Genetic variations in the coding sequence of human VKORC1 in patients requiring high dose of a vitamin K antagonist.
\r\n\tDespite their limitations such as encapsulation efficiency, liposomes are a well-established choice for a number of unconventional and conventional biological applications. The versatility of these lipid-based vesicles presents the importance of these nanoparticles in the future applications of nanotechnology besides targeted drug delivery. Overall, this book provides the necessary and relevant information about various aspects of liposomes and their use in nanomedicine.
\r\n\t
Vitamin K antagonists (VKA) are inhibitors of the regeneration cycle of vitamin K. The diminution of the available and usable vitamin K in the body induced by VKA leads indirectly to a hypocoagulable status of the blood. The use of VKA in humans and rodents pursues this status. Nevertheless, the final aim is different for each. In the human case, VKA anticoagulants are used to prevent venous and arterial thrombotic event. In spite of the increasing use of new oral anticoagulants, VKA and, more precisely, warfarin are the most commonly prescribed anticoagulants [1]. Considering rodents, VKA are used in pest population management. In this case, death resulting from hemorrhages is pursued. VKA are currently the most used and one of the best rodenticides for two reasons. First, the delay between VKA administration and death is of several days, which avoids association between bait and death by the other rodents. Second, conversely to other rodenticides, VKA have an antidote: the vitamin K, which increases their safety for the human population and nontarget species.
\nIn humans, VKA anticoagulants have a narrow therapeutic range [2]. Under- and overdoses can have serious consequences by the lack of efficacy or adverse event. Warfarin has been ranked number 9 among primary suspect drugs having serious outcomes in the United States during the beginning of the 2000’s decade [3]. Indeed, the VKA dose has to be modulated, reflecting the genotype of patients more than other common drugs. Thus, it is necessary to identify and characterize each gene and mutation which may influence the VKA dose. In this task, the VKA research on pest management can be helpful. Indeed, management of rodent population has to deal with VKA resistances as well as in human medicine. Many mechanisms of resistances are common in humans and rodents. Moreover, with the large use of vitamin K antagonist rodenticides, the resistant phenotype is over-represented in some rodent populations. Consequently, some resistance mechanisms with a low prevalence in the human population have a higher prevalence in rodent population; thus, they can be more studied in rodents.
\nAfter a rapid presentation of the basis of vitamin K and VKA mechanisms, this chapter presents the different methods to assess VKA resistance mechanisms. Then, an assessment of the VKA-resistant pathways described in humans and in different rodent species is performed.
\nThe name “vitamin K” gathers a great number of molecules. All vitamin K are based on a naphthoquinone core and are sorted in three classes, numbered from 1 to 3. The substitution on the carbon 3 of the core determinates the class of the vitamin K. Vitamin K1 is composed of only one molecule, the phylloquinone, where the carbon 3 is substituted by a phytyl moiety. It was the first vitamin K described in 1935 by Dam [4], and chemically identified and synthesized by Doisy [5]. Vitamin K2 regroups the menaquinones. The substitute is a chain of prenyl, and the number of prenyls is indicated in the name. For example, the menaquinone 4 side chain is composed of 4 prenyl. Finally, vitamin K3 or menadione is only constituted by the naphthoquinone core (Figure 1).
\nPhylloquinone is synthesized by plants [6]. Menaquinones are synthesized from phylloquinone. The number of prenyls of the synthesized menaquinone depends on the bacteria, fungi, and animals which synthesize them. Mammals are only able to synthesize menaquinone 4 with the help of the
Examples of vitamin K: (A) menadione; (B) phylloquinone; (C) menaquinone 4; (D) menaquinone 7.
As many other fat-soluble vitamins, vitamin K’s absorption increases with fatty intake [11]. The absorption of vitamin K occurs in the gut, nevertheless its mechanism has been unclear during many years [12]. Recently, a study suggested that the cholesterol transporter, the Niemann-Pick C1-like 1 protein, would be responsible for the vitamin K’s absorption [13].
\nThe name of the vitamin K comes from the German word “koagulation.” Indeed, when vitamin K was discovered, its deficiency involved bleeding [4]. Nevertheless, it is only in the 1970s that we began to understand the vitamin K’s mechanism of action. Vitamin K is a cofactor of a post-transcriptional gamma-carboxylation which activates vitamin-K dependent proteins (VKDP) [14]. Four clotting factors of the coagulation cascade are the VKDPs, factors II, VII, IX, and X, which explain the bleeding issues observed in case of deficiency. Proteins C, S, and Z are also VKDPs involved in coagulation, but they have an antithrombotic effect. Nevertheless, the main effect of VKA is anticoagulation, even though the rapid decrease of these antithrombotic molecules can lead to a transient hypercoagulable state at the beginning or at the end of treatment with possible adverse events [15, 16].
\nThe second great role of vitamin K is bone regulation with two VKDPs: osteocalcin and matrix GLA protein [17, 18]. This last protein is also involved in the protection against tissue calcification [19]. Vitamin K is involved in many other biological functions which are reviewed in Refs. [20, 21].
\nIn spite of the low vitamin K level in food, vitamin K deficiency is rare [22]. Indeed, vitamin K is recycled by cells. The cycle is composed of two great steps: the use of vitamin K hydroquinone by the GGCX enzyme to activate VKDPs and the regeneration of the vitamin K hydroquinone from the epoxide form by VKORC1 (Figure 2).
\nVitamin K regeneration cycle.
In order to chelate calcium and to be active, the glutamate residues (Glu) of VKDPs have to be carboxylated to carboxyglutamic acid (Gla). This reaction is mediated by gamma-glutamyl carboxylase (GGCX). GGCX recognizes the VKDPs with the the help of their propeptide [23, 24]. Then, GGCX removes the gamma-hydrogen of Glu residues and adds CO2; the oxidation of vitamin K hydroquinone (KH2) to vitamin K epoxide (K > 0) provides the required energy [25]. This reaction is performed in the endoplasmic reticulum [26].
\nThe
A complete review of the current knowledge on the VKORC1 structure has been recently done [33]. VKORC1 is a membrane protein of the endoplasmic reticulum. The activity of VKORC1 seems to be due to CXXC patterns. VKORC1 presents two CXXC patterns, with cysteines positioned at Cys43, Cys51, Cys132, and Cys135 in human VKORC1. These cysteines are widely conserved through species, which might indicate that they have a key role in VKOR activity [34]. Cys132 and Cys135 are located in a transmembrane domain. They seem to be essential for the VKORC1 activity and might lead the nucleophilic attack supposed by a biochemical model of the VKOR reaction [34, 35]. Mutation of one of them to serine abolishes the enzymatic VKOR activity [36]. To reduce vitamin K, VKORC1 needs to be itself reduced by aphysiological partner. This partner and its mechanism of action are currently unknown. Schulman et al. proposed that the partner might reduce the loop cysteines (Cys43 and Cys51). Then the loop cysteines would transfer the reducing power to Cys132 and Cys135 of the active site [37]. However, other studies have reported that the mutation of one of these cysteines to serine has no consequence on the VKORC1 activity [38–40]. Moreover, the conformation of VKORC1 is still under debate between a topology with three transmembrane domains or four [41]. This last point is determining for the comprehension of the possible role of the loop cysteines. Indeed, they are either in the cytosol for the three transmembrane model or in the endoplasmic reticulum’s lumen for the other model.
\nVKORC1 presents a strong homology between rodents and humans, allowing to compare the mutation between them. Mammals and bacterial VKORs are homologs, but their conformation and reaction seem different [42].
\nMammals have another enzyme able to reduce the vitamin K epoxide, the VKORC1L1. It is mainly expressed in the extrahepatic tissues [43–45] and has a great similarity with VKORC1 [46]. Its inhibition by VKA is lower than its homolog [43]. Nevertheless, due to its low hepatic expression, its influence on the anticoagulant resistance is negligible. However, it might explain that the other vitamin K functions are not significantly impacted by VKA treatments.
\nFirst VKA has been discovered in 1941 and then isolated in spoiled sweet clover by Hueber and Link [47]. Sweet clover (
Three VKA families are used: the 4-hydroxycoumarin derivatives, the 4-hydroxy-thiocoumarin derivatives, and the indane-1,3-dione derivatives (Figure 3). All derivatives are used against rodents. Conversely, in human medicine, only the 4-hydroxycoumarin derivatives (for instance, warfarin) and the indane-1,3-dione derivatives (for instance, fluindione) are used. Moreover, in order to deal with rodent resistances, second generation of 4-hydroxycoumarin derivatives and of 4-hydroxy-thiocoumarin derivatives have been designed with complex radicals (Figure 3C and D).
\nExamples of some VKA: (A) warfarin; (B) fluindione; (C) difethialone; (D) brodifacoum.
Vitamin K antagonists stop the vitamin K recycling by performing noncompetitive inhibition of the VKORC1 enzyme [51, 52]. Nevertheless, the binding of VKA with VKORC1 enzyme is still a gray area. The reversibility of the binding is presently unknown [52–54], as well as the binding site. First, the binding site has been located at the level of the TYA motif (residues 138–140 in human VKORC1) close to the CXXC active site. Indeed, the mutation of the 139 tyrosine of this motif is associated with warfarin resistance in humans and rodents [55, 56], and by analogy the dicoumarol’s binding site on NQO1 is also a TYA motif [57]. However, these mutations are moderately susceptible to second generation VKAs in rats [55, 58], which can suggest that other amino acids might be involved in this binding. Recently, Czogalla et al. have proposed a model involving three binding interfaces between warfarin and human VKORC1 [59].
\nThe VKA treatments are established on the long term. Consequently, their elimination is a key factor which determines their liver concentration and finally their efficiency. The elimination pathway seems to depend on the molecule and on its enantiomeric form. Indeed, enantiomers of warfarin are eliminated differently. The (S)-enantiomer is metabolized exclusively by the hepatic cytochrome P450 isoform 2C9 (CYP2C9), while (R)-enantiomer is metabolized by isoforms CYP1A2, CYP2C19, CYP3A, and hepatic ketoreductase [60, 61]. Although the (R)-enantiomer has a longer half-life, it is less efficient, and the modulation of its elimination has no significant impact on the coagulation [62–64]. However, the activity of CYP2C9 is critical in the determination of the warfarin dose. Indeed, CYP2C9 activity is influenced by many drug interactions [65–68], and polymorphism of CYP2C9 can also modulate the sensitivity to warfarin.
\nSince the discovery of rats that are resistant to warfarin in 1960 by Boyle [69], the assessment and the study of resistance mechanisms have become a key issue for the rodent population management and in human medicine. Many methods have been developed to study these resistance mechanisms. Their purpose is to isolate the possible origins of the resistance in a standardized model and to evaluate if the induced resistance factor is of the same order as that one observed
Later, new methods based on blood clotting test have been developed [70–72]. They were standardized by the Rodenticide Resistance Action Committee in order to obtain a discriminating dose for each VKA [73]. These doses of anticoagulants, called effective doses 50 (ED50), were determined to quantify the susceptibility of rats to anticoagulants. ED50 is the dose leading to 50% of animals tested with a fivefold increase of the international normalized ratio 24 h after the administration of anticoagulants. This technique is more precise and rapid. Nevertheless, this method gives few information on the mechanism of resistance.
\nThe origins of resistances in wild strain can be multifactorial. For example, they can involve VKORC1-linked resistance and cytochrome-linked resistance. It is possible to refine
If the animal
The VKOR activity can be reproduced
This simple experiment pattern allows us to assess the efficiency of large origins of enzymatic system. As the VKOR proteins are located in the membrane of the endoplasmic reticulum, they are present in the microsomal fraction of tissues. The commonly used microsomal preparation methods are described in Ref. [76]. Microsomes are prepared from other cell components by differential centrifugation. Microsomal enzymatic activity evaluates the enzymatic efficiency of whole microsomal VKOR activity and not only of the VKORC1 enzyme activity. Indeed, Hammed et al. have pinpointed that a modeling with two enzymes (VKORC1L1 and VKORC1) is necessary to explain the inhibition of the testis microsomal activity by warfarin [43]. Moreover, as for
To isolate the activity of one enzyme or to perform enzymatic activity with human-like enzyme or mutated enzyme, it is possible to perform a heterologous expression in yeast (
The purification of VKORC1 was for many years a big business [77, 78]. Indeed, this enzyme loses its activity during the solubilization. It was only in 2006 than Chu et al. have purified the recombinant human VKORC1 produced from a baculovirus in insect cells which was still active after purification [79]. In this experiment, microsomes were washed from non-VKORC1 proteins. The artificial membrane inclusion of VKORC1 after heterologous expression in
The enzymology studies are the basis of our current understanding of VKORC1 mutations and interaction with VKA. It is currently the technique with the best reproducibility and more reliability. Nevertheless, some issues are still pending with these methods. The major issue comes from the DTT which gives the reducing power to VKORC1 in experiments. DTT is a powerful reductor which might bypass some dysfunctional mechanisms of mutated enzyme by directly activating the active site [37]. Moreover, high concentration of DTT (>1 mM) add a background level. To limit it, Krettler et al. proposed the use of tris(3-hydroxypropyl)phosphine instead of DTT [82]. Nevertheless, there is not enough knowledge currently on this new methods and its VKORC1 interaction to change the method. Moreover, tris(3-hydroxypropyl)phosphine is less efficient in VKORC1 enzyme reduction than DTT at usual concentration.
\nAnother issue might be that these methods study only the impact of VKA and resistant VKORC1 enzyme on the vitamin K regeneration cycle and not on the vitamin K-dependent protein gamma carboxylation. The required lipid environment and detergents are different for the activity between GGCX and VKORC1. Thus, it is currently difficult to study the interaction between both enzymes in an
In order to evaluate the complete reaction from vitamin K reduction to gamma-carboxylation and to solve some enzymatic study issues, the functional study of the vitamin K cycle in mammalian cells has been recently developed by Tie et al. [83], which was then adapted by other teams [84, 85]. In these studies, the production of a complete carboxylated protein by cell culture was assessed. The cells were HEK 293 cells transfected with the studied
This new method is not standardized yet, and there is still a gray area in the interpretation of the obtained results. Indeed, some discrepancies exist between enzymatic assay and cell assay results [84, 88] and even between cell assay results [40, 59]. The origin of these discrepancies might be the interference of the cell’s endogenous enzymes, in particular VKORC1L1, which is naturally more resistant than the wild VKORC1 enzyme [43]. In this way, standard cell assays have showed that all tested mutations were resistant [59, 84]. Tie et al. have dealt with this by knocking out endogenous
The second issue for the interpretation of cell assay is the lack of knowledge and control on it. This kind of assay is more complex than simple enzymatic activity; it involves many mechanisms that are currently uncontrolled or unknown: the level of the recombinant VKORC1 enzymes and the recombinant VKDP; the quantity and the efficiency of the physiological partner of VKOR enzymes, which are still unknown; the level of the endogenous GGCX protein; finally, the possible other mechanisms currently undescribed. All these elements determine if the studied enzymes are not bypassed and if the vitamin K reduction is the limiting reaction. These two conditions have to be fulfilled to validate completely the cell assay. However, some studies have pinpointed that the limiting reaction might be the VKORC1 enzyme reduction by its physiological partner and not the vitamin K reduction [89–91].
\nAlthough cell assays are recent and still have a gray area in the interpretation of their results, there is no doubt that they will become a key element of the study of VKA resistance mechanisms.
\nThe pharmacogenomics studies are the main source of
The pharmacogenomic studies and the reports of warfarin treatment failures have pinpointed two kinds of polymorphisms linked to VKORC1 which influence the warfarin dose requirements. The first is linked to the polymorphism in the noncoding region and the second is linked to missense mutations.
\nThe polymorphism in the noncoding region is the origin of the majority of VKA dose variations [92–95]. Indeed, the noncoding region influences the transcription level of VKORC1 [94]. Nevertheless, these variations are minor, few milligrams of increase or decrease. So, it is not really resistance to VKA, but rather a slight modulation of VKA sensibility.
\nConversely, the VKORC1 coding mutations are rare, and some involve a real resistance to VKA. They are characterized by a dose to stabilize the anticoagulation, which is higher than the high-dose threshold defined by Watzka: phenprocoumon 3.0 mg/day, acenocoumarol 3.5 mg/day, warfarin (W) 7.1 mg/day, and fluindione 19.8 mg/day, for mean age patients [56]. Please note that the definition of warfarin resistance is not well-defined. Currently, there are more than 27 mutations that have been described in patients with high requirements of VKA dose. They are summarized in Table 1.
\nMutation | \nNumber of patients | \nMolecule | \nDose (mg /day) | \nStable anticoa- gulation | \nRef. | \nConfirmation of resistance by | \n
---|---|---|---|---|---|---|
A26P | \n1 | \nW F | \n20 100 | \nNo No | \n[106] | \nYes [88] | \n
A26T | \n1 | \nW | \n6 | \nNo | \n[56] | \nNo [88] | \n
L27V | \n1 | \nW F | \n7 60 | \nYes No | \n[107] | \nNo [88] | \n
H28Q | \n1 | \nP | \n10 | \nyes | \n[56] | \nNo [88] | \n
V29L | \n2 | \nW P | \n14 26 | \n? Yes | \n[32, 56] | \n\n |
A34P | \n1 | \nW | \n27 | \nYes | \n[108] | \n\n |
D36Y | \n31 | \nW F A P | \n16.1 [3–36]* 45 7 7 [6.9–7.1] | \n~ No No Yes | \n[56, 96, 105, 106, 109 –112] | \nNo [88] | \n
D36G | \n1 | \nW | \n20 | \nYes | \n[56] | \nNo [88] | \n
A41S | \n1 | \nW | \n16 | \n? | \n[94] | \nNo [88] | \n
V45A | \n1 | \nW | \n45 | \nNo | \n[32] | \nNo [88] | \n
S52L | \n1 | \nP | \n9 | \nNo | \n[113] | \nYes [40] | \n
S52W | \n1 | \nP | \n10 | \nYes | \n[56] | \nNo [40] | \n
V54L | \n2 | \nW F A | \n21 [10–32] 60 8 | \n~ No No | \n[105, 106] | \nYes [88] | \n
S56F | \n1 | \nP | \n15 | \nNo | \n[56] | \nNo [88] | \n
R58G | \n1 | \nW | \n34 | \n? | \n[32] | \nNo [88] | \n
W59R | \n3 | \nA P | \n9.3 [8–12] 9 | \nNo No | \n[113, 114] | \nYes [40] | \n
W59C | \n1 | \nP | \n11 | \nNo | \n[56] | \nNo [88] | \n
W59L | \n1 | \nP | \n15 | \nNo | \n[56] | \nYes [40] | \n
V66M | \n15 | \nW P | \n31.5 [20–42]** 9.5 [9–10] | \nYes ~ | \n[56, 103, 105, 106, 108] | \nNo [40] | \n
V66G | \n1 | \nP | \n8 | \nYes | \n[56] | \nNo [40] | \n
H68Y | \n1 | \n– | \n– | \n– | \n[115] | \nYes [88] | \n
G71A | \n1 | \nP | \n6 | \nNo | \n[56] | \nNo [40] | \n
N77S | \n1 | \nP | \n9 | \nNo | \n[56] | \nYes [40] | \n
N77Y | \n1 | \nW | \n25 | \nYes | \n[56] | \nNo [40] | \n
I123N | \n1 | \nP | \n21 | \nNo | \n[56] | \nYes [88] | \n
L128R | \n16 | \nW F A P | \n44 80 13 30 | \nNo No No No | \n[32, 105, 106, 116] | \nYes [40] | \n
Y139H | \n1 | \nP | \n9 | \nNo | \n[56] | \nYes [88] | \n
Genetic variations in the coding sequence of human VKORC1 in patients requiring high dose of a vitamin K antagonist.
Adapted and completed with permission from Ref. [88].
* A case report, which includes a 2-year-old girl, is not included [117].
** A report of two cases was not used due to its imprecision on the doses [118].
† Results of the Oldenburg’s team are not reported [59, 84].
? no data are present on the stabilization of the anticoagulation in study.
~ only some patients have a stabilization of their anticoagulation.
Conversely, another mutation has been described by Rost in two Libyan families, the R98W mutation. Homozygous patients with this mutation have a combined deficiency of vitamin-K-dependent clotting factor type 2 which causes bleeding [32]. This deficiency can be treated by a daily dose of vitamin K. Rost et al. have shown in enzymatic assays that R98W-muted VKORC1, which was expressed in HEK cell, has a VKOR activity diminished of 90% [32].
\nSome mutations have a higher prevalence in some populations. Thus, the D36Y mutation is relatively well represented in some African populations [96]. The Ethiopian population and the Ashkenazi Jews population have a D36Y allele frequency of respectively 15% and 4% [97–99], while this mutation is absent in South African or in Chinese populations [100, 101]. Concerning the V66M mutation, it has been described in African and African-descent populations [102–104]. Finally, the L128R mutation has been described in different families [32, 105].
\nNevertheless, the other reported mutations have been described only one time and sometimes on patient with unstabilized anticoagulation. These elements reduce the possibilities to determine a resistance factor for each. Moreover, the mutations have been often described as fortuitous events of pharmacogenomics studies [94]. Finally, the interactions with other mutations on cytochromes, GGCX, or noncoding part of
In order to deal with the described bias, the
Resistances have evolved differently in rodents according to their species. Indeed, the anticoagulant pressure is exerted differently on each. These differences depend on the behavior of the rodents, and more particularly the feeding behavior. Thus, some rodents feed preferentially on one food source (rat), while others feed on many sources (house mice). Thus, rats eat a lot of poisoned grains, whereas mice eat few poisoned baits and dilute them with other food sources.
\nResistances have been largely described in house mice (
Concerning the Norway rat, it has been the first target of the VKA rodenticides and the first to develop resistances [69]. The first description occurred in Scotland, and rapidly the resistance spread all over Great Britain [119, 120]. Denmark has been the second country with warfarin-resistant rats [121]. Entrapments have pinpointed that 24.2% of Denmark’s rats were resistant in the 1960s [122]. Since then, resistances have been brought to light from all around the world [123, 124].
\nCurrently, 25 mutations have been described in Norway rats [125]. Nevertheless, only few mutations are widely present and linked with important resistances. The five main mutations in Europe are L120Q, L128Q, Y139C, Y139F, and Y139S [126]. These mutations have different frequencies depending on the geographical areas. Thus, Y139C is the main mutation in Germany and Denmark [126, 127], and Y139F in France [128]. Concerning Great Britain, important discrepancies on the frequencies of mutations have been pinpointed between counties [126, 129, 130]. The frequencies of rat mutations are disproportionate comparatively to human coding mutation frequency. Thus, Y139F mutation is detected in 21% of the French rats [128], but less than 1% of the world human population carries one coding mutation. Moreover, in some areas, the prevalence of the resistant rats is of 100% [131].
\nConcerning the house mice, their mutations have been described in 1961 in many countries [132]. Currently, more than 10
The presence of
Five amino acid positions of the VKORC1 enzyme carry a described mutation in both humans and rodents. They are the positions A26, R58, W59, L128, and Y139. Nevertheless, only the mutations A26T, R58G, and W59R are identical. These three mutations are not common in humans, and the reported cases did not have a stable anticoagulation. The A26T mutation does not seem to enhance the resistance in the rat [125]. These results were obtained with rat
The mutations at positions L128 and Y139 are the major mutations of the Norway rat. Moreover, the studies on the Y139F mutations have shown that the resistance factor of this mutation is conserved between
As aforementioned, some mutations decrease the efficiency of the VKOR activity. Matagrin has studied the origins of this loss of efficiency for the Y139 mutation [135]. He showed that Y139 mutations involve a diminution of the VKOR activity and the creation of inactive vitamin K metabolites (3-OH vitamin K) which are eliminated. This induces an increase of the food requirements of vitamin K in rodents carrying these mutations [136, 137]. In humans, the influence of coding mutations on nutritional requirement of vitamin K has not been well studied [22]. However, by analogy with rodent mutations, human mutations might be involved in cardiovascular diseases without VKA treatment [138]. Thus, the rodents carrying these mutations might be use to model and to better understand the possible consequences of these mutations on the human health.
\nCytochromes are essential elements in the elimination of xenobiotics. Thus, it would be expected that their polymorphism might result in an origin of resistances. But in human medicine, the cytochrome polymorphism is associated with an increase in the patient’s VKA sensibility [93, 97]. Moreover, the polymorphism of CYP2C9 is a key element in the prediction of the VKA treatment dose [97]. Thus, no VKA resistance linked to cytochrome has been described in human medicine.
\nIn rodents, expression profiles of cytochromes are different between sensitive and resistant rats carrying a Y139C mutation on VKORC1 [139]. Nevertheless, it is difficult to identify the part of the resistance due to VKORC1 mutation and the one due to the expression profiles of cytochromes. Nevertheless, one example of warfarin resistance linked to cytochrome has been described without association with VKORC1 mutation in roof rats from Tokyo [140, 141]. This rat population overexpresses the cytochrome 3A2. Thus, the concentration of blood warfarin 1 h after the warfarin administration is eightfold lower in resistant rats. However, it is currently the only reported case of cytochrome-linked resistance.
\nThe assessment and the comprehension of the resistance mechanisms are essential in the safety and the efficiency of VKA treatments and in the rodent population management. However, the complexity of the mechanisms and the interactions between them prevent the use of only one studying method. The understanding of the VKA actions and their interaction with individual variability can only be achieved by a multiscale approach which combines humans, rodents, and
Neurological disorders are devastating diseases which usually occur in the brain, spinal cord, cranial nerves, peripheral nerves, and so on. It has reported that there are more than 600 kinds of neuropathological conditions including epilepsy, brain tumor, Parkinson’s disease, Alzheimer’s disease, and stroke. Nowadays, it is estimated that more than 1 billion people suffer from neurological disorders, seriously affecting people’s life quality [1]. These kinds of diseases are especially prevalent in developing countries at any stage of age [2, 3]. There are several factors contributing to etiology of neurological disorders such as aggravating tendency of aging population, irregular diet, and insufficient exercise [4].
\nDrug therapy is an important way for curing neurological diseases in the clinic. Nevertheless, serious neurological disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are usually incurable in late stages of diseases with current therapeutic intervention [5, 6]. In the meantime, drug treatment often becomes less effective and causes serious side effects due to individual differences. Taking epilepsy as example, nearly 30% of epileptic patients are unable to obtain seizure control following treatment with marketed drugs [7, 8]. In addition, they have no significant effect on the improvement of cognitive dysfunction in patients with severe epilepsy [9]. Thus, it is essential for investigation of more effective and/or less toxic CNS targeted drugs.
\nDrug repurposing, also known as drug reprofiling or drug repositioning, includes the development of new uses and dosage forms for existing drugs or drug candidates. It is regarded as an economic and practical strategy [10]. Drug repurposing avoids the defects of new drug development. Compared to the drug repurposing, development of new drugs consumes much more time and huge investments. It is roughly reported that the cost from basic research for a new drug to clinical trials is 2.6 billion US dollars [11] and it often takes an average of 13–15 years [12]. Although more and more drug candidates are developed, many cases have failed in recent years [13]. Most of new drugs are withdrawn from the market due to unsatisfactory efficacy or intolerable side effects [14, 15]. Therefore, reusing existing drugs, namely, drug repurposing, has attracted great attention, as this approach has the capacity of saving cost and expediting drug development process.
\nThe purpose of this chapter is to discuss the role of drug repurposing in human diseases especially neurological diseases and summarize repurposing candidates currently in clinical trials for neurological diseases and potential mechanisms as well as preliminary results. Subsequently we also list drug repurposing approaches and limitations and challenges in the future investigations.
\nPrior to development of repurposed drugs for neurological diseases therapeutics, it is emphasized how the drug reposition process is carried out. Generally, there are three stages in drug repurposing. First, diverse approaches including serendipitous clinical observation, cellular drug activity assays, in silico drug screens, and data mining of clinical drug interaction are employed to obtain drug candidates [16]. The detailed illustrations in grounds of methodologies are summarized as mentioned above [17]. Second, preclinical investigations including in vivo rodent models and in vitro cell lines for these drugs are conducted in neurological diseases [18]. Finally, large-scale and multicenter clinical trials are implemented for evaluating efficacy and safety of repurposed drugs [19]. Up to date, there are plenty of drugs which are repurposed in neurological diseases through the above approaches. Then, in the following section, we also cite several repurposed drugs to elaborate how they function in neurological diseases. Table 1 summarizes various repurposed drugs in the treatment of neurological disorders.
\nName of drug | \nOriginal indication | \nNovel indication | \nTarget | \nSummarization of evidence | \n
---|---|---|---|---|
Verapamil | \nHypertension Angina pectoris Arrhythmia | \nIntractable epilepsy Subarachnoid hemorrhage Stroke Resistant depression | \nP-glycoprotein | \n\n
| \n
Bumetanide | \nLiver disease Heart failure Stubborn edema Acute and chronic renal failure | \nEpilepsy Autism | \nNKCC1 protein | \n\n
| \n
Minocycline | \nAntibacterial | \nEpilepsy Spinal cord injury Brain inflammation Neurodegenerative diseases | \nActivated microglia IL-6, TNF-α TrkB/BDNF PPAR-γ/NF-κB LKB1/AMPK | \n\n
| \n
Fenfluramine | \nSimple obesity Diabetes Hypertension | \nEpilepsy Parkinson’s disease | \n5-HT receptors | \n\n
| \n
Propranolol | \nHypertension Supraventricular tachycardia Prolonged Q-T interval Thyrotoxicosis | \nMigraine Traumatic brain injury Parkinson’s disease | \nIL-6 β-adrenergic | \n\n
| \n
Sunitinib | \nGastrointestinal stromal tumor Non-small-cell lung cancer Renal cell carcinoma | \nGlioma Pheochromocytoma Alzheimer’s disease’ | \nAcetylcholinesterase CGNs, SH-SY5Y | \n\n
| \n
Angiotensin receptor blockers | \nEssential hypertension Renal disease Diabetes | \nAlzheimer’s disease Episodic migraine | \nAT1 receptor Angiotensin II | \n\n
| \n
Amantadine | \nAntiviral | \nParkinson’s disease Chronic traumatic brain injury | \nN-methyl-D-aspartate (NMDA) Anticholinergic | \n\n
| \n
List of repurposed drugs in neurological disease.
Verapamil, a classical calcium channel blocker, is mainly used in the treatment of hypertension, angina pectoris, arrhythmia, and other diseases, especially for paroxysmal supraventricular tachycardia [20]. It has been found that administration of verapamil greatly improves seizure control in drug-resistant epileptic patients via inhibiting P-glycoprotein (Pgp). Pgp is responsible for the transport of antiepileptic drug (AED) into the blood vessels through the blood–brain barrier (BBB). And there is evidence supporting that overexpression of Pgp in the brain represents a major mechanism underlying drug resistance in epileptic patients [21]. Verapamil is found to suppress Pgp expression and subsequently facilitates the entry of this drug into epileptogenic zones. As a marketed drug, verapamil treatment in patients with intractable epilepsy can doubtfully alleviate brain injury caused by repetitive seizures [22]. Actually, in clinical trials, verapamil has previously shown to exhibit great efficacy in intractable depression or mania via inhibiting the function of Pgp [23, 24]. Moreover, it is documented that verapamil has been approved to treat cerebral vasospasm secondary to subarachnoid hemorrhage due to its vasodilatory effects [25]. Intra-arterial (IA) treatment with verapamil, which was physiologically feasible, safe, and neuroprotective as a therapeutic adjunct in stroke, significantly reduces infarct volume and improved functional outcome [26], although there are still some mysteries about the mechanism.
\nAs a potent diuretic agent, bumetanide, which is mainly employed to cure liver disease, heart failure, and various kinds of stubborn edema in clinic [27], is a specific inhibitor of Na+-K+-2Cl− cotransporter isoform 1 (NKCC1) [28]. Mechanically, NKCC1 significantly modulates the content of intracellular Cl−. Upregulation of NKCC1 leads to elevation of intracellular concentration of Cl−, which is associated with pathogenesis of neurological diseases. It has been unequivocally proven that many of the available drugs have anti-seizure potential via activating GABAA-mediated hyperpolarization due to accumulation of neuronal Cl− [29]. Indeed, current investigations have confirmed that bumetanide exerts antiepileptic effect via switching the GABA-mediated inhibitory postsynaptic potential in neurons from depolarization to hyperpolarization, resulting in decreased neuronal discharge [30, 31]. In addition, previous work reinforces that bumetanide can enhance the anticonvulsant effect of phenobarbital in hypoxic rats [32]. It suggests that the combination of phenobarbital and bumetanide may provide a promising therapeutic strategy for ceasing seizures in neonatal epilepsy and may increase the neuroprotective effect of hypothermia on asphyxiated newborns [33]. Persuasively, a current clinically pilot study further demonstrated that bumetanide, as a specific NKCC1 antagonist, considerably reduced seizure frequency in adult patients with temporal lobe epilepsy [34]. Additionally, as a consequence of a randomized controlled trial, bumetanide may also be effective for treatment of autism [35]. It should be considered that there are two obstacles for bumetanide treatment in neurological disorders [31, 36]. It has been shown that the highly potent diuretic effect of bumetanide can lead to hypokalemic alkalosis and the poor penetration into brain exists. This indicates that reuse of bumetanide in neurological diseases brings about opportunities and challenges in the future.
\nMinocycline is the second generation of semisynthetic broad-spectrum antibacterial tetracycline analogues. It has immunomodulatory, anti-inflammatory, and anti-apoptosis effects. Minocycline has neuroprotective effects in rodent models of ischemia, spinal cord injury, and infection [37]. It can efficiently penetrate the BBB and has a good effect on activated microglia, which indicates a possible role in the treatment of epilepsy. Minocycline may have synergistic effects with other compounds in manipulating epilepsy. Minocycline has been found to remarkably obviate epileptic conditions and reduce seizure-induced brain impairment at early stage [38]. In addition, minocycline also inhibits pro-inflammatory cytokines through caspase-dependent and caspase-independent pathways, thus inhibiting cell death in kainic acid-induced status epilepticus [39]. An obvious improvement of seizure phenotype is also observed in a rat model of amygdala kindling [40]. Additionally, increasing studies have reported the neuroprotective effects of minocycline in neurologic diseases, such as ischemic stroke, multiple sclerosis (MS), and traumatic brain injury (TBI) [41, 42, 43]. In in vivo animal model, minocycline promotes M2 microglia polarization via activation of tyrosine kinase receptor B (TrkB)/brain-derived neurotrophic factors (BDNF) pathway and facilitates neurogenesis after intracerebral hemorrhage (ICH) [44]. In the process of acute cerebral infarct, minocycline also effectively inhibits oxidative stress via elevating the activity of superoxide dismutase (SOD) and activating the liver kinase B1 (LKB1)/adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway [45]. However, repurposing of minocycline in treating neurological diseases requires to be re-evaluated as there is a clinical study showing serious neurodegeneration TBI [46].
\nFenfluramine, which has been successfully applied in obesity, diabetes, and hypertension [47], is a potent 5-hydroxytryptamine (5-HT) releaser activating multiple 5-HT receptor subtypes. Of note, elevation of extracellular 5-HT levels inhibits focal and generalized seizures, while depletion of 5-HT lowers the threshold of epileptic seizures [48]. Therefore, 5-HT agonist fenfluramine is assessed for treatment of epilepsy. In a small-scale retrospective study, it has reported that adjuvant treatment with fenfluramine has evidently obtained seizure control in patients with Dravet syndrome. As the side effects is not serious, it does not lead to the termination of treatment [49]. This drug may have anticonvulsant effects on other severe epilepsy syndromes, especially those characterized by photosensitive or induced convulsions [50, 51]. Encouragingly, a recent investigation has unveiled that fenfluramine significantly reduces convulsive seizure frequency compared with placebo and exhibits good tolerance [52]. It indicates that fenfluramine could be functioned as a potent novel therapeutic regime for patients with Dravet syndrome. It is noteworthy that fenfluramine also alleviates L-DOPA-induced dyskinesia via stimulation of 5-HT1A receptor in PD [53].
\nPropranolol as a β-adrenoceptor antagonist (b-blocker) has been commonly used in hypertension, supraventricular tachycardia, prolonged Q-T interval, and thyrotoxicosis in clinic [54]. Since 1996, in patients who were being treated for angina pectoris, Rabkin et al. has disclosed the therapeutic effect of propranolol on migraine headache [55]. Meanwhile, further clinical studies have noted that administration of propranolol within 24 h of admission after TBI triggers lower mortality [56]. The evidence also arises from a recent study that propranolol blocks the upregulation of IL-6 and prevents neuronal cell necrosis in CA1 and CA3 hippocampus in a pig model of TBI [57]. Given that propranolol has neuroprotective potential in neuropathological conditions, it is likely to serve as a neuroprotective drug in epilepsy. Additionally, both clinical and experimental studies have demonstrated the potential of propranolol to resist dyskinesia in PD, as modulation of β-adrenergic receptors (βAR), which is abundantly, expressed in striatum, is involved L-DOPA-induced dyskinesia (LID) [58, 59].
\nSunitinib, which is an oral, small molecule receptor tyrosine kinase inhibitor approved by the US Food and Drug Administration, has been currently implemented in the treatment of various cancers such as gastrointestinal stromal tumor (GIST), non-small-cell lung cancer, and renal cell carcinoma [60]. Clinical evidence has revealed that oral administration of sunitinib penetrates the BBB and subsequently facilitates the entry into central nervous system [61]. Furthermore, on the basis of its potent antiangiogenic and antitumoral characteristics, it has discovered that sunitinib can alleviate glioma-induced neurodegeneration and glioma progression in vivo models [60]. Meanwhile, sunitinib has been found to exert therapeutic effects on learning and memory deficits in a mouse model of AD through inhibition of acetylcholinesterase (AChE) [62]. Additionally, sunitinib has also demonstrated to prevent neuronal death induced by neurotoxins via inhibiting NO overproduction in cerebellar granule neurons (CGNs) and SH-SY5Y cells following exposure with low potassium or 1-methyl-4-phenylpyridinium ion (MPP+)-induced neuronal apoptosis [63]. It indicates that sunitinib may improve brain dysfunction via inhibition of oxidative stress.
\nIn in vitro studies, angiotensin receptor blockers (ARBs) are generally known to treat essential hypertension by influencing the level of angiotensin II (Ang II) via two distinct pathways, namely, through interrupting the AT1 receptor and augmentation of Ang II processing which plays a critical role in cognition regulation [64]. For example, valsartan, which has previously been found to penetrate BBB and elicit antihypertensive responses in the brain, has been demonstrated to reduce Aβ accumulation and aggregation in vivo and in vitro [65]. Actually, similar situation exists in losartan and telmisartan, which are also classical ARBs [66, 67]. Overall, it indicates ARBs are potential candidates for treating AD. Significantly, several clinically epidemiological studies and RCTs certify the efficacy of ARBs in AD. A large-scale retrospective cohort study has revealed an obvious reduction of dementia in patients treated with ARBs compared with other cardiovascular agents [68]. Likewise, the further UK-based study also reports a similar trend, with a 50% reduction in AD after ARBs treatment [69]. In brief, ARBs, the conventional cardiovascular medicine, have been confirmed to exert a vital effect in AD, and it is further deserved to identify the most suitable dosage in clinic.
\nAmantadine is a classic antiviral compound which has been found to moderately ameliorate impaired motor behavior in Parkinson’s disease [70]. Intriguingly, in 1969, it was coincident that Schwab et al. found an improvement of motor symptoms in a female PD patient, who took 200 mg amantadine daily for antiviral prophylaxis [71]. Subsequently, three potential mechanisms have been proposed to explain the efficacy of amantadine in PD. Several preclinical data demonstrate an activation of the dopamine system’s both presynaptic and postsynaptic actions [72], and amantadine also inhibits the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors [72, 73]. The mild anticholinergic effect is also involved [74]. Surprisingly, PD is well known to be frequently associated with depression, and antagonism of NMDA receptors is also a promising target for new antidepressants, although there is no definite evidence to certify its efficacy in depressive disorder.
\nThere are three important stages in the field of drug repurposing: generation of candidate compounds, preclinical investigation, and clinical trial. Determination of appropriate drugs for potential indications is crucial for production of candidate compounds. At present, two approaches are widely used for drug repurposing including experimental screening approaches and molecular docking by computer. In the following items, we make a detailed description of these two methods in drug repurposing process.
\nExperimental screening approaches are usually regarded as the first stage in the process of drug discovery and drug repurposing. Proteomic techniques such as affinity chromatography and mass spectrometry have been widely employed to identify drug candidates [75]. Nowadays, drug target analysis and drug repurposing are inseparable. Drug repurposing is distinct from drug discovery in terms of alteration of drug target. Cellular thermo stability assay technique can predict the affinity of drug ligands by mapping the contact patterns of intracellular targets [76]. The molecular on and off targets have been disclosed for many clinically approved drugs via this method. Especially in the field of kinases, new targets of well-known drugs are obtained through affinity matrices [77, 78]. For example, imatinib, a tyrosine kinase inhibitor, has been successfully reused in the treatment of gastrointestinal stromal tumors [79].
\nIn addition, chemical compounds with disease-related effects can be defined in the model through phenotype screening [80]. Phenotype screening has always been more successful than target screening in the facet of drug development [81, 82]. In the case of drug repurposing, if the compounds selected through phenotypical assays are approved clinical drugs or ongoing clinical trials, they are probable to reuse. Several drugs approved for tobacco dependence have been evaluated, and it has been found that topiramate changes nicotine- or ethanol-induced behavior in zebrafish models [83]. However, there are some challenges that the efficacy of drug candidates in in vitro experiments require to be validated in human diseases [84].
\nMolecular docking by a computer is also an important method for evaluating drug target binding kinetics and drug residence times of existing drugs or drug candidates [85]. Large amounts of computational drug repositioning methods choose transcriptomic data to identify potential new indications for drugs. Furthermore, these methods have applied techniques such as comparison of gene expression profiles between a disease model and drug-treated condition [86], network integration [87], prediction of drug-protein interactions [88], and utilization of genotype–phenotype associations. Recently, a proteotranscriptomic-based computational drug repositioning method named Drug Repositioning Perturbation Score/Class (DRPS/C) for Alzheimer’s disease occurs on the basis of inverse associations between disease-induced or drug-induced gene and protein perturbation patterns [89]. Briefly, these approaches can be applicable to discovery of drug targets or biomarkers.
\nIt should be considered that for many neurological disorders, drugs require good penetration into BBB. Then, the therapeutic approaches of targeting brain have been classified as invasive and noninvasive categories [90, 91]. The invasive approaches contain the temporary increase of BBB permeability, and noninvasive approaches involve modification of drug molecule via physiological, chemical, or colloidal carrier system approach. Meanwhile, these methods are also related to computational approaches. Influx clearance into the brain (
Drug repurposing is a vital strategy for developing new therapeutic values of existing drugs or drug candidates due to its ability to save time and reduce cost [96]. This type of innovative concept will undoubtedly expedite the drug development process. Meanwhile, some limitations need to be considered during drug repurposing process in neurological diseases. Owing to complex molecular and cellular signaling mechanisms in neuropathological states, drug repurposing may be difficult. Additionally, drugs not only respond to a single target but also affect multiple targets [97], causing a variety of adverse reactions. A comprehensive assessment of the advantages and disadvantages of these side effects can help us understand drug repositioning from a more all-round perspective [98, 99].
\nIn order to overcome limitations faced during drug repurposing, we make proposals in the following descriptions. Firstly, it is foremost to establish a comprehensive data analysis platform to maximize data sharing. Information science services and artificial intelligence can help unlock and reanalyze the large amount of data accumulated by approved drugs or drug candidates to clinical trials. These data may be stored in a diversified way. Storage locations, formats, and types may vary, including different storage locations, formats, and types. The data obtained from clinical trials and biological databases are too large and complex that the traditional data processing methods cannot deal with it, which leads to the bottleneck in the research process [99]. Big data can significantly improve our understanding of the disease and make more accurate disease-related strategies. However, there is a big gap between generating biomedical data and data analysis [99, 100]. To ensure the efficiency of research, it takes time, energy, and expertise to find technical solutions to integrate them. Secondly, it is encouraged to provide more financial support for clinical trials of drug repurposing, including technical support. The preclinical research of drug repurposing requires financial support to obtain the data in clinical trials. In this case, drugs that can be developed to treat rare diseases are more likely to apply in clinical neurological diseases therapeutics [101]. Finally, in order to facilitate drug repurposing process, we advocate it is indispensable to solve patent restrictions and take reasonable supervision. All applications of drug repurposing should be accompanied by a risk management plan. Drug’s safety can be supported by clinical trial data or post marketing data.
\nIn conclusion, drug repurposing is a novel approach for expediting drug development process in neurological diseases. Repurposed drugs may provide an efficient avenue for improving a plethora of pathological conditions including neurological disorders. In the future, it is essential to exploit molecular mechanisms during drug repurposing processes due to the possibility that targets of repurposed drugs in neurological diseases are distinct from original targets in treating other diseases, in order to make these drugs more effective and safe.
\nThe authors apologize to all the investigators whose work cannot be cited in this paper due to space constraint. This work was partly supported by the National Natural Science Foundation of China (No. 81974502 and 81671293).
\nThere is no potential conflict of interest.
CNS | central nervous system |
AD | Alzheimer’s disease |
PD | Parkinson’s disease |
AED | antiepileptic drug |
BBB | blood–brain barrier |
Pgp | P-glycoprotein |
NKCC1 | Na+-K+-2Cl-cotransporter isoform 1 |
GABAA | gamma-aminobutyric acid |
MS | multiple sclerosis |
TBI | traumatic brain injury |
TrkB | tyrosine kinase receptor B |
BDNF | brain-derived neurotrophic factors |
ICH | intracerebral hemorrhage |
SOD | superoxide dismutase |
LKB1 | liver kinase B1 |
AMPK | adenosine 5′-monophosphate (AMP)-activated protein kinase |
5-HT | 5-hydroxytryptamine |
LID | L-DOPA-induced dyskinesia |
βAR | β-adrenergic receptors |
AChE | acetylcholinesterase |
CGNs | cerebellar granule neurons |
ARBs | angiotensin receptor blockers |
Ang II | angiotensin II |
NMDA | N-methyl-D-aspartate |
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nOAI-PMH
\\n\\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\\n\\nPeer Review Policies
\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\\n\\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\\n\\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
\\n\\n\\n"}]'},components:[{type:"htmlEditorComponent",content:'
The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. 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We discuss “space motion sickness,” sensorimotor coordination disorders, cardiovascular deconditioning, muscular atrophy, bone loss, and anemia/immunodeficiency, including their causes and mechanisms. In addition to the previously described deconditioning, new problems related to microgravity, spaceflight-associated neuro-ocular syndrome (SANS), and structural changes of the brain by magnetic resonance imaging (MRI) are also explained. Our proposed countermeasure, artificial gravity produced by a short-arm centrifuge with ergometric exercise, is also described in detail, and we confirmed this system to be effective in preventing the abovementioned deconditioning caused by microgravity exposure.",book:{id:"7632",slug:"beyond-leo-human-health-issues-for-deep-space-exploration",title:"Beyond LEO",fullTitle:"Beyond LEO - Human Health Issues for Deep Space Exploration"},signatures:"Satoshi Iwase, Naoki Nishimura, Kunihiko Tanaka and Tadaaki Mano",authors:[{id:"76278",title:"Prof.",name:"Satoshi",middleName:null,surname:"Iwase",slug:"satoshi-iwase",fullName:"Satoshi Iwase"},{id:"321445",title:"Dr.",name:"Naoki",middleName:null,surname:"Nishimura",slug:"naoki-nishimura",fullName:"Naoki Nishimura"},{id:"321447",title:"Dr.",name:"Kunihiko",middleName:null,surname:"Tanaka",slug:"kunihiko-tanaka",fullName:"Kunihiko Tanaka"},{id:"321448",title:"Dr.",name:"Tadaaki",middleName:null,surname:"Mano",slug:"tadaaki-mano",fullName:"Tadaaki Mano"}]},{id:"72944",doi:"10.5772/intechopen.93281",title:"Aerocapture, Aerobraking, and Entry for Robotic and Human Mars Missions",slug:"aerocapture-aerobraking-and-entry-for-robotic-and-human-mars-missions",totalDownloads:564,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"This chapter provides an overview of the aeroassist technologies and performances for Mars missions. We review the current state-of-the-art aeroassist technologies for Mars explorations, including aerocapture, aerobraking, and entry. Then we present a parametric analysis considering key design parameters such as interplanetary trajectory and vehicle design parameters (lift-to-drag ratio, ballistic coefficient, peak g-load, peak heat rate, and total heat load) for aerocapture, aerobraking, and entry. A new perspective on a rapid aerobraking concept will be provided. The analysis will include first-order estimates for thermal loading, thermal protection systems material selection, and vehicle design. Results and discussion focus on both robotic missions and human missions as landed assets and orbiters.",book:{id:"8556",slug:"mars-exploration-a-step-forward",title:"Mars Exploration",fullTitle:"Mars Exploration - a Step Forward"},signatures:"Ye Lu",authors:[{id:"313126",title:"Prof.",name:"Ye",middleName:null,surname:"Lu",slug:"ye-lu",fullName:"Ye Lu"}]},{id:"67679",doi:"10.5772/intechopen.86728",title:"Oral Tissue Responses to Travel in Space",slug:"oral-tissue-responses-to-travel-in-space",totalDownloads:1027,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"The oral cavity functions in taste, mastication, solubilization and digestion of nutrients, as well as in respiration and speech, and participates in innate and adaptive immunity. Saliva creates and regulates the environment of the oral cavity, and changes in its composition and rate of secretion have significant effects on oral tissues as well as on systemic health. The effects of microgravity on the salivary glands, mandible and teeth were studied in mice flown on US space shuttle STS-131 and STS-135 missions, and the Russian Bion-M1 biosatellite. Significant changes in morphology and secretory protein expression occurred in parotid glands; submandibular glands were affected only on the 30-day Bion-M1 mission, indicating tissue specificity of the effects due to changes in gravity which may be similar to those taking place in humans. Changes also occurred in mandibular bone and incisor teeth. Collection of saliva is a non-invasive procedure for assessing physiological status and diagnosis of several disorders and provides a simple method for monitoring astronaut health during extended spaceflight.",book:{id:"7632",slug:"beyond-leo-human-health-issues-for-deep-space-exploration",title:"Beyond LEO",fullTitle:"Beyond LEO - Human Health Issues for Deep Space Exploration"},signatures:"Maija I. Mednieks and Arthur R. 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High-quality wind data are required to build mathematical models of the Mars climate; therefore, powerful techniques are necessary to eliminate aerodynamic perturbations produced by the rover presence over wind measurements. This chapter is dedicated to the characterization of the aerodynamics around the Mars 2020 rover and its interaction with the rover Mars surface vehicle in order to get information to correct wind data coming from Mars.",book:{id:"8556",slug:"mars-exploration-a-step-forward",title:"Mars Exploration",fullTitle:"Mars Exploration - a Step Forward"},signatures:"Rafael Bardera, Suthyvann Sor and Adelaida García-Magariño",authors:[{id:"275076",title:"Dr.",name:"Suthyvann",middleName:null,surname:"Sor Mendi",slug:"suthyvann-sor-mendi",fullName:"Suthyvann Sor Mendi"},{id:"275078",title:"Dr.",name:"Rafael",middleName:null,surname:"Bardera",slug:"rafael-bardera",fullName:"Rafael Bardera"},{id:"313617",title:"Dr.",name:"Adelaida",middleName:null,surname:"García-Magariño",slug:"adelaida-garcia-magarino",fullName:"Adelaida García-Magariño"}]},{id:"71209",doi:"10.5772/intechopen.91021",title:"Psychosocial Aspects of a Flight to Mars",slug:"psychosocial-aspects-of-a-flight-to-mars",totalDownloads:693,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The first experiments modeling peoples’ behavior during a long-term cosmic flight revealed the need for a more systematic monitoring of the development of the crew’s mutual relationships, particularly in terms of collaboration and work-related communication. For this reason, in order to examine team dynamics, the sociomapping method was developed, which was first used in the HUBES 94 and ECOPSY 95 experiments. This method allows for an analysis and visualization of the continuous changes in communication and collaboration, including decreases in their quality and quantity. Sociomapping was used to monitor and analyze the communication and collaboration in simulations of flights to Mars in the Mars-105 and Mars-500 experiments. Based on the aforementioned experiments, it can be noted that statistically significant and nonrandom declines of the quantity and quality of team communication may occur during long-term missions, which may be related to changes in the team’s performance. These changes are influenced by exterior stress factors, as well as cultural and linguistic differences and the length of the flight itself. In this chapter, the main findings of the experiment, as well as the resulting recommendations for a successful management of the psychological aspects of a flight to Mars, will be summarized.",book:{id:"8556",slug:"mars-exploration-a-step-forward",title:"Mars Exploration",fullTitle:"Mars Exploration - a Step Forward"},signatures:"Radvan Bahbouh",authors:[{id:"155311",title:"Dr.",name:"Radvan",middleName:null,surname:"Bahbouh",slug:"radvan-bahbouh",fullName:"Radvan Bahbouh"}]}],mostDownloadedChaptersLast30Days:[{id:"71802",title:"Autonomous Navigation for Mars Exploration",slug:"autonomous-navigation-for-mars-exploration",totalDownloads:816,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The autonomous navigation technology uses the multiple sensors to percept and estimate the spatial locations of the aerospace prober or the Mars rover and to guide their motions in the orbit or the Mars surface. In this chapter, the autonomous navigation methods for the Mars exploration are reviewed. First, the current development status of the autonomous navigation technology is summarized. The popular autonomous navigation methods, such as the inertial navigation, the celestial navigation, the visual navigation, and the integrated navigation, are introduced. Second, the application of the autonomous navigation technology for the Mars exploration is presented. The corresponding issues in the Entry Descent and Landing (EDL) phase and the Mars surface roving phase are mainly discussed. Third, some challenges and development trends of the autonomous navigation technology are also addressed.",book:{id:"8556",slug:"mars-exploration-a-step-forward",title:"Mars Exploration",fullTitle:"Mars Exploration - a Step Forward"},signatures:"Haoting Liu",authors:[{id:"314772",title:"Associate Prof.",name:"Haoting",middleName:null,surname:"Liu",slug:"haoting-liu",fullName:"Haoting Liu"}]},{id:"70846",title:"Aerodynamics of Mars 2020 Rover Wind Sensors",slug:"aerodynamics-of-mars-2020-rover-wind-sensors",totalDownloads:684,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Environmental factors in Mars atmosphere are a part of the research issues of the future Mars 2020 mission. The new rover surface vehicle will transport different instruments to investigate the geology, biology, and meteorology of Mars. Amongst these instruments, the Mars Environmental Dynamics Analyzer (MEDA) will be dedicated to the measurement of environment parameters. Two wind sensors will be included in the meteorological station MEDA because wind plays a very important role in Martian climate. High-quality wind data are required to build mathematical models of the Mars climate; therefore, powerful techniques are necessary to eliminate aerodynamic perturbations produced by the rover presence over wind measurements. This chapter is dedicated to the characterization of the aerodynamics around the Mars 2020 rover and its interaction with the rover Mars surface vehicle in order to get information to correct wind data coming from Mars.",book:{id:"8556",slug:"mars-exploration-a-step-forward",title:"Mars Exploration",fullTitle:"Mars Exploration - a Step Forward"},signatures:"Rafael Bardera, Suthyvann Sor and Adelaida García-Magariño",authors:[{id:"275076",title:"Dr.",name:"Suthyvann",middleName:null,surname:"Sor Mendi",slug:"suthyvann-sor-mendi",fullName:"Suthyvann Sor Mendi"},{id:"275078",title:"Dr.",name:"Rafael",middleName:null,surname:"Bardera",slug:"rafael-bardera",fullName:"Rafael Bardera"},{id:"313617",title:"Dr.",name:"Adelaida",middleName:null,surname:"García-Magariño",slug:"adelaida-garcia-magarino",fullName:"Adelaida García-Magariño"}]},{id:"67679",title:"Oral Tissue Responses to Travel in Space",slug:"oral-tissue-responses-to-travel-in-space",totalDownloads:1027,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"The oral cavity functions in taste, mastication, solubilization and digestion of nutrients, as well as in respiration and speech, and participates in innate and adaptive immunity. Saliva creates and regulates the environment of the oral cavity, and changes in its composition and rate of secretion have significant effects on oral tissues as well as on systemic health. The effects of microgravity on the salivary glands, mandible and teeth were studied in mice flown on US space shuttle STS-131 and STS-135 missions, and the Russian Bion-M1 biosatellite. Significant changes in morphology and secretory protein expression occurred in parotid glands; submandibular glands were affected only on the 30-day Bion-M1 mission, indicating tissue specificity of the effects due to changes in gravity which may be similar to those taking place in humans. Changes also occurred in mandibular bone and incisor teeth. Collection of saliva is a non-invasive procedure for assessing physiological status and diagnosis of several disorders and provides a simple method for monitoring astronaut health during extended spaceflight.",book:{id:"7632",slug:"beyond-leo-human-health-issues-for-deep-space-exploration",title:"Beyond LEO",fullTitle:"Beyond LEO - Human Health Issues for Deep Space Exploration"},signatures:"Maija I. Mednieks and Arthur R. Hand",authors:[{id:"296192",title:"Emeritus Prof.",name:"Arthur",middleName:null,surname:"Hand",slug:"arthur-hand",fullName:"Arthur Hand"},{id:"296354",title:"Dr.",name:"Maija",middleName:null,surname:"Mednieks",slug:"maija-mednieks",fullName:"Maija Mednieks"}]},{id:"72944",title:"Aerocapture, Aerobraking, and Entry for Robotic and Human Mars Missions",slug:"aerocapture-aerobraking-and-entry-for-robotic-and-human-mars-missions",totalDownloads:564,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"This chapter provides an overview of the aeroassist technologies and performances for Mars missions. We review the current state-of-the-art aeroassist technologies for Mars explorations, including aerocapture, aerobraking, and entry. Then we present a parametric analysis considering key design parameters such as interplanetary trajectory and vehicle design parameters (lift-to-drag ratio, ballistic coefficient, peak g-load, peak heat rate, and total heat load) for aerocapture, aerobraking, and entry. A new perspective on a rapid aerobraking concept will be provided. The analysis will include first-order estimates for thermal loading, thermal protection systems material selection, and vehicle design. 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Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,annualVolume:11410,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,annualVolume:11411,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. 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He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. 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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science and Technology from the Department of Chemistry, National University of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013. She relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the National Institute of Fundamental Studies from April 2013 to October 2016. She was a senior lecturer on a temporary basis at the Department of Food Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is currently Deputy Principal of the Australian College of Business and Technology – Kandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI) Ambassador to Sri Lanka.",institutionString:"Australian College of Business & Technology",institution:null}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. 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It has become a massive part of our daily lives, making predictions based on experience, making this a fascinating area that solves problems that otherwise would not be possible or easy to solve. This topic aims to encompass algorithms that learn from experience (supervised and unsupervised), improve their performance over time and enable machines to make data-driven decisions. It is not limited to any particular applications, but contributions are encouraged from all disciplines.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",keywords:"Intelligent Systems, Machine Learning, Data Science, Data Mining, Artificial Intelligence"},{id:"27",title:"Multi-Agent Systems",scope:"Multi-agent systems are recognised as a state of the art field in Artificial Intelligence studies, which is popular due to the usefulness in facilitation capabilities to handle real-world problem-solving in a distributed fashion. The area covers many techniques that offer solutions to emerging problems in robotics and enterprise-level software systems. Collaborative intelligence is highly and effectively achieved with multi-agent systems. Areas of application include swarms of robots, flocks of UAVs, collaborative software management. Given the level of technological enhancements, the popularity of machine learning in use has opened a new chapter in multi-agent studies alongside the practical challenges and long-lasting collaboration issues in the field. It has increased the urgency and the need for further studies in this field. We welcome chapters presenting research on the many applications of multi-agent studies including, but not limited to, the following key areas: machine learning for multi-agent systems; modeling swarms robots and flocks of UAVs with multi-agent systems; decision science and multi-agent systems; software engineering for and with multi-agent systems; tools and technologies of multi-agent systems.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",keywords:"Collaborative Intelligence, Learning, Distributed Control System, Swarm Robotics, Decision Science, Software Engineering"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:{title:"Artificial Intelligence",id:"14"},selectedSubseries:null},seriesLanding:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. This series is intended for doctors, engineers, and scientists involved in biomedical engineering or those wanting to start working in this field.",coverUrl:"https://cdn.intechopen.com/series/covers/7.jpg",latestPublicationDate:"May 7th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:3,numberOfPublishedChapters:96,numberOfPublishedBooks:12,editor:{id:"50150",title:"Prof.",name:"Robert",middleName:null,surname:"Koprowski",fullName:"Robert Koprowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTYNQA4/Profile_Picture_1630478535317",biography:"Robert Koprowski, MD (1997), PhD (2003), Habilitation (2015), is an employee of the University of Silesia, Poland, Institute of Computer Science, Department of Biomedical Computer Systems. For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},subseries:[{id:"7",title:"Bioinformatics and Medical Informatics",keywords:"Biomedical Data, Drug Discovery, Clinical Diagnostics, Decoding Human Genome, AI in Personalized Medicine, Disease-prevention Strategies, Big Data Analysis in Medicine",scope:"Bioinformatics aims to help understand the functioning of the mechanisms of living organisms through the construction and use of quantitative tools. The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",annualVolume:11403,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"Tzallas",fullName:"Alexandros Tzallas",profilePictureURL:"https://mts.intechopen.com/storage/users/5886/images/system/5886.png",institutionString:"University of Ioannina, Greece & Imperial College London",institution:{name:"University of Ioannina",institutionURL:null,country:{name:"Greece"}}},{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",fullName:"Lulu Wang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRX6kQAG/Profile_Picture_1630329584194",institutionString:null,institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}},{id:"225387",title:"Prof.",name:"Reda",middleName:"R.",surname:"Gharieb",fullName:"Reda Gharieb",profilePictureURL:"https://mts.intechopen.com/storage/users/225387/images/system/225387.jpg",institutionString:"Assiut University",institution:{name:"Assiut University",institutionURL:null,country:{name:"Egypt"}}}]},{id:"8",title:"Bioinspired Technology and Biomechanics",keywords:"Bioinspired Systems, Biomechanics, Assistive Technology, Rehabilitation",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. Osma",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSDv7QAG/Profile_Picture_1626602531691",institutionString:null,institution:{name:"Universidad de Los Andes",institutionURL:null,country:{name:"Colombia"}}},{id:"69697",title:"Dr.",name:"Mani T.",middleName:null,surname:"Valarmathi",fullName:"Mani T. Valarmathi",profilePictureURL:"https://mts.intechopen.com/storage/users/69697/images/system/69697.jpg",institutionString:"Religen Inc. | A Life Science Company, United States of America",institution:null},{id:"205081",title:"Dr.",name:"Marco",middleName:"Vinícius",surname:"Chaud",fullName:"Marco Chaud",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSDGeQAO/Profile_Picture_1622624307737",institutionString:null,institution:{name:"Universidade de Sorocaba",institutionURL:null,country:{name:"Brazil"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/62715",hash:"",query:{},params:{id:"62715"},fullPath:"/profiles/62715",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()