Taxonomic classification of the family Trombiculidae.
\r\n\tThere will be a chapter on secondary causes of sexual dysfunction disorders related to diabetes, cardiovascular disease, and obesity. A chapter on remedial measures to enhance sexual activity and maintain human relationships will be discussed. As there is a growing number of cancer survivors a chapter on cancer-related sexual dysfunction will be welcomed for including it.
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Dr. Sheriff has authored five books including a textbook on medical biochemistry with additional interest in human sexology. He had editorials written in the British Journal of Sexology, Journal of Royal Society of Medicine, Postgraduate Medicine, and Scientist. 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Moreover, a comprehensive review of the responsibility of chiggers as infectious disease vectors and agents of troublesome dermatitis is given. The following pages cover, for the first time in a unique chapter, the current knowledge of chigger mites.
Trombiculid mites (Acari: Trombiculidae) are widespread ectoparasites of a wide range of vertebrates. More than 50 species have been recorded attacking humans, and about 20 of them are considered to be medically important because they cause dermatitis or due to their role as vectors of human pathogens. The most relevant species are
Phylum | \n\t\t\tArthropoda | \n\t\t
Subphylum | \n\t\t\tChelicerata | \n\t\t
Class | \n\t\t\tArachnida | \n\t\t
Subclass | \n\t\t\tAcari | \n\t\t
Superorder | \n\t\t\tAcariformes | \n\t\t
Order | \n\t\t\tTrombidiformes | \n\t\t
Suborder | \n\t\t\tProstigmata | \n\t\t
Superfamily | \n\t\t\tTrombiculoidea | \n\t\t
Family | \n\t\t\tTrombiculidae | \n\t\t
Taxonomic classification of the family Trombiculidae.
Trombiculids are distributed worldwide, but they show their greatest diversity in the subtropical, tropical and southern temperate zones [3]. Table 2 shows the main trombiculid species and their geographical distribution.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\tHungary, Spain, Moldova, Ukraine, Russia, Sumatra, Malaysia, and Africa | \n\t\t\tTrombiculiasis | \n\t\t
\n\t\t\t\t | \n\t\t\tKorea | \n\t\t\tScrub typhusa\n\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\tEurope | \n\t\t\tTrombiculiasis | \n\t\t
\n\t\t\t\t | \n\t\t\tCanada, South of United States (except for the southwest), South and Central America (including West Indies) | \n\t\t\tTrombiculiasis | \n\t\t
\n\t\t\t\t | \n\t\t\tBolivia, Mexico, Central and South America, southwestern and southeastern United States | \n\t\t\tTrombiculiasis | \n\t\t
\n\t\t\t\t | \n\t\t\tUnited States: from Alabama and Tennessee West to Arkansas, Oklahoma and Kansas | \n\t\t\tTrombiculiasis | \n\t\t
\n\t\t\t\t | \n\t\t\tSoutheast Asia, Australia and the Pacific Islands | \n\t\t\tTrombiculiasis | \n\t\t
\n\t\t\t\t | \n\t\t\tEastern United States (from the Gulf Coast North to Massachusetts, Minnesota) and Ontario | \n\t\t\tTrombiculiasis | \n\t\t
\n\t\t\t\t | \n\t\t\tJapan, Southeast Asia, Australia, and Pacific Islands | \n\t\t\tTrombiculiasis | \n\t\t
\n\t\t\t\t | \n\t\t\tItalia, Austria, and Bulgaria | \n\t\t\tTrombiculiasis | \n\t\t
\n\t\t\t\t | \n\t\t\tJapan, China, Southeast Asia, Indonesia, Philippines, and New Guinea | \n\t\t\tScrub typhus | \n\t\t
\n\t\t\t\t | \n\t\t\tMalaysia, Indonesia, and Thailand | \n\t\t\tScrub typhus | \n\t\t
\n\t\t\t\t | \n\t\t\tThailand | \n\t\t\tScrub typhus | \n\t\t
\n\t\t\t\t | \n\t\t\tChina, Taiwan, Sri Lanka, Nepal, Bangladesh, India, Myanmar, Vietnam, Cambodia, Thailand, Singapore, Brunei, Malaysia, Indonesia, Philippines, New Guinea, southwestern Pacific Islands, northern Australia, Pakistan, Kazakhstan, Uzbekistan, and Afghanistan | \n\t\t\tScrub typhus | \n\t\t
\n\t\t\t\t | \n\t\t\tSoutheast Asia, Malaysia, New Guinea, Philippines, Indonesia, and Melanesia | \n\t\t\tScrub typhus | \n\t\t
\n\t\t\t\t | \n\t\t\tJapan | \n\t\t\tScrub typhusa\n\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\tChina | \n\t\t\tScrub typhus | \n\t\t
\n\t\t\t\t | \n\t\t\tThailand | \n\t\t\tScrub typhus | \n\t\t
\n\t\t\t\t | \n\t\t\tJapan | \n\t\t\tScrub typhusa\n\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\tJapan | \n\t\t\tScrub typhusa\n\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\tJapan, Korea, and Primorye region of Russia | \n\t\t\tScrub typhusa\n\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\tJapan, Korea, and Primorye region of Russia | \n\t\t\tScrub typhus | \n\t\t
\n\t\t\t\t | \n\t\t\tJapan, Korea, and Primorye region of Russia | \n\t\t\tScrub typhusa\n\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\tSiberia and Primorye region of Russia | \n\t\t\tScrub typhus | \n\t\t
\n\t\t\t\t | \n\t\t\tJapan, northern China, Korea, Thailand, and Malaysia | \n\t\t\tScrub typhus Hantavirusa\n\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\tSouth Africa | \n\t\t\tTrombiculiasis | \n\t\t
\n\t\t\t\t | \n\t\t\tEurope (including British Isles, excluding Norway, Sweden, Finland, and northern Russia), Turkey, and Turkmenistan | \n\t\t\tTrombiculiasis | \n\t\t
\n\t\t\t\t | \n\t\t\tSpain, Czech Republic, England, Austria, Germany, Bulgaria, France, states of former Yugoslavia, Ukraine, Russia, Romania, Hungary, Slovakia, and Poland | \n\t\t\tTrombiculiasis | \n\t\t
\n\t\t\t\t | \n\t\t\tKorea, Europe | \n\t\t\tScrub typhusa\n\t\t\t\t Trombiculiasis | \n\t\t
\n\t\t\t\t | \n\t\t\tJapan, China, and Russia | \n\t\t\tTrombiculiasis | \n\t\t
\n\t\t\t\t | \n\t\t\tEurope | \n\t\t\tTrombiculiasis | \n\t\t
\n\t\t\t\t | \n\t\t\tSoutheast Asia, Australia, and the Pacific Islands | \n\t\t\tTrombiculiasis | \n\t\t
\n\t\t\t\t | \n\t\t\tJapan | \n\t\t\tScrub typhusa\n\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\tSoutheast Asia, Australia, and the Pacific Islands | \n\t\t\tTrombiculiasis | \n\t\t
\n\t\t\t\t | \n\t\t\tAustria | \n\t\t\tTrombiculiasis | \n\t\t
Members of this family are known by several names depending on their distribution (Table 3). They are often confused with other mites or insects and are mistakenly named as Mower’s mites [common name of
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Harvest bug, harvest mite, harvest lice, red bug, red mite, berry mite, scrub-itch mite | \n\t\t\tNorth-America, Asia | \n\t\t
Harvest mite | \n\t\t\tEurope | \n\t\t
Aoutats, rouget, bête rouge | \n\t\t\tFrance | \n\t\t
Orange tawny | \n\t\t\tIreland | \n\t\t
Augustelingen | \n\t\t\tGermany | \n\t\t
Bicho colorado, coloradilla, ácaro rojo | \n\t\t\tSouth America | \n\t\t
Isango | \n\t\t\tPeru | \n\t\t
Tlazahuate | \n\t\t\tMexico | \n\t\t
Coloradita, chivacoa | \n\t\t\tVenezuela | \n\t\t
Trombiculid mites undergo seven stages in their life cycle: egg, deutovum, larva, protonymph, deutonymph, tritonymph, and adult (Figure 1). This cycle is characterized by alternating active and inactive instars, being the larva, deutonymph, and adult the active ones. Active postlarval stages are soil dwellers that prey on various arthropods and their eggs. Deutonymphs look almost identical to adult mites. Both present eight legs, but deutonymphs are slightly smaller. Sexual dimorphism is not apparently evident [23]. Larvae parasitize all groups of vertebrates, except fishes, whereas the small mammals and birds are the main hosts [1,5,19,24]. There are just a few reports of chiggers feeding on invertebrates [3]. Humans are only accidental hosts. However, the question of the host specificity of trombiculids still arises. Most likely, trombiculids are associated with specific habitats and attack and feed on the first available animal within their favorite habitat, although they can have preference for a particular host among the available ones [23,25].
Schematic description of the trombiculids’ life cycle. (Adapted from Takahashi
During their life cycle, eggs are laid in well-drained soil, and six-legged larvae emerge from them. The general term “chigger” refers to the parasitic larval stage, and this is the name commonly given to trombiculid mites due to the importance of this instar. Chiggers are usually reddish but can vary between yellow and orange [1,26]. These tiny larvae (about 200 µm) climb onto low vegetation, where they aggregate into clusters to wait for a suitable host. On the host, chiggers mainly move to areas where the skin is especially thin and feed on lymph and tissue fluids of the dermal layer (but not blood). Ears, head, armpits, abdomen, genitalia, and the area around the tail are preferred in animals [4,27]. In humans, bites occur mainly in body exposed areas and at sites where the clothing constricts [17,28]. Once engorged (development to subsequent stage cannot take place unless larvae have fed on the host), larvae fall to the ground and develop to the nymphal stages and subsequently to adults (900–1,200 µm).
Trombiculid mites live in moist soil covered with vegetation such as grassy and weedy areas. In general, optimal living conditions require a relative air humidity of 80% (what explains that chiggers are not typically found on vegetation higher than 30 cm off the ground) and neutral to slightly alkaline soil. The optimum activity of chiggers occurs at temperatures of 25–30°C [26,29].
Trombiculid mites often form localized “mite islands” (or “mite focus”, “larvae focus”) in suitable areas inhabited by potential hosts [30]. Therefore, chiggers have a patchy distribution on the vegetation. Mite islands are quite clearly defined, and larvae could not be detected in their immediate vicinity [26,31]. A possible explanation for this focalization may be that chiggers apparently do not move more than a few meters from where they hatched. Chiggers would temporarily disperse if a host approached. On the contrary, if physical contact were not managed or if the host were not close enough for them to drop on it, chiggers would invariably and promptly return to the cluster and would continue waiting [32].
The life cycle of trombiculid mites has been mainly studied in the laboratory. The most outstanding feature of the life cycle is the constant duration of quiescent periods and the variable duration of active stages. Trombiculid mites usually have one generation per year, but with overlapping generations, each well synchronized with the seasons because they can overwinter in most stages (egg, larva, deutonynph, and adult) and because the adult mites have a long life span [33]. In boreal species, an egg-to-egg cycle ranges from 150 to 400 days, but it is shorter in tropical species [23]. In nature, the life cycle is supposed to be completed in 2–12 months or longer, depending on the species and environmental conditions. In temperate areas, there may be 1 to 3 generations per year, whereas in tropical regions the life cycle is shorter and continuous throughout the year [1]. In Europe, the duration has been estimated in five to seven months under favorable conditions [26].
As mentioned above, trombiculid mites only act as parasites during their larval stage. Thus, the greatest attention has been paid to chiggers. In addition, adults and deutonymphs of the majority of trombiculid species have never been observed on the soil surface (in fact, their habitats are mostly unknown). Therefore, the taxonomy of trombiculid mites is based solely on their larvae [34]. It is estimated that only the postlarval stage of less than 10% of the total of Trombiculidae species are known [7]. This is the case of some tropical species in contrast to the difficulty of finding active postlarval instars in northern countries [23].
It is well known that when feeding on hosts, chiggers develop a characteristic feeding tube (stylostome) in the host’s skin. The stylostome is mostly formed of the larval salivary secretions solidifying in the host’s epidermis [7]. Larva cuts the stratum corneum with its rather short chelicerae and stylostome allows chigger to reach the underlying connective tissue layer from which it obtains nutrients. The host’s tissues around the stylostome are destroyed and necrotized. Beneath the distal end of the stylostome, an interstitial food cavity containing lymphoid and epithelioid cellular liquid elements is formed [23]. The feeding period in animal host, both in nature and reared in the laboratory, usually lasts 3–6 days [26,35]. However, feeding on humans may typically vary from 3 - 8 h to 1–2 days for most non-infectious chiggers, but 2–10 days for scrub typhus vectors [1,29,36,37]. It is supposed that more than 6 h are required for the transmission of the bacterium [14]. During this period, the larva remains on the skin surface. For this reason, most trombiculid larvae can be classified as ectoparasites. Larvae of some genera, however, can partly or even entirely embed within the skin of different body cavities frequently forming various types of capsules during feeding on amphibians and mammals [23]. In such cases, the feeding time is prolonged up to several weeks or even months. In lizards, specific adaptive structures of skin, known as “mite pockets”, may evolve to decrease the possible damage from mite feeding [38]. It is generally thought that the organization and location of stylostome is species specific in trombiculid larvae, irrespectively of the host species and of the particular feeding site on the host, whereas the length of the stylostome is mostly a result of the width of the epidermal layer and the presence or absence of scabs at the attachment site [39].
Although different microorganisms have been detected in different species of chiggers, their role as vectors of infectious diseases has been only demonstrated for scrub typhus.
Scrub typhus or tsutsugamushi disease [from Japanese words meaning disease (
The disease was widely reported in soldiers during World War II [40] and now is an important illness for travelers to the endemic regions [41]. More than half (55%) of the world population lives in areas where scrub typhus is endemic, so over one billion people are at risk of acquiring the infection [42]. Approximately one million new cases have been estimated to occur annually [43]. However, this is surely an underestimation because recognition of the disease is difficult due to its overlapping clinical spectrum with other common causes of fever in this population, the lack of awareness among affected people, and the limitations of current diagnostic methods [44].
The etiological agent of scrub typhus,
There are three prototype strains: Gilliam, Karp, and Kato; however, more than 20 antigenically distinct serotypes are present in endemic areas [46], and currently over 70 strains of
Chiggers act as reservoir and vector of
Endemic regions are characterized by rice fields, scrubland, and the presence of primary deforestation [55,56]. Chiggers harboring the bacterium bite exposed individuals in vulnerable niches such as forests and infested undergrowth during occupational or recreational activities.
Several studies suggest the evidence of human infection with more than one strain of
Seasonal occurrence of scrub typhus is determined by the time of appearance of chiggers because humans are infected through bites of the larva. In temperate zones, scrub typhus season is observed mainly in the autumn but also in the spring [61]. More than 45 species of trombiculid mites are known to be infected with
Scrub typhus is confined to a 13,000,000-km2 definite geographic region, the “tsutsugamushi triangle,” where it is widely distributed (Figure 3). It extends from northern Japan, Korea, and far-eastern Russia in the North, to northern Australia in the South and to Pakistan and Afghanistan in the West, as well as the islands of the western Pacific and Indian Oceans, including Taiwan, Philippines, New Guinea, Indonesia, and Sri Lanka [62].
Tsutsugamushi triangle.
Several reports of scrub cases typhus-like infections have been described in unusual areas, indicating that a wider geographic distribution should be taken into account [47]. Thus, the recent isolation of
The disease is considered rural, and the risk of infection is closely related to occupation. In areas where scrub typhus is prevalent, most cases are acquired through agricultural exposure. Most travel acquired cases of scrub typhus are associated with outdoor activities such as camping, rafting, or trekking in endemic areas [50]. Outbreaks related to military operations have been reported [66]. The impact of scrub typhus in pregnancy is less explored. Acute scrub typhus can be transmitted vertically but congenital malformation due to infection
Scrub typhus ranges in severity from mild and self-limiting to fatal depending on the duration of the illness, the strain of
The fever appears abruptly frequently accompanied by headache, myalgia, and malaise, with peaks on the 3rd–4th day of the disease and persists for more than 3 weeks in untreated cases. About a week after the onset of the symptoms, the eschar, which is not always present, is developed. It represents localized cutaneous necrosis at the site of mite feeding and is a typical scrub typhus marker, which is considered almost diagnostic [67]. It starts as a small papule that enlarges and subsequently undergoes central necrosis, and it eventually acquires a blackened crust with an erythematous halo that resembles a cigarette burn (Figure 4).
Eschar and erythema on the fifth day of illness in the left arm of a patient of a 36-year-old patient (photo provided by Dr. Takahashi).
The common sites for finding an eschar are trunk, arms, and legs, but it also appears on the scalp, axilla, genitalia, waist, and other exposed parts of the body [14,49]. The prevalence of eschars in patients diagnosed by scrub typhus ranges from 7% to 97% [67,70]. These differences may be may be due to the difficulty in detecting small eschars in dark-skinned individuals and atypical appearance of eschars in areas of damp and moist skin. Multiple eschars have been reported in 0.6% to 2.2% of patients with confirmed scrub typhus [70]. Uncommonly, a maculopapular rash with centrifugal distribution may appear a week after the onset of these symptoms, starting on the chest, abdomen, or whole trunk and spreading to the limbs. Rash lasts a few days to a week [13,71]. Regional lymphadenopathy, characterized by tenderness and enlargement of the draining lymph node around the primary eschar, arises at the end of the first week after the disease onset [13]. Generalized lymphadenopathy appears 2–3 days later in some cases [72].
From the second week onwards, a proportion of patients (especially those untreated) will evidence of severe systemic infection. The extended vasculitis helps to explain the great diversity of clinical manifestations that have been described [49]. Respiratory symptoms, including interstitial pneumonia, acute respiratory distress, and pulmonary edema, are frequent. In fact, about 40% of scrub typhus patients complain of cough at the time of admission. Gastrointestinal symptoms comprise nausea, vomiting, abdominal pain, diarrhea, or gastrointestinal bleeding. Alterations in liver function and pancreatitis are also common. The central nervous system (CNS) is frequently affected. Indeed,
At the beginning of the infection,
The basic histopathologic findings reveal multiplication of
Due to the severity of
As in other infectious diseases, the gold standard of the diagnosis of scrub typhus is the isolation of the etiological agent by culture. Isolation of
The mainstay in scrub typhus diagnostics remains serology [79,80]. Nevertheless, despite their widespread use, all currently available serologic tests have limitations. The Weil–Felix OX-K agglutination reaction was the earliest serological tests used for clinical diagnosis of scrub typhus. It is inexpensive, easy to perform, and results are available overnight; however, it lacks specificity and sensitivity [46]. To date, the gold standard assay for the serologic detection of scrub typhus antibodies is the indirect immunofluorescence assay (IFA) [79]. Most frequently, IFA uses antigen from serotypes Karp, Kato, and Gilliam [46]. IFA is sensitive, and results are available in a couple of hours. Although it is accepted that a ≥4-fold increase in antibody titer between two consecutive samples (acute and convalescent-phase) is diagnostic, this is a retrospective diagnosis and cannot guide initial treatment [79]. Anyway, IFA is expensive and requires a level of technical expertise and equipment that may not be available in rural areas. Indirect immunoperoxidase is an alternative that eliminates the expense of a fluorescent microscope by substituting peroxidase for fluorescein [80].
The development of PCR amplification-based approaches have been incorporated to the diagnoses of infectious diseases even in nonreference laboratories. PCR has potential benefits in detecting
The diagnosis and subsequently the antibiotic treatment are often missed or made late due to the lack of effective commercially available diagnostic tests and the lack of specificity of the early clinical presentation. It is important to remark that treatment must begin whenever scrub typhus is clinically suspected, without waiting for microbiological confirmation. It is well known that delayed treatment leads to complications such as adult respiratory distress syndrome, disseminated intravascular coagulation, acute renal failure, meningitis, meningoencephalitis, and gastrointestinal tract bleeding [57]. Bacterial proliferation and the time of antibiotic treatment are very important predictors of lethality.
The clinical discrimination of scrub typhus from other undifferentiated fevers is often very difficult because the clinical symptoms are similar. In patients presenting an eschar and/or rash, and generalized or regional lymphadenopathy in a endemic area, scrub typhus should be considered in the differential diagnosis along with rickettsialpox, Mediterranean spotted fever, dengue, leptospirosis, and murine typhus [55,71].
Mortality in the pre-antibiotic era was variable and in some series approached 60%, but specific and effective antimicrobial chemotherapy is now available [80]. Doxycycline and chloramphenicol are both effective oral or intravenous agents against scrub typhus, dissipating fever in 24 h in most patients [71]. Although the disease can be treated effectively with these antibiotics, reinfection and relapse frequently occur due to the wide variety of antigenically distinct serotypes [85]. Azithromycin and rifampicin are alternative drugs [61].
Currently, effective chemoprophylaxis or vaccination approaches for dealing with
Nowadays,
There are a lot of references in the old scientific literature that associate chiggers with the transmission of several pathogens, being
Several rickettsiae previously found in humans as
Chiggers are also suspected to be vectors of viral diseases [96]. The role of
“Trombiculiasis,” also called “trombiculosis,” “trombidiosis,” “chigger dermatitis,” “scrub itch,” or “seasonal dermatitis” is defined as an skin allergic reaction (dermatitis) caused by the salivary secretion of biting chiggers [1,99]. In our experience, as well as it is described in the literature, trombiculiasis is a common but underreported ectoparasitosis that is probably often misdiagnosed [100]. In many cases, trombiculiasis was primarily confused with a plant allergy [29], as it was the case in our country. The better understanding of trombiculid mites’ life cycle and their interaction with humans have made possible a proper knowledge of this disease.
Although not often reported in the literature, trombiculiasis is prevalent all over the world, except for the Arctic region [20]. However, it can be easily missed because it is normally transient and no systemic signs are present.
In nontropical areas, bites are particularly common in the late summer and early autumn, when outdoor activities are maximal and the peak of abundance of chiggers occurs [19,20,26,28,101]. Thus, trombiculiasis is also an important threat to travelers that visit infested areas being unaware of chiggers [37].
Mite islands are usually found in cleared land and scrub bush with grassy vegetation, warm soil temperatures, and high humidity. Suitable habitats also require the presence of potential hosts [31]. Trombiculids are also found in parks, gardens, lawns, and moist areas alongside lakes and streams [1]. Clusters of chiggers are usually waiting at elevated points of the ground-level vegetation, such as the end of grass stalk or on dried tree branches, until an animal or human passes by [8] (Figure 5).
Cluster of unfed chiggers. Original contribution.
People are usually bitten during outdoor activities for recreational or professional purposes such as hunting, hiking, mushroom picking, forestry work, etc. [8,28,101]. Although the rate of people bitten is very high, apparently some persons are preferred by the chiggers, resulting in massive parasitization, while others remain unmolested even in highly infested areas [26,28].
More than 3,000 species of chiggers are known, but about 15 frequently bite humans and domestic animals causing cutaneous reactions [102] (Table 2). Species currently considered as the most frequent cause of trombiculiasis are
Seven chigger species are proven to cause trombiculiasis in Europe:
Although well known in many European regions, the scientific description of trombiculiasis cases have been only reported from Italy [36] and Spain [28]. Moreover, four different cases suspected of trombiculiasis caused by
In Southeast Asia, Australia, and the Pacific Islands, the main involved mite is
A single case of trombiculiasis has been reported in Africa.
It is generally accepted that to suffer from trombiculiasis, the antecedent of direct contact with vegetation is required. Nevertheless, it is important to remark that one of the patients reported in Guarneri
Another example of disease caused by chiggers but without direct contact to vegetation is also a case of conjunctivitis induced by
Previously, patients were rarely referred for dermatologist review unless symptoms were severe. Over the last 15 years, cases of severe trombiculiasis have increased in western Germany and in the United Kingdom [31,107]. The influence of climate and environmental variations, changes in leisure habits, and broader environmental awareness in the population have been speculated as possible explanations of this increase [26].
Chigger bites are initially painless, and frequently the only sign of exposure is a severe itching. Then small, red bite like lesions appears on the skin [1,19]. Typical 1–2 mm diameter, pruritic, erythematous papules appear at the sites of the bites 3–24 h after exposure (Figure 7). [10,28,37,101,103].
Typical papules of trombiculiasis in a patient bitten in La Rioja, Spain. Original contribution.
The presence of papulovesicles, which may gradually progress to pustules, crusty, scabby, eczematous, and ulcerated confluent forms of skin lesions, has also been described [17,26,103]. The pruritus is very intense, especially at night in bed. Although the chigger is not present, the papules and discomfort may persist up to 2–3 weeks, but regression of localized itching is generally observed in 1 week [26]. Since trombiculid mites share habitat with hard ticks, people may result coinfested. In fact, a patient suffering from trombiculiasis and having an “erythema migrans” (related to Lyme disease) was treated in our hospital. Furthermore, during an episode of trombiculiasis, two affected people and their dog had
Chiggers usually “attack” in large numbers due to the clustering phenomenon, resulting in multiple grouped bites on infested hosts [32]. Given their preference for attaching where the skin is thin or in tighter contact with clothes, the bites tend to be concentrated around the knees, antecubital fossae, and ankles, thighs, axillary region, groins and genitalia, and wrists, and in areas constricted by clothing, such as along the belt line or the elastic borders or undergarments [1,17,26,28,101].
Trombiculiasis-causing chiggers do not survive more than 1–2 days feeding on humans due to the adverse host reaction and because they are remove by scratching [1,23]. The irritant effect of chiggers’ saliva seems to induce both dermal inflammatory reaction of moderate intensity and an adaptive immune response. These salivary components generally reveal relatively moderate lytic properties and weak immunological characters [111]. The type of skin inflammatory response during the feeding of trombiculid larvae is determined by concomitant factors such as the site of the parasite localization, condition of the host’s skin, among others [39]. Repeated exposures result in a more rapid and intense adaptive immune response [102]. Anyway, permanent or long-term human residents in an infested area increase their immunity as a result of continued bites, and some people can develop a high degree of tolerance to the antigenic substances injected by chiggers. However, the occurrence of unusual outbreaks of urticaria, increasingly severe pruritus or bulla formation, are indications of hypersensitivity to such antigenic substances [5]. It is clear that the natural hosts of trombiculids have to be sensitized with respect to parasites that may lead the development of the strong specific inflammatory response [39, 111].
Diagnosis is based on the clinical manifestations, taking into consideration the history of being in contact with vegetation and the seasonality. As the etiological agent of the trombiculiasis is rarely found in the skin of the patients, these reactions are often misinterpreted and has been wrongly associated to plant allergies, flea or mosquito bites, or even scabies [26]. Cutaneous findings are nonspecific, so clinical examination would probably lead to a wrong diagnosis of a nonspecific itchy dermatitis, leading to use inadequate or needless medications. Then an accurate anamnesis is essential for making such challenging diagnosis. Chigger bites should be considered whenever any unexplained skin eruption is presented to the physician.
Chiggers are not easily seen on human’s skin with the naked eye, and common magnification lenses and even dermoscopy (×10 magnifications) have some limitations. Recently, videodermatoscopy (×150 magnification) has been used to diagnose trombiculiasis caused by
Differential diagnosis includes infestations with other mite species (e.g., the itch mite
Treatment is primarily symptomatic and consists of antipruritics, antihistamines, and topical corticosteroids [112]. In our medical consultation, supportive measures such as oatmeal baths are also highly recommended. Antibiotics might be needed in case bacterial superinfection resulting from repeated scratching occurs.
After being in known areas of chigger activity, the dermatitis can be minimized, and the recovery time can be significantly shortened, by taking a hot soapy shower or bath and washing clothes with soap and hot water. These good practices are recommended immediately after exposure, in order to remove both unattached and attached chiggers, before they have firmly anchored to the skin (generally within 3–6 h following attachment) [1,26]. Once the papules are present, scratching should be avoided in order to prevent to excoriate the lesions and the infection.
Patients should be advised on preventive measures, including avoidance of high-risk areas when larvae are active. Since in many cases these results are unreasonable and contact with trombiculid mites is unavoidable, chigger infestation may be minimized by wearing protective clothing and soaking socks and trouser legs with insect repellents [112]. Usually, the use of repellent sprays and lotions containing benzyl benzoate or diethyltoluamide has been recommended [29]. Permethrin was successfully used as a clothing treatment for personal protection against chigger mites [113]. However, the active ingredient is no longer available for this purpose in the European Union [10,26].
Although better than before, our contemporary knowledge on the biology and ecology of these mites is still extremely limited. Currently, no reliable recommendations for the control of mites, except from personal protection, can be given [26].
Apart from trombiculiasis, chiggers are responsible for other less frequent conditions. The summer penile syndrome is a seasonal acute hypersensitivity reaction attributed to chigger bites [114,115]. It occurs in young boys with a history of bites or outdoor exposure, and it is characterized by the rapid onset of edema and pruritus of the penile skin. It has been described most commonly in the spring and summer in different regions of United States [114,115]. Another example is the unique case of conjunctivitis induced by
Chiggers are worldwide distributed ectoparasites that have to be taken into account as human pathogens. Their medical importance is based on their role as vectors of scrub typhus and as causative agents of trombiculiasis.
Scrub typhus remains as one of the most life-threatening infection in Asian Pacific regions. The development of a prophylactic vaccine against
More research studies are necessary in order to clarify the relationship of chiggers with other bacterial or viral infections.
Trombiculiasis is an extended but underreported condition that should be considered when pruritic dermatitis in people exposed to vegetation occurs. In risky areas, personal protection is the unique recommendation to reduce the parasitation. A deeper understanding of chiggers’ life cycle, epidemiology and seasonality of trombiculiasis is required for a correct management of this annoying dermatitis.
We are grateful to all members from the Centre of Rickettsiosis and Arthropod-Borne Diseases, Hospital San Pedro-Centre of Biomedical Research (CIBIR), Logroño (La Rioja), Spain. We also thank to Dr. Shatrov and Dr. Stekolnikov from the Zoological Institute of the Russian Academy of Science, St.-Petersburg, Russia, and Dr. Takahashi from the Saitama Medical University, Saitama, Japan, for providing us the pictures and for their invaluable help. Financial support was provided in part by two grants (FOMENTA 2007/14 and PREDOC 2008/29) from “Consejería de Educación, Cultura y Deporte del Gobierno de La Rioja”, Spain.
Glycans are long chains of carbohydrate-based polymers composed of repeating units of monosaccharide monomers bound together by glycosidic linkages. Complex and diverse glycans appear to be ever-present macromolecules in all cells in nature, and essential to all biological systems. Glycans play physical, structural, and metabolic roles in living organisms [1]. In the last century, knowledge on the biochemistry and biology of nucleic acids and proteins rapidly increased. Nevertheless, it has been much more difficult to understand the biology of glycans, which are main component of the cell surface [2]. The biosynthesis mechanism of glycans is totally different from those of nucleic acids and proteins. Biological mechanism of glycans is complex, which makes analysis of them extremely difficult and limits our understanding of mechanisms responsible for biological functions of glycans [3]. After the genomics revolution and development of high-throughput technologies, scientific interests increased to understand the characterization, function, and interaction of other significant biomolecules (e.g., DNA transcripts, proteins, lipids, and glycans) for the cell. These interests resulted in emergence of other omic types such as transcriptomics, proteomics, metabolomics, lipidomics and glycomics [4]. From the perspective of evolutionary conservation, conservation decreased in the order genomics, transcriptomics, proteomics, metabolomics, lipidomics, and glycomics. On the other hand, reverse order is present for informational diversity of these fields of omics (Figure 1) [5].
\nThe degree of evolutionary conservation and informational diversity for the omics fields.
With the progress in high-throughput technologies, studies on glycobiology increased to screen cells quickly and generate huge glycomics data sets. Moreover, advanced analytical techniques and tools for data analysis provide possibility to improve high-throughput techniques for screening glycans as a marker of diseases and to classify structure of glycans in therapeutic proteins [6].
\nGlycans are linear or branched sugar macromolecules composed of repeating monosaccharides linked glycosidically. Beside nucleic acids and protein, glycans are known as the third dimension in molecular biology [7, 8]. These macromolecules can be found in the form of heteropolysaccharides or homopolysaccharides. Furthermore, glycoconjugates (glycolipid, glycoprotein and proteoglycan), can be also considered as glycan despite the fact that the carbohydrate part of glycoconjugates are only oligosaccharides [9]. In glycoproteins, oligosaccharides and proteins can be linked in different forms, namely N-linked glycans and O-linked glycans. N-acetylglucosamine is linked to the amide side chain of asparagine in N-linked glycans. C-1 of N-acetylgalactosamine is linked to the hydroxyl function of serine or threonine in O-linked glycans [10].
\nWith the increasing researches in glycoscience, many different roles of glycans in biological systems have been revealed in the last decades. Significant functions of glycans have been determined in numerous research areas such as immunity, development and differentiation, biopharmaceuticals, cancer, fertilization, blood types, infectious diseases, etc. Glycans are called as “cloths of cells” since they are present on the surface of the cell and responsible for the signaling and communications between cells. Glycans can be classified in several ways. Varki divided the biological roles of glycans into four main categories: (1) structural and modulatory roles, (2) extrinsic (interspecies) recognition of glycans, (3) intrinsic (intraspecies) recognition of glycans, and (4) molecular mimicry of host glycans. A total of 50 distinct roles are defined under these main categories [1].
\nGlycans perform huge range of biological function due to the diversity of them, and they have significant roles in several physiological and pathological events, such as cell growth, cell signaling, cell-cell interactions, differentiation, and tumor growth [11, 12, 13]. In biological systems, information is carried by glycans, which are significant biomarker candidates for many diseases such as cardiovascular diseases, deficiencies of immune system, genetically inherited disorders, several cancer types, and neurodegenerative diseases [14, 15, 16]. Alteration of glycan expression is observed during the development and progression of these diseases, which is caused by misregulated enzymes such as glycosyltransferases and glycosidases. As a result, altered glycan structures have potential use for the identification of these diseases at an early stage. Besides significant role of glycans in diagnosis and management of disease, they can be used as therapeutics, markers for identification and isolation of special cell types, and targets in discovery of drugs [17, 18, 19]. Moreover, glycans can be considered as an ideal target for vaccines due to the presence of them on the surface of several different pathogens and malignant cells. High affinity and exquisite specificity of other molecules to recognize glycans are a vital point of developments in the research of glycans and related diagnostics and therapeutic applications.
\nGlycosylation plays significant roles in many biological processes including growth and development of cell, tumor growth and metastasis, immune recognition and response, intercommunication of cells, and microbial pathogenesis. As a result, glycosylation of proteins is the one of the most common and significant posttranslational modifications of proteins [20, 21]. Furthermore, more than half of proteins undergo glycosylation [6]. Many issues such as genetic factors, nucleotide levels of monosaccharides, cytokines, metabolites, hormones, and ecological factors can affect and change glycosylation process [20, 21, 22, 23, 24]. Thus, integration of omics approaches (e.g., proteomics, genomics, transcriptomics, and metabolomics) to the field of glycobiology is essential to view the big picture of the whole biological system [20, 21, 25]. Furthermore, for the analysis of glycans and glycosylation pathways, many glycoinformatics tools and databases are now accessible [6].
\nGlycomics is one of the most recent types of omics area which is responsible for the structure and function evaluations of glycans in bio-systems [26]. Integrating glycomics to other fields of omics provides new system-scale insights in integrative biology [27].
\nMoreover, glycomics informs other crucial scholarships such as systems glycobiology and personalized glycomedicine that collectively aim to explain the role of glycans in person-to-person and between population variations in disease susceptibility and response to health interventions such as drugs, nutrition, and vaccines. Glycosylation is present in both normal and diseased individuals [1]. Abnormal glycosylation is observed in a variety of diseases. Difference between glycosylation patterns of healthy and diseased individuals can be used as glycobiomarkers in personalized medicine [28]. As a result, many new medical implications will be enabled by glycobiology and glycopathology [29]. Development of glycomedicine can be contributed by holistic approach of functional and structural glycomics, which have applications in therapy development, fine-tuning immunological responses and the performance of therapeutic antibodies and boosting immune responses [28, 30]. Many applications of glycan arrays are present in many fields, from basic biochemical research to biomedical applications [31]. In addition to shotgun glycan microarrays [32], cell-based array resource has been developed [33]. These developments enable deeper understanding of the many biological roles of the glycome. Nevertheless, multiplatform and multiomics technologies are expected to further extend the knowledge of molecular mechanisms of glycans.
\nMonosaccharides represent four free hydroxyl groups for the linkage of another monosaccharide. As a result of this, glycans have more complex structure compared to structure of peptides and nucleic acids. It is known that glycans are more than the sequential monosaccharides; monomer types, modifications, the position of modifications around the ring of sugar, glycopolymer branching, and linkages chirality are the factors that are responsible for the complexity. As a result, sequencing techniques used for peptides or DNA (Sanger or Edman sequencing) are not appropriate for glycans. Moreover, most of the glycans are present as a part of a glycoconjugate. Therefore, glycan part should be released from lipid or protein part, by the use of enzymatic or chemical methods and isolated for analysis.
\nIn the last decades, a number of techniques developed and applied to determine structure of the glycans with different degrees of detail [34]. A traditional method is to label the glycoconjugates radioactively and then apply anionic exchange, gel filtration, or paper chromatographic analyses prior and subsequent to enzymatic or chemical treatments. Still, it is difficult to figure out the definition of the actual structure; in consequence, in earlier studies, if adequate amounts were present, gas chromatography together with mass spectrometry (GC-MS) and/or nuclear magnetic resonance (NMR) studies were performed. However, these analyses involve special expertise to perform the research and interpret the results, particularly if standards were unavailable to compare with results.
\nHPLC and UPLC have superseded simple chromatography systems in recent years, and radioactive labeling has been replaced by fluorescent labeling. Nowadays, variable columns such as graphitized carbon, reversed-phase (RP), anion exchange, normal phase, or hydrophilic interaction resins can be used along with suitable enzymatic/chemical treatments. A less used alternative is to analyze glycans at elevated pH. As a result of this, the hydroxyl side chain deprotonation occurs, that enables the usage of anion exchange together with amperometric detection (HPAEC-PAD). On the other hand, glycan structure cannot be defined only by HPLC retention times, and for the unknown structure, analyses in the absence of standards should be interpreted with attention [35].
\nWith the improvements in the types and the sensitivity, contribution of mass spectrometer to studies of glycans and glycoconjugates has increased in the last decades [36, 37]. At first, for the analysis of variable types of glycopolymers from different sources, researchers used fast atom bombardment mass spectrometers (FAB-MS). For the analyses with FAB-MS, chemical modifications such as methylation and acetylation were required. As an alternative method, matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was developed and analysis of both permethylated and native glycans can be performed with MALDI-TOF MS. Furthermore, current numerous electrospray techniques with many detector types have significance in glycomics. Mainly, a significant point in MS-based analysis is the capability to obtain glycan fragments. Besides, the preparation and separation techniques are of great importance to obtain the best results. As a consequence, liquid chromatography-mass spectrometry (LC-MS) in a number of forms is in general necessary since glycans with low abundancy or poor ionization capacity can be suppressed in the case of whole glycome examination. Moreover, reanalysis after the treatment of a chemical and an enzyme results in maximization of the ability to obtain clear results from the existing data.
\nGlycan is generally a part of the glycoconjugate; thus, glycoproteomics and glycolipidomics that consider both peptide/lipid and glycan parts are significant fields. At this point, mass spectrometry technique comes into prominence [38]. Both glycan and polypeptide/lipid parts can be studied with this technique. On the other hand, glycan parts of glycoproteins and glycolipids can be in various forms even if the polypeptide/lipid part is same, defined as microheterogeneity. The nature of glycan modifications is non-template driven and that leads to mentioned microheterogeneity [39].
\nBlotting technique can be used for simple screens. Reagents such as lectins and anti-carbohydrate antibodies with low specificity are often used for this technique; as a result, misleading results are often obtained [40]. Still, lectins, and antiserums have significance for immune responses in animals. New array-based systems can provide essential clues on proteins bounded to glycans [41].
\nDevelopments in integrative informatics and systems biology of glycans based on a holistic approach can make available a more comprehensive analysis. It elucidates annotation of glycans, enzyme levels, abundances of glycans biosynthesis pathways, and other omics data sets which are complementary. Though, several tools are developed for proteomics and genomics data sets and standard bioinformatics approaches are used in these tools, the complex relationships between diverse components (such as glycans, enzymes, transporters, and sugar nucleotides) of the glycosylation process are not considered by most of the existing bioinformatics tools. Consequently, the use of these tools for glycomics data sets has some limitations. The genome does not encode glycans directly and unlike proteins, interconnected action of many enzymes provides assembly of glycans. Due to mentioned limitations, developments in glycan analysis tools and methods have been delayed and most of the present glycoinformatics tools are special for single type data analysis [42, 43, 44, 45]. For instance, database matching between obtained MS results and specific glycans in a glycan library is used as a mutual method for MS-based glycoprofiling for the purpose of individual peak annotation [46, 47]. If the complexity of glycosylation is wanted to be considered, enzymes of the organism which synthesize the studied glycans should generate glycan structures used for the annotation of the spectrum [48]. Due to this alignment, activities of enzyme and those structures assigned to each peak in the same spectrum will be consistent.
\nAlthough many omics approaches have significant progress in the last decades, existing techniques of bioinformatics are still unsatisfactory for the integration of varied data sets [49, 50, 51]. For instance, relations between expression levels of gene and specific glycan linkages abundance are investigated by statistical database-driven approaches, and these approaches could not predict quantity of detailed glycan distributions [50, 51]. This indicates the necessity of glycoinformatics and systems biology tools integration for the identification of glycan structure and these should be also linked to the information of gene expression responsible for glycosylation enzymes which synthesize these glycans. In order to understand levels of mRNA which is related with the distribution and quantity of glycans present within healthy and diseased cells, mathematical modeling of glycosylation is considered as a promising method [48, 49, 52].
\nVariability in the platform of analytical high-throughput experiments can be reduced by data integration approach. Increased confidence of biomarker predictions and recommendations can be obtained if different data from experiments such as glycogenes expression information or mass spectra profile confirm the results from integrative glycoinformatics and systems glycobiology tools. Although integrated glycoinformatics tools have limitations in analytical sensitivities, analysis and comparison of various results with various platforms are enabled by these tools [6].
\nThe integration of glycomics with other various omics data is promising for further innovation in diagnosis and treatment of diseases [30]. The start point of multiomics data integration is to sort the data based on the omics level. In the following part, association between glycomics and other omics levels will be represented.
\nIntegration of glycomics with genetic sequence can be occur in a number of ways. For instance, glycosylation site can be gained or lost with the variation of sequence. A single-nucleotide polymorphism (SNP) affects glycosylation of prostate-specific antigen (PSA) and an altered function of it increases the risk of prostate cancer. Functional analysis indicated that the stability and structural conformation of PSA are affected by missense variant rs61752561, which causes an additional extra glycosylation site [53]. Furthermore, computational studies revealed that variations in cancer somatic cells have potential to cause gain or loss of glycosylation. In addition to SNP, variations in structure and abnormalities in cytogenetics could be integrated with glycomics. Cytogenetic abnormalities have been associated with glycome expression [54]. A particular glycosyltransferase can glycosylate numerous proteins, so genetic variants of it have extraordinary significance because function of many glycoproteins can be affected by a single difference in activity of enzyme. Several downstream pathways and cell metabolism can be affected by a genetic or epigenetic variant that is called pleiotropic effect of genetic or epigenetic variant on glycosylation [55].
\nMost of the glycomics research have been done at the level of transcriptome, which can be performed either at a particular locus or with a technology of microarray. In colorectal cancer (CRC), glycosyltransferase ST6GAL1 is associated with cancer, and altered ST6GAL1 expression was found by The Cancer Genome Atlas (TCGA) mining [56]. Moreover, in order to identify differential expression of glycosylation-related genes Saravanan et al. [57] used GLYCOv2 glycogene microarray technology. In the further studies, myeloma was compared with normal plasma cell samples and 60 upregulated and 20 downregulated genes were found among 243 genes in glycan-biosynthesis pathway [54]. A novel molecular signature that is enriched for enzymes of glycosylation was revealed by meta-analysis performed for gene expression of prostate cancer [58]. Additionally, hepatocellular carcinoma was investigated by reviewing gene expressions that are related with core fucosylation of the disease [59]. More systematic reviews and meta-analyses are required to develop reliable biomarkers.
\nStudies on glycoproteomics include peptide structures, glycan structures, and sites of glycosylation [30]. Single site on the peptide chain can be glycosylated by different glycans, and by this way, glycans can modulate function of the protein [60]. In the literature, diverse techniques were associated with different phenotypes, for instance, breast cancer, colon cancer, liver cancer, skin cancer, ovary cancer, bladder cancer, and neurodegenerative diseases, and additionally, a number of structural variations including sialylation, fucosylation, degree of branching, and specific glycosyltransferases expression [61, 62, 63]. For instance, cerebrospinal fluid N-glycoproteomics is of significant importance in early diagnosis of Alzheimer’s disease. Glycosylation patterns were assessed in patients and therapeutics targets such as glycoenzymes were suggested [63]. For the diagnosis of pancreatic cancer, specific glycoforms together with protein levels should be measured to improve potential for diagnosis [64]. Glycoproteins constitute the majority of protein tumor markers approved by Food and Drug Administration (FDA), and they are also used currently in clinical practice. Many of these glycoproteins have alterations of glycosylation in cancer [60]. MUC-1 (CA15-3/CA27.29) [65] and plasminogen activator inhibitor (PAI-1) [66] are biomarkers of breast cancer; beta-human chorionic gonadotropin (Beta-hCG) [67] is biomarker of colorectal cancer; alpha-fetoprotein (AFP) [68] is a biomarker of liver cancer and germ cell tumors; chromogranin A (CgA) [69] is a biomarker of neuroendocrine tumors; MUC16 (CA-125) [70] and HE4 [71] are biomarkers of ovarian cancer; and many other biomarkers are present for a variety type of cancer. Most of the results in the existing publications are heterogeneous; thus, systematic integrative reviews of the literature are required for further development of glycoproteomics.
\nMetabolomics is the large-scale study of the small molecule substrates that investigates variations in the metabolites within cells, biofluids, tissues, or organism. Metabolomics and glycomics were investigated in the research of post-traumatic stress [72]. According to the researchers of this study, these biomarkers together with omics markers should be integrated to understand the biological differences responsible for this stress. For discovery of liver cancer biomarker, proteomics, glycomics, and metabolomics were integrated and this integration enhanced performance when compared to separate omics data [73]. Physiological and pathological conditions are reflected by metabolomic and glycomic data in individuals. Similar to metabolites, small glycans can be quantified easily [74]. Human Metabolome Database (HMDB) is the most inclusive metabolite source that offers significant resource for the discovery of biomarkers in glycomics [75].
\nGlycolipidomics is a scientific field that identifies and quantifies glycolipids. For the determination of physiological and pathological conditions of individual, glycolipids can be used as a specific biomarker. They take role in development of neurological and neurodegenerative diseases, such as Lewy body dementia, Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia [30]. Furthermore, glycosphingolipids are associated with cancer and they are promising molecules for diagnosis as biomarkers and for malignant tumor immunotherapy as target [76]. More recently, Dehelean et al. [77] reviewed trends in the discovery of glycolipid biomarker by MS.
\nInteractomics is the research field that investigates whole set of interactions between molecules including glycans. Interaction of glycans with glycan-binding proteins (GBPs) is of significant importance in immune response, signaling, cell recognition, infections, neurodegenerative diseases, and cancer. High-throughput technologies ease studies also on interactomics [78]. UniLectin3D is a database that catalog lectins that are most studied GBPs. Database consists of curated information on 3D structures and interacting ligands [79]. Lectin-glycan interaction on surface of the cell is a significant factor for the regulation in corneal biology (i.e., corneal infection) and pathophysiology (i.e., inflammation) [80]. The whole protein-glycan interactome information has not been obtained yet [41]. For future studies, estimated number of interactions is of importance. GenProBiS is a bioinformatics tool that analyzes binding sites between peptide-peptide, peptide-nucleic acid, and peptide-compound and also sites of glycosylation and other posttranslational modifications. Furthermore, it provides maps between sequence variations and structure of protein. More developments of bioinformatics tools analyzing huge data will prioritize the objections for experimental verification and provide contribution to interactomics development.
\nIn future studies, many other omics fields should be associated with glycomics such as comparative genomics, epigenomics, regulomics, NcRNomics, MiRNomics, LncRNomics, etc. Although glycomics is the significant field related with molecular interactions, information about how these complex processes controlled by regulatory network is still inadequate. In addition to classic omics fields, omics applications such as iatromics, environmental omics, pharmacogenomics, and nutrigenomics should also be reviewed.
\nGlycoinformatics combines bioinformatics tools with glycome. Glycomics data is collected by the tools and databases to investigate, reveal, and associate with other repository of related data of proteomics, genomics, and interactomics. Commonly used tools and databases are summarized in Table 1.
\n\n | Name | \nDescription | \nLink | \n
---|---|---|---|
Databases | \nCAZY | \nDescribes the families of structurally related catalytic and carbohydrate binding modules (or functional domains) of enzymes that degrade, modify, or create glycosidic bonds | \n\nhttp://www.cazy.org/\n | \n
KEGG GLYCAN | \nThe KEGG GLYCAN structure database is a collection of experimentally determined glycan structures. It contains all unique structures taken from CarbBank, structures entered from recent publications, and structures present in KEGG | \n\nhttps://www.genome.jp/kegg/glycan/\n | \n|
Glycan Library | \nA list of approximately 830 lipid-linked sequence-defined glycan probes derived from diverse natural sources or chemically synthesized | \n\nhttps://glycosciences.med.ic.ac.uk/glycanLibraryIndex.html\n | \n|
GlycoMob | \nAn ion mobility-mass spectrometry collision cross-section database for glycomics | \n\nhttp://www.glycomob.org\n | \n|
GlycoBase 3.2 | \nA database of over 650 N- and O-linked glycan structures of HPLC, UPLC, exoglycosidase sequencing, and mass spectrometry (MALDI-MS, ESI-MS, ESI-MS/MS, LC-MS, LC-ESI-MS/MS) data | \n\nhttps://glycobase.nibrt.ie/glycobase/show_nibrt.action\n | \n|
Glyco3D | \nA portal of 3D structures of mono-, di-, oligo-, and polysaccharides and carbohydrate recognizing proteins (lectins, monoclonal antibodies, glycosyltransferases) and glycosaminoglycan binding proteins | \n\nhttp://glyco3d.cermav.cnrs.fr/home.php\n | \n|
GlyMAP | \nAn online resource mapping of the variational landscape of glycoactive enzymes | \n\nhttp://glymap.glycomics.ku.dk/\n | \n|
Glycosciences.de | \nA collection of databases and bioinformatics tools for glycobiology and glycomics | \n\nhttp://glycosciences.de/index.php\n | \n|
UniProtKB | \nThe universal protein sequence database with information on glycosylated proteins | \n\nhttp://www.uniprot.org/\n | \n|
UniCarbKB | \nUniCarbKB is a curated and annotated glycan database which curates information from the scientific literature on glycoprotein-derived glycan structures. It includes data previously available from GlycoSuiteDB | \nhttp://www.unicarbkb.org/ | \n|
UniCarbDB | \nUniCarbDB is a platform for presenting glycan structures and fragment data characterized by LC-MS/MS strategies. The database is annotated with high-quality datasets and is designed to extend and reinforce those standards and ontologies developed by existing glycomics databases | \n\nhttp://unicarb-db.biomedicine.gu.se/\n | \n|
UniPep | \nA database for human N-linked glycosites: a resource for biomarker discovery | \n\nhttp://www.unipep.org\n | \n|
SugarBindDB | \nSugarBindDB provides a collection of known carbohydrate sequences to which pathogenic organisms specifically adhere via lectins or adhesins. The data were compiled through an exhaustive search of literature published over the past 30 years by glycobiologists, microbiologists, and medical histologists | \nhttp://sugarbind.expasy.org/ | \n|
Consortium for Functional Glycomics (CFG) | \nThe CFG serves to combine the expertise and glycomics resources to reveal functions of glycans and glycan-binding proteins (GBPs) that impact human health and disease. The CFG offers resources to the community, including glycan array screening services, a reagent bank, and access to a large glycomics database and data analysis tools | \n\nhttp://www.functionalglycomics.org/\n | \n|
GLYCONAVI | \nA Website for carbohydrate research. It consists of the “GlycoNAVI database” for molecular information of carbohydrates, and chemical reactions of carbohydrate synthesis, the “Route Searching System for Glycan Synthesis,” and “GlycoNAVI tools” for editing two-dimensional molecular structure of carbohydrates | \n\nhttp://www.glyconavi.org/GlycoNAVI\n | \n|
GlycoGeneDataBase (GGDB) | \nGlycogene includes genes associated with glycan synthesis such as glycosyltransferase, sugar nucleotide synthases, sugar-nucleotide transporters, sulfotransferases, etc. | \n\nhttps://acgg.asia/ggdb2\n | \n|
Carbohydrate Structure Data Base (CSDB) | \nCSDB covers information on structures and taxonomy of natural carbohydrates published in the literature and mostly resolved by nuclear magnetic resonance (NMR). CSDB is composed of two parts: Bacterial and Archeal (BCSDB) and Plant and Fungal (PFCSDB) | \n\nhttp://csdb.glycoscience.ru/database/core/help.php?topic=rules\n | \n|
EXPASy | \nThis section of the ExPASy server gathers a toolbox for processing data as well as simulating, predicting, or visualizing information, relative to glycans, glycoproteins, and glycan-binding proteins | \nhttp://www.expasy.org/glycomics | \n|
TOOLS | \nCASPER | \nA tool for calculating NMR chemical shifts of oligo- and polysaccharides | \n\nhttp://www.casper.organ.su.se/casper/\n | \n
Glycan Builder | \nA software library and set of tools to allow the rapid drawing of glycan structures with support for all of the most common symbolic notation formats | \n\nhttp://www.unicarbkb.org/builder\n | \n|
GlycoDomainViewer | \nAn online resource to study site glycosylation with respect to protein context and conservation | \n\nhttp://glycodomain.glycomics.ku.dk/\n | \n|
Glynsight | \nGlynsight offers visualization and interactive comparison of glycan expression profiles. The tool was initially developed with a focus on IgG N-glycan profiles but it was extended to usage with any experiment, which produces N- or O-linked glycan expression data | \n\nhttps://glycoproteome.expasy.org/glynsight/\n | \n|
GlycoMinestruct | \nA new bioinformatics tool for highly accurate mapping of the human N-linked and O-linked glycoproteomes by incorporating structural features | \n\nhttp://glycomine.erc.monash.edu/Lab/GlycoMine_Struct/\n | \n|
GlyMAP | \nAn online resource mapping out the variational landscape of glycoactive enzymes | \n\nhttp://glymap.glycomics.ku.dk/\n | \n|
GlycoMod | \nAn online tool to predict oligosaccharide structures on proteins from experimentally determined masses | \n\nhttp://web.expasy.org/glycomod/\n | \n|
GlycoMiner/GlycoPattern | \nSoftware tools designed to detect, characterize, and perform relative quantitation of N-glycopeptides based on LC-MS runs | \n\nhttp://www.szki.ttk.mta.hu/ms/glycominer/\n | \n|
Glycosciences.de | \nA collection of databases and bioinformatics tools for glycobiology and glycomics | \n\nhttp://glycosciences.de/index.php\n | \n|
RINGS | \nA Web resource providing algorithmic and data mining tools to aid glycobiology research | \n\nhttp://rings.t.soka.ac.jp/\n | \n|
MonosaccharideDB | \nA comprehensive reference source for monosaccharide notation | \n\nhttp://www.monosaccharidedb.org/start.action\n | \n|
NetOGlyc | \nNext generation prediction of O-glycosylation sites on proteins | \n\nhttp://www.cbs.dtu.dk/services/NetOGlyc/\n | \n|
GlycoSpectrumScan | \nA Web-based bioinformatic tool designed to link glycomics and proteomics analyses for the characterization of glycopeptides. GlycoSpectrumScan is a MS platform which is independent, freely accessible, and profiles glycopeptide MS data using beforehand separately acquired released glycan and proteomics information. Both N- and O-glycosylated peptides as well as multiply glycosylated peptides can be analyzed | \n\nhttps://github.com/wliu1197/glycospectrumscan\n | \n|
SimGlycan | \nA predictive carbohydrate analysis tool for MS/MS data | \n\nhttp://www.premierbiosoft.com/glycan\n | \n|
SugarQb | \nSugarQb enables genome-wide insights into protein glycosylation and glycan modifications in complex biological systems. This is a collection of software tools (Nodes) which enable the automated identification of intact glycopeptides from HCD‐MS/MS data sets, using commonly use peptide-centric MS/MS search engines | \n\nhttp://www.imba.oeaw.ac.at/SugarQb\n | \n|
GlycoDigest | \nGlycoDigest is a tool that simulates exoglycosidase digestion based on controlled rules acquired from expert knowledge and experimental evidence available in GlycoBase | \n\nwww.glycodigest.org/\n | \n|
Virtual Glycome | \nThis Website is focused on presenting selected computational tools and experimental resources that can be used to better understand the processes regulating cellular glycosylation at multiple levels | \n\nhttps://virtualglycome.org/\n | \n|
SweetUnityMol | \nSoftware to display 3-D structures of carbohydrates, polysaccharides, and glycoconjugates | \n\nhttp://sourceforge.net/projects/unitymol/files/\n | \n
Tools and databases used in glycoinformatics.
System-based analyses applied smoothly to network of signaling, metabolic processes, and physiological modeling; however, applications in systems glycobiology still have problems in computational and analytical studies and this situation arises from prominent bottlenecks [81]: (i) there is no accepted standard for model building; (ii) glycoinformatics databases are underdeveloped; (iii) and insufficient quantitative data are from glycoproteomics experiments.
\nIn recent years, many systems based models have been developed to simulate biosynthesis of glycans. Nevertheless, difficulty in the incorporation of glycan structure and specificity data of enzymes related with glycosylation into mathematical models. As a result of this difficulty, systematic model building is still not present in this field. Moreover, limited number of the current models is available in Systems Biology Markup Language (SBML) format [82], which is the obstacle to develop, share, and validate computational models.
\nIn the last decades, many databases related to glycoscience have emerged. Nevertheless, functional information is limited when compared to glycan structure and taxonomy data. In the future, relation of glycan structure to specific enzymes that synthesize them, the rates of their synthesis, and also their function are required in order to build model.
\nFor the measurement of glycome, two main approaches are common. In the first approach, enzymes or mild hydrolysis is used to separate the glycans from the peptide backbone. Next, to obtain information about the composition and relative abundance of the carbohydrate structures, permethylation of glycans and MS analysis are used [83]. The bottleneck is the lack of well-developed software. For the data analysis of glycoproteomics and correspondingly acceleration of system-based model building and validation, more sophisticated computational tools are required.
\nMathematical models of glycosylation are developed in three main stages: (i) biological information gathering; (ii) model formulation; (iii) and simulation and postsimulation analysis. First step includes definition of components (enzyme, substrate, and product) crucial for the model. All of the components present in the biochemical network and connections between them are cataloged in this step. The process relies on information of biochemistry and cell biology, and analytical tools. In the next step, behavior in the steady state of the system is investigated by using simple linear algebra and principles of optimization. If time is a variable, the computer model can incorporate ordinary differential equations (ODEs) or Boolean networks. Proper kinetic/thermodynamic/stochastic/optimization parameters are collated depending on the formulation nature of the model and processes which are specified by enzymatically/nonenzymatically. The last step is performed to simulate the experimental system in the computer and to define unknown parameters of model by the help of fitting experimental data [81]. Visualization of multidimensional results is significant because numerous diverse models may attempt to fit one data set obtained from time labor and concentration-dependent experiments. As a result, consolidation of the findings obtained by simulations of complex reaction network and generation of hypotheses that can be tested experimentally require network analysis strategies.
\nGlycomics is a very comprehensive research area of science and interacts with several different omics fields. As many other omics types, it consists of a huge number of genomics components. In the future, techniques in high-throughput analysis and bioinformatics will be developed and enable the integration of all available data of glycomics into a particular diagram and by this way, it will be possible to develop biomarker and identify potential new therapeutic targets. Moreover, progresses in the field reveal that integrative multiomics approach should include glycomics in order to develop new biomarkers for robust diseases. One of the specific fields of systems biology is the systems glycobiology. It is based on a holistic approach that indicates process of complex glycosylation and associations between its constituents. A more complete glycome overview is targeted by using enzyme levels, abundances of glycans, pathways for biosynthesis, glycan annotation, and related omics data sets.
\nAn approach of systems glycobiology is constructed in combination of various data sets of glycomics with that of other omics fields by the use of glycoinformatics tools to clarify understanding on process of glycosylation from various data sets. With the presented chapter, main aspects of glycobiology, glycomics, and systems glycobiology are summarized. However, these fields are still developing and further developments provide more insight to this specific research area.
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It is a cofactor for enzymes involved in regulating photosynthesis, hormone biosynthesis, and regenerating other antioxidants; which also regulates cell division and growth, is involved in signal transduction, and has roles in several physiological processes, such as immune stimulation, synthesis of collagen, hormones, neurotransmitters, and iron absorption, has also roles in detoxifying the body of heavy metals. Severe deficiency of vitamin C causes scurvy, whereas limited vitamin C intake causes symptoms, such as increased susceptibility to infections, loosening of teeth, dryness of the mouth and eyes, loss of hair, dry itchy skin, fatigue, and insomnia. In contrast, vitamin C can also act as a prooxidant, especially in the presence of transition metals, such as iron and copper, starting different hazardous radical reactions. Vitamin C can both act as a strong, efficient, and cheap antioxidant agent and, at the same time, behave as a radical promoter. Further investigations are needed to illuminate the dual roles of vitamin C",book:{id:"5940",slug:"vitamin-c",title:"Vitamin C",fullTitle:"Vitamin C"},signatures:"Fadime Eryılmaz Pehlivan",authors:[{id:"200567",title:"Dr.",name:"Fadime",middleName:null,surname:"Eryılmaz Pehlivan",slug:"fadime-eryilmaz-pehlivan",fullName:"Fadime Eryılmaz Pehlivan"}]},{id:"56440",doi:"10.5772/intechopen.70162",title:"Vitamin C: Sources, Functions, Sensing and Analysis",slug:"vitamin-c-sources-functions-sensing-and-analysis",totalDownloads:6423,totalCrossrefCites:15,totalDimensionsCites:28,abstract:"Vitamin C is a water-soluble compound found in living organisms. It is an essential nutrient for various metabolism in our body and also serves as a reagent for the preparation of many materials in the pharmaceutical and food industry. In this perspective, this chapter can develop interest and curiosity among all practicing scientists and technologists by expounding the details of its sources, chemistry, multifunctional properties and applications.",book:{id:"5940",slug:"vitamin-c",title:"Vitamin C",fullTitle:"Vitamin C"},signatures:"Sudha J. Devaki and Reshma Lali Raveendran",authors:[{id:"187911",title:"Associate Prof.",name:"Sudha",middleName:null,surname:"J Devaki",slug:"sudha-j-devaki",fullName:"Sudha J Devaki"},{id:"204937",title:"Mrs.",name:"Reshma",middleName:null,surname:"Laly Ravindran",slug:"reshma-laly-ravindran",fullName:"Reshma Laly Ravindran"}]},{id:"50921",doi:"10.5772/63712",title:"Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet",slug:"menaquinones-bacteria-and-foods-vitamin-k2-in-the-diet",totalDownloads:3315,totalCrossrefCites:10,totalDimensionsCites:21,abstract:"Vitamin K2 is a collection of isoprenologues that mostly originate from bacterial synthesis, also called menaquinones (MKs). Multiple bacterial species used as starter cultures for food fermentation are known to synthesize MK. Therefore, fermented food is the best source of vitamin K2. In the Western diet, dairy products are one of the best known and most commonly consumed group of fermented products.",book:{id:"5169",slug:"vitamin-k2-vital-for-health-and-wellbeing",title:"Vitamin K2",fullTitle:"Vitamin K2 - Vital for Health and Wellbeing"},signatures:"Barbara Walther and Magali Chollet",authors:[{id:"184784",title:"Dr.",name:"Barbara",middleName:null,surname:"Walther",slug:"barbara-walther",fullName:"Barbara Walther"},{id:"188194",title:"Mrs.",name:"Magali",middleName:null,surname:"Chollet",slug:"magali-chollet",fullName:"Magali Chollet"}]},{id:"66098",doi:"10.5772/intechopen.84445",title:"Golden Rice: To Combat Vitamin A Deficiency for Public Health",slug:"golden-rice-to-combat-vitamin-a-deficiency-for-public-health",totalDownloads:3377,totalCrossrefCites:12,totalDimensionsCites:17,abstract:"Vitamin A deficiency (VAD) has been recognised as a significant public health problem continuously for more than 30 years, despite current interventions. The problem is particularly severe in populations where rice is the staple food and diversity of diet is limited, as white rice contains no micronutrients. Golden Rice is a public-sector product designed as an additional intervention for VAD. There will be no charge for the nutritional trait, which has been donated by its inventors for use in public-sector rice varieties to assist the resource poor, and no limitations on what small farmers can do with the crop—saving and replanting seed, selling seed and selling grain are all possible. Because Golden Rice had to be created by introducing two new genes—one from maize and the other from a very commonly ingested soil bacterium—it has taken a long time to get from the laboratory to the field. Now it has been formally registered as safe as food, feed, or in processed form by four industrialised counties, and applications are pending in developing countries. The data are summarised here, and criticisms addressed, for a public health professional audience: is it needed, will it work, is it safe and is it economic? Adoption of Golden Rice, the next step after in-country registration, requires strategic and tactical cooperation across professions, non-governmental organisations (NGOs) and government departments often not used to working together. Public health professionals need to play a prominent role.",book:{id:"7978",slug:"vitamin-a",title:"Vitamin A",fullTitle:"Vitamin A"},signatures:"Adrian Dubock",authors:[{id:"273220",title:"Ph.D.",name:"Adrian",middleName:null,surname:"Dubock",slug:"adrian-dubock",fullName:"Adrian Dubock"}]},{id:"62836",doi:"10.5772/intechopen.79350",title:"The Role of Thiamine in Plants and Current Perspectives in Crop Improvement",slug:"the-role-of-thiamine-in-plants-and-current-perspectives-in-crop-improvement",totalDownloads:1564,totalCrossrefCites:7,totalDimensionsCites:11,abstract:"Current research is focusing on selecting potential genes that can alleviate stress and produce disease-tolerant crop variety. The novel paradigm is to investigate the potential of thiamine as a crop protection molecule in plants. Thiamine or vitamin B1 is important for primary metabolism for all living organisms. The active form, thiamine pyrophosphate (TPP), is a cofactor for the enzymes involved in the synthesis of amino acids, tricarboxylic acid cycle and pentose phosphate pathway. Recently, thiamine is shown to have a role in the processes underlying protection of plants against biotic and abiotic stresses. The aim of this chapter is to review the role of thiamine in plant growth and disease protection and also to highlight that TPP and its intermediates are involved in management of stress. The perspectives on its potential for manipulating the biosynthesis pathway in crop improvement will also be discussed.",book:{id:"6709",slug:"b-group-vitamins-current-uses-and-perspectives",title:"B Group Vitamins",fullTitle:"B Group Vitamins - Current Uses and Perspectives"},signatures:"Atiqah Subki, Aisamuddin Ardi Zainal Abidin and Zetty Norhana\nBalia Yusof",authors:[{id:"240031",title:"Dr.",name:"Zetty-Norhana Balia",middleName:null,surname:"Yusof",slug:"zetty-norhana-balia-yusof",fullName:"Zetty-Norhana Balia Yusof"},{id:"261167",title:"Mr.",name:"Aisamuddin Ardi",middleName:null,surname:"Zainal Abidin",slug:"aisamuddin-ardi-zainal-abidin",fullName:"Aisamuddin Ardi Zainal Abidin"},{id:"261169",title:"Ms.",name:"Atiqah",middleName:null,surname:"Subki",slug:"atiqah-subki",fullName:"Atiqah Subki"}]}],mostDownloadedChaptersLast30Days:[{id:"56440",title:"Vitamin C: Sources, Functions, Sensing and Analysis",slug:"vitamin-c-sources-functions-sensing-and-analysis",totalDownloads:6423,totalCrossrefCites:15,totalDimensionsCites:28,abstract:"Vitamin C is a water-soluble compound found in living organisms. It is an essential nutrient for various metabolism in our body and also serves as a reagent for the preparation of many materials in the pharmaceutical and food industry. In this perspective, this chapter can develop interest and curiosity among all practicing scientists and technologists by expounding the details of its sources, chemistry, multifunctional properties and applications.",book:{id:"5940",slug:"vitamin-c",title:"Vitamin C",fullTitle:"Vitamin C"},signatures:"Sudha J. Devaki and Reshma Lali Raveendran",authors:[{id:"187911",title:"Associate Prof.",name:"Sudha",middleName:null,surname:"J Devaki",slug:"sudha-j-devaki",fullName:"Sudha J Devaki"},{id:"204937",title:"Mrs.",name:"Reshma",middleName:null,surname:"Laly Ravindran",slug:"reshma-laly-ravindran",fullName:"Reshma Laly Ravindran"}]},{id:"56013",title:"Vitamin C: An Antioxidant Agent",slug:"vitamin-c-an-antioxidant-agent",totalDownloads:7808,totalCrossrefCites:26,totalDimensionsCites:59,abstract:"Vitamin C or ascorbic acid (AsA) is a naturally occurring organic compound with antioxidant properties, found in both animals and plants. It functions as a redox buffer which can reduce, and thereby neutralize, reactive oxygen species. It is a cofactor for enzymes involved in regulating photosynthesis, hormone biosynthesis, and regenerating other antioxidants; which also regulates cell division and growth, is involved in signal transduction, and has roles in several physiological processes, such as immune stimulation, synthesis of collagen, hormones, neurotransmitters, and iron absorption, has also roles in detoxifying the body of heavy metals. Severe deficiency of vitamin C causes scurvy, whereas limited vitamin C intake causes symptoms, such as increased susceptibility to infections, loosening of teeth, dryness of the mouth and eyes, loss of hair, dry itchy skin, fatigue, and insomnia. In contrast, vitamin C can also act as a prooxidant, especially in the presence of transition metals, such as iron and copper, starting different hazardous radical reactions. Vitamin C can both act as a strong, efficient, and cheap antioxidant agent and, at the same time, behave as a radical promoter. Further investigations are needed to illuminate the dual roles of vitamin C",book:{id:"5940",slug:"vitamin-c",title:"Vitamin C",fullTitle:"Vitamin C"},signatures:"Fadime Eryılmaz Pehlivan",authors:[{id:"200567",title:"Dr.",name:"Fadime",middleName:null,surname:"Eryılmaz Pehlivan",slug:"fadime-eryilmaz-pehlivan",fullName:"Fadime Eryılmaz Pehlivan"}]},{id:"69402",title:"Vitamin D Deficiency and Diabetes Mellitus",slug:"vitamin-d-deficiency-and-diabetes-mellitus",totalDownloads:1600,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Vitamin D (VD) is a molecule that can be synthesized directly in the humans’ body or enter the organism with food in the form of inactive precursors. To exert its biological action, VD undergoes two-stage hydroxylation (at the 25th and 1st position) catalyzed by cytochromes P450, the presence of which has already been shown in almost all tissues of the human body. The product of hydroxylation is hormone-active form of vitamin D–1,25(OH)2D. 1,25(OH)2D binds to specific vitamin D receptor (VDR) and regulates the expression of genes involved in bone remodeling (classical function) and genes that control immune response, hormone secretion, cell proliferation, and differentiation (nonclassical functions). VD deficiency is prevalent around the globe and may be one of the key factors for diabetes development. The direct association between vitamin D deficiency and type 1 (T1D) and type 2 (T2D) diabetes has been proven. Detection of VDR in pancreas and adipose tissue, skeletal muscles, and immune cells allowed implying the antidiabetic role of vitamin D by enhancing insulin synthesis and exocytosis, increasing the expression of the insulin receptor, and modulating immune cells’ functions. This chapter summarizes data about relationship between VD insufficiency/deficiency and development of T1D and T2D, and their complications.",book:{id:"7038",slug:"vitamin-d-deficiency",title:"Vitamin D Deficiency",fullTitle:"Vitamin D Deficiency"},signatures:"Ihor Shymanskyi, Olha Lisakovska, Anna Mazanova and Mykola Veliky",authors:null},{id:"76108",title:"Vitamin D Metabolism",slug:"vitamin-d-metabolism",totalDownloads:493,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Vitamin D plays an important role in bone metabolism. Vitamin D is a group of biologically inactive, fat-soluble prohormones that exist in two major forms: ergocalciferol (vitamin D2) produced by plants in response to ultraviolet irradiation and cholecalciferol (vitamin D3) derived from animal tissues or 7-dehydrocholesterol in human skin by the action of ultraviolet rays present in sunlight. Vitamin D, which is biologically inactive, needs two-step hydroxylation for activation. All of these steps are of crucial for Vitamin D to show its effect properly. In this section, we will present vitamin D synthesis and its action steps in detail.",book:{id:"10631",slug:"vitamin-d",title:"Vitamin D",fullTitle:"Vitamin D"},signatures:"Sezer Acar and Behzat Özkan",authors:[{id:"29878",title:"Dr.",name:"Behzat",middleName:null,surname:"Özkan",slug:"behzat-ozkan",fullName:"Behzat Özkan"},{id:"348287",title:"Dr.",name:"Sezer",middleName:null,surname:"Acar",slug:"sezer-acar",fullName:"Sezer Acar"}]},{id:"50754",title:"Medicinal Chemistry of Vitamin K Derivatives and Metabolites",slug:"medicinal-chemistry-of-vitamin-k-derivatives-and-metabolites",totalDownloads:1915,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Vitamin K acts as a cofactor for γ‐glutamyl carboxylase. Recently, various biological activities of vitamin K have been reported. Anti‐proliferative activities of vitamin K, especially in vitamin K3, are well known. In addition, various physiological and pharmacological functions of vitamin K2, such as transcription modulators as nuclear steroid and xenobiotic receptor (SXR) ligands and anti‐inflammatory effects, have been revealed in the past decade. Characterization of vitamin K metabolites is also important for clinical application of vitamin K and its derivatives. 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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. 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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:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{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:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{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:"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:"322007",title:"Dr.",name:"Maria Elizbeth",middleName:null,surname:"Alvarez-Sánchez",slug:"maria-elizbeth-alvarez-sanchez",fullName:"Maria Elizbeth Alvarez-Sánchez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",country:{name:"Mexico"}}},{id:"337443",title:"Dr.",name:"Juan",middleName:null,surname:"A. 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\r\n\tGlobally, the ecological footprint is growing at a faster rate than GDP. This phenomenon has been studied by scientists for many years. However, clear strategies and actions are needed now more than ever. Every day, humanity, from individuals to businesses (public and private) and governments, are called to change their mindset in order to pursue a virtuous combination for sustainable development. Reasoning in a sustainable way entails, first and foremost, managing the available resources efficiently and strategically, whether they are natural, financial, human or relational. In this way, value is generated by contributing to the growth, improvement and socio-economic development of the communities and of all the players that make up its value chain. In the coming decades, we will need to be able to transition from a society in which economic well-being and health are measured by the growth of production and material consumption, to a society in which we live better while consuming less. In this context, digitization has the potential to disrupt processes, with significant implications for the environment and sustainable development. There are numerous challenges associated with sustainability and digitization, the need to consider new business models capable of extracting value, data ownership and sharing and integration, as well as collaboration across the entire supply chain of a product. In order to generate value, effectively developing a complex system based on sustainability principles is a challenge that requires a deep commitment to both technological factors, such as data and platforms, and human dimensions, such as trust and collaboration. Regular study, research and implementation must be part of the road to sustainable solutions. Consequently, this topic will analyze growth models and techniques aimed at achieving intergenerational equity in terms of economic, social and environmental well-being. It will also cover various subjects, including risk assessment in the context of sustainable economy and a just society.
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