\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"889",leadTitle:null,fullTitle:"Robotic Systems - Applications, Control and Programming",title:"Robotic Systems",subtitle:"Applications, Control and Programming",reviewType:"peer-reviewed",abstract:"This book brings together some of the latest research in robot applications, control, modeling, sensors and algorithms. Consisting of three main sections, the first section of the book has a focus on robotic surgery, rehabilitation, self-assembly, while the second section offers an insight into the area of control with discussions on exoskeleton control and robot learning among others. The third section is on vision and ultrasonic sensors which is followed by a series of chapters which include a focus on the programming of intelligent service robots and systems adaptations.",isbn:null,printIsbn:"978-953-307-941-7",pdfIsbn:"978-953-51-5583-6",doi:"10.5772/1398",price:159,priceEur:175,priceUsd:205,slug:"robotic-systems-applications-control-and-programming",numberOfPages:640,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"e560d53a4116a307638d95c63c1a78a3",bookSignature:"Ashish Dutta",publishedDate:"February 3rd 2012",coverURL:"https://cdn.intechopen.com/books/images_new/889.jpg",numberOfDownloads:121166,numberOfWosCitations:62,numberOfCrossrefCitations:71,numberOfCrossrefCitationsByBook:2,numberOfDimensionsCitations:113,numberOfDimensionsCitationsByBook:2,hasAltmetrics:1,numberOfTotalCitations:246,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:"80372",title:"Dr.",name:"Ashish",middleName:null,surname:"Dutta",slug:"ashish-dutta",fullName:"Ashish Dutta",profilePictureURL:"https://mts.intechopen.com/storage/users/80372/images/3530_n.jpg",biography:"Dr. Ashish Dutta obtained his PhD in Systems Engineering from Akita University, Japan. From 1994 to 2000 he was with the Bhabha Atomic Research Center (India) where he worked on telemanipulator design and control for nuclear applications. Since 2002 he has been working with the department of mechanical engineering in the Indian Institute of Technology Kanpur, in addition to working as an assistant professor in Nagoya University, Japan from 2006 to 2007 in the department of Mechanical Science and Engineering. His research interests are in the areas of humanoid robotics, micro sensors and actuators, intelligent control systems and rehabilitation engineering.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Indian Institute of Technology Kanpur",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1270",title:"Remote Surgery",slug:"remote-surgery"}],chapters:[{id:"27400",title:"Modular Robotic Approach in Surgical Applications – Wireless Robotic Modules and a Reconfigurable Master Device for Endoluminal Surgery –",doi:"10.5772/26617",slug:"modular-robotic-approach-in-surgical-applications-wireless-robotic-modules-and-a-reconfigurable-mast",totalDownloads:3970,totalCrossrefCites:3,totalDimensionsCites:4,hasAltmetrics:0,abstract:null,signatures:"Kanako Harada, Ekawahyu Susilo, Takao Watanabe, Kazuya Kawamura, Masakatsu G. 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In certain regions, such as Australia, North America, and Western Europe, including the United Kingdom, the prevalence of the disease has increased over the past 50 years [1, 2].
HD is characterized by the loss of specific neurons within the striatum. The most sensitive cell population is the gamma-aminobutyric acid (GABA)ergic medium spiny neurons (MSNs). Neuropathologically, the disease leads to about 57% loss of cross-sectional area from the caudate nucleus and about 65% loss of the putamen (in
HD is caused by the expansion of trinucleotide Cytosine-Adenine-Guanine (CAG) repeat, located in the first exon of the HD gene, also known as HTT or IT15 gene (locus 4p16.3, OMIM 613004), which encodes the huntingtin protein (Htt). Since the discovery of HTT gene mutation (in 1993), it has been recognized that larger CAG expansions are associated with early-onset in HD, especially for AOHD. Generally, unaffected individuals have less than 35 CAG repeats (common rage in humans: 17–25), while affected individuals have 36–250 CAG repeats. The CAG repeat range of 36–39 might be found in affected individuals and asymptomatic individuals (reduced penetrance alleles), whereas individuals with over 40 CAG repeats always develop the disease (fully penetrance alleles) [4].
The wild-type allele of the HTT gene (i.e., <35 CAG repeats) typically segregates and stably as a polymorphic locus. However, the allele carrying higher-normal CAG repeats (27–35 repeats) has increased instability. For this reason, individuals with 27–35 CAG repeats have a high risk of passing on repeats in the affected size range to their offspring. HTT gene encodes the huntingtin protein (Htt), a sizeable soluble protein (350 kDa), consisting of 3114 amino acids, which is expressed in all metazoans, is highly conserved among vertebrates. Although, all tissues ubiquitously express the HTT gene, Htt protein is found higher expressed in the brain, represented by all neurons and glial cells [4].
The Htt protein is crucial for developing and maintaining central nervous systems (CNS) homeostasis since the protein is engaged in many cellular and biological functions, including transcription, transport, vesicular trafficking, and coordination of cell division, energy metabolism, and antiapoptotic activity. For this reason, it is not surprised that Htt co-localizes with many organelles, such as the nucleus, endoplasmic reticulum, Golgi complex, endosomes, mitochondria, and synaptic vesicles. Furthermore, cells expressing mRNA of the HTT gene were described by in situ hybridization in the usual human 20 to 23-week fetal brain, suggesting that huntingtin protein is crucial for the development of the CNS. Studies also demonstrated that the deletion of the mouse homolog of the HTT gene is lethal in the embryo before the brain is formed. By contrast, heterozygote mice for the HTT gene usually develop but exhibit motor deficits and cell loss in basal ganglia. Altogether, these data confirm that the Htt protein is mandatory for CNS development and function [5].
The Htt protein is characterized by the presence of (i) the N-terminal 17 amino acids (or N17 region), which is followed by (ii) the polyglutamine (poly Q) tract (encoded by the CAG repeats), (iii) a proline-rich region (PRR), (iii) clusters of Huntingtin, Elongation factor 3, PR65/A regulatory subunit of PP2A and target of rapamycin 1 (HEAT) repeats (α-helix-loop-α-helix motif), and (iv) caspase and calpain cleavage sites (in higher vertebrates). The N17 region has been identified as a critical region that plays a role in Htt localization, aggregation, and toxicity. It is subject to several post-translational modifications, including acetylation, SUMOylation, phosphorylation, and ubiquitination. The polyQ tract is encoded by the CAG trinucleotide repeats, which code for the glutamine (Q) amino acid. PRP region is exclusively found in mammals and is essential for the Htt interactions with proteins containing tryptophans or Src homology 3 domains. In addition, PRP encodes the polyproline (polyP) region, which interacts with polyQ, increasing the Htt protein stability and solubility. HEAT repeats consist of around 50 amino acids and contains two antiparallel α-helices forming a hairpin, which acts as a scaffold for various protein complexes and mediates inter and intramolecular interactions. Sixteen HEAT repeats organized into four clusters were identified in the Htt protein. Htt protein also has several proteolytic cleavage sites, including proline, glutamic acid, serine, and threonine domains. These domains are found in both Htt and mHtt proteins. Thus, these proteins can be cleaved by caspase 3 at amino acid 513 and 552, caspase 1 at amino acid 572, caspase 2 at amino acid 552, and caspase 6 at position 586. In addition, two calpain cleavage sites are located at amino acid 469 and 536, and the metalloproteinase (MMP)-10 cleaves Htt our mHtt at amino acid 402 [5].
The Htt protein interacts with over 200 other proteins, many of them involved in microtubule-mediated axon traffickings, such as the Huntingtin-associated protein 1 (HAP1), which mediates the interaction between Htt protein with microtubule motor proteins and their co-factors (kinesin, dynactin subunit p150, and dynein). Htt protein also mediates long- and short-range axonal transport and vesicle trafficking. This is because the Htt protein binds to the endocytic pathway-related proteins (clathrin and dynamin), as well as endocytic organelle trafficking proteins (α-adaptin, Hip1, Hip14, HAP40, PACSIN1, SH3GL3/endophilin 3). Htt protein is enriched at synaptic terminals and interacts with cytoskeletal and synaptic vesicle proteins to regulate synaptic activity in neurons. However, by exhibiting a C-terminus containing a nuclear export signal (NES), Htt protein can traffics between cytoplasm and nucleus. In addition, the N17 region also interacts with a nuclear pore protein (TRP), which has nuclear translocation activity. The N-terminal domain also forms an amphipathic alpha-helical membrane-binding domain that reversibly mediates association with the endoplasmic reticulum (ER), endosomes, and autophagic vesicles. Thus, it is not surprising that Htt protein also interacts with various transcription factors and transcriptional regulatory proteins, acting as a positive regulator of brain-derived neurotrophic factor (BDNF) transcription (a protein in which expression levels are found reduced in individuals with HD), stimulating the BDNF vesicular trafficking in neurons.
However, by increasing the number of glutamine residues in poliQ, the CAG trinucleotide expansion, verified in HD, reduces the solubility of mutated huntingtin protein (mHtt), resulting in intracellular aggregates (inclusions) in the brain, particularly in GABAergic medium spiny neurons (MSNs), located within the striatum. This event occurs because the expanded polyQ sequence in mHtt protein undergoes conformational changes to form a Β-pleated sheet prone to aggregation. In addition, the early phases of aggregate formation appear to accelerate the hydrophobic interactions with an amphipathic α-helical structure of N17. Under physiological conditions, proteostasis balances protein synthesis, folding, trafficking, and degradation. The impairment of the proteostasis systems aggravates the aggregation of the misfolded mHtt. In addition, posttranslational modifications influence the mHtt toxicity, aggregation propensity, and intracellular localization. For example, proteolytic cleavage of mHtt generates N-terminal fragments with an increased tendency to aggregate. Furthermore, the mHtt inclusions can block the axonal transport between the cell body and the synaptic cleft and recruit other polyQ-containing proteins, which interact with mHtt, leading to loss of biological function, therefore, cell death. In addition, mHtt also silences the activity of RE1-Silencing Transcription Factor (REST), increasing the binding of REST to RE1/neuron restrictive silencer element, producing transcriptional dysfunction [6, 7].
The mHtt inclusions promote mitochondrial dysfunction, decreasing the activity of mitochondrial respiratory complexes II, III, and IV, which was already verified in
Moreover, the mHtt can be cleaved by caspase 6. The fragments of cleaved mHtt protein bind to several transcription regulators, including the tumor suppressor, p53, thus regulating genes involved in mitochondrial function. Therefore, the mHtt increased the levels of p53, which in turn increased Bax and Puma expression, resulting in mitochondrial dysfunction and neuronal loss. These actions increase the reactive oxygen species (ROS) production, justifying the oxidative damage commonly observed in the plasma of HD patients, HD
Cumulative evidence has also demonstrated that mHtt protein causes a reduction in TORC1, the most potent transcriptional activator of (peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1 (PCG-1α) [12, 13, 14]. In addition, the mHtt protein also increases transglutaminase (Tgase) activity, which impairs the transcription of PCG-1α. Thus, mHtt downregulates the expression levels of PCG-1α [14]. The last is recognized as a critical transcriptional coactivator, which interacts with a broad range of transcription factors within a variety of biological processes. In addition, PCG-1α is involved in the regulation of mitochondrial biogenesis, OXPHOS, antioxidant defense, adaptive thermogenesis, and glucose/fatty acid metabolism. Under physiological conditions, the PGC-1α forms heteromeric complexes with nuclear respiratory factors (NRF-1 and NRF-2), and with the nuclear receptors (PPARα, PPARδ, PPARγ and estrogen-related receptor α (ERRα)). These heterodimers regulate the expression of many nuclear-encoded mitochondrial genes, including cytochrome c, complexes I–V, and the mitochondrial transcription factor A (Tfam), as well as antioxidant genes, including superoxide dismutase (SOD) and glutathione peroxidase (GPX). Thus, the mitochondrial dysfunctions promoted by the mHtt-mediated PCG-1α downregulation lead to an increase in oxidative stress [12, 13, 15].
In addition, the mHtt accumulation in neurons promotes microglial activation, increasing oxidative stress. In addition, microglial cells that express mHtt show significant elevations in nuclear factor kappa B (NF-κB). This elevation occurs because the mHtt interacts with the IκB kinase (IKK) γ subunit, promoting the assembly and activation of the IKK complex (comprised by IKKα and IKKβ subunits). The IKKβ kinase phosphorylates IκBα causes the liberation of NF-κB, promotes the gene expression of the pro-inflammatory cytokine, including interleukin (IL)-6, resulting in neuroinflammation [16, 17]. The neuroinflammatory cytokines produced in response to mHtt protein accumulation leading to the activation of microglial cells considered the brain’s resident immune cells. Under physiological conditions, i.e., in the absence of inflammatory stimulus, microglia are in a surveilling state, being responsible for maintaining synapses and synaptic plasticity. In addition, Microglia also facilitates the growth and development of surrounding neural networks by secreting neurotrophic factors, such as BDNF, nerve growth factor (NGF), and insulin-like growth factor (IGF-1) [18]. Moreover, significant evidence suggests the microglia promotes neurogenesis by phagocytosing apoptotic neural cells, facilitating the migration and differentiation of neural progenitor cells, and secreting soluble factors related to neurogenesis. However, microglia become activated upon detecting inflammatory stimuli, such as the increase in ROS or cytokine production [19]. When activated, microglia can adopt different polarization states, such as M1 and M2. Interestingly, microglia can alternate between these states. For this reason, recently, studies have suggested using M1/M2 terminology to categorize activated microglial cells. M1 microglia exhibit a proinflammatory phenotype, the significant initiators of innate and adaptive immunity in the brain. In addition, these cells elicit a phagocytic function and release cytotoxic factors, including nitric oxide and ROS. M2 microglia also carry out phagocytosis, but contrary to the role of M1 microglia, M2 microglia exhibit an anti-inflammatory phenotype, releasing anti-inflammatory cytokines such as interleukin (IL)-4, IL-13, and transforming growth factor-beta (TGF-β), which suppress inflammatory responses. The continued activation of microglia, stimulated by the inclusions of mHtt, prolonged the production of inflammatory mediators, resulting in chronic inflammation. The last is implicated in further tissue damage, justifying the microglia activation in striatal GABAergic neurons verified by Positron Emission Tomography (PET) in HD patients. Interestingly, studies based on PET also reported the presence of microglia activation in striatal GABAergic neurons in presymptomatic HD gene carriers, suggesting that microglial activation is an early characteristic of HD before symptom onset. However, the activation of microglia increases oxidative stress, resulting in both nuclear and mitochondrial DNA oxidative damages and protein and lipid oxidation. These damages lead to progressive cell death, particularly of MSN’s [20, 21].
Studies based on animal models of HD demonstrate that cell death in the striatum serves as a potent stimulator of progenitor cell proliferation (which are resident into the subventricular zone – SVZ), neuroblast migration, and neurogenesis. This is because, in the transgenic mouse model of HD (in which there is minimal cell loss in the striatum), the SVZ is unaltered, while in rat striatal-lesion models of HD (in which there is a cell loss in the striatum), there is a marked increase in SVZ progenitor cell proliferation and neurogenesis. The SVZ of the lateral ventricle is the resident niche of stem cells. These stem cells give rise to proliferative progenitor cells during brain development, which migrates to the cortex or the basal ganglia, where they differentiate into neurons. SVZ preserves its critical developmental characteristics in the adult brain, responsible for the continuous generation of migrating neuroblasts destined for the olfactory bulb or other areas of cell death in the brain. Thus, the maintenance of SVZ is crucial for neuron replacement along adulthood [22, 23, 24].
Supporting the involvement of SVZ with the physiopathology of HD, several studies revealed that the SVZ of HD patients is enriched in endogenous factors and receptors that actively regulate the cell cycle and the differentiation of precursors, such as the neuropeptide Y. Furthermore, studies already showed a significant increase of GABAA, receptor subunit γ2 (involved in the desensitization of the receptor complex to GABA) in SVZ in HD. GABA is an essential trophic factor for neurons during development. High levels of GABA are found in the normal SVZ and the SVZ of HD patients, suggesting that the SVZ maintains a germinal capacity for proliferation and neurogenesis in response to neurodegenerative cell death in adult life. However, it was proved that, while the Htt protein interacts with cAMP response element-binding protein (CREB) and specificity proetin1 (Sp1), conferring anti-apoptotic action, the mHtt protein triggers a pathogenic cascade involving Sp1 transcription factor activation, which leads to repressor element-1 silencing transcription factor (REST) upregulation, repressing neuronal genes [22, 23, 24].
With the progression of HD, others brain areas, besides the substantia nigra, are subjected to neuronal loss, leading to cognitive and neuropsychiatric dysfunctions. This occurs because the mHtt (as the Htt) is widespread to different brain areas through extracellular vesicles (EVs).The EVs comprise a heterogeneous group of phospholipid bilayer-enveloped particles that are naturally produced and secreted into the extracellular environment by almost all cell types. According to their size, biogenesis, and content, these vesicles are classified as (i) microvesicles, (ii) exosomes, and (iii) apoptotic bodies. Among these vesicles, exosomes are the most investigated. This is because, due to the repertoire of bioactive molecules carried by these vesicles (coding and non-coding RNA, proteins, lipids, and metabolites), the exosomes play an important role in cell-to-cell communication and intercellular signaling, regulating both physiological and pathophysiological processes. Moreover, in the function of their nanosize (30–200 nm), exosomes easily cross the blood-brain barrier [1, 25].
The growing interest in this class of EV has been reflected in the creation of distinct databases that compile data on exosome content, such as Exocarta (http://www.exocarta.org/), EVpedia (http://bigd.big.ac.cn/databasecommons/database/id/4354) and Vesiclepedia (http://microvesicles.org/), which are constantly updated with released studies.
Exosomes are formed by endocytosis and released by exocytosis. During the biogenesis of these vesicles, the inward budding of the plasma membrane results in small intracellular vesicles. These small vesicles fuse, forming early endosomes. The invagination of the early endosome membrane results in the formation of intraluminal vesicles (ILVs) within large multivesicular bodies (MVBs). In contrast, cytoplasmic molecules such as coding and non-coding RNA, proteins, lipids, and metabolites are engulfed and enclosed into the ILV lumen. Along with the maturation of early endosomes to late endosomes, some proteins are directly integrated into the invaginating membrane. However, this process depends on the endosomal sorting complexes required for transport (ESCRTs), which are comprised of four proteins (ESCRT-0, ESCRT-I, ESCRT-II, and ESCRT-III) that work cooperatively to facilitate the MVB formation, vesicle budding, and protein cargo sorting [1, 25]. The exosomes biogenesis also occurs through an ESCRT-independent pathway mediated by tetraspanins and ceramide-enriched lipid rafts. Tetraspanins are recruited at early steps to endosome membranes before ILV formation, and at least CD9, CD63, CD81, and CD82 are found in endosome and exosome membranes [1, 25].
Ceramides and their derived metabolites are organized in raft-based microdomains that interact with proteins, such as flotillins. The lipid-enriched structures are involved not only in endosomal membrane invagination for ILV formation but also in cargo loading. The selective cargo loading occurs during exosome biogenesis through tetraspanins-dependent and/or ESCRT-dependent mechanisms [1, 25]. Although, the biological cargo of exosomes varies widely according to their cell type of origin, they mainly consist of proteins, nucleic acids (particularly RNA) and lipids. More than 2400 different RNAs and, 4000 proteins were already identified and characterized in exosomes [1, 25].
Due to their endosomal origin, the exosomes are enriched in several proteins engaged in the biogenesis of MVBs, including clathrin, which can bind to hunting protein. Moreover, exosomes contain CD9, CD63, CD81, CD82, CD54, and CD11b tetraspanins, which serve as specific molecules. In addition, the exosomes contain heat shock proteins (HSP90, HSP70, and HSP60), which act as chaperones and play an essential role in cellular responses related to environmental stress. Besides this, exosomes also carry mRNA and a multitude of long non-coding (lnc) RNA and small RNA (particularly miRNA) that can be transferred into recipient cells, inducing cellular responses [1, 25, 26, 27].
The interaction of MVBs with actin and microtubules is essential for their transport to the plasma membrane. The translocation of MVB toward the plasma membrane depends on several molecules via the cytoskeleton. Rab GTPases such as RAB11, RAB27A/B, and RAB35 are mediators of selective sorting of MVB to the plasma membrane and exosome release. The MVBs are decorated with tethering protein complexes, such as HOPS and SNAREs, that mediate the fusion of these vesicles with the plasma membrane, The presence of tetraspanins and lysosomal-associated membrane proteins LAMP1 and LAMP2 in late endosomes also facilitate the fusion of MVB with the plasma membrane [1, 25].
After secretion, the exosomes will dock into the membrane of the target cells and activate signaling events or be internalized through specific receptor-ligand interactions. The transmembrane proteins present in the surface of exosomes (tetraspanins) can be recognized by signaling receptors in the target cells, resulting in activation of transduction pathways and modulation of the intracellular process without entering the target cells. Exosomes can merge with the target cells’ plasma membrane, releasing its cargo directly into the cytosol by a low pH-dependent mechanism. However, the main route for exosome uptake can occur by clathrin-mediated or caveolin-dependent endocytosis, and the presence of lipid rafts in the membrane facilitates the process [1, 25].
After internalization, exosomes are sorted into MVB with two possible fates: (i) to be released again to neighboring cells or (ii) to be degraded after fusion of LE/MVB with lysosomes [1, 25]. The uptake of exosomes by brain cells seems to be cell type-dependent. For instance, neurons and glial cells seem to uptake exosomes by clathrin-mediated endocytosis. Some neurons can also use specific receptors from the SNARE family, such as SNAP25, for exosome uptake. Interestingly, the uptake of exosomes seems to be a selective pathway. Exosomes derived from cortical neurons were primarily internalized by hippocampal neurons, whereas astrocytes and oligodendrocytes took up exosomes released by neuroblastoma cell line N2A. Exosomes derived from oligodendrocytes are mainly internalized by microglia but not by neurons or astrocytes. In addition, the uptake of exosomes was also more active in pre-synaptic regions, which might indicate that these vesicles use constitutive endocytosis processes at these regions for neuronal cell entrance [1, 25].
Initially, exosomes were considered vehicles for the elimination of cellular components. However, current studies have provided evidence that exosomes play multiple physiological roles in the nervous system. Exosomes are released by neural cells, including neurons, astrocytes, microglia, and oligodendrocytes, playing essential physiological roles in neurogenesis, synaptic activity and plasticity, myelination, and protection and regeneration neurons after injury and disease. Thus, it is not surprising that exosomes mediate the pathogenesis of neurodegenerative disorders, such as HD. This is because the misfolded proteins related to these disorders can be selectively integrated into ILVs of MVBs, and subsequently released into the extracellular environment within exosomes [28].
In HD, cumulative evidence has demonstrated that exosomes are implicated in the physiopathology of HD, serving as a vehicle for the expanded polyglutamine tract of HTT RNA and protein (mHtt), as well as mHtt aggregates transport to different brain areas. Supporting this evidence, it was verified that exosomes could deliver expanded trinucleotide repeat RNAs among cells and facilitate the propagation of mHtt protein [29, 30, 31, 32]. It was shown that the injection of fibroblast-derived exosomes from an HD patient into a newborn mouse brain ventricles triggered the manifestation of HD-related behavior and pathology [31]. Moreover, it is known that the Htt protein regulates anterograde and retrograde transport of endocytic vesicles by interacting with several mediators, such as α-adaptin, Hip1, Hip14, HAP1, HAP40, SH3GL3, clathrin, and dynamin [29, 30]. This process is coordinated by the phosphorylation of Htt, which serves as a molecular decision marker for the anterograde or retrograde direction of vesicle transport. Thus, while the Htt promotes axonal BDNF vesicle trafficking, mHtt interacts with HIP1 and dynactin, leading to de-railing of molecular motors from microtubules tracks and cessation of transport [33].
Animal models for HD have been successfully used for more than three decades to identify pathways involved in HD pathology or for preclinical testing of therapeutic strategies. These models are divided into (i) monogenetic and (ii) genetic murine models. However, none of these models can mimic the main feature of HD since no rodent model develops the chorea. For this reason, herein, we summarize the pros and cons of each animal model, considering their utility for preclinical test purposes [34, 35, 36].
Historically, monogenetic models have dominated the field of HD disease. These models are based on the use of toxins that typically induce cell death either by excitotoxic mechanism or by disruption of mitochondrial machinery. Among the excitotoxicity toxins used to obtain murine models for HD are quinolinic acid (QA) and kainic acid (KA). These neurotoxins induce cell death by binding to their cognate receptors, N-methyl-d-aspartic acid (NMDA) and non-NMDA, respectively, on striatal neurons. The QA or KA rat models exhibits motors (hyperkinesia, apomorphine-induced dystonia, and dyskinesia) and cognitive symptoms of HD (visuospatial deficits, procedural memory deficits, and poor memory recall). However, for various reasons, QA became the preferred excitotoxin for use in HD studies. The QA is formed from the metabolism of tryptophan via the kynurenine pathway, which is found in high quantities in the urine of rats that received a diet high in tryptophan. Interestingly, the tryptophan crosses the blood-brain barrier (BBB) using transporters shared by other neutral amino acids. In the brain, tryptophan is taken up by astrocytes, macrophages, microglia, and dendric cells and converted into kynurenine. In the presence of the enzymatic 3-hydroxyanthranilic acid oxygenase, a series of enzymatic reactions converts kynurenine to QA. Thus, the expected level of QA does not cause damage, but only small increases in QA levels cause toxicity. Moreover, it was verified that the administration of QA in the mouse models promotes the upregulation of Htt protein, linking the levels of this neurotoxin with HD pathogenesis. However, the QA is incapable of crossing the BBB. For this reason, the QA has been administrated directly within the brain [37, 38, 39].
Unlike the QA, the mitochondrial toxin 3-nitropropionic acid (3-NP) crosses the BBB and could be systemically administrated through intraperitoneal or subcutaneous injection [40, 41, 42].
The 3-NP is a plant (Indigofera endecapylla) and fungal (Aspergillus flavus, Astragalus, Arthrinium) toxin, which acts as an irreversible inhibitor of succinate dehydrogenase. It inhibits both the Krebs cycle and the mitochondrial complex II of the electron transport chain. The toxin also induces caspase-9 activation, which in turn requires the simultaneous presence of Apaf-1, cytochrome c, and ATP, suggesting that neuronal death may occur in the presence of intense ATP depletion. Moreover, the 3-NP induces oxidative and nitrate stress due to excessive ROS/RNS production and lack of the antioxidant system [40, 43, 44, 45]. Interesting, numerous studies demonstrated that the chronic systemic administration of 3-NP in rats impairs energy metabolism and results in striatal lesions, inducing a spectrum of HD-like pathology in rat striatum. In addition, in 1993, Beal et al. [41] showed that the 3-NP model causes selective striatal lesions characterized by the loss of medium spiny neurons (MSNs) and astroglial proliferation, replicating the histological and neurochemical features of HD. Although, the loss of MSNs in 3-NP rat models causes motor and cognitive symptoms analogous to those verified in HD, this model does not exhibit chorea.
However, the 3-NP model is capable of mimicking both hyperkinetic and hypokinetic symptoms of HD depending on the time course of administration. Thus, while the administration of 3-NP in two individual doses causes hyperkinetic movements analogous to those observed in early to mid-stage HD, the administration of more than four injections of 3-NP causes hypokinetic movements similar to those that appear in late-stage HD [40, 43, 44, 45]. Nevertheless, the response to the 3-NP changes according to the murine (CD1, C57BL/6, BALB/c, Sebster/Swiss and 129sEMS) or rat strain (Fischer, Lewis, and Wistar). In this sense, it is recognized that rats are most vulnerable to the toxic action of 3-NP treatment than mice. Fisher rats are the most susceptible to the 3-NP toxin but display significant variability in response to the toxin due to the difficulty of controlling damage caused by this toxin. In contrast, Lewis rats are less susceptible to 3-NP but respond more stably and consistently to 3-NP in behavioral alterations and lesions. Wistar and Sprague-Dawley rats are also sensitive to the 3-NP, developing lesions and behavioral modifications of extraordinary value for studying possible routes involved in HD and testing new therapeutic strategies. Although, the 3-NP model leads to a (i) massive cell death induced by the toxin, (ii) serving as a helpful model for (ii) analyzing and studying neuroprotective and (iii) neurorestorative therapies for HD patients, (iv) allowing to study the mechanisms involved in HD pathogenesis, including energy deregulations and ROS production, this model does not express the mHtt protein.
The genetic or transgenic animal models emerge as an alternative to nongenetic models since they express the mHtt protein [46, 47]. Transgenic models are divided into (i) those expressing transgenes with a truncated section of human HTT carrying the CAG repeats or full-length human HTT gene, and (ii) those with long CAG repeats replacing mouse Htt. Instability of the CAG repeat has been observed in many of the mouse models and was noted in the first HD model (R6 series). Although, different rodent models have been used to understand the biology of HD or employed in preclinical trials to investigate the therapeutic potential of products candidates to alleviate HD symptoms, they are limited in their ability to provide evidence of the effects of genetic modifiers of disease. In addition, there are many differences among the transgenic rodent models that can lead to different results, especially for preclinical trials.
In this sense, in two independent studies, it was demonstrated that a version of the R6/2 mouse with 90 CAG repeats (R6/2(CAG)90) shows earlier mHtt nuclear aggregation when compared to the R6/2 mouse with 200 CAG repeats (R6/2(CAG)200). Moreover, the R6/2(CAG)90 brains contain nuclear aggregates with a diffuse punctate appearance which remained partly detergent soluble, which correlated with the onset of transcriptional changes. In contrast, the R6/2(CAG)200 brains contain cytoplasmic aggregates that gave larger inclusion bodies related to behavioral changes. These data indicate that CAG length gives different phenotypes [48, 49, 50].
Several models encoding glutamine but using a mixed CAACAG rather than a pure CAG tract were developed to prevent germline and somatic expansion of CAG trinucleotide. An example of these models is the BACHD models with 97 glutamines encoded by a diverse CAACAG tract. These mice have five copies of the transgene integrated into their genome and express BACHD HTT, an estimated three-fold level of the transcript, and 1.5 to 2-fold protein level (mHtt).
BACHD rats show string impairment in muscle endurance at 2 months of age. Altered circadian rhythmic and locomotor activity are also observed in these animals [51, 52, 53]. However, the BACHD model is not commercially available, difficult to access this model.
When discovered, stem cells—therapeutic cells gain exceptional attention due to their capacity to produce precursors and differentiated cells. Propose, therefore, was to use stem cells in tissue regeneration [26, 27]. Stem cells showed differentiation potential
MSC secretes a large number of biologically active molecules, growth factors, hormones, interleukins, etc. [29]. These biomolecules can be found in free form or contained in exosomes, which are recognized as a key component in paracrine regulation [1, 25]. These molecules provide beneficial effects on injured tissues. For example, they induce angiogenesis and tissue regeneration and inhibit fibrosis, apoptosis, and inflammation [30, 31, 32]. In addition, which is essential for HD disease, MSCs and MSC’s secretomes provide neurogenic, neuroprotective, and synaptogenic effects [33]. They improve the abnormal dopamine transmission and inflammatory reaction in the transgenic HD model [34]. Animal models showed that they produce factors protecting retinal ganglion cells against glutamate excitotoxicity, neurotrophins expressed by MSCs inhibit pro-inflammatory cytokine secretion, MSCs fight oxidative stress and others [35, 36]. Due to the characteristics above, MSCs called medicinal signaling cells or simply therapeutic cells [37].
Medicinal signaling cells (MSC) have been used in a variety of preclinical studies, which were focused on behavioral and memory outcomes, reduction of brain damage and minimization of striatal degeneration. “Native” MSC isolated from different adult tissues such as bone marrow, adipose tissue and umbilical cord were used in these studies. Due to their ability to adhere to plastic, MSC can be easily isolated and expanded
Stem cell-based therapies are important to reconstruct damaged brain areas in HD patients. These therapies have a dual role: stem cell paracrine action, stimulating local cell survival, and brain tissue regeneration through the production of new neurons from the intrinsic and likely from donor stem cells. Initially, preclinical studies were mainly focused on the neuroprotective function of MSC. Since these cells express a variety of neurotrophins and in particular brain-derived neurotrophic factor (BDNF), which is implicated in the survival of striatal neurons. BDNF expression is reduced in Huntington’s disease (HD) contributing to striatal neurodegeneration.
Initially, preclinical studies mainly discussed the neuroprotective function of MSC. Since these cells express BDNF, which is implicated in the survival of striatal neurons, its expression is reduced in Huntington’s disease (HD) contributing to striatal neurodegeneration. The regenerative approaches of MSC potentially can cause the (i) promotion of endogenous neuronal growth; (ii) amelioration of the synaptic connection from damaged neurons; (iii) decrease of apoptosis of endogenous neurons; (iv) reduction of the levels of free radicals; (v) immunomodulation. Our group widely discussed these MSC functions in animal models in previous publications (Figure 1) [43, 44].
Schematic representation of the paracrine and cellular mechanism of MSC action observed in pre-clinical studies in Huntington and other degenerative diseases. Paracrine action mainly includes neurotrophins and other soluble factors, including growth factors, small molecules, and cytokines, providing signals to cells and resulting in different cell actions such as survival, proliferation, and differentiation. The paracrine factors are secreted directly into the intercellular matrix or included in extracellular vesicles (exosomes) before secretion. The cellular effect includes mitochondria transfer and MSC mediated autophagy. MSC acting by paracrine and cellular mechanisms showed significant therapeutic potential.
Furthermore, MSC can transfer larger molecules and even organelles, therefore, their use as delivery vehicles for therapeutic RNA inhibition was suggested [45]. MSC can transfer larger molecules and even organelles; therefore, suggesting their use as delivery vehicles for therapeutic RNA inhibition [45].
In addition, more recent findings suggest the potential therapeutic effect of MSC on different pathophysiological aspects of HD, such as (i) mitochondrial dysfunction; (ii) transcriptional dysregulation [49, 50]; (iii) altered axonal transport of critical factors [51, 52]; (iv) disrupted calcium signaling [53, 54]; (v) abnormal protein interactions [55]; (vi) impaired autophagy [56, 57]. However, here we will focus our review on HD mitochondrial dysfunction and MSC mitochondria transfer.
Figure 1 combines the well-known paracrine mechanism of MSC action and a novel cellular mechanism mediated by mitochondria transfer and autophagy. Both, paracrine and cellular, mechanisms provide clinical, cellular and molecular benefits in HD [43, 44, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59]. The complex mechanisms of MSC action and her multi-target orientation are the unique biological tool that could act on multiple pathophysiological aspects of HD cited above.
Mitochondria roles in neurons differ from only a cell power source. Mitochondria are also dynamic organelles that fragment and fuse to achieve a maximal bioenergetics action. They are transported along microtubules, regulated intracellular calcium homeostasis through the interaction with the endoplasmic reticulum. In addition, they produce free radicals and participate in cell apoptosis [60]. These activities have been demonstrated to be changed in HD, potentially contributing to neuronal dysfunction in early pre-symptomatic HD phases. Thus, a polyglutamine-expansion disorder that primarily affects the striatum and the cerebral cortex has been described as mitochondrial dysfunction, an early pathological mechanism presenting selective HD neurodegeneration [61, 62]. One of the hallmarks of HD is an altered mitochondrial morphology that can be seen in different cell types and neurons, which are characterized by increased mitochondrial fragmentation [63]. The cells with altered mitochondrial morphology in HD cells showed a decrease in electron transport chain activity, oxygen consumption, Ca2+ buffering, and decreased ATP and NAD+ production [64]. It has been suggested that mitochondrial abnormalities can significantly affect MSNs due to the high-energy demand of this neuronal subtype [65]. Therefore, the mitochondria are a central regulatory organelle in HD-affected neurons.
In addition, mitochondria act as a reservoir for pro-apoptotic factors, thus regulating cell death. The mitochondrial permeability transition pore (mPTP) is opened due to mitochondrial dysfunction, Ca2+ overload, and accumulation of reactive oxygen species (ROS). The transition pore opening initiates the intrinsic apoptotic pathway, which is connected with the mitochondrial outer membrane permeabilization, awakening cytochrome c release, and activation of caspase-3 [66, 67]. Bcl-2 inhibits the activation of proapoptotic factors such as Bcl-2-associated X protein (Bax) and Bcl-2-associated K protein (Bak), thus suppressing the release of cytochrome c from mitochondria. The Bax/Bcl-2 ratio imbalance often occurs during the process of apoptosis [68]. MSC mitochondrial transfer through regulation of the balance of Bax/Bcl-2 and reduction of the expression of caspase-3 can reduce apoptosis levels and promote cell viability in recipient cells [69, 70].
Recent studies have demonstrated that MSCs have the potential to transfer the defective mitochondria between MSCs and aging cells [71]. For the first time, the MSC mitochondria transfer was shown in A549 cells with mtDNA deletions after their co-culture with human MSCs. This work demonstrated the recovery of function by mitochondrial activities such as increased oxygen consumption, membrane potential, and intracellular ATP levels [72].
It is worth mentioning that the transfer of dysfunctional mitochondria from damaged cells to MSC also can occur. Gozzelino et al. showed that mitochondria released from damaged cardiomyocytes or endothelial cells could be “swallowed” by MSCs. This event rigger increases the expression of Heme oxygenase-1 (HO-1), a protein that protects against programmed cell death, and increases mitochondria in MSCs, which in turn induces an adaptive reparative response [73, 74].
Fluorescence microscopy studies revealed MSC mitochondria transfer in astrocytes and neuron-like pheochromocytoma cells. MSC mitochondria transfer to astrocytes was more efficient when the astrocytes were subjected to ischemic damage associated with elevated ROS levels. The ROS accumulation in normal aging or disease leads to increasing the rate of mitophagy and decreasing the level of mitochondrial biogenesis, which reduces mitochondrial mass [75]. Such mitochondria transport re-established the bioenergetics of the recipient cells and stimulated their proliferation. Furthermore, the authors showed that MSCs mitochondria transferability may be enhanced by upregulation of Miro1 (adaptor protein participating in mitochondria moving along microtubules [76] therefore, this study showed that mitochondrial impairment in differentiated cells can be restored after MSC healthy mitochondria transfer and this approach may serve as a promising treatment for neurological diseases [77].
Tissue injury or degeneration is usually followed by inflammation, which is a driving force for mitochondrial transfer. In HD, massive neuroinflammation in the striatum and caudate nucleus are already present before patients develop any symptoms [21, 78, 79]. The therapeutic effects of MSC are mediated mainly by its secretome/exosomes since in response to a combination of molecules present in the inflamed microenvironment, these cells undergo a process activation or “licensing,” acquiring an anti-inflammatory phenotype and producing large amounts of immunomodulation factors, growth factors and specific chemoattractants, being able to modulate significantly innate and adaptive immune cells [38, 80].
The MSCs secreted cytokines that immunomodulate various immune cells, such as T cells, B cells, natural killer cells, and macrophages [81]. Recent studies demonstrated that between MSCs and immune cells MSC mitochondrial transfer can occur, such influencing the functions of the immune cells. Jackson et al. showed MSC mitochondria transfer occurs in an acute respiratory distress syndrome (ARDS) model. MSC provides mitochondria to host macrophages, thus enhancing the phagocytic capacity and bioenergetics of macrophages. This MSC mitochondria transfer leads to improved clearance of pathogenic bacteria [82]. Using the same model Morrison et al. showed that MSC exosomes mediated transfer of mitochondria, which can induce monocyte-derived macrophages to differentiate to an M2 phenotype with a high phagocytic capacity [58]. In addition, MSC mitochondria transfer regulates T cell differentiation. Some authors reported that when healthy donor-derived bone marrow-derived MSC (BMMSC) is cocultured with primary Th17 effector cells, the mitochondrial transfer occurs, increasing respiration in recipient Th17 cells [59].
HD demonstrates typical cellular and molecular features of inflammation, such as cytokine expression and microglia activation. However, no immune cell infiltration from the bloodstream was observed [83, 84]. Nevertheless, HD is characterized by a chronic increase of systemic pro-inflammatory cytokine production. Microglia and astrocytes are non-neuronal cells in the brain that participate in tissue homeostasis and support neuronal function. Under pathologic conditions, these cells become ‘activated.’ They start to produce numerous mediators promoting inflammation. These cells change their morphology and, can divide, thus increasing cell numbers, an event named ‘gliosis.’ Recent studies suggest that cell-autonomous pro-inflammatory activation of microglia occurs due to the expression of mutant HTT, thus contributing to the progression of HD pathogenesis [21].
MSC’s metabolic state is characterized by the balance between the intrinsic necessities of the cell and limitations imposed by extrinsic conditions. Under pathogenic conditions or inflammation, MSCs respond to reactive oxygen species (ROS), damage-associated molecular patterns (DAMPs), damaged mitochondria, and mitochondrial products, thus transferring their mitochondria to damaged cells. MSC therapies can protect the potentially damaged cells by regulating cellular metabolism in injured tissues, modulating ROS and endogenous MSCs.
Furthermore, to treat such complex diseases like Huntington’s, we should develop new complex therapies acting on multiple targets. MSC, due to the wide range de therapeutic molecules they produced and the different mechanisms they used to fight the disease, these cells are a good candidate for the new class of such therapeutics.
For a long, it was considered that the therapeutic effects of the stem cells were associated with the replacement of dead cells [73, 74]. However, in a model of kidney injury caused by the injection of toxic doses of glycerol, it was verified that transplanted stem cells remain in the injury site for up few days and, subsequently, are not found in the tissue [73, 75, 76]. These data provide evidence that the therapeutic potential of MSCs is mediated by trophic factors naturally produced and secreted by these cells in an accessible form or into EVs [1]. However, whereas the bioactive molecules present in the extracellular medium are subjected to rapid hydrolysis and oxidative effects, the biomolecules present in EVs are more stable [73]. For this reason, the EVs (particularly exosomes) have been biotechnology explored in a novel therapeutic approach known as cell-free therapy [26, 77, 78].
Cell-free therapy possesses different advantages when compared with cell-based treatment. Among these advantages are: [1] EVs can be easily prepared, stored for a relatively long period without any toxic cry preservative such as dimethylsulphoxide (DMSO) and transported; [2] therapeutic application of exosomes have been demonstrated to be well tolerated; [3] the use of EVs instead of whole cells avoids possible complications associated with pulmonary embolism after intravenous infusion of MSCs; [4] avoids the risk of unlimited cell growth and tumor formation since EVs are not dividing; [5] exosomes from MSCs, and epithelial cells do not induce toxicity when repeatedly injected; [6] EV may be isolated from unmodified or genetically modified human stem cells; [7] evaluation of culture medium for safety and efficacy is much simpler and analogous to conventional pharmaceutical agents [1, 73, 79, 80, 81, 82]. Further, the cell-free therapy allows biotechnologically exploring the use of the culture medium, which is generally discarded as a byproduct of the in vitro expansion of MSCs. This is because this culture medium—also termed conditioned medium (CM) [79]—is an essential source of bioactive molecules, which can find in an accessible form or an extracellular vesicle (EVs) [1].
Although, different strategies have been successfully used to isolate exosomes, they represent the main obstacle to the therapeutic application of EV since these procedures are time-consuming and generally provide few quantities of EVs [1, 73]. However, novel methodologies have been proposed to solve these problems. Based on this, we aimed to summarize the pros and cons of each available method for isolating exosomes.
Ultracentrifugation (UC) and commercial kit rooted in polymer-based precipitation are the most well-established and standard methods used for isolating exosomes [74], being adopted as a strategy in about 81% of researches [78]. Ultracentrifugation-based methods can be divided into two major types of techniques according to the separation mechanism: (i) differential ultracentrifugation and (ii) density gradient ultracentrifugation [78]. For both methods, death cells, cellular debris, and large EVs (>200 nm) are separated using low centrifugal forces (300–2000 ×
Another strategy commonly employed to isolate exosomes is coprecipitation. This method uses polymers, such as polyethylene glycol (PEG) 6000 or 8000, which can coprecipitate with hydrophobic proteins and lipid molecules present in exosome membranes [78]. Although, most simple and less expensive than the methods based on ultracentrifugation, the isolation using coprecipitation is not scalable, limiting its use for therapeutic purposes. Moreover, this technique requires sample incubation with the polymers for a long time (generally 12–16 h) [1].
The differential expression of specific surface biomarkers, such as CD9, CD63, and CD83, also provides an excellent opportunity to develop immunoaffinity-capture-based techniques for exosomes isolation using modified magnetic beads or microchannels surfaces with specific antibodies [1, 78]. Although, this technique allows isolating only exosomes, it works with few volumes, limiting its use for therapeutic purposes, which require scalable methods. Moreover, this method generally requires a pre-enrichment step, which is commonly performed using commercial kits based on coprecipitation, resulting in PEG contamination [1].
Another strategy used to isolate exosomes is the size-based isolation technique. This technique can be based on sequential filtration, size-exclusion chromatography (SEC), and size-dependent microfluids. These methods allow isolating the EVs according to their size [78]. EVs are separated using membrane filters with different size or molecular weight exclusion limits in sequential filtration. First, the CM is filtered using a 0.22 μm membrane filter. Then, proteins with a 500 kDa molecular weight are purified using a dialysis bag. Finally, the samples are filtered with a 100 nm membrane filter [78]. The SEC is based on particle size filtration through a porous stationary phase composed of spherical gel beads with pores of specific size [78]. Large particles are eluted when the sample passes through the stationary phase, whereas small particles pass through the pores [78]. The size-dependent microfluidics uses a viscoelastic microfluidics device, composed of a microchannel, two inlets, and three inlets, to fractionate exosomes from other types of EVs [78]. These techniques are faster than those based on ultracentrifugation and do not require special equipment. Moreover, they avoid PEG contamination, frequently observed in coprecipitation-based methods. However, the size-based isolation techniques are relatively expensive and cannot separate exosomes from other EVs, requiring additional steps for exosome purification [1].
Due to their ability to cross the blood-brain barrier and biocompatibility, exosomes are promising therapeutic drug carriers into the CNS. In HD, exosomes are exceptionally efficient in delivering specific microRNAs (miRs), short non-coding RNAs of about 22 nucleotides that regulate gene expression by suppressing the translation of mRNA, which are found deregulated in HD patients.
In this sense, several miRs had already been identified as deregulated in HD, including the miR-124, which was found downregulated in HD patients [85]. The decreased expression of miR-124 increases the levels of its target gene (REST), which acts as a repressor of BDNF [85]. By contrast, the expression of miR-124 induces adult neurogenesis in the subventricular zone (SVZ) and regulates the cell cycle in striatal neurons. Considering that the HD striatum exhibits decreased neurogenesis, which leads to brain atrophy, it was hypothesized that the delivery of miR-124 may be a feasible way to induce neural regeneration. However, naked miRs are vulnerable to degradation.
In this regard, exosomes emerge as candidates for the miR-124 delivery to recipient cells. Based on this, Lee et al. [85] injected exosomes derived from HEK 293 cells overexpressing miR-124 within (Exo-124) the striatum of 6-week-old R6/2 transgenic mice. Using ex vivo imaging, the authors demonstrated the presence and maintenance of the exosomes within the striatum even after one week later the Exo-124 administration. Furthermore, it was verified that Exo-124-treated R6/2 mice exhibited slightly higher levels of miR-124 when compared to the non-treated mice (control). However, no statistically significant differences between the treated and control mice were reported. By contrast, the Exo-124-treated R6/2 mice exhibited lower levels of REST protein concerning the control. Although, the study had provided a proof of concept for exosome-based delivery of miRNAs to the brain, the therapeutic efficacy of Exo-124 was modest, suggesting the need to increase the dose of miRNAs packed in the exosomes or to combine this miRNA with other candidate miRNAs such as miR-9, miR-22, miR-125b, miR-146a, miR-150, and miR-214.
In this sense, the exosomes derived from MSCs can be considered an important source of these miRs and other mRNAs and proteins deregulated in HD physiopathology. Supporting this, Lee et al. [86] showed that exosomes derived from an adipose-derived stem cell (ASC-exo) decreased mHtt aggregates in R6/2 mice-derived neuronal cells through the upregulation of PGC-1, phospho-CREB.
In this review, we demonstrated that Huntington’s disease is devastating and affects brain cells and the organism as a whole. Although, the main cause of HD patients’ death is medium spiny neurons, many specific events occur at presymptomatic and symptomatic HD phases. Currently, Huntington’s chorea is in the focus of pharmaceutical companies, producing drugs able to combat this HD symptom. However, these drugs are always not possible to delay the disease and present moderate to severe side effects.
In contrast to conventional drugs, MSC is safe, and they did not present any side effects as shown in multiple clinical trials. MSC showed therapeutic potential distinct from, for example, small molecules and biologics. Cells are deposited multiple drugs, they can sense diverse signals, migrate to specific sites in the body, make decisions, and carry out complex responses inside one specific tissue environment.
Our knowledge about the biology and therapeutic potential of these cells is still minimal; however, as demonstrated by scientific literature, these cells and their derivatives as exosomes and mitochondria have tremendous therapeutic potential. Pre-clinical studies provided evidence about the paracrine effect of these cells’ such as regenerative, anti-apoptotic, anti-fibrotic anti-inflammatory, immunosuppressive, immunomodulatory, and angiogenic.
More recently, the potential effect of MSC against different pathophysiological aspects of HD, such as mitochondrial dysfunction; transcriptional dysregulation; altered axonal transport of critical factors; disrupted calcium signaling; abnormal protein interactions, and impaired autophagy, has been demonstrated.
This review tries to provide insight into cellular and cell-free technologies from the exact cellular origin. These cell and cell-free products may share similar features and present specific characteristics, as demonstrated for MSC, exosomes, and mitochondria. We tried to clarify that these products aim at different cellular targets or molecular pathways involved in Huntington’s disease. Therefore, we should study how to use these new therapeutics, which can delay or even stop neurodegenerative devasting diseases.
We believe financial barriers should not prevent researchers from publishing their findings. With the need to make scientific research more publicly available and support the benefits of Open Access, more and more institutions and funders are dedicating resources to assist faculty members and researchers cover Open Access Publishing Fees (OAPFs). In addition, IntechOpen provides several further options presented below, all of which are available to researchers, and could secure the financing of your Open Access publication.
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\\n\\nThe application process is open after your submitted manuscript has been accepted for publication. To apply, please fill out a Waiver Request Form and send it to your Author Service Manager. If you have an official letter from your university or institution showing that funds for your OA publication are unavailable, please attach that as well. The Waiver Request will normally be addressed within one week from the application date. All chapters that receive waivers or partial waivers will be designated as such online.
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\n\nHowever, as Open Access becomes a more commonly used publishing option for the dissemination of scientific and scholarly content, in addition to institutions, there are a growing number of funders who allow the use of grants for covering OA publication costs, or have established separate funds for the same purpose.
\n\nPlease consult our Open Access Funding page to explore some of these funding opportunities and learn more about how you could finance your IntechOpen publication. Keep in mind that this list is not definitive, and while we are constantly updating and informing our Authors of new funding opportunities, we recommend that you always check with your institution first.
\n\nFor Authors who are unable to obtain funding from their institution or research funding bodies and still need help in covering publication costs, IntechOpen offers the possibility of applying for a Waiver.
\n\nOur mission is to support Authors in publishing their research and making an impact within the scientific community. Currently, 14% of Authors receive full waivers and 6% receive partial waivers.
\n\nWhile providing support and advice to all our international Authors, waiver priority will be given to those Authors who reside in countries that are classified by the World Bank as low-income economies. In this way, we can help ensure that the scientific work being carried out can make an impact within the worldwide scientific community, no matter where an Author might live.
\n\nThe application process is open after your submitted manuscript has been accepted for publication. To apply, please fill out a Waiver Request Form and send it to your Author Service Manager. If you have an official letter from your university or institution showing that funds for your OA publication are unavailable, please attach that as well. The Waiver Request will normally be addressed within one week from the application date. All chapters that receive waivers or partial waivers will be designated as such online.
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Saxena",hash:"d92a4085627bab25ddc7942fbf44cf05",volumeInSeries:2,fullTitle:"Current Perspectives in Human Papillomavirus",editors:[{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Bacterial Infectious Diseases",value:3,count:2},{group:"subseries",caption:"Parasitic Infectious Diseases",value:5,count:4},{group:"subseries",caption:"Viral Infectious Diseases",value:6,count:7}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:249,paginationItems:[{id:"274452",title:"Dr.",name:"Yousif",middleName:"Mohamed",surname:"Abdallah",slug:"yousif-abdallah",fullName:"Yousif Abdallah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274452/images/8324_n.jpg",biography:"I certainly enjoyed my experience in Radiotherapy and Nuclear Medicine, particularly it has been in different institutions and hospitals with different Medical Cultures and allocated resources. Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:null},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"338222",title:"Mrs.",name:"María José",middleName:null,surname:"Lucía Mudas",slug:"maria-jose-lucia-mudas",fullName:"María José Lucía Mudas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}},{id:"147824",title:"Mr.",name:"Pablo",middleName:null,surname:"Revuelta Sanz",slug:"pablo-revuelta-sanz",fullName:"Pablo Revuelta Sanz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}}]}},subseries:{item:{id:"12",type:"subseries",title:"Human Physiology",keywords:"Anatomy, Cells, Organs, Systems, Homeostasis, Functions",scope:"Human physiology is the scientific exploration of the various functions (physical, biochemical, and mechanical properties) of humans, their organs, and their constituent cells. The endocrine and nervous systems play important roles in maintaining homeostasis in the human body. Integration, which is the biological basis of physiology, is achieved through communication between the many overlapping functions of the human body's systems, which takes place through electrical and chemical means. Much of the basis of our knowledge of human physiology has been provided by animal experiments. Because of the close relationship between structure and function, studies in human physiology and anatomy seek to understand the mechanisms that help the human body function. The series on human physiology deals with the various mechanisms of interaction between the various organs, nerves, and cells in the human body.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/12.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11408,editor:{id:"195829",title:"Prof.",name:"Kunihiro",middleName:null,surname:"Sakuma",slug:"kunihiro-sakuma",fullName:"Kunihiro Sakuma",profilePictureURL:"https://mts.intechopen.com/storage/users/195829/images/system/195829.jpg",biography:"Professor Kunihiro Sakuma, Ph.D., currently works in the Institute for Liberal Arts at the Tokyo Institute of Technology. He is a physiologist working in the field of skeletal muscle. He was awarded his sports science diploma in 1995 by the University of Tsukuba and began his scientific work at the Department of Physiology, Aichi Human Service Center, focusing on the molecular mechanism of congenital muscular dystrophy and normal muscle regeneration. 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This includes, but is not limited to: single-neuron modeling, sensory processing, motor control, memory, and synaptic plasticity, attention, identification, categorization, discrimination, learning, development, axonal patterning, guidance, neural architecture, behaviors, and dynamics of networks, cognition and the neuroscientific basis of consciousness. 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