to-well-defined erythema was observed in 4 of 5 males and all females, and slight-to-moderate edema was observed in 2 of 5 males and all females. Signs of irritation were not observed at days 7 and 14 [12].
According to Costa [89], vitamin E has a wetting action and in an
An
Topical application of tocopherol acetate significantly reduces the severity of erythema, edema and skin sensitivity associated with sunburn by UVB. Magnetic resonance images showed that there was no increase in skin thickness associated with edema. However, the cytotoxic effects of UV exposure as measured in Chinese hamster embryo cells can also be reversed by the presence of other antioxidants as well as a-tocopherol, ascorbic acid, butylated hydroxytoluene (BHT) and GSH. However, before exposure UV these components do not protect against cytotoxicity. In this study, it was observed that high dietary levels of vitamin E can restore the level of incorporation of thymidine dimers into DNA, in UV-exposed epidermal cells in relation to control non irradiated cells. The DNA was isolated and determined by the method of Gendominico Record et al. 1991 [90].
Gaspar and Campos [72], evaluated photoprotective formulations with a combination of photostable (octyl methoxycinnamate, benzophenone-3 and octocrylene or photoinstable filters (octyl methoxycinnamate, avobenzone and 4-methylbenzilidene camphor), both in addition to A, C and E. vitamins The combination of photostable filters showed a better response compared to the others. The filter components and vitamins were quantified by HPLC analysis and spectrophotometry. The formulation containing only vitamins, showed irritation and hairless in mouse skin, this was observed by histopathology.
Ferulic acid, by protecting vitamins C and E, can prevent UV-induced thymine dimer formation when applied topically to skin evaluated by fluorescence microscope coupled with a camera. Studies mentioned a presence of mutations in thymine dimer in keratoses and squamous cell carcinomas of skin, so this result requires that this combination can prevent skin cancer [74]. The photoprotective actions demonstrated by the topical application of alpha-tocopherol in mice may not be restricted to the action of itself [91]. It is likely that the dimers formed from UVB photo-oxidation of alpha-tocopherol, and perhaps the trimers as well, may themselves confer photoprotection, this was observed by similarities in the UV absorbance spectrum. Vitamin E slowed melanoma growth by promoting tumor cell apoptosis and inhibiting VEGF-mediated angiogenesis. The mechanism of the
Some studies suggest that a poor diet of vitamin E could be related with skin disorders. Oral supplementation of vitamin E is recommended in therapy of yellow nail syndrome in a dosage of 1000 IU once a day for a period of 6 months; epidermolysis bullosa (300–600 IU/day); in cutaneous ulcers with treatment of pressure sores in doses of 800 IU/L gradually increasing to 1600 IU/L; in wound healing with zinc and vitamin C for pressure ulcers and burns; in subcorneal pustular dermatosis (d-alpha-tocopheryl acetate) 100 IU/day, gradually increasing to 400 IU/day for 4 weeks; in scleroderma, morphea, calcinosis cutis, and Raynaud’s phenomenon respond to vitamin E in a range from 200 to 1200 IU per day; in Hailey–Hailey disease with derivative of vitamin E
Vitamin E has been reported to be effective in inflammatory diseases with attenuation of pro-inflammatory cytokine TNF, evaluated by a section of skin mice by quantitative ELISA kit [64]. In a combination of oral vitamins, A, C, and E with or not proanthocyanidin there was a significant reduction of pigmentation in melasma and pigmented contact dermatitis lesions in two randomized clinical double-bind study [5, 92]. Oral vitamin E (400 IE/day) for 8 months, improvement and near remission of atopic dermatitis and a 62% decrease in serum IgE levels [93]. In oral combination with carotenoids (ß-carotene and lycopene), vitamins C and E, selenium and proanthocyanidins there was decreases the UV-induced expression of Metalloproteinases 1 and 9, that means prevention of sunburn reaction as well as subsequent chronic skin damage, evaluated by clinical trials [94].
In chronic leprosy a topical combination of vitamin E and with an amniotic membrane mesenchymal stem cell decreased the diameter of these lesions, evaluated by randomized controlled trial and monitored weekly [73]. In a dressing based on the association of Vitamin E and
Chung
Studies show that there was an improvement in the healing of wounds in diabetic rats by topical vitamin E [95]. According to Kuriyama et al. [9], some animal’s studies even suggest that topical vitamin E at a concentration of 20% suppressed allergic and irritant contact dermatitis, exerting a comparable effect to 0.5% prednisone ointment. Those skin conditions are generally self-reported as dry skin [96].
With the onset of xerosis, several inappropriate situations can arise, such as the release of inflammatory mediators, hyperproliferation of keratinocytes and interruption of epidermal differentiation, in addition to changes in lipid structure and enzymatic activity [97]. Skin aging, specifically after age 65, presents several constitutional and functional changes in all layers of the skin, such as cellular senescence, decreased proliferative capacity, decreased ability to repair cellular DNA, abnormalities related to chromosomes, loss of telomeres, DNA extranuclear related mutations, oxidative stress and genetic mutations, promoting the formation of wrinkles, loss of elasticity and dryness of the skin [98, 99]. According to Rhie et al., 2001, the alpha-tocopherol concentration in the epidermis is negatively affected with aging and especially with photoaging, in this case the levels found are even lower when compared to young skin [100].
Over the years, the main histological changes occur with the basal cells, which suffer from dyscrasia, presenting an increase in volume and size, which can be accentuated by the action of UV radiation. As for the functionality of the basal cells, there is a decrease in mitotic activity and an increase in the cell cycle time and the cell migration time, which can promote changes in the outermost layer of the skin. The horny extract does not change its thickness, however, the replacement of lipids happens slowly, which significantly affects the function of barrier, protection and maintenance of natural hydration [101, 102].
Thus, the topical use of vitamin E is adequate for its recognized antioxidant and protective activities, favoring the improvement of the skin barrier due to its lipophilic character and also, effectively avoiding lipid peroxidation by protecting cell membranes from the action of free radicals [103]. Gehring et al. [63] evaluated the hydration capacity of the stratum corneum by the use of vitamin E (5%) in water/oil and oil/water emulsions, demonstrating moisturizing activity in the stratum corneum, in addition to providing indications that indicate retention of water in the stratum corneum. Gonullu and collaborators [104] also report that the topical use of vitamin E for a period of two to four weeks can improve the ability of water to retain in the skin, favoring hydration.
While aging decreases keratinocyte proliferation, the abnormal hyperproliferation those cells are seen in psoriasis. Psoriasis is a chronic inflammatory process of the skin which affects 1–2% of the population and can affect the quality of life. It is most characterized by the presence of erythematous plaques with silvery scale on various regions of the body including the scalp, extensor regions of the extremities, and intertriginous areas of the skin [19, 105, 106]. Studies on the influence of vitamin E on psoriasis include oral and topical treatment evaluation of the vitamins combination, minerals, among others (vitamins A, C, D, E, B1, B2, B3, B5, B6, B12, magnesium, zinc, selenium, folic acid, copper, lysine and proline), that act on oxidative stress, energy metabolism, the immune system and optimized collagen formation. The consumption of olive oil, a vitamin E source, is also associated with improvement in psoriasis symptoms, acting positively in the suppression of serum levels of metalloproteinase-3 (MMP-3), protein of the cartilage olimeric matrix (COMP) as well as the levels of pro-inflammatory cytokines (TNF-α, IL-1β and IL-17) [107]. Topical treatments include the application of products added with plant extracts containing vitamin E and other derivatives, the results are representative in relieving the symptoms of psoriasis induced in the mouse model, suppressing the levels of Interleukin-22 involved in extensive proliferation of keratinocytes and pathogenesis of psoriasis. The critical importance of the interleukin axis for the pathogenesis of psoriatic disease has resulted in new biological treatments targeting these cytokines, indicating that vitamin E is a component of interest in the treatment of psoriasis [106, 107, 108, 109].
Antioxidants consumed orally or topically may impact several organs in the body and among them, the skin. Systemic or centralized effects of these molecules can be modulated by the administration pathway and cellular machinery involved in their metabolization. When compared with other natural bioactive compounds, vitamin E has a specific mechanism of activation in skin due its lipophilicity. Alpha-tocopherol is the active molecule, but several derivatives are available in the market to address solubility, cost and pharmacotechnical necessities. The acetate and succinate esters exhibit better oxidation stability and are often associated with surfactants to improve water-solubility. The hydrolyzation of those molecules is mandatory to achieve biological effects and is mainly driven by enzymatic complexes in skin. The application of derivatives is an interesting alternative for slow delivery of this vitamin since the necessity of activation may lead to accumulation and a reservoir effect [110].
The natural lipophilicity of vitamin E impacts also its biological effects in skin. Vitamin E structure forms complexes with lipids in the cellular membrane and therefore acts promptly against the ROS formation due UV or pollution exposure [111]. The reduction/blockage of oxidative stress’ cascade protects skin against several damages visible as wrinkles, melasma and cancer. Besides the lipid peroxidation, vitamin E has an important role in DNA integrity and epigenetic gene modulation [112]. As a natural component of the healthy tissue, vitamin E is associated with impaired skin treatments, such as psoriasis, dry skin, atopic dermatitis and other skin disorders related to oxidative stress and inflammation [5].
The presence of vitamin E is expected in skin, which makes permeation experiments, bioavailability studies and quantification analysis more challenging. Raman confocal spectroscopy showed good sensibility to evaluate the health benefits and safety of vitamin E in human skin
The cosmetic market is always releasing innovative products despite vitamin E is considered a very classic dermatological active. New delivery systems focused on better absorption, deeper permeation or simpler hydrolysis are the R&D main targets. Since vitamin E is generally recognized as safe (GRASA) food ingredient and used in over-the-counter products with broader concentration range (1.0 to 5.0%), there is little regulatory concern about the exploration of this molecule in cosmetics and supplements. The focus of this chapter is topical applications and therefore, the oral toxicity data was not extensively covered. Safety assessment of alpha-tocopherol and its most used esters showed no phototoxicity, no genotoxicity and no ocular and dermal sensibilization [12]. The use of vitamin E in topical applications is a safe, effective and well accepted worldwide, especially in association with other antioxidants.
Vitamin E, more specifically alpha-tocopherol, can be considered a substance with antioxidant activity with the ability to protect long-chain unsaturated fatty acids. It is also capable of playing an important role in a wide variety of physiological and biochemical functions, mediated by the antioxidant function or by its stabilizing effect on cell membranes, breaking down the peroxyl chain propagation reactions and eliminating the efficient lipid peroxyl radicals. Is has been used for decades and is still a very good a widespread ingredient for dermatological products and formulations, especially when associated with other antioxidants such as vitamin C. However, it is important to emphasize the need for more in-depth studies on the use of its derivatives and associations, regarding the conversion speed and the converted amount of vitamin E in skin. There are few studies related to the topical safety and efficacy of vitamin E in the literature, although it is widely used in cosmetics and dermatologic products. A low incidence of contact dermatitis has been reported. However, more studies would be needed for a conclusive answer regarding its topical safety. The definition of optimal dosage in cosmetics depends on the derivative molecule and the type of cosmetic formulation.
This chapter describes the application of Evolutionary Computation to the task of digital circuit design. Although many Electronic Design Automation (EDA) tools exist to aid designers, digital circuit design remains a time consuming and expensive task that requires skilled engineers.
The cost of errors in silicon is enormous and this has led to extremely powerful and accurate simulators that designers use to verify their designs before committing them to silicon. These simulators provide a huge opportunity for Evolutionary Computation as they can be used to test individuals.
This chapter gives an overview about how digital integrated circuits are designed and how the tools used to develop them have evolved over the past few decades. These tools, when linked together with GE produce a system we call the Automatic Design of Digital Circuits (ADDC), which can evolve circuits using massive levels of abstraction rather than simple logic gates.
We demonstrate the system on three real-world problems, including one with
Digital circuit design began in the 1960’s with the arrival of semiconductor transistor based circuits and the Integrated Circuit (IC). Up until the 2010’s,
Integrated circuits come in three different varieties; Digital, Analogue or Mixed-Signal. Digital integrated circuits process digital information, often represented using bits, bytes or words. Many of these circuits employ the use of one or more processors (often referred to as a core) with support logic, memories and I/O interfaces. The microprocessor is a famous example of a digital circuit. Analogue integrated circuits are used for handling continuous-time signals and to perform operations such as amplification, analogue filtering and power management. Mixed-Signal integrated circuits contain both analogue and digital circuitry in the same package and use ADC (Analogue to Digital Converters) and DACs (Digital to Analogue Converters) to share information between both domains.
In modern circuit design, signal processing tends to be performed in the digital domain instead of the analogue domain. This is due to the reliability of digital circuitry and the existence of advanced digital algorithms with performance that cannot be obtained with analog circuitry alone [1]. This move towards using digital designs for signal processing has required the use of circuit representations like Hardware Description Languages (HDLs) to be used to describe these extremely complex circuits. New devices such as Complex Programmable Logic Devices (CPLDs) and Field Programmable Gate Arrays (FPGAs) are increasingly being used due to their ability to replicate the behaviour of these circuits without requiring the fabrication of new chips. The following sections will go more in-depth into HDLs, the differences between CPLD and FPGA devices and an overview of the Digital Design Flow.
The first modern HDL, Very High Speed Integrated Circuit Hardware Description Language (VHSIC-HDL), more commonly known as VHDL, was created in 1983. VHDL was developed for the US Department of Defense as part of the VHSIC project. The project was launched in 1980 [2], while the first version of VHDL was launched in 1983 by Intermetrics Inc., Texas Instruments and IBM [3, 4]. VHDL is a verbose and strongly-typed language. It grew steadily in popularity, resulting in both logic simulators and logic synthesis tools being developed for it. IEEE Standard VHDL was standardised in 1986 [5] with the adoption of VHDL version 7.2 and was finalised in 1987 in the IEEE Standard 1076-1987 [5]. VHDL would become the first HDL language that would gain widespread adoption, and is still in use today.
Another modern HDL developed around this time was Verilog, created by Phil Moorby in 1983 [6] while working for Gateway Design Automation, who were acquired by Cadence Design Systems in 1989 [7]. In comparison to VHDL, Verilog is less verbose and is a weakly-typed language. Originally it was designed only for logic simulation, but later had logic synthesis features added after the language gained widespread popularity. Verilog-XL, a Verilog simulator owned by Cadence, became the
VHDL | SystemVerilog |
---|---|
Standardised in 1987 | Standardised in 1995 (Verilog) and 2005 (SystemVerilog) |
More Verbose | Less Verbose |
ADA-like | C-like |
Case Insensitive | Case Sensitive |
Support for Digital, Analog and Mixed-Signal Designs | Support for Digital Designs only |
A comparison between VHDL and verilog hardware description languages.
With the introduction of Hardware Description Languages for digital circuit design, two discrete time based simulation methods came into prominence. Both cycle-driven and event-driven simulation methods were orders of magnitude faster than the traditional continuous time based simulation method “SPICE”. One limitation of the cycle-driven simulation method is that the output is only updated on each clock edge This means it can only be used for synchronous digital designs, but is much faster than event-driven simulation. It also cannot detect glitches and doesn’t take the timing of the design into consideration.
Event-driven simulation updates the output on any input event meaning it can be used for both synchronous and asynchronous designs. Although still quicker than SPICE methods, it is much slower than cycle-driven simulation. Modern circuit designs utilise techniques such as clock and power gating, allowing parts of a design to be “turned off”. This can help reduce the simulation time of an event-driven simulation, bringing it closer to cycle-driven simulation while providing a more accurate simulation. Table 2 provides a comparison between cycle-driven and event-driven simulation methods. Practically all commercial and open-source simulation tools today utilise one of these methods.
Cycle-driven simulation | Event-driven simulation |
---|---|
Evaluation every clock cycle | Evaluation at minimum time-step or greater |
Synchronous Designs only | Synchronous and Asynchronous Designs |
Behavioural Simulation only | Behavioural, Functional and Timing Simulations |
Faster Simulation Speed | Slower Simulation Speed |
A comparison between cycle-driven simulation and event-driven simulation.
As digital designs grew in complexity, early Programmable Logic Devices (PLD) such as Programmable Array Logic (PAL) became obsolete as they could only replicate the behaviour of a few hundred logic gates. To address this shortcoming, PALs were soon replaced by Complex Programmable Logic Devices (CPLD). Modern CPLDs are able to replicate the behaviour of hundreds of thousands of logic gates. One advantage of CPLD devices is that they use non-volatile memory to store their configuration. As a result, their logic is already configured at power-up. This makes them ideal devices for systems where the logic is required to be ready for initialisation, such as glue logic for circuits.
Figure 1 shows the internal structure of a CPLD. These logic blocks consist of programmable PAL blocks. The inputs can be connected together to different AND gates using programmable fuses. The OR gate connections are fixed and cannot be reconfigured. Although less configurable than a PLA (which contains both programmable AND and OR planes), this reduction in complexity makes PAL blocks cheaper to manufacture. In order for PAL blocks to be able to implement sequential designs, a D flip-flop can be used to store the state of the output. CPLDs can connect multiple logic blocks together using the programmable interconnection matrix in order to implement more complex designs.
Structure of a Complex Programmable Logic Device (CPLD) and Programmable Array Logic (PAL) block. The programmable AND plane and the fixed OR plane are shown on the right.
While CPLD devices are still used for specific tasks, the most common PLD in use today is the Field Programmable Gate Array (FPGA). These devices are quite similar in structure to the mask-programmed gate array (MPGA) [11] which was one of the first commercial programmable PLDs available. One benefit of using FPGAs is that they can be electronically reconfigured, whereas the previous MPGAs configuration was specified at the time of manufacture. The first FPGA, the Xilinx XC2064 was invented by Ross Freeman and Bernard Vonderschmitt in 1985 [12]. Early FPGAs were mainly used in the telecommunications and networking sectors as they were often cheaper than manufacturing custom silicon for these tasks.
Figure 2 shows the internal structure of the FPGA. Similarities can be seen between FPGA and CPLD devices where a programmable interconnect is used to connect programmable logic blocks. In an FPGA, the Configurable Logic Blocks (CLB) consist of Look Up Tables (LUTs). The output of these programmable memories are defined by their input signals. The multiplexer then selects either the output of the LUT or the D flip flop to allow for combinational or sequential logic, similar to PAL blocks in CPLDs. These blocks can then be connected together using the Switching Blocks (SB). Modern FPGAs are able to replicate the behaviour of tens of millions of logic gates and contain logic like RAM and multipliers. Today, they are often used in high-performance computing applications due to their performance and efficiency over processor-based algorithms.
Structure of a Field Programmable Gate Array (FPGA). The Complex Logic Block (CLB) consists of a programmable memory called a Look Up Table (LUT), a D flip flop to store state and a multiplexer to select the output signal. The programmable Switching Block (SB) is used to connect the CLBs together.
In digital design, it is often not practical to use gate-level descriptions. Instead, a representation called Register Transfer Level (RTL) is used. RTL allows for a high-level model of the design to be represented without having to think about the low-level logic structures required to implement the functionality [13]. This abstraction uses constructs like logic statements, arithmetic operations and control flow. Similarities can be drawn between programming using mnemonics in Assembly Language compared to functional programming in C. Using RTL allows the designer to focus on the functionality of the design rather than on the implementation. Figure 3 presents the different stages a digital design must goes through in order to convert a RTL representation into an implementable design.
A flowchart showing the different stages of the logic synthesis/digital design process.
When a high level language is used for programming, the code written by the programmer must first go through a process called compilation before the code is executed. Similarly with digital hardware, a design specified using RTL (often using a HDL like VHDL or SystemVerilog) must go through a process called logic synthesis. This process analyses the given RTL and converts it into a set of primitives that is functionally equivalent. Primitives are the basic building blocks of any logic design and consists of both combinational and sequential blocks. Examples include boolean logic (NOT/AND/OR/XOR etc.), multiplexers and flip-flops. This output is stored in a file called a net-list, which contains a list of all the primitive blocks and the nets that connect them together.
The net-list generated from the logic synthesis is not optimized and must go through a process known as logic minimization. There can be many parameters to optimize for, such as area usage, power consumption and timing delay. There are many different methods that can be used to perform this optimization. Some early algorithmic methods include Karnaugh maps [13] and the Quine–McCluskey algorithm [14]. However as designs have become increasing complex, these algorithmic methods are not computationally feasible. This has lead to the use of heuristic optimizers such as ESPRESSO [15] and BOOM [16]. When using heuristic optimizers, it cannot be guaranteed that the minimized design is the global minimum. However in practice, these methods are sufficient and are widely used in logic synthesis tools today.
Following the logic minimization process, the optimized net-list is in an intermediate representation. A process called Technology Mapping must be performed before the design can be implemented in silicon or on a PLD. For silicon, this intermediate representation is compared against a library of available “building blocks” called leaf-level cells. The mapper then selects and connects these leaf-level cells, rebuilding the circuit. Further optimization may be performed here as the available leaf cells may be able to replace multiple blocks in the intermediate representation. For PLDs, the process is similar. The PAL blocks in CPLDs and the LUTs in FPGAs can be configured to replace one or multiple blocks. These are then connected together using the programmable interconnects. In comparison to logic minimization, the optimizations performed here are much simpler. After the technology mapping process is complete, the designer now has an implementable design. This is often in the GDSII/OASIS format for silicon manufacturing and in a bitstream format for PLDs. The top EDA companies for ASIC digital design tools include Cadence Design Systems, Siemens and Synopsys, with Xilinx and Intel providing FPGA tools.
Grammatical Evolution (GE), the tool used in this chapter and described in detail in the next section, has been used to evolve Verilog circuits, such as the one-bit adder and D-type latch at the gate level [17]. Notably, the one-bit adder is frequently used as a case study to evolve combinational circuits at the gate-level through GE [18, 19, 20]. However, gate-level evolution is less likely to scale to highly complex circuits from scratch [21]. In response to scalability issues inherent in gate level evolution, [22] proposed functional level evolution through Genetic Algorithms, which uses higher-level functions such as multiplexers, adders, subtractors instead of primitive gates to help reduce the search space. Similarly, [23] evolved a 3-bit multiplier using only binary multiplexers. 9- and 25-Median approximate circuits have also been designed at the functional level through Cartesian GP [24]. We address the scalability concern by performing circuit evolution through GE at a more abstract level – RTL modeling, where the focus is on describing the circuit’s behavior [25, 26].
Biological evolution has been a source of inspiration for many techniques that formed the field of evolutionary computation (EC), and has been used to address a wide range of problem domains ranging from the small to the huge, solving molecular to astronomical related problems. One of the most successful evolutionary techniques is GP, introduced by John R. Koza in his book “Genetic Programming—On the programming of Computers by Means of Natural Selection” [27], which mimics natural selection in an iterative way to find an optimal (best) solution. Algorithm 1 details the steps required to implement a standard GP. A survey of the different GP techniques current available in the literature is out of the scope of this work, the interested reader can find in [28] a comprehensive review of various aspects and techniques of GP and their categorization.
Grammatical evolution (GE) is an evolutionary computation and, more specifically, a genetic programming (GP) technique [29] that addresses the closure issue of Koza-style GP, which effectively confines GP to single-type problems. This is achieved through the use of a grammar, generally in Backus-Naur Form (BNF) [29, 30], or Attribute Grammar (AG) [31, 32, 33, 34].
The GE system shown in Figure 4 automatically generates programs using three main components: (i) grammar; (ii) cost function; and (iii) search engine. The grammar describes the program’s syntax, the cost function evaluates the quality of each program, and the search engine, typically a GA, searches within the program space defined by the grammar.
The GE system uses a search engine (typically a GA) to generate solutions for a given problem, by recombining the genetic material (genotype) and mapped onto programs (phenotype) according to a language specification (interpreter/compiler).
In GE, a typical representation for an individual is a binary string grouped into codons (e.g. 8 bits). The linear representation of the genome allows the application of genetic operators such as crossover and mutation in the manner of a typical GA, unlike tree-based GP.
In GP, the standard initialisation is the ramped-half-and-half (RHH) technique, introduced in [27]. In order to ensure diversity in the population, GP individuals typically represented as trees are created with different depths. The RHH technique uses two methods to create a tree: full and grow. Typically there is a probability of 0.5 to select either method for a particular individual. The full method creates trees with full branches at the maximum specified depth, whereas the grow method creates trees with different length of branches and different depth size up to the maximum allowed.
Generally, GE uses a one-point crossover as it has been shown to be effective [36]. In crossover, two individuals are selected as parents and a single crossover point within each parent’s genome is randomly chosen, dividing the genome into two halves: left and right sub-genomes. The right sub-genomes of both parents are swapped to create two offspring. However, crossover points that lie within non-coding regions (unused codon(s) from the mapping step) may not be so useful. As a result, a variant of one-point crossover known as
To illustrate the application of GE, we first explain the evolutionary process using a mathematical optimisation problem as study case.
GE begins with the start symbol of the grammar, then the codons are used to select and apply the grammar production rules to finally build a program. This mapping process is illustrated in Figure 5 with a simple example, where the production rules in the grammar contains a set of user-defined functions:
Example of a GE genotype-phenotype mapping process for the Iris dataset, where the binary genotype is grouped into codons (e.g. 8 bits; red & blue), transcribed into an integer string, then used to select production rules from a predefined grammar (BNF-Grammar), and finally translated into a sequence of rules to build a solution (phenotype).
The production rules for each non-terminal are indexed starting from 0 and, when selecting a production rule (starting with the left-most non-terminal of the developing program) the next codon value in the genome is read and interpreted using the formula:
To prevent reaching the end of the genome without consuming all the available codons, then a wrapping process is used to continuing reading from the beginning of the genome. This mapping process stops when all of the non-terminal symbols have been replaced, in order to get a valid program. An exemption to this process is in the case when it fails to replace all of the non-terminal symbols after a maximum number of iterations, then it is considered an invalid individual and it is penalized with the lowest possible fitness.
ADDC is an evolutionary HDL circuit design framework mainly driven by GE. ADDC requires a grammar and a testbench as inputs for circuit evolution and verification respectively. The designed grammar must be BNF compliant and must satisfy the grammar sufficiency property. Thus, the grammar must contain all the necessary building blocks required to potentially evolve an optimal circuit. ADDC is technology agnostic and easily configurable as the choice of HDL and simulator are left to the user to choose. Illustrated in Figure 6 is ADDC’s design flow for functional evolution of circuits.
ADDC Functional Circuit Evolution Overview.
During the initial phase of the circuit design process, ADDC creates an initial population of circuit designs using a suitable GE initialisation routine such as sensible initialisation. These individuals then undergo fitness evaluation. The fitness evaluation phase entails a number of steps. First, the genotype (genome) of each individual is translated to a HDL (SystemVerilog in this work) circuit design (phenotype) by the GE mapper, using the grammar designed for the circuit. Functional simulation of each circuit takes place, assuming all circuit designs are valid. For these experiments,
The next phase is reproduction, where usually individuals with either good overall fitness score or individuals that perform best on certain cases are selected for crossover and mutation to create a new population of circuit designs. Lexicase selection performs well on circuit design benchmarks [25, 26], hence selected as the choice of selection routine. Also, depending on the genetic algorithm (GA) of choice, for example steady state, generational GAs etc., events like replacement or elitism may take place in creating the new population. The new population undergoes fitness evaluation in similar manner as described in the previous section. The process continues until the termination criterion is satisfied and the best circuit design returned as solution.
Three circuit benchmark problems are considered, namely:
Hamming codes are a linear error-correcting codes capable of detecting a single error and at most two errors, but are only capable of correcting a single error. They belong to a category of codes referred to as Linear Block Codes. A Hamming Code (7,4) Encoder encodes a 4-bit data word into a 7-bit code word prior to data transmission by generating and adding three parity bits to the data word.
The structure of the code words generated by hamming codes can be classified into two categories:
The grammar designed for evolving the Hamming Code (7,4) Encoder is shown in Figure 7. The circuit’s interface is defined using the
Hamming code (7,4) encoder grammar.
A Seven Segment Display is an electronic device used for the display of decimal numerals. It is also capable of displaying letters, though some letters such as
Seven segment display grammar.
A multiplexer is a multiple-input single-output device that accepts data (data lines) and an address (select lines) as inputs and uses the address to select the corresponding data line to be transmitted. The 16-to-4 multiplexer has 16 data lines and 4 select lines.
Figure 9 shows the grammar designed to evolve the multiplexer. Similar to the Seven Segment Display Grammar, the 16-to-4 Multiplexer Grammar also uses the always procedural block. However, here an
16-to-4 multiplexer grammar.
Experimental parameters used for running the experiments are shown in Table 3. The generation number and population size were selected based on preliminary experiments. The generation sizes used for the preliminary experiments were 50, 100 and 200; the population sizes were 100, 200, 500, 1000 and 2000. For each problem, 5 independent runs were conducted. The choice of generation number and population size for the actual experiments were based on setups with majority of the runs with mean best fitness of the final generation within the fourth quartile of the maximum fitness. The other parameters used remain the same as used in [25, 26].
Parameter | Value |
---|---|
Initialization | Sensible Initialization |
No of generations | 50 |
Mutation rate | |
Crossover rate | |
Replacement rate | |
No of independent runs | |
Population | 1,000 |
Selection | Lexicase Parent Selection |
Experimental run parameters.
50 generations were used for evolving the Hamming Code (7,4) Encoder, while 100 generations was used for each of the Seven Segment Display and 16-to-4 Multiplexer designs as preliminary results revealed these problems were relatively challenging to evolve compared to the Hamming Code (7,4) Encoder. All other parameters remain the same for all benchmark problems.
The number of training and testing cases are tabulated in Table 4.
Benchmark problem | No of training cases | No of testing cases |
---|---|---|
Hamming Code (7,4) Encoder | 112 | — |
Seven Segment Display ( | 16 | — |
16-to-4 Multiplexer | 4100 | 5000 |
Number of training and testing cases.
Each of the Hamming Code (7,4) Encoder and Seven Segment Display have only 16 cases. However, for the Hamming Code (7,4) Encoder every correct bit in each bit position in the codeword is counted as part of the total fitness score for a candidate circuit, giving a total of 112 (
On the other hand, the 16-to-4 Multiplexer has
Results obtained from experiments conducted demonstrate ADDC is ideal for evolving digital circuit designs due to the use GE and a HDL which permits designs to be done at a more abstract level. The evolutionary performance for the experiments conducted for Hamming Code (7,4) Encoder, Seven Segment Display and 16-to-4 Multiplexer described in Section 5.1 are visualized in Figures 10–12 respectively. The success rate per benchmark problem is tabulated in Table 5. A representative solution per each circuit benchmark problem is shown in Figures 13–15 in the Appendix. The advantages and disadvantages of the proposed approach is discussed in Section 5.7.
Mean best and mean average across runs for hamming code (7,4) encoder.
Mean best and mean average across runs for seven segment display.
Mean best and mean average across runs for 16-to-4 multiplexer.
Benchmark problem | Success rate |
---|---|
Hamming Code (7,4) Encoder | |
Seven Segment Display ( | |
16-to-4 Multiplexer |
Success rate for benchmark problems.
A successful run is a single independent evolutionary run that evolved an optimal circuit for the target problem. Fifty independent runs were conducted for all three benchmark problems. The success rate is the number of successful runs divided by the total number of evolutionary runs (i.e. 50) as tabulated in Table 5. A 100% success rate was attained for the Hamming Code (7,4) Encoder. The Seven Segment Display and 16-to-4 Multiplexer obtained 60 and 86% success rates, respectively.
Visualization of the evolutionary performance as evolution progressed for Hamming Code (7,4) Encoder, Seven Segment Display and 16-to-4 Multiplexer are shown in Figures 10–12 respectively.
The red line represents the mean best fitness per generations across the 50 independent runs conducted, while the black line represents the mean average fitness. Also plotted are error bars representing the standard error. The error bars are short to non-existent indicating small variability between the fitnesses of individuals. Furthermore, all three plots reveal a steady and progressive increase in fitness as the evolution progressed indicating the evolutionary search is continuously searching regions of the solutions where fitter individuals are located. Hamming Code (7,4) Encoder and 16-to-4 Multiplexer problems discover individual(s) that solve more that 50% of the test cases from the initial generations while the Seven Segment Display evolves individual(s) that solve 25% of the test cases on average.
First, evolved circuit designs are quite interpretable compared to gate-level designs. This is due to the high level of abstraction at which these designs are performed which focuses on evolving circuit behaviours as opposed to evolving gate-level designs. Gate-level design approaches are challenging to scale to complex circuits [40]. The use of constructs such as
Third, like any other methodology, there exist few disadvantages. The use of HDL requires the user to have technical knowledge about the HDL of choice— how to design grammars free of syntax errors and modelling errors. Syntax errors are easier to find and fix as most simulators will report such errors at the functional simulation phase. Modelling errors are a bit more challenging to fix, as they are only noticeable during synthesis (conversion of RTL or high level designs to gate-level representation) phase of the circuit design when designed grammars do not adhere to the guidelines of the HDL of choice. For example, fully functional representative solutions for the 16-to-4 Multiplexer and Seven Segment Display shown in Figures 13 and 14 respectively may not be directly synthesizable (depending on the synthesis tool), as the
The choice of operators to use for evolving circuits is key as it has been shown to increase simulation time of circuits if inappropriate operators are chosen [26]. Furthermore, some circuit designs may contain redundant block of code which impede interpretability as observed in representative best solutions for 16-to-4 Multiplexer and Seven Segment Display shown in Figures 13 and 14 respectively in Appendix. Only 16 of the if conditions and case statements are valid for the 16-to-4 Multiplexer and Seven Segment Display representation circuit designs respectively.
We have presented a system for the automated design of digital circuits, ADDC. ADDC is the next logical step in the evolution of Electronic Design Automation and this chapter has described how the history of integrated circuits has led to the confluence of GE, circuit simulators and HDLs. ADDC has been demonstrated on three difficult, real-world problems and was successful on all three of them, including one with
The HDLs employed here are hugely powerful and expressive. Digital designers often operate at very high levels of abstraction using
As the problems scale up, the number of test cases can become astronomical, as was the case in this chapter. While in this case we randomly sampled the training and test cases, it is also possible to use a more intelligent approach. Recent work [41] has investigated using clustering to select a representative set of test cases. This will permit us to operate at greater scales with confidence.
A circuit that functions correctly on a simulator is not guaranteed to be fit for purpose when rendered in silicon. This is because there are often other considerations, such as silicon area, power dissipation and delay. Future work will use multi-objective optimisation to include pressure on individuals to adhere to these constraints too.
While some of our automatically generated circuits have successfully been implemented in silicon on a Xilinx Artix-7 FPGA, e.g., an 8-to-1 multiplexer [25], ADDC does not yet include that step in its toolchain; to be fully automated it will need to include this.
The authors are supported by Research Grants 13/RC/2094 and 16/IA/4605 from the Science Foundation Ireland and by Lero, the Irish Software Engineering Research Centre (www.lero.ie). The third is partially financed by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brazil (CAPES), Finance Code 001, and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ).
The authors declare no conflict of interest.
16-to-4 multiplexer representative solution.
Seven segment display representative solution.
Hamming code (7,3) encoder representative solution.
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Noteworthy, the stroke — related brain tissue metabolic damages involve an essential ATP deplete clash along with a suppression of brain specific nucleotide — associated kinases and ATP synthase, both Mg2+ — dependent complex enzyme “machineries”. This itself makes the latter’s a legitimate target for some advanced pharmaceuticals as long as the drug — induced overstimulation of corresponding enzymatic activity is the case. Thus, magnetic isotope effects (MIE) of the nuclear spin possessing paramagnetic 25Mg2+ ions might modulate the brain creatine kinase, alfa-glycerophosphate kinase and pyruvate kinase catalytic activities in a way of a remarkable ATP hyperproduction required to compensate the hypoxia caused acute metabolic breakdown. To realize the Magnesium-25 pharmacological potential, a low-toxic amphiphilic cationite nanoparticles were introduced lately. 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Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. 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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. 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She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. 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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. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}},{id:"441116",title:"Dr.",name:"Jovanka M.",middleName:null,surname:"Voyich",slug:"jovanka-m.-voyich",fullName:"Jovanka M. Voyich",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Montana State University",country:{name:"United States of America"}}},{id:"330412",title:"Dr.",name:"Muhammad",middleName:null,surname:"Farhab",slug:"muhammad-farhab",fullName:"Muhammad Farhab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"349495",title:"Dr.",name:"Muhammad",middleName:null,surname:"Ijaz",slug:"muhammad-ijaz",fullName:"Muhammad Ijaz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}}]}},subseries:{item:{id:"93",type:"subseries",title:"Inclusivity and Social Equity",keywords:"Social contract, SDG, Human rights, Inclusiveness, Equity, Democracy, Personal learning, Collaboration, Glocalization",scope:"
\r\n\tThe environment is subject to severe anthropic effects. Among them are those associated with pollution, resource extraction and overexploitation, loss of biodiversity, soil degradation, disorderly land occupation and planning, and many others. These anthropic effects could potentially be caused by any inadequate management of the environment. However, ecosystems have a resilience that makes them react to disturbances which mitigate the negative effects. It is critical to understand how ecosystems, natural and anthropized, including urban environments, respond to actions that have a negative influence and how they are managed. It is also important to establish when the limits marked by the resilience and the breaking point are achieved and when no return is possible. The main focus for the chapters is to cover the subjects such as understanding how the environment resilience works, the mechanisms involved, and how to manage them in order to improve our interactions with the environment and promote the use of adequate management practices such as those outlined in the United Nations’ Sustainable Development Goals.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/39.jpg",keywords:"Anthropic effects, Overexploitation, Biodiversity loss, Degradation, Inadequate Management, SDGs adequate practices"},{id:"38",title:"Pollution",scope:"\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",keywords:"Human activity, Pollutants, Reduced risks, Population growth, Waste disposal, Remediation, Clean environment"},{id:"41",title:"Water Science",scope:"