These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\n
This collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\n
To celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\n
Initially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\n
These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\n
This collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\n
To celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
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For this reason, noise control plays an increasingly central role in the development of modern industrial and engineering applications. Nowadays, the noise control problem excites and attracts the attention of a great number of scientists in different disciplines. Indeed, noise control has a wide variety of applications in manufacturing, industrial operations, and consumer products. The main purpose of this book, organized in 13 chapters, is to present a comprehensive overview of recent advances in noise control and its applications in different research fields. The authors provide a range of practical applications of current and past noise control strategies in different real engineering problems. It is well addressed to researchers and engineers who have specific knowledge in acoustic problems. I would like to thank all the authors who accepted my invitation and agreed to share their work and experiences.",isbn:null,printIsbn:"978-953-307-918-9",pdfIsbn:"978-953-51-6099-1",doi:"10.5772/1375",price:139,priceEur:155,priceUsd:179,slug:"noise-control-reduction-and-cancellation-solutions-in-engineering",numberOfPages:310,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"7219da94d49d88629388cfcd200075ae",bookSignature:"Daniela Siano",publishedDate:"March 2nd 2012",coverURL:"https://cdn.intechopen.com/books/images_new/866.jpg",numberOfDownloads:36329,numberOfWosCitations:14,numberOfCrossrefCitations:6,numberOfCrossrefCitationsByBook:2,numberOfDimensionsCitations:16,numberOfDimensionsCitationsByBook:3,hasAltmetrics:0,numberOfTotalCitations:36,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 26th 2011",dateEndSecondStepPublish:"February 23rd 2011",dateEndThirdStepPublish:"June 30th 2011",dateEndFourthStepPublish:"July 30th 2011",dateEndFifthStepPublish:"November 27th 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"9960",title:"Dr.",name:"Daniela",middleName:null,surname:"Siano",slug:"daniela-siano",fullName:"Daniela Siano",profilePictureURL:"https://mts.intechopen.com/storage/users/9960/images/system/9960.jpg",biography:'Daniela Siano was born in Naples - Italy, and graduated in Aeronautical Engineering from the University of Naples “Federico II”, Italy in 1994. Until 2001, she was a researcher in the Acoustic and Vibration Department at C.I.R.A. (Italian Aerospace Research Center). From 2001 until now, she has been a researcher at the National Research Council of Italy (CNR) in the field of acoustic and vibration in the transport field. She is responsible for the Acoustic and Vibration Laboratory. She is qualified to University Associate Professor – Sector Machines and Systems for Energy and Environment, and is also qualified in the Engineer Profession. She had a scholarship granted by M.A.R.S.- Microgravity Advanced Research and Support - Dornier GmbH (Friedrichshafen - Germany), Euromaster in \\"Total Quality Management\\" at DIMP – Department of Mechanical and Production Engineering – University of Naples Federico II – Italy, as well as assistant in “Fluid Machines I”, “Fluid Machines II”, and “Applied Mechanics”. She is the tutor of more than 30 Master\\\'s students and 7 Ph.D. students. 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\r\n\tThe members of the Enterobacteria are prevalent and involved in different types of infections (nosocomial, urinary tract infections, respiratory infections, gastroenteritis, food poisoining, different outbreaks, etc.), and they need to be reviewed after a period of time as different variants and species evolve and cause different infections that need to be studied thoroughly.
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1. Introduction
Multiple sclerosis (MS) is among the most enigmatic disorders of the central nervous system, affecting a substantial number of patients, at any age from childhood to senility, inducing a large spectrum of physical and mental disability in a considerable number of them, with a high prevalence in Europe and North America [1].
The clinical diagnosis of multiple sclerosis is not always an easy task, due to the polymorphic and multidimensional pattern of the clinical manifestations of the disease, which might be associated with other disorders.
The phenomena and the severity of the disease would be evaluated based on the criteria of the expanded disability status scale (EDSS) [2].
The pathogenesis of MS, which has been considered as a chronic immune-mediated disorder of the central nervous system (CNS) [3], has to be further clarified, although some risk factors such as genetic predisposition, viral, bacterial, or parasitic infections [4], climatic, environmental, and dietary factors [5], head trauma, and physical or psychological distress may play a substantial role in the puzzling etiological background of the disease.
Besides, the multidimensional underlying pathological mechanisms of multiple sclerosis, involving numerous cell interactions, molecular reactions, and activation of autoimmune responses via a multitude of signaling factors, result in inflammatory infiltration, demyelination, gliosis, and axonal damage, which compose a very complicated labyrinthine pattern, causing a reasonable difficulty in the effectivity of any targeted therapeutical approach of the disease [6].
Among the many cellular components, which participate actively in the process of demyelination and remyelination, during the continuous neuropathological alterations and interactions in the brain and the spinal cord, during the long course of multiple sclerosis, the pericytes being heterogeneous cells [7] described by Rouget, originally called Rouget cells [8] and named pericytes by Zimmermann [9], seem to play a substantial role at any stage of the disease.
It is well known that brain pericytes are pluripotent progenitor cells of neuroectodermal origin [10, 11], which are located mostly around the blood vessels (peri, περι = around) and serve as substantial components of the blood-brain barrier (BBB), being in direct contact with the endothelial cells, sharing a common basement membrane with them, and developing many functional interactions with endothelial cells, astrocytes, perivascular microglia, and macrophages [12].
It is important that the pericytes contribute to the formation of the functional neurovascular unit (NVU), which is composed of endothelial cells, pericytes, astrocytes, and neurons, and serve as a crucial structure for the integrity and functional stability of the central nervous system [13, 14]. The pericytes participate also in the development of the wall of small vessels, such as pre-capillary arterioles, capillaries, and post-capillary venules, enveloping the endothelium and being separated from them by a basement membrane (BM). Over most, the fact that the pericytes play a crucial role in the function of the blood-brain barrier [15] is of particular importance, particularly in the development of the tight junctions and in the vesicle trafficking in the endothelial cells, controlling the permeability of the BBB and participating effectively in its reconstruction and remodeling, in cases of anatomical disruption or functional decline, contributing therefore essentially in the stability of brain homeostasis [16].
A substantial body of evidence revealed that inducible pericyte knockdown in experimental animals resulted in disruption of the blood-brain barrier and rapid loss of neurons [17, 18].
It is important that the pericytes do frequently migrate in the neuropile space and even proliferate into different cellular types participating in a multitude of cell interactions [19].
Besides, pericytes participate in autoimmune reactions and modulations, mediating the neuroinflammation [19], and controlling the penetration of immune cells via BBB, playing an active role in lymphocytic trafficking and functional regulation via cytokine secretion and activation [20, 21, 22], and eventually contributing in glial scar formation [23].
The fact that pericytes are involved in the remyelination of the CNS, by modulating oligodendrocytes and stimulating the differentiation of oligodendrocyte progenitors [24], is of substantial validity.
The density of the pericytes varies from tissue to tissue, being the highest in the CNS, apart from the retina [25]. However, their number is not definitely stabilized, given that they could differentiate into other cell types, including glial cells and neurons under various conditions, in reaction to tissue injury [26].
For a further observation and detailed analysis of the gradual neuropathological phenomena and the cellular interactions, which occur in multiple sclerosis, animal models have been created by active immunization of susceptible recipients [27]. Among them, the experimental allergic encephalomyelitis (EAE) is the most frequently used animal model [27], which has been induced in genetically susceptible animals such as rats, mice, guinea pigs, rabbits, and monkeys by injecting compounds that would stimulate the immune system, resulting in developing inflammatory perivascular infiltrates in the CNS [28].
In the majority of the experimental models, the injected immunogenic factor is derived from CNS proteins such as myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG). The injected animals may develop neurological manifestations due to creation of inflammatory foci and demyelination in random areas of the CNS, in analogy to MS [29, 30].
Among the cellular components, the pericytes [31], the microglial cells, and the perivascular macrophages (PVM) [32] may play a substantial role in mediating neuroinflammation in the CNS in the EAE, as well as in MS and other autoimmune neurological conditions [32, 33, 34].
In the present study, we attempted to study the ultrastructural alterations of the pericytes around the capillaries and the venules of the brain in animals, which developed experimental allergic encephalomyelitis, knowing that there are some substantial limitations, due to the different pathogenetic mechanisms of the EAE, in correlation with MS [35].
2. Material and methods
2.1 Material
Sixty adult Lewis rats (AgB1) of both sexes (30 male and 30 female animals), of 150–200 mean body weight, were immunized by slow injection in their hind footpads of 50 μm of guinea pig myelin basic protein, emulsified in Freund’s complete adjuvant.
All the rats were clinically examined and scored daily following the immunization. The first clinical findings appeared between the 10th and 12th day following the injection. On the 18th day after the immunization, all the clinical manifestations of the animals were quantified and scored based on a 0–5 disease severity scale, where 0 means no clinical findings, 1 means loss of the tone of the nail, 2 means weakness of the hind limb, 3 means paralysis of the hind limb, 4 means paralysis of the hind limb and severe weakness or paralysis of the forelimb, and 5 means expiring condition or death [36, 37].
From the 60 immunized animals according to the final clinical evaluation, 2 of them were scored 0, 12 were scored 1, 10 were scored 2, 22 were scored 3, and 14 were scored 4. No one died.
Then, under ether anesthesia, all the rats were sacrificed, by perfusion with 200 ml buffer solution (buffered physiologic saline) followed by 250 ml οf Sotelo fixing solution [38] containing 2.5% glutaraldehyde, 1% paraformaldehyde in 0.2 cacodylate buffer, adjusted at pΗ 7.35. For the perfusion, a Holter pump (flow 25 ΗΡΜ) was used.
After the fixation, the skull of each animal was opened as well as the spinal canal, and the brain and the spinal cord were quickly removed and immersed in newly prepared Sotelo solution at 4°C.
2.2 Method
Coronal sections of the brain hemispheres were performed. The brain stem, the cerebellum, and the spinal cord were cut into sections of 2 mm thickness. Samples were taken under a dissecting microscope and immediately processed for electron microscopy.
All the specimens were immersed in newly prepared Sotelo fixing solution, for 3 h, then they were postfixed in 1% of osmium oxide for 30 min at room temperature and dehydrated in graded alcohol solutions and propylene oxide. After the dehydration, the specimens were embedded in Araldite mixture.
Semi-thin sections were performed on a Porter-Blum microtome and stained with 1% toluidine blue. Thin sections of silver-gray inference color were cut in a Reichert ultratome, mounted on bare 400 mesh grids, contrasted, with uranyl acetate and lead citrate, and studied in an electron microscope Zeiss 9As.
Besides, multiple sections of the brain hemispheres, the brain stem, the cerebellum, and the spinal cord, were prepared for histological examination. Thus paraffin-embedded sections were stained with hematoxylin and eosin and were serially studied in the light microscope at a magnification of 25× and 100×.
The histological diagnosis of the experimental allergic encephalomyelitis was based on the identification and quantitation of the perivascular infiltrates of mononuclear cells and lymphocytes in the brain, the cerebellum, and the spinal cord.
3. Results
3.1 In light microscopy
The histological examination of the H and E stained sections revealed a substantial number of perivenular and pericapillary infiltrations in the brain hemispheres, the brain stem, and the cerebellum of the animals, with the greatest amount of infiltrations seen in animals, which were scored 4 and 5. The spinal cord was seriously involved showing the highest number of perivascular infiltrates in all animals. No infiltrations were observed in animals scored 0.
The semi-thin sections of Araldite embedded tissue, which were studied in light microscopy revealed, besides the perivascular infiltrates, alterations of the myelin sheath of the myelinated axons in the brain hemispheres, the cerebellum, and extensively in the spinal cord in animals scored 4 and 5.
3.2 In electron microscopy
By electron microscopy, the pericytes were seen in the wall of the brain capillaries, around the endothelial cells (Figure 1). They are characterized by their large round or ovoid nucleus, with rough distribution of the chromatin, the plenty of mitochondria and ribosomes perikaryon, and the basal lamina, which surrounds the cell body. They interacted with the endothelial cells, which create gap junction, surrounding them.
Figure 1.
Pericyte (P) in the wall of a brain capillary near the endothelial cell (E). Electron micrograph (mag. 35,000×).
A substantial proliferation of pericytes was noticed in the spinal cord and the cerebellum around the capillaries and the venules, escaping the basal lamina (Figure 2) particularly in animals scored 4 or 5. All of them extend long processes, on the one hand surrounding the wall of the blood capillaries and on the other approaching the astrocytes in the perivascular space.
Figure 2.
Pericyte escaping the basal membrane (bm) around a brain capillary. The mitochondrial alterations are obvious. Electron micrograph (mag.128,000×).
Morphologically, the majority of the pericytes and the endothelial cells demonstrated aggregations of many small mitochondria around the nucleus, dilatation of the cisternae of Golgi apparatus, and large lysosomes (Figures 2 and 3). The nucleus of the activated perivascular pericytes was mostly round or ovoid, distinguished clearly from the very elongated nuclei of the endothelial cells (Figure 4). The nucleus of the perivascular pericytes demonstrated, as a rule, a rough distribution of heterochromatin in the periphery. The perikaryon included large number of small round mitochondria, with fragmentation of the cristae in the majority of them. A substantial number of endothelial cells demonstrated dilatation or disruption of the tight junctions (Figure 5).
Figure 3.
Alterations of the mitochondria and dilatation of the smooth endoplasmic reticulum (ser) in an endothelial cell of the wall of a brain capillary. Electron micrograph (mag. 128,000×).
Figure 4.
An endothelial cell of a brain capillary, showing abundant peripheral accumulation of heterochromatin and disruption of the tight junction (Tj). Electron micrograph (mag. 35,000×).
Figure 5.
Disruption of the tight junctions (Tj) of a brain capillary. Electron micrograph (mag. 128,000×).
Many capillaries showed marked perivascular edema and accumulation of lymphocytes and monocytes. It was noticed that pericytes in the neuropile space were intermixed with astrocytic processes (Figure 6).
Figure 6.
Pericytes (P) in the neuropile space around the endothelial cell (E) of a dilated brain capillary. There is a marked perivascular edema. Electron micrograph (mag. 35,000×).
A large number of pericytes demonstrated an increased number of pinocytotic vesicles, large lipid granules, and mitochondrial alterations, and marked dilatation of the cisternae of the smooth endoplasmic reticulum (Figures 2 and 3).
4. Discussion
Pericytes are polymorphic perivascular cells, which collaborate with the endothelial cells for the regulation of the blood–brain barrier’s permeability [39]. A substantial body of evidence, derived from morphometric observations in light and electron microscope, revealed that the ratio of pericytes to endothelial cells in the majority of the structures of the central nervous system is approximately 1:1 [39]. However, not all of the perivascular cells are pericytes, given that some of them are macrophages or adventitia cells [40], presumably derived from the pericytes, which as pluripotent cells can generate other cell types, to maintain the brain homeostatic equilibrium [22].
In MS, the proliferation or the degeneration of the pericytes associated with dysfunction or disruption of the blood-brain barrier is one of the initial neuropathological phenomena [41], triggering a cascade of inflammatory reactions and cellular interactions.
In the model of the experimental allergic encephalomyelitis, alterations of the blood-brain barrier have been described in electron microscopy by many authors [42, 43, 44]. The role of the pericytes in inducing those alterations may be crucial, given that perivascular pericytes regulate endothelial transcytosis, which would increase the permeability of the blood-brain barrier [45].
In the model of pericyte-deficient mice, an increased expression of leukocyte adhesion molecules has been described in association with polarization defect of astrocyte end feet in the vessels of the brain, underlining the importance of the pericytes for the integrity of the blood-brain barrier [46].
On the contrary, the proliferation of the pericytes suggests that they participate in the immune reactions of the brain, a fact that is noticed and described also in multiple sclerosis [21]. It was noticed that the pathological alterations in experimental allergic encephalomyelitis mimic to some degree, in many aspects, the morphological alterations, which occur in multiple sclerosis [47, 48].
Many histological observations revealed that the morphology of the pericytes varies considerably in the various structures of the brain in normal and pathological conditions. Among other conditions, proliferation of pericytes was described in early cases of Alzheimer’s disease, associated with disruption of the BBB [49] as well as in traumatic brain injuries [50].
Although many markers have been used for the identification of pericytes in various conditions, none is unanimously accepted as the precise and definite one, given that pericytes retain the multipotential properties of stem cells [51] or express a macrophage-like function [52].
The proliferation of the pericytes around the capillaries and the venules in the central nervous system has been observed mostly at the initial stages of the inflammatory conditions, autoimmune reactions, and degeneration of the brain, given that as the process advances, the pericytes further migrate into the neuropile space, and the ratio between them and the endothelial cells declines consequently [53].
In many pathological conditions, the pericytes contribute to the restoration of the BBB substantially, either by their contact with the endothelial cells or through proper signaling [54, 55], a fact that is beneficial for the establishment of the brain homeostasis.
A reasonable therapeutic approach to multiple sclerosis may be attempted by enforcing the interactions between pericytes, endothelial cells, and astrocytes, which may result in the restoration of the blood-brain barrier [56, 57].
It would also be emphasized that the observation that activated pericytes may contribute substantially to the differentiation of the oligodendrocyte progenitors, enabling consequently the restoration of the myelin sheath, and the protection of the axons is of substantial importance for finding an escape from the labyrinth of the disease [58]. This novel role of pericytes may open new therapeutic horizons in the field of demyelinating conditions [59, 60], as a catharsis from the drama of multiple sclerosis.
5. Conclusions
Pericytes play a very important role in the formation and mentainance of the blood-brain barrier (BBB), as a substantial component of the neurovascular unit.
Pericytes participate actively in the autoimmune reactions of the central nervous system (CNS), having the capacity to interact with oligodendrocytes and astrocytes and even to generate other cell lines.
In the experimental model of multiple sclerosis (MS), the experimental allergic encephalomyelitis (EAE), the electron microscopy shows clearly the proliferation of the perivascular pericytes, their migration into neuropile space, their morphological alterations, and even their collaboration with endothelial cell, for the restoration of the disrupted BBB.
Activated pericytes may contribute to the differentiation of the oligodendrocyte progenitors, a fact that may enable the restoration of the myelin sheath and increase the axonal protection.
Therapeutic regimes protecting the pericytes in the early stages of demyelinating conditions may open new promising horizons in the treatment of multiple sclerosis.
Conflict of interest
The author declares no conflict of interest.
\n',keywords:"pericytes, demyelinating conditions, electron microscope, BBB, EAE",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/80998.pdf",chapterXML:"https://mts.intechopen.com/source/xml/80998.xml",downloadPdfUrl:"/chapter/pdf-download/80998",previewPdfUrl:"/chapter/pdf-preview/80998",totalDownloads:25,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:0,impactScoreQuartile:0,hasAltmetrics:0,dateSubmitted:"December 6th 2021",dateReviewed:"February 10th 2022",datePrePublished:"March 28th 2022",datePublished:"May 4th 2022",dateFinished:"March 28th 2022",readingETA:"0",abstract:"The pericytes play a very important role in the central nervous system (CNS), concerning the formation of the functional neurovascular unit, serving as a substantial component in the development and maintenance of the stability of the blood-brain barrier (BBB). Besides, as pluripotent cells of neuroectodermal origin, the pericytes participate in autoimmune reactions and modulations, controlling the penetration of immune cells via BBB and playing an active role in lymphocytic trafficking and functional regulation, via cytokine secretion and activation. In demyelinating conditions, they participate in the restoration of the myelin sheath by modulating oligodendrocytes and stimulating the differentiation of oligodendrocyte progenitors. In the experimental model of allergic encephalomyelitis (EAE), electron microscopy reveals the proliferation and the morphological alterations of the pericytes as well as their interactions with endothelial cells and astrocytes, thus underlining the crucial role that pericytes play in the integrity of the BBB and the immune reactions of the CNS.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80998",risUrl:"/chapter/ris/80998",book:{id:"10222",slug:"demyelination-disorders"},signatures:"Stavros J. Baloyannis",authors:[{id:"156098",title:"Emeritus Prof.",name:"Stavros J.",middleName:"J.",surname:"Baloyannis",fullName:"Stavros J. Baloyannis",slug:"stavros-j.-baloyannis",email:"sibh844@otenet.gr",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/156098/images/system/156098.jpg",institution:{name:"Aristotle University of Thessaloniki",institutionURL:null,country:{name:"Greece"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Material and methods",level:"1"},{id:"sec_2_2",title:"2.1 Material",level:"2"},{id:"sec_3_2",title:"2.2 Method",level:"2"},{id:"sec_5",title:"3. Results",level:"1"},{id:"sec_5_2",title:"3.1 In light microscopy",level:"2"},{id:"sec_6_2",title:"3.2 In electron microscopy",level:"2"},{id:"sec_8",title:"4. Discussion",level:"1"},{id:"sec_9",title:"5. 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1. Introduction
Huntington’s disease (HD) is a neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline as well as psychiatric disturbance [1, 2]. The prevalence of HD is estimated to be between 0.4 and 5.70 per 100,000. Since HD is a genetic disorder, the prevalence depends strongly on the study population and it is higher in Europe, North America, and Australia than in Asia [3]. HD is caused by a dominantly inherited CAG repeat expansion in the huntingtin gene (HTT). The disease develops in individuals bearing a number of repetitions greater than 40, whereby greater CAG repeats found in the huntingtin gene are associated with early-onset forms of the disorder, fast rate of disease progression, and the most severe neurological deficits [4].
The mean age of HD onset is around 40 years, meanwhile the Juvenile Onset Huntington’s Disease (JOHD), occurs in individuals bearing more than 60 CAG repeats, which usually starts at the age of 21. HD eventually leads to death 15–20 years after the symptomatic onset [5]. It is believed that mutant huntingtin (mHTT) affects many cellular functions and leads to cell death, preferentially subpopulations of GABAergic medium spiny projection neurons and neurons in the cerebral cortex [1, 6]. This leads to imbalances in diverse neurotransmission, including the dopaminergic (DA) and glutaminergic systems. In the early stages of HD, DA neurotransmission is increased, whereas expression of DA receptors is reduced. However, in the course of the disease DA neurotransmission decreases. In turn, time-dependent abnormal DA neurotransmission affects glutamate receptor modulation, which may cause excitotoxicity [7, 8]. As DA plays a crucial role in the control of coordinated movements, motivation, and reward as well as cognitive function, alterations in DA balance in the striatum and provoke neurological and psychiatric symptoms of HD. The early stages of the disease are often characterized by chorea, followed by akinesia, while dystonia is more typical for the late stages [9]. Major non-motor symptoms include apathy and depression, anxiety, irritability, or aggressive behavior [9]. Impairment in cognitive functioning eventually ending in dementia, which has been mentioned by George Huntington in his first report, is another integral part of the disease [10]. Until today, there is no cure for HD, and treatment is only symptomatic, targeting mainly dopaminergic and glutaminergic systems [11].
2. Possible role of the endocannabinoid system in Huntington’s disease
Over the last 30 years, the endocannabinoid system (ECS) has emerged as an important neuromodulatory system, which could be efficiently targeted in a number of neurological diseases, including HD [8, 12, 13]. The primary cannabinoid receptor subtypes are cannabinoid receptors type 1 (CB1) and type 2 (CB2). The CB1 receptor is a protein-coupled receptor, highly expressed in the central nervous system (CNS), particularly in the neocortex, hippocampus, basal ganglia, cerebellum, and brainstem. In addition to its CNS location, CB1 has also been identified in numerous peripheral tissues and cell types [14]. On the other hand, the CB2 receptor is expressed mainly outside CNS, predominantly in the immune system. However, it has also been identified in the CNS, especially in the glial cells and brainstem neurons [15, 16]. The abovementioned high distribution of the CB1 receptor in basal ganglia indicates an indispensable role of the ECS in the control of movements by inhibitory modulation of other neurotransmitter systems [16]. Moreover, the CB1 receptors regulate glutamatergic neurotransmission under both physiological and pathological conditions and thus are able to downregulate excitotoxic glutamate release [17].
3. Studies in animal models
Studies in animal models suggest that the pathogenesis of HD may be related to an early and widespread reduction in the ECS, particularly to the loss of CB1 receptors [16, 18, 19] and decreased endocannabinoid levels in the striatum, which in turn may lead to hyperkinesia [19]. The administration of substances, which increase endocannabinoid activity led to a significant improvement of motor disturbances in a rat model of HD [16, 20]. In particular, Lastres-Becker et al. [17] hypothesized that substances that increase the endocannabinoid activity could be applied for the treatment of hyperkinetic symptoms. To test this hypothesis the authors created a rat model of HD through bilateral striatal injections of 3-nitropionic acid that leads to impaired striatal GABAergic neurotransmission. As a result, these rats started suffering from abnormal movements followed by motor depression. In addition, they demonstrated that the severity of motor hyperkinesias was correlated with decreased concentration of several neurotransmitters, such as GABA, dopamine, and their metabolites. Moreover, mRNA levels for the CB1 receptor were depleted in the caudate-putamen of 3-nitropropionic acid (3-NP) injected rats. In addition, the authors demonstrated a reduction in CB1 receptor binding in the caudate-putamen, the globus pallidus, and also substantia nigra. Finally, the administration of AM404, an inhibitor of endocannabinoid uptake, led to the alleviation of motor disturbances. The same group from Madrid [21] explored the status of CB1 receptors in the HD94 transgenic mouse model of HD. To investigate this problem, the authors analyzed mRNA levels of the CB1 receptor and the number of specific binding sites, and the activation of GTP-binding proteins by the CB1 receptor agonist. As a result, they have demonstrated that mRNA transcripts of the CB1 receptor were significantly decreased in selected regions of the brain, such as caudate in the HD transgenic mice compared to controls. This depletion was correlated with a marked reduction of reception density in the caudate, globus pallidus, and substantia nigra pars reticulata. In addition, the efficacy of CB1 receptor activation was depleted in the globus pallidus and there was a trend toward a decrease in substantia nigra.
Another significant contribution was done by the group from the Autonomous University in Madrid led by Isabel Lastres-Becker [22]. The scientists used a previously mentioned rat model of HD for this purpose created via bilateral intrastriatal injections of 3-NP. As a result, CB1 receptor binding and activation of GTP-binding proteins were also reduced in the basal ganglia. In parallel, the authors demonstrated a significant decrease of two endocannabinoids, anandamide and 2-arachidonoylglycerol in the striatum of affected rats, while there was an increase in anandamide concentration in the substantia nigra. Importantly, both CB1 receptors concentration, as well as endocannabinoid levels, were not changed in the cerebral cortex. Another study by the same group [23] has shown that compounds acting at the endocannabinoid systems reduce hyperkinesia in a rat model of HD. In particular, they applied AM404, an inhibitor of the endocannabinoid reuptake, which was able to reduce hyperkinesia and provoke recovery from neurochemical deficits.
As for exocannabinoids used in the treatment of neurological and psychiatric disorders, in one study [24], delta9-tetrahydrocannabinol (THC), a nonselective cannabinoid receptor agonist, and SR141716, a selective antagonist for the CB1 receptor, were tested in an animal model of HD. Surprisingly enough, the administration of THC increased malonate-induced striatal lesions, but SR141716 enhanced the same effect to an even greater extent. Another study examined the long-term effects of exocannabinoid exposure in animal models of HD. In this case, they used transgenic mice R6/1 of HD and administered THC for 8 weeks. This chronic treatment preserved CB1 receptors in the R6/1 striatum, suggesting that the manipulation of endocannabinoid levels warrants further exploration.
Similarly, Sagredo et al. [25] examined the neuroprotective effect of cannabinoids in rats with 3NP striatal lesions. To tackle this question, the authors used the CB1 agonist arachidonyl-2-chloroethylamide (ACEA), the CB2 agonist HU-308, and cannabidiol (CBD). Interestingly enough, the application of CBD, but not ACEA or HU-308 reversed the effects of 3NP. In particular, CBD reversed 3NP-induced reductions in GABA contents and mRNA levels of substance P (SP), neuronal-specific enolase (NSE), and superoxide dismutase-2 (SOD-2). The authors concluded that CBD has neuroprotective values, but mainly on striatal neurons projecting to substantia nigra. This neuroprotective effect was not reversed by the CB1 receptor antagonist SR141716. Pintor et al. [26] demonstrated that the cannabinoid receptor agonist, WIN 55,212–2, attenuates the effects induced by quinolinic acid (QA) in the rat striatum. In this study, QA was introduced in the rat striatum and this, in turn, led to the reproduction of clinical features typical for HD. The administration of WIN 55,212–2 blocked the increase in extracellular glutamate induced by QA. During in vivo experiment, WIN 55,212–2 significantly improved the striatal damage induced by QA, but no effect was observed on a behavioral ground. Valdeolivas et al. [27] also explored the neuroprotective potential of cannabinoids in an experimental model of HD. In particular, they investigated Sativex®, a combination of tetrahydrocannabinol (THC) and CBD at a ratio of 1:1, to monitor the potential neuroprotective effects of cannabinoids. The authors applied both histological and biochemical markers. As a result, the application of malonate in the striatum led to an increase in edema, while Sativex® reduced it. Moreover, Sativex® led to a reduction in neurodegeneration and glial activation. Furthermore, the authors found that both CB1 and CB2 receptors are involved in the positive effects of cannabinoids on HD symptoms. Similar findings were reported by Sagredo et al. [28], who used an animal model of HD to examine the potential neuroprotective effects of compounds influencing the endocannabinoid system. Interestingly enough, only compounds activating CB2 receptors had neuroprotective effects. The authors confirmed this statement by using the selective CB2 receptor antagonist, SR144528, which, in turn, led to increased vulnerability to malonate. What is more, the activation of CB2 receptors reduced the levels of tumor necrosis factor-alpha (TNF-alpha) that had been increased in the malonate-induced model of HD.
Another study by de Lago et al. [29] examined whether arvanil, an endocannabinoid „hybrid,” could lead to symptom reduction in the rat model of HD. It was demonstrated that arvanil reduced ambulation and stereotypic movements. The same group [30] demonstrated that UCM707, an inhibitor of the anandamide uptake, could be used as a symptom control agent in an animal model of HD and multiple sclerosis (MS), but failed to delay the disease progression.
Furthermore, a number of other studies have suggested that therapies with CB-activating compounds might lead to neuroprotective effects against excitotoxic striatal toxicity through both CB receptor-mediated and independent effects [21, 31, 32, 33, 34, 35]. However, in several studies, no benefit or even exacerbation of neurotoxicity could be observed [22, 25, 29].
An overview of studies investigating the relevance of the endocannabinoid system in HD pathogenesis in animal models is shown in Table 1.
AM404 reduced hyperkinesia in lesioned animals VDM11 and AM374 did not improve hyperkinesia. Capsaicin and CP55,940 reduced hyperkinesia. Capsaicin improved GABA and dopamine deficits in basal ganglia.
HU-308 was neuroprotective and reduced proinflammatory markers (TNF-alpha). These effects were reversed by SR144528. CBD and ACEA were not neuroprotective.
THC/CBD was neuroprotective. SR141716 and AM630 reduced its neuroprotective effects
Table 1.
Studies investigating the relevance of endocannabinoid system in HD pathogenesis in animal models. Studies are presented in chronological order.
HD: Huntington disease; CB1R: cannabinoid receptor type 1; CB2R: cannabinoid receptor type 2; 3 NP mice: 3-nitropropionic acid; eCBRI: endocannabinoid re-uptake inhibitor; TRPV1: the transient receptor potential cation channel subfamily V member 1 (TrpV1); GABA: γ-aminobutyric acid; THC: tetrahydrocannabinol; CBD: cannabidiol; and ACEA: arachidonyl-2-chloroethylamide.
4. Clinical research
The post-mortem examination of brain tissue in individuals with HD as well as PET imaging studies in vivo showed that CB1 receptors are severely reduced in all regions of the basal ganglia in comparison to other receptor changes in HD, which strengthens the hypothesis of a possible role of cannabinoids in the progression of neurodegeneration in HD [38, 39].
First reports of using cannabinoids in patients with HD were contradictory [24, 28, 30]. In 1991, Consroe et al. conducted the first double-blind randomized cross-over study to evaluate the efficacy and safety of oral CBD (10 mg/kg/day for 6 weeks) in 15 neuroleptic-free patients with HD [28]. The therapeutic response was evaluated with the use of the Marsden and Quinn chorea severity scale [40]. In this study, no statistically significant improvement has been shown. There was also no significant difference between the CBD and placebo groups in terms of side effects. In 1999 Müller-Vahl et al. published a case of a 58-year-old male with HD who was treated with a single dose of 1.5 mg of a CB1 agonist, nabilone. In this individual, a severe deterioration of chorea was observed [24]. In 2006, Curtis et al. described a case of a 43-year-old female, whose chorea and irritability improved after medication with 1 mg of nabilone [30]. A double-blind placebo-controlled randomized cross-over trial using nabilone was conducted in 2009 by the same author. This time 37 patients were treated with 1 mg or 2 mg of nabilone daily for 5 weeks. For primary measures, the patients were assessed with Unified Huntington’s Disease Rating Scale (UHDRS) total motor score and UHDRS subsections for chorea, cognition and behavior, and neuropsychiatric inventory (NPI) for secondary measures. There were no statistically significant differences in total UHDRS between the groups. However, statistically, significant improvements were noted for the UHDRS chorea scale and the neuropsychiatric inventory. There were no statistical differences reported between the 1 and 2 mg. Adverse effects were reported for placebo and nabilone similarly. There was one Serious Adverse Event (SAE) related to nabilone—one of the patients withdrew due to severe sedation. Importantly, no psychoses were reported [23]. In 2016, the results of a study conducted by Moreno et al. using nabiximols in the treatment of HD were published [36]. Nabiximols (tradename Sativex®) is an oromucosal spray, containing 2.7 mg THC and 2.5 mg cannabidiol (CBD) per puff licensed in most European countries for symptomatic treatment of multiple sclerosis [35]. Both Sativex and placebo were handed to 25 patients in a form of an oral spray, to be administered up to 12 sprays/day for 12 weeks. The main aim of the study was to investigate the safety of nabiximols in HD patients, assessed by the absence of SAE and lack of impairment of motor, cognitive, behavioral, and functional scales during the active treatment. The secondary objective was a clinical improvement of Unified Huntington Disease Rating Scale scores. As a result, safety and tolerability were confirmed. No statistically significant improvement in UHDRS in the nabiximols group was noted with respect to the placebo group. Moreover, no significant changes in the biomarkers could be observed [35].
An overview of all available studies investigating the efficacy and safety of CBM in HD is provided in Table 2.
Double-blind, randomized, cross-over, placebo-controlled, pilot trial
No SAE or clinical worsening; no significant improvement; no significant changes of biomarkers
Table 2.
An overview of studies investigating efficacy and safety of CBM in HD.
CBM: cannabis based medicine; HD: Huntington disease; SAE: severe adverse events; CBD: cannabidiol; UHDRS: United Huntington Disease Rating Scale; and SAE: serious adverse events.
5. Safety profile of cannabis-based medicines in patients with HD
Even today, very little is known about the safety of CBM in patients with HD due to the limited number of studies exploring this issue. However, the available preliminary results suggest that the safety profile of CBM in HD is similar to that in other groups of patients. A recently conducted meta-analysis, including diverse populations of patients treated with CBM, showed that administration of cannabinoids can be associated with a greater risk of adverse events (AE), including serious adverse events (SAE) [46]. The most common short-term AEs included dizziness, dry mouth, nausea or vomiting, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucinations. So far, there has been no study evaluating the long-term AEs of cannabinoids [46]. Up to this point, only two CBM-related SAEs in HD have been reported and both occurred after the treatment with nabilone. A 58-year-old male described by Müller-Vahl experienced an exacerbation of chorea. Moreover, the patient noticed the deterioration of short-term memory [42]. During the study performed by Curtis et al. [44], one of the patients experienced severe sedation and had to withdraw from the trial. Importantly, none of the patients enrolled in this study suffered from exacerbation of chorea or psychosis. The most frequent AE was drowsiness and forgetfulness. In the recent study conducted by Moreno et al. [45], dizziness or disturbance in attention were the two most common AEs. No serious alterations in psychiatric or neurological conditions of the participants were noted [45].
6. Conclusions
There is increasing evidence that the endocannabinoid system is a new promising therapeutical target in patients with HD. However, larger well-designed controlled studies are urgently needed to confirm the efficacy and safety of this treatment.
\n',keywords:"chorea, Huntington’s disease, experimental therapies, cannabis-based medicine, dronabinol",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/81976.pdf",chapterXML:"https://mts.intechopen.com/source/xml/81976.xml",downloadPdfUrl:"/chapter/pdf-download/81976",previewPdfUrl:"/chapter/pdf-preview/81976",totalDownloads:21,totalViews:0,totalCrossrefCites:0,dateSubmitted:"December 19th 2021",dateReviewed:"March 18th 2022",datePrePublished:"June 17th 2022",datePublished:null,dateFinished:"May 26th 2022",readingETA:"0",abstract:"Huntington’s disease (HD) is a progressive, neurodegenerative disorder manifested by chorea as well as a variety of psychiatric abnormalities. Up to this date, only symptomatic treatment exists. Therefore, there is an urgent need for further therapies. Several neuroanatomical circuits are involved in the pathophysiology of HD, mainly the dopaminergic system. Animal studies and limited studies in humans have shown that abnormalities in the endocannabinoid system could also play an important role in the pathophysiology of HD. These findings have important clinical implications since cannabis-based medicines could potentially be used in the treatment of HD. The aim of this chapter is to summarize the current state of the research regarding the involvement of the endocannabinoid system in HD.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/81976",risUrl:"/chapter/ris/81976",signatures:"Kamila Saramak and Natalia Szejko",book:{id:"10783",type:"book",title:"From Pathophysiology to Treatment of Huntington's Disease",subtitle:null,fullTitle:"From Pathophysiology to Treatment of Huntington's Disease",slug:null,publishedDate:null,bookSignature:"M.D. Natalia Szejko",coverURL:"https://cdn.intechopen.com/books/images_new/10783.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-427-3",printIsbn:"978-1-80355-426-6",pdfIsbn:"978-1-80355-428-0",isAvailableForWebshopOrdering:!0,editors:[{id:"249604",title:"M.D.",name:"Natalia",middleName:null,surname:"Szejko",slug:"natalia-szejko",fullName:"Natalia Szejko"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Possible role of the endocannabinoid system in Huntington’s disease",level:"1"},{id:"sec_3",title:"3. Studies in animal models",level:"1"},{id:"sec_4",title:"4. Clinical research",level:"1"},{id:"sec_5",title:"5. Safety profile of cannabis-based medicines in patients with HD",level:"1"},{id:"sec_6",title:"6. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'Ross CA, Tabrizi SJ. Huntington’s disease: From molecular pathogenesis to clinical treatment. The Lancet Neurology. 2011;10:83-98'},{id:"B2",body:'Tabrizi SJ, Flower MD, Ross CA, Wild EJ. Huntington disease: New insights into molecular pathogenesis and therapeutic opportunities. Nature Reviews Neurology. 2020;16:529-546'},{id:"B3",body:'Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, Jette N. The incidence and prevalence of Huntington’s disease: A systematic review and meta-analysis. Movement Disorders. 2012;27:1083-1091'},{id:"B4",body:'Walker FO. 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Neuropharmacology. 2006;51:1004-1012'},{id:"B27",body:'Valdeolivas S, Satta V, Pertwee RG, Fernández-Ruiz J, Sagredo O. Sativex-like combination of phytocannabinoids is neuroprotective in malonate-lesioned rats, an inflammatory model of Huntington’s disease: Role of CB1 and CB2 receptors. ACS Chemical Neuroscience. 2012;3:400-406'},{id:"B28",body:'Sagredo O, González S, Aroyo I, Pazos MR, Benito C, Lastres-Becker I, et al. Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: Relevance for Huntington’s disease. Glia. 2009;57:1154-1167'},{id:"B29",body:'de Lago E, Urbani P, Ramos JA, Di Marzo V, Fernández-Ruiz J. Arvanil, a hybrid endocannabinoid and vanilloid compound, behaves as an antihyperkinetic agent in a rat model of Huntington’s disease. Brain Research. 2005;1050:210-216'},{id:"B30",body:'De Lago E, Fernández-Ruiz J, Ortega-Gutiérrez S, Cabranes A, Pryce G, Baker D, et al. UCM707, an inhibitor of the anandamide uptake, behaves as a symptom control agent in models of Huntington’s disease and multiple sclerosis, but fails to delay/arrest the progression of different motor-related disorders. European Neuropsychopharmacology. 2006;16:7-18'},{id:"B31",body:'Pertwee RG. Cannabinoid pharmacology: The first 66 years. British Journal of Pharmacology. 2006;147:S163-SS71'},{id:"B32",body:'Pertwee RG. Emerging strategies for exploiting cannabinoid receptor agonists as medicines. British Journal of Pharmacology. 2009;156:397-411'},{id:"B33",body:'Collin C, Davies P, Mutiboko I, Ratcliffe S, Group SSiMS. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. European Journal of Neurology. 2007;14:290-296'},{id:"B34",body:'Scotter E, Goodfellow C, Graham E, Dragunow M, Glass M. Neuroprotective potential of CB1 receptor agonists in an in vitro model of Huntington’s disease. British Journal of Pharmacology. 2010;160:747-761'},{id:"B35",body:'Palazuelos J, Aguado T, Pazos MR, Julien B, Carrasco C, Resel E, et al. Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity. Brain. 2009;132:3152-3164'},{id:"B36",body:'Lastres-Becker I, Bizat N, Boyer F, Hantraye P, Fernández-Ruiz J, Brouillet E. Potential involvement of cannabinoid receptors in 3-nitropropionic acid toxicity in vivo. Neuroreport. 2004;15:2375-2379'},{id:"B37",body:'Dowie M, Howard M, Nicholson L, Faull R, Hannan A, Glass M. Behavioural and molecular consequences of chronic cannabinoid treatment in Huntington’s disease transgenic mice. Neuroscience. 2010;170:324-336'},{id:"B38",body:'Glass M, Dragunow M, Faull R. The pattern of neurodegeneration in Huntington’s disease: A comparative study of cannabinoid, dopamine, adenosine and GABAA receptor alterations in the human basal ganglia in Huntington’s disease. Neuroscience. 2000;97:505-519'},{id:"B39",body:'Van Laere K, Casteels C, Dhollander I, Goffin K, Grachev I, Bormans G, et al. Widespread decrease of type 1 cannabinoid receptor availability in Huntington disease in vivo. Journal of Nuclear Medicine. 2010;51:1413-1417'},{id:"B40",body:'Mestre TA, Forjaz MJ, Mahlknecht P, Cardoso F, Ferreira JJ, Reilmann R, et al. Rating scales for motor symptoms and signs in Huntington’s disease: Critique and recommendations. Movement Disorders Clinical Practice. 2018;5:111-117'},{id:"B41",body:'Consroe P, Laguna J, Allender J, Snider S, Stern L, Sandyk R, et al. Controlled clinical trial of cannabidiol in Huntington’s disease. Pharmacology Biochemistry. 1991;40:701-708'},{id:"B42",body:'Müller-Vahl KR, Schneider U, Emrich HM. Nabilone increases choreatic movements in Huntington’s disease. Movement Disorders. 1999;14:1038-1040'},{id:"B43",body:'Curtis A, Rickards H. Nabilone could treat chorea and irritability in Huntington’s disease. The Journal of Neuropsychiatry. 2006;18:553-554'},{id:"B44",body:'Curtis A, Mitchell I, Patel S, Ives N, Rickards H. A pilot study using nabilone for symptomatic treatment in Huntington’s disease. Movement Disorders. 2009;24:2254-2259'},{id:"B45",body:'Moreno JLL-S, Caldentey JG, Cubillo PT, Romero CR, Ribas GG, Arias MAA, et al. A double-blind, randomized, cross-over, placebo-controlled, pilot trial with Sativex in Huntington’s disease. Journal of Neurology, Neurosurgery and Psychiatry. 2016;263:1390-1400'},{id:"B46",body:'Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for medical use: A systematic review and meta-analysis. JAMA. 2015;313:2456-2473'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Kamila Saramak",address:null,affiliation:'
Department of Neurology, Hochzirl Hospital, Zirl, Austria
Department of Bioethics, Medical University of Warsaw, Poland
Department of Neurology, Medical University of Warsaw, Poland
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These glasses were characterized using X-ray diffraction (XRD), Fourier-transform infrared (FTIR) and Raman spectroscopes, differential scanning calorimetry (DSC), optical absorption, and electron paramagnetic resonance (EPR). XRD and DSC analysis confirmed the glassy nature of the prepared samples. The physical properties such as density (ρ), molar volume (Vm), oxygen packing density (OPD), and the molar volume of oxygen (Vo) were calculated and discussed. FTIR and Raman studies showed that the glass network consists of BO3 and BO4 units in various borate groups. From DSC, it was found that the glass transition temperature (Tg) varies nonlinearly with the addition of ZnO content in place of CdO. Both EPR and optical absorption results have confirmed that the Cu2+ ions are in octahedral coordination with a strong tetrahedral distortion. 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UK Research and Innovation (former Research Councils UK (RCUK) - including AHRC, BBSRC, ESRC, EPSRC, MRC, NERC, STFC.) Processing charges for books/book chapters can be covered through RCUK block grants which are allocated to most universities in the UK, which then handle the OA publication funding requests. It is at the discretion of the university whether it will approve the request.)
UK Research and Innovation (former Research Councils UK (RCUK) - including AHRC, BBSRC, ESRC, EPSRC, MRC, NERC, STFC.) Processing charges for books/book chapters can be covered through RCUK block grants which are allocated to most universities in the UK, which then handle the OA publication funding requests. It is at the discretion of the university whether it will approve the request.)
Wellcome Trust (Funding available only to Wellcome-funded researchers/grantees)
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De Cooman, Kwang-geun Chin and Jinkyung Kim",authors:[{id:"16743",title:"Prof.",name:"Bruno Charles",middleName:null,surname:"De Cooman",slug:"bruno-charles-de-cooman",fullName:"Bruno Charles De Cooman"}]},{id:"13343",doi:"10.5772/13286",title:"Materials in Automotive Application, State of the Art and Prospects",slug:"materials-in-automotive-application-state-of-the-art-and-prospects",totalDownloads:64773,totalCrossrefCites:45,totalDimensionsCites:97,abstract:null,book:{id:"1355",slug:"new-trends-and-developments-in-automotive-industry",title:"New Trends and Developments in Automotive Industry",fullTitle:"New Trends and Developments in Automotive Industry"},signatures:"Elaheh Ghassemieh",authors:[{id:"13695",title:"Dr.",name:"Elaheh",middleName:null,surname:"Ghassemieh",slug:"elaheh-ghassemieh",fullName:"Elaheh Ghassemieh"}]},{id:"42787",doi:"10.5772/55492",title:"Smart Vehicles, Technologies and Main Applications in Vehicular Ad hoc Networks",slug:"smart-vehicles-technologies-and-main-applications-in-vehicular-ad-hoc-networks",totalDownloads:6883,totalCrossrefCites:17,totalDimensionsCites:60,abstract:null,book:{id:"3328",slug:"vehicular-technologies-deployment-and-applications",title:"Vehicular Technologies",fullTitle:"Vehicular Technologies - Deployment and Applications"},signatures:"Anna Maria Vegni, Mauro Biagi and Roberto Cusani",authors:[{id:"19747",title:"Dr.",name:"Anna Maria",middleName:null,surname:"Vegni",slug:"anna-maria-vegni",fullName:"Anna Maria Vegni"},{id:"19749",title:"Prof.",name:"Roberto",middleName:null,surname:"Cusani",slug:"roberto-cusani",fullName:"Roberto Cusani"},{id:"159351",title:"Dr.",name:"Mauro",middleName:null,surname:"Biagi",slug:"mauro-biagi",fullName:"Mauro Biagi"}]},{id:"19571",doi:"10.5772/20271",title:"Electrical Vehicle Design and Modeling",slug:"electrical-vehicle-design-and-modeling",totalDownloads:14327,totalCrossrefCites:46,totalDimensionsCites:60,abstract:null,book:{id:"447",slug:"electric-vehicles-modelling-and-simulations",title:"Electric Vehicles",fullTitle:"Electric Vehicles - Modelling and Simulations"},signatures:"Erik Schaltz",authors:[{id:"38188",title:"MSc",name:"Erik",middleName:null,surname:"Schaltz",slug:"erik-schaltz",fullName:"Erik Schaltz"}]},{id:"19583",doi:"10.5772/17048",title:"DC/DC Converters for Electric Vehicles",slug:"dc-dc-converters-for-electric-vehicles",totalDownloads:23269,totalCrossrefCites:16,totalDimensionsCites:48,abstract:null,book:{id:"447",slug:"electric-vehicles-modelling-and-simulations",title:"Electric Vehicles",fullTitle:"Electric Vehicles - Modelling and Simulations"},signatures:"Monzer Al Sakka, Joeri Van Mierlo and Hamid Gualous",authors:[{id:"27098",title:"Dr.",name:"Monzer",middleName:null,surname:"Al Sakka",slug:"monzer-al-sakka",fullName:"Monzer Al Sakka"},{id:"40637",title:"Prof.",name:"Joeri",middleName:null,surname:"Van Mierlo",slug:"joeri-van-mierlo",fullName:"Joeri Van Mierlo"},{id:"40638",title:"Prof.",name:"Hamid",middleName:null,surname:"Gualous",slug:"hamid-gualous",fullName:"Hamid Gualous"}]}],mostDownloadedChaptersLast30Days:[{id:"19583",title:"DC/DC Converters for Electric Vehicles",slug:"dc-dc-converters-for-electric-vehicles",totalDownloads:23269,totalCrossrefCites:16,totalDimensionsCites:48,abstract:null,book:{id:"447",slug:"electric-vehicles-modelling-and-simulations",title:"Electric Vehicles",fullTitle:"Electric Vehicles - Modelling and Simulations"},signatures:"Monzer Al Sakka, Joeri Van Mierlo and Hamid Gualous",authors:[{id:"27098",title:"Dr.",name:"Monzer",middleName:null,surname:"Al Sakka",slug:"monzer-al-sakka",fullName:"Monzer Al Sakka"},{id:"40637",title:"Prof.",name:"Joeri",middleName:null,surname:"Van Mierlo",slug:"joeri-van-mierlo",fullName:"Joeri Van Mierlo"},{id:"40638",title:"Prof.",name:"Hamid",middleName:null,surname:"Gualous",slug:"hamid-gualous",fullName:"Hamid Gualous"}]},{id:"19571",title:"Electrical Vehicle Design and Modeling",slug:"electrical-vehicle-design-and-modeling",totalDownloads:14327,totalCrossrefCites:46,totalDimensionsCites:60,abstract:null,book:{id:"447",slug:"electric-vehicles-modelling-and-simulations",title:"Electric Vehicles",fullTitle:"Electric Vehicles - Modelling and Simulations"},signatures:"Erik Schaltz",authors:[{id:"38188",title:"MSc",name:"Erik",middleName:null,surname:"Schaltz",slug:"erik-schaltz",fullName:"Erik Schaltz"}]},{id:"64509",title:"Options and Evaluations on Propulsion Systems of LNG Carriers",slug:"options-and-evaluations-on-propulsion-systems-of-lng-carriers",totalDownloads:4239,totalCrossrefCites:7,totalDimensionsCites:13,abstract:"The LNG carriers are undergoing a period of rapid and profound change, with much larger size ships and novel propulsion systems emerging for fulfilling the market trends of LNG shipping industry. There are various proposed propulsion solutions for LNG carriers, ranging from the conventional steam turbine and dual fuel diesel electric propulsion, until more innovative ideas such as slow speed dual fuel diesel engine, combined gas turbine electric & steam system, and hybrid propulsion based on steam turbine and gas engine. Since propulsion system significantly influenced the ship’s capital, emission regulation compliance and navigation safety, the selection of a proper propulsion option with technical feasibility and economic viability for LNG carriers is currently a major concern from the shipping industry and thus must be comprehensively assessed. In this context, this chapter investigated the main characteristics of these propulsion options in terms of BOG treatment, fuel consumption, emission standards compliance, and plant reliability. Furthermore, comparisons among different propulsion system were also carried out and related evaluation was presented.",book:{id:"7198",slug:"propulsion-systems",title:"Propulsion Systems",fullTitle:"Propulsion Systems"},signatures:"Tu Huan, Fan Hongjun, Lei Wei and Zhou Guoqiang",authors:[{id:"265951",title:"Mr.",name:"Huan",middleName:null,surname:"Tu",slug:"huan-tu",fullName:"Huan Tu"}]},{id:"19573",title:"Control of Hybrid Electrical Vehicles",slug:"control-of-hybrid-electrical-vehicles",totalDownloads:15650,totalCrossrefCites:5,totalDimensionsCites:13,abstract:null,book:{id:"447",slug:"electric-vehicles-modelling-and-simulations",title:"Electric Vehicles",fullTitle:"Electric Vehicles - Modelling and Simulations"},signatures:"Gheorghe Livinţ, Vasile Horga, Marcel Răţoi and Mihai Albu",authors:[{id:"25879",title:"Prof.",name:"Gheorghe",middleName:null,surname:"Livint",slug:"gheorghe-livint",fullName:"Gheorghe Livint"},{id:"40500",title:"Dr.",name:"Vasile",middleName:null,surname:"Horga",slug:"vasile-horga",fullName:"Vasile Horga"},{id:"40501",title:"Prof.",name:"Marcel",middleName:null,surname:"Ratoi",slug:"marcel-ratoi",fullName:"Marcel Ratoi"},{id:"40502",title:"Dr.",name:"Mihai",middleName:null,surname:"Albu",slug:"mihai-albu",fullName:"Mihai Albu"}]},{id:"41416",title:"Energy Efficiency of Electric Vehicles",slug:"energy-efficiency-of-electric-vehicles",totalDownloads:7664,totalCrossrefCites:6,totalDimensionsCites:9,abstract:null,book:{id:"3196",slug:"new-generation-of-electric-vehicles",title:"New Generation of Electric Vehicles",fullTitle:"New Generation of Electric Vehicles"},signatures:"Zoran Stevic and Ilija Radovanovic",authors:[{id:"30692",title:"Dr.",name:"Zoran",middleName:"M.",surname:"Stevic",slug:"zoran-stevic",fullName:"Zoran Stevic"}]}],onlineFirstChaptersFilter:{topicId:"124",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81390",title:"From Nobel Prizes to Safety Risk Management: How to Identify Latent Failure Conditions in Risk Management Practices",slug:"from-nobel-prizes-to-safety-risk-management-how-to-identify-latent-failure-conditions-in-risk-manage",totalDownloads:33,totalDimensionsCites:0,doi:"10.5772/intechopen.98960",abstract:"The aim of the Chapter is to introduce readers to the Cognitive Biases found in Railway Transport Planning and Management domain. Cognitive biases in planning of railway projects lead to cost overruns, fail to achieve performance and fulfil safety objectives as well is noted in the economics, business management and risk management literature as well. Unbiased decision making is a core goal of systems engineering, encouraging careful consideration of stakeholder needs, design alternatives, and programmatic constraints and risks. However, Systems engineering practices dealing with Railway Transport Planning and Management fields do not pay attention to the human factors and organisational factors at initial stages of planning where driveability of European Railway Traffic Management System (ERTMS) Trains emerges as a concern in real time operations is noted in the Railway Transport Planning and Management domain. Therefore, there is a case for studying the Cognitive Biases in this domain. The System for Investigation of Railways (SIRI) Cybernetic Risk Model (2006), (2017) is a Systems engineering response to the internal research brief by RSSB, a GB Railways Safety Body. The SIRI Cybernetic Risk Model (2017) incorporating the “Heuristics and Biases” approach was published by the UK Transport Select Commission as a Written Evidence in 2016 on the occasion of the Inquiry theme of Railway Safety. The validity of the SIRI Risk Model (Swiss Cheese Model) is further illustrated through the 2019 historical survey of railway accidents and the two recent RAIB investigations of track worker fatal accident and signalling related near miss event in the form of Swiss Cheese Model. The data and information in the RAIB Reports (17/2019) and (11/2020) is supplemented by further research and the author’s own past studies of accident analyses. The results of the study show that the Guide to Railway Investment Process (GRIP) (2019) (now deleted by Network Rail) has no provision for incorporating measures to address to deficiencies raised by the accident reports or safety analysis reports as the RSSB (2014) Taking Safe Decisions Framework does not include all Hueristics and the biases they lead in the information used for taking decisions. Thus, the Duty Holder Investment process fails to meet the requirements of the mandatory regulatory requirements of the Common Safety Method-Risk Assessment (CSM-RA) Process. The results of the Case Studies in the Chapter remain the same despite the proposed changes in the Shapps-Williams Reform Plan (2021) as the safety related matters are not yet addressed by the plan. The author hopes when the lessons that are learnt from the Case Studies are embedded in railway organisations then we may see improvements in the railway planning and management practices by considering the risk factors at the conceptual stage of the projects and meet the requirements of ISO Standard 27500 (2016) for Human Centred Organisation. National Investigations Bodies (NIB) also may be benefitted.",book:{id:"10988",title:"Railway Transport Planning and Management",coverURL:"https://cdn.intechopen.com/books/images_new/10988.jpg"},signatures:"Sanjeev Kumar Appicharla"},{id:"79558",title:"Analysis of Methods Used to Diagnostics of Railway Lines",slug:"analysis-of-methods-used-to-diagnostics-of-railway-lines",totalDownloads:65,totalDimensionsCites:0,doi:"10.5772/intechopen.100835",abstract:"Complex diagnostics of railway lines involves techniques based on discrete and continual data acquisition. While discrete measurements belong to conventional methods, the modern continual ones use automated robotized instruments with continuous recording. Observations have become more time-efficient, but the processing epoch has become longer to evaluate a large number of data. Railway line diagnostics is realized by relative methods lead to determine relative track parameters as the track gauge, elevation, and track gradients and absolute, geodetic techniques determine directional and height ratios of the track, defined in a global coordinate and height system.",book:{id:"10988",title:"Railway Transport Planning and Management",coverURL:"https://cdn.intechopen.com/books/images_new/10988.jpg"},signatures:"Jana Izvoltova, Libor Izvolt and Janka Sestakova"},{id:"78929",title:"New Approach Measuring the Wheel/Rail Interaction Loads",slug:"new-approach-measuring-the-wheel-rail-interaction-loads",totalDownloads:118,totalDimensionsCites:0,doi:"10.5772/intechopen.100031",abstract:"This chapter suggested new methods for monitoring the dynamic processes of rolling stock/rail interaction. This study develops a new technical solution for measuring the wheel/rail interaction forces on a significant part of the sleeper. The theoretical part of this study, using FEM, confirm the ability of piecewise continuous recording of vertical and lateral forces from the wheel/rail interaction by measuring the stresses in two sections of the rail. Also, the optimum location of strain gauges and the effective length of the measuring zone have been determined. The experimental part of this study has been carried out on the stands and the railway track to confirm the effectiveness of the method to determine the vertical and lateral wheel/rail interaction forces, increase the reliable statistical data, improve the measurement accuracy, reducing the time and cost compared with current testing methods. The developed method is recommended to determine the wheel/rail interaction forces and identify defects on the wheels when diagnosing rolling stock on operational and travel regimes.",book:{id:"10988",title:"Railway Transport Planning and Management",coverURL:"https://cdn.intechopen.com/books/images_new/10988.jpg"},signatures:"Yuri P. Boronenko, Rustam V. Rahimov and Waail M. Lafta"},{id:"78422",title:"An Integrated Approach of Strategic Planning and Multi-Criteria Analysis to Evaluate Transport Strategies in Railway Network",slug:"an-integrated-approach-of-strategic-planning-and-multi-criteria-analysis-to-evaluate-transport-strat",totalDownloads:135,totalDimensionsCites:0,doi:"10.5772/intechopen.99609",abstract:"This chapter presents a methodology for selecting transport strategy for railway passenger transport development. The strategic planning, as Political, Economic, Social, Technological, Legal, and Environmental (PESTLE) analysis and Strengths - Weaknesses – Opportunities - Threats (SWOT) analysis integrated with Multiple-criteria decision-making (MCDM) have been applied as a tool to make decision. The proposed methodology consists five stages. The first stage formulates the alternatives of the policies for railway manager. The criteria in each PESTLE group have been defined in the second step. The total number of 24 criteria has been studied. In third stage, the SIMUS method based on linear programming has been applied to rank the alternatives and assess the criteria in PESTLE groups. The fourth stage represents the ranking by application the different multi0criteria approaches as distance based, utility based and outranking methods to make decision. The combination the PESTLE analysis with SWOT analysis for strategic planning is done in the fifth stage. The integration of the PESTLE with technical, economic, technological and environmental (TETE) analysis in presented. The application of methodology has been demonstrated with an example for Bulgarian railway network. Three strategies of railway transport development have been evaluated and compared. It was found that the most important are the political (0.29), social (0.25) and technological (0.25) groups in PESTLE analysis.",book:{id:"10988",title:"Railway Transport Planning and Management",coverURL:"https://cdn.intechopen.com/books/images_new/10988.jpg"},signatures:"Svetla Stoilova"},{id:"78167",title:"Hydrogen as a Rail Mass Transit Fuel",slug:"hydrogen-as-a-rail-mass-transit-fuel",totalDownloads:110,totalDimensionsCites:0,doi:"10.5772/intechopen.99553",abstract:"There is a continually growing need for mass transport and along with customer desire for greater comfort and speed, its consumption of energy will grow faster still. The fiscal cost of energy plus global warming has spurred efficiency improvement and thoughts now concentrate on fuels. In the UK for major lines for trains, this is electricity generated in a benign fashion in large facilities nominally remote from the train and track. Electric trains tend to be lighter, hence more efficient and demand less maintenance than their diesel counterpart. Similar arguments, including pollution emissions apply to city mass transit systems. For medium density and lower density routes, whether fuel cells or the next generation of IC or GT engines are employed, hydrogen is a prime energy candidate and here we examine its feed, production, distribution, and application, including generator location. Hydrogen from steam hydrocarbon reformers have even been installed in ships. Other countries have similar desires to those of the UK, including Saudi Arabia, but their problems are different and outline examples from Australia and Saudi Arabia are included.",book:{id:"10988",title:"Railway Transport Planning and Management",coverURL:"https://cdn.intechopen.com/books/images_new/10988.jpg"},signatures:"Stephen A. Lloyd, Luke L.B.D. Lloyd and W.J. 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The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null,scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n
\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
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\r\n\t
\r\n
\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
\r\n
\r\n\t
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
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He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:"Manufacturing and Technology Integrated Campus – SENAI CIMATEC",institution:null},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356823",title:"MSc.",name:"Seonghee",middleName:null,surname:"Min",slug:"seonghee-min",fullName:"Seonghee Min",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Daegu University",country:{name:"Korea, South"}}},{id:"353307",title:"Prof.",name:"Yoosoo",middleName:null,surname:"Oh",slug:"yoosoo-oh",fullName:"Yoosoo Oh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Yoosoo Oh received his Bachelor's degree in the Department of Electronics and Engineering from Kyungpook National University in 2002. He obtained his Master’s degree in the Department of Information and Communications from Gwangju Institute of Science and Technology (GIST) in 2003. In 2010, he received his Ph.D. degree in the School of Information and Mechatronics from GIST. In the meantime, he was an executed team leader at Culture Technology Institute, GIST, 2010-2012. In 2011, he worked at Lancaster University, the UK as a visiting scholar. In September 2012, he joined Daegu University, where he is currently an associate professor in the School of ICT Conver, Daegu University. Also, he served as the Board of Directors of KSIIS since 2019, and HCI Korea since 2016. From 2017~2019, he worked as a center director of the Mixed Reality Convergence Research Center at Daegu University. From 2015-2017, He worked as a director in the Enterprise Supporting Office of LINC Project Group, Daegu University. His research interests include Activity Fusion & Reasoning, Machine Learning, Context-aware Middleware, Human-Computer Interaction, etc.",institutionString:null,institution:{name:"Daegu Gyeongbuk Institute of Science and Technology",country:{name:"Korea, South"}}},{id:"262719",title:"Dr.",name:"Esma",middleName:null,surname:"Ergüner Özkoç",slug:"esma-erguner-ozkoc",fullName:"Esma Ergüner Özkoç",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Başkent University",country:{name:"Turkey"}}},{id:"346530",title:"Dr.",name:"Ibrahim",middleName:null,surname:"Kaya",slug:"ibrahim-kaya",fullName:"Ibrahim Kaya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"419199",title:"Dr.",name:"Qun",middleName:null,surname:"Yang",slug:"qun-yang",fullName:"Qun Yang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Auckland",country:{name:"New Zealand"}}}]}},subseries:{item:{id:"20",type:"subseries",title:"Animal Nutrition",keywords:"Sustainable Animal Diets, Carbon Footprint, Meta Analyses",scope:"An essential part of animal production is nutrition. Animals need to receive a properly balanced diet. One of the new challenges we are now faced with is sustainable animal diets (STAND) that involve the 3 P’s (People, Planet, and Profitability). We must develop animal feed that does not compete with human food, use antibiotics, and explore new growth promoters options, such as plant extracts or compounds that promote feed efficiency (e.g., monensin, oils, enzymes, probiotics). These new feed options must also be environmentally friendly, reducing the Carbon footprint, CH4, N, and P emissions to the environment, with an adequate formulation of nutrients.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/20.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11416,editor:{id:"175967",title:"Dr.",name:"Manuel",middleName:null,surname:"Gonzalez Ronquillo",slug:"manuel-gonzalez-ronquillo",fullName:"Manuel Gonzalez Ronquillo",profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",biography:"Dr. Manuel González Ronquillo obtained his doctorate degree from the University of Zaragoza, Spain, in 2001. He is a research professor at the Faculty of Veterinary Medicine and Animal Husbandry, Autonomous University of the State of Mexico. He is also a level-2 researcher. He received a Fulbright-Garcia Robles fellowship for a postdoctoral stay at the US Dairy Forage Research Center, Madison, Wisconsin, USA in 2008–2009. He received grants from Alianza del Pacifico for a stay at the University of Magallanes, Chile, in 2014, and from Consejo Nacional de Ciencia y Tecnología (CONACyT) to work in the Food and Agriculture Organization’s Animal Production and Health Division (AGA), Rome, Italy, in 2014–2015. He has collaborated with researchers from different countries and published ninety-eight journal articles. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. 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