Genetic alterations and SHFM-related phenotypes
\\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:"10350",leadTitle:null,fullTitle:"Sleep Medicine and the Evolution of Contemporary Sleep Pharmacotherapy",title:"Sleep Medicine and the Evolution of Contemporary Sleep Pharmacotherapy",subtitle:null,reviewType:"peer-reviewed",abstract:"Sleep is a fundamental physiological feature experienced by all known mammalian, and most non-mammalian, species. Underscoring its importance is the wide array of neural and cellular processes that have evolved to govern when and how it occurs, its duration, sequence of phases, and the influence it exerts on numerous other brain functions. This book takes up the growing prevalence of sleep disorders affecting these processes and the panorama of pharmaceutical tools that have evolved for their medical care. Its wide-ranging discussion promises not only recent updates on their clinical management but a contemporary window into sleep’s cross-cutting relevance for the many neurological dysfunctions now known to associate with sleep disturbances.",isbn:"978-1-83969-822-4",printIsbn:"978-1-83969-821-7",pdfIsbn:"978-1-83969-823-1",doi:"10.5772/intechopen.91536",price:119,priceEur:129,priceUsd:155,slug:"sleep-medicine-and-the-evolution-of-contemporary-sleep-pharmacotherapy",numberOfPages:198,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"65adb695b7195972208b5da128f531ba",bookSignature:"Denis Larrivee",publishedDate:"January 7th 2022",coverURL:"https://cdn.intechopen.com/books/images_new/10350.jpg",numberOfDownloads:1039,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:0,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 20th 2021",dateEndSecondStepPublish:"May 18th 2021",dateEndThirdStepPublish:"July 17th 2021",dateEndFourthStepPublish:"October 5th 2021",dateEndFifthStepPublish:"December 4th 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"206412",title:"Prof.",name:"Denis",middleName:null,surname:"Larrivee",slug:"denis-larrivee",fullName:"Denis Larrivee",profilePictureURL:"https://mts.intechopen.com/storage/users/206412/images/system/206412.jpeg",biography:"Dr. Denis Larrivee is a visiting scholar at the Mind and Brain Institute, Las Vegas; University of Navarra Medical School, Spain; and Loyola University Chicago. He has held professorships at Weill Cornell University Medical College, NYC, and Purdue University, Indiana. A former fellow at Yale University\\'s Medical School Dr. Larrivee received the Association for Research in Vision and Ophthalmology\\'s first-place award for studies on photoreceptor degenerative and developmental mechanisms. He is the chief editor of several medical and scientific texts, including topics on brain- computer interfacing, Alzheimer’s disease, neuromodulation and neurostimulation procedures, neuroethics, and sleep pharmacotherapies. He is an editorial board member of the journals Annals of Neurology and Neurological Sciences and EC Neurology. An International Neuroethics Society Expert he is the author of more than ninety papers and book chapters in such varied journals/venues as Neurology and Neurological Sciences, Journal of Neuroscience, Journal of Religion and Mental Health, and IEEE Explore. In 2018 he was a finalist in the international Joseph Ratzinger Expanded Reason Award sponsored by the Francis Vittorio University of Madrid.",institutionString:"Loyola University Chicago",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"5",institution:{name:"Loyola University Chicago",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"201",title:"Somnology",slug:"somnology"}],chapters:[{id:"79284",title:"Introductory Chapter: The Promise of Sleep Pharmacotherapy - Healing Systems Level Dysfunction",doi:"10.5772/intechopen.101177",slug:"introductory-chapter-the-promise-of-sleep-pharmacotherapy-healing-systems-level-dysfunction",totalDownloads:77,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Denis Larrivee",downloadPdfUrl:"/chapter/pdf-download/79284",previewPdfUrl:"/chapter/pdf-preview/79284",authors:[{id:"206412",title:"Prof.",name:"Denis",surname:"Larrivee",slug:"denis-larrivee",fullName:"Denis Larrivee"}],corrections:null},{id:"78603",title:"Neurophysiology of Basic Molecules Affecting Sleep and Wakefulness Mechanisms, Fundamentals of Sleep Pharmacology",doi:"10.5772/intechopen.100166",slug:"neurophysiology-of-basic-molecules-affecting-sleep-and-wakefulness-mechanisms-fundamentals-of-sleep-",totalDownloads:157,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"As part of the biological rhythm, the human brain has a healthy functioning with the ability to differentiate between day and night hours in any given day (sleep rhythm, life rhythm). From the control of hormone levels to muscle tonus, from the regulation of respiratory rate to the content of our thoughts, sleep has an impact on all bodily and cognitive functions. It is not surprising to see such effects of sleep on the body as it leads to significant changes in the electrical activity of the brain in general. Electrical signal changes in the brain (sleep-wakefulness rhythm) are regulated by neurohormonal molecules and their receptors in the body. Neurotransmitters that control sleep and wakefulness can be listed as “Glutamate, Acetylcholine, Histamine, Norepinephrine and GABA”. Main hormones are: Melatonin, Corticotropin Releasing Hormone (CRH), cortisol, prolactin, Growth Hormone (GH), Insulin like Growth Factor (IGF-1, Somatomedin-C), Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH), progesterone, estrogen, testosterone, catecholamines, leptin and neuropeptide Y″. The effects of pharmacological agents on sleep and wakefulness cycles are materialized through the following molecules and their receptors: Hypnotics (GABA A agonists, benzodiazepines, gabapentin, tiagabine), sedative antidepressants (tricyclic antidepressants, trazadone, mitrazapine), antihistamines, medications used for the treatment of sleeplessness (melatonin and melatonin analogues), amphetamine (most commonly used stimulant), secretion of monoamines (dopamine), non-amphetamine stimulants used in the treatment of hypersomnia and narcolepsy (modafinil, bupropion, selegiline, caffeine) and other substances (alcohol, nicotine, anesthetics). To the extent we can conceptualize the physiological mechanisms of these basic molecules listed above and the regions they affect, we can appreciate the effects of these substances on sleep physiology and sleep disorders.",signatures:"Murat Kayabekir",downloadPdfUrl:"/chapter/pdf-download/78603",previewPdfUrl:"/chapter/pdf-preview/78603",authors:[{id:"265598",title:"Associate Prof.",name:"Murat",surname:"Kayabekir",slug:"murat-kayabekir",fullName:"Murat Kayabekir"}],corrections:null},{id:"78493",title:"Narcolepsy Treatment: Present and Future",doi:"10.5772/intechopen.99777",slug:"narcolepsy-treatment-present-and-future",totalDownloads:152,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Narcolepsy is a chronic, disabling sleep disorder with a significant diagnostic delay. Nowadays, treatment is focused on managing symptoms that impacts patient’s life, such as at workplace, social events or even at school, but not aimed cure the disease. However, we have pharmacological treatments that effectively help control the main symptoms (excessive daytime sleepiness, cataplexy, fragmentation of nocturnal sleep, sleep paralysis and hypnagogic and hypnopompic hallucinations). On the other hand, pharmacological treatment must be individualised as there are great variations in severity, order of appearance symptoms and development of the disease. We intend to expose the different symptomatic treatments recommended by clinical guidelines and the clinical management from a practical point of view. Future treatments include therapies based on the replacement of hypocretin or the administration of agonist receptors. Other techniques such as hypothalamic stem cell transplantation, gene replacement therapy or immunotherapy are also being investigated.",signatures:"Juan José Ortega-Albás, Raquel López García, Alfonso Martínez Martínez, Sonia Carratalá Monfort, Juan Antonio Royo Prats, Laura Albiol Varela and Patricia Ortega Gabás",downloadPdfUrl:"/chapter/pdf-download/78493",previewPdfUrl:"/chapter/pdf-preview/78493",authors:[{id:"417140",title:"Associate Prof.",name:"Juan José",surname:"Ortega-Albás",slug:"juan-jose-ortega-albas",fullName:"Juan José Ortega-Albás"},{id:"427118",title:"M.D.",name:"Raquel",surname:"López García",slug:"raquel-lopez-garcia",fullName:"Raquel López García"},{id:"427119",title:"Dr.",name:"Alfonso",surname:"Martínez Martínez",slug:"alfonso-martinez-martinez",fullName:"Alfonso Martínez Martínez"},{id:"427120",title:"Dr.",name:"Sonia",surname:"Carratalá Monfort",slug:"sonia-carratala-monfort",fullName:"Sonia Carratalá Monfort"},{id:"427121",title:"Dr.",name:"Juan Antonio",surname:"Royo Prats",slug:"juan-antonio-royo-prats",fullName:"Juan Antonio Royo Prats"},{id:"427122",title:"Dr.",name:"Laura",surname:"Albiol Varela",slug:"laura-albiol-varela",fullName:"Laura Albiol Varela"},{id:"427124",title:"Mrs.",name:"Patricia",surname:"Ortega Gabás",slug:"patricia-ortega-gabas",fullName:"Patricia Ortega Gabás"}],corrections:null},{id:"78877",title:"The Pharmacology of Parasomnias and Movement Disorders of Sleep",doi:"10.5772/intechopen.100472",slug:"the-pharmacology-of-parasomnias-and-movement-disorders-of-sleep",totalDownloads:139,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The treatment of parasomnias and sleep related movement disorders is not always pharmacologic, indeed, some of these disorders respond to behavioral approaches without the risks of pharmaceuticals. This chapter endeavors to pull forward the disorders in which pharmacologic treatment is the best choice and lay out the pharmacologic properties of the treatments. It is not the goal of this chapter to present an encyclopedic review of the parasomnias and sleep related movement disorders. It is, however, the intent of this chapter to comprehensively review pharmacologic treatments used in the management of the disorders in which drug use is most necessary. The pharmacokinetic and pharmacodynamic properties and known risks of these pharmaceuticals are presented and discussed. When more than one pharmaceutical is used clinically within a class of drugs, thorough review of selected drugs is presented. The chapter includes investigations, mostly human studies, of the drugs discussed. The author’s extensive experience in pharmacology, neurology, and sleep medicine take the chapter through pharmacological information a clinician needs to guide the management of these disorders.",signatures:"Gregory S. Carter",downloadPdfUrl:"/chapter/pdf-download/78877",previewPdfUrl:"/chapter/pdf-preview/78877",authors:[{id:"418748",title:"Dr.",name:"Gregory S.",surname:"Carter",slug:"gregory-s.-carter",fullName:"Gregory S. Carter"}],corrections:null},{id:"78739",title:"Impact of Insomnia in the Elderly: The Correlation between Snoring and Apnea/Hypopnea Index",doi:"10.5772/intechopen.100167",slug:"impact-of-insomnia-in-the-elderly-the-correlation-between-snoring-and-apnea-hypopnea-index",totalDownloads:103,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The purpose of this study was to examine the relationship between snoring and obstructive sleep apnea/hypopnea index in community dwelling older men and women. In this retrospective case-series study, the author was using a sequential collection of clinical datum design. There were 124 community-dwelling elders (mean age=71.85 years, Standard Deviation=4.85 years) with complaints of sleep disturbance. Including 46 females (F: M= 1:1.71), all the total subjects with sleep disturbance, after meeting the following criteria of exclusion: age below 65 years, heart failure, and chronic obstructive lung disease, were admitted to the sleep medicine laboratory where sleep questionnaire was used. They underwent in laboratory over-night polysomnography (PSG). The period of this study was 13 months; the total number of subjects whom took PSG in this Sleep Center Laboratory was 1,087 individuals during this period. The proposed neural model used is a generalized regression neural network (GRNN). This neural model has some advantages such as cost and time efficiencies in relation to experimental measurements. The training speed of the proposed technique is faster and the network architecture is simpler. In all likelihood, this model can be used in clinical applications that can reduce the necessity of in-laboratory nocturnal sleep studies since it has surpassed current classification approaches in terms of accuracy, simplicity, cost, time efficiency, and generalization. The correlation between snoring and AH1 was evaluated, though there was no measurement of vasopressin-positive and vasoactive-intestinal-polypeptide (AVP) neurons in postmortem examination of suprachiasmatic nucleus (SCN), as there was no death case. To the contrary, focus was set on the analysis of sleep disturbances that could be interpreted as the result of altered SCN function. The relationship between Snoring and AHI for the elderly with regard to its clue and impact on INSOMNIA is presented. The relationship between clinical sleep apnea and the physiological events surrounding the octogenarians was assessed. Clinically no indication for any brain tissue biopsy.",signatures:"Bing Tang",downloadPdfUrl:"/chapter/pdf-download/78739",previewPdfUrl:"/chapter/pdf-preview/78739",authors:[{id:"95530",title:"Dr.",name:"Bing",surname:"Tang",slug:"bing-tang",fullName:"Bing Tang"}],corrections:null},{id:"78822",title:"Elements of Diagnosis and Non-surgical Treatment of Obstructive Sleep Apnea in Adults from the Dental Medicine Perspective",doi:"10.5772/intechopen.100419",slug:"elements-of-diagnosis-and-non-surgical-treatment-of-obstructive-sleep-apnea-in-adults-from-the-denta",totalDownloads:75,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Dentists hold a key role in the context of ever-growing concerns regarding the management of Obstructive Sleep Apnea (OSA) in adults. Dentists’ contribution in this domain starts with the screening of patients with possible OSA. An earlier intervention for correcting a dento-maxillary anomaly or a parafunction will often serve as a preventive treatment with regard to possible OSA. Furthermore, dental medicine offers nowadays, apart from orthodontic and surgical treatment, a set of therapeutical methods, the most commonly used being the oral appliance and myofunctional therapies. Another important sphere of professional responsibility of the dentist involved in the treatment of OSA consists of periodical examinations focused on assessing clinical evolution, corrective interventions on oral appliances and interventions for preventing local complications. On the other hand, recent studies indicate the potential of different pharmacotherapy agents on OSA pathophysiology, severity and treatment. These agents have shown promising results in improving the efficacy of other therapies dedicated to OSA, therefore, current topics in modern scientific research include the evaluation of standard, even higher doses of single agents or the combination of different agents on the evolution of OSA, as well as the assessment of the association of diverse pharmacotherapy agents with other OSA therapies.",signatures:"Teodor Trăistaru, Mihaela Pantea, Ana Maria Cristina Țâncu and Marina Imre",downloadPdfUrl:"/chapter/pdf-download/78822",previewPdfUrl:"/chapter/pdf-preview/78822",authors:[{id:"327901",title:"Dr.",name:"Ana Maria",surname:"Țâncu",slug:"ana-maria-tancu",fullName:"Ana Maria Țâncu"},{id:"363195",title:"Dr.",name:"Marina",surname:"Imre",slug:"marina-imre",fullName:"Marina Imre"},{id:"417512",title:"Dr.",name:"Mihaela",surname:"Pantea",slug:"mihaela-pantea",fullName:"Mihaela Pantea"},{id:"419059",title:"Prof.",name:"Teodor",surname:"Traistaru",slug:"teodor-traistaru",fullName:"Teodor Traistaru"}],corrections:null},{id:"78349",title:"Sleep and the Fitness to Drive: A Swiss Perspective",doi:"10.5772/intechopen.99791",slug:"sleep-and-the-fitness-to-drive-a-swiss-perspective",totalDownloads:105,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Medical conditions and behavioral patterns affecting sleep are a largely underestimated threat to traffic safety. Unsupervised or even illegal self-treatment of sleep issues by, for example, anti-histamines, cannabis products, or stimulants, questions safe driving and the fitness to drive as well as low compliance/adherence to treatments (CPAP, medication, etc.) of medical conditions, such as OSAS, or narcolepsy. In such cases, Swiss law calls for a medical assessment of the fitness to drive by experts in traffic medicine. With increasing complexity, this medical assessment is escalated in a four-tiered system of qualified experts, ranging from a qualified practitioner to experts in traffic medicine, at, for example, an Institute for Legal Medicine. The following overview provides insight in the Swiss framework of traffic medicine assessments that – with all caveats and potential drawbacks – helps mitigating the risk of sleep-related accidents. For this, we first introduce Swiss traffic medicine and then argue for consistent terms and measurements to assess sleepy driving. A concise summary of those sleep related conditions most relevant in traffic medicine is followed by an overview over potential issues of sleep-medication.",signatures:"Stefan Lakämper and Kristina Keller",downloadPdfUrl:"/chapter/pdf-download/78349",previewPdfUrl:"/chapter/pdf-preview/78349",authors:[{id:"416593",title:"Dr.",name:"Kristina",surname:"Keller",slug:"kristina-keller",fullName:"Kristina Keller"},{id:"416595",title:"Dr.",name:"Stefan",surname:"Lakämper",slug:"stefan-lakamper",fullName:"Stefan Lakämper"}],corrections:null},{id:"78358",title:"Circadian Rhythm Disorders",doi:"10.5772/intechopen.99816",slug:"circadian-rhythm-disorders",totalDownloads:124,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Circadian rhythm disorders are a group of sleep conditions that involve a misalignment of an individual’s internal timekeeping system with that of one’s desired sleep-wake time. This desynchrony can compromise sleep health as well as the functioning of other organ system, and significantly diminish one’s quality of life. There are six well-defined circadian rhythm disorders that can be classified as either intrinsic or extrinsic, based on the underlying factors that contribute to the condition. Intrinsic circadian disorders include the following: 1) advanced sleep-wake phase disorder, 2) delayed sleep-wake phase disorder, 3) irregular sleep-wake rhythm disorder, and 4) non-24-hour sleep-wake rhythm disorder. The two circadian disorders caused by external factors include 1) shift work disorder, and 2) jet lag disorder, both of which are due to behaviorally mediated misalignments of circadian system. This chapter serves to summarize these disorders, guide clinicians towards screening and evaluation of these conditions, and introduce basic treatment strategies that can be applied by non-sleep medicine clinicians.",signatures:"Ajay Sampat and Armand Ryden",downloadPdfUrl:"/chapter/pdf-download/78358",previewPdfUrl:"/chapter/pdf-preview/78358",authors:[{id:"416407",title:"Assistant Prof.",name:"Ajay",surname:"Sampat",slug:"ajay-sampat",fullName:"Ajay Sampat"},{id:"426799",title:"Dr.",name:"Armand",surname:"Ryden",slug:"armand-ryden",fullName:"Armand Ryden"}],corrections:null},{id:"79099",title:"Sleep Disorders in Pregnancy",doi:"10.5772/intechopen.100300",slug:"sleep-disorders-in-pregnancy",totalDownloads:108,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Sleep disturbances and changes in circadian rhythms are commonly observed in pregnant women. These disorders can result from anatomical, physiological, psychological, and hormonal alterations that can influence sleeping during this phase. Sleep disorders during pregnancy can be responsible for detrimental effects on both mother and foetus. In this chapter we will focus on the epidemiology of sleep disorders, physiological sleep mechanisms and their alterations during pregnancy, as well as on risk factors for sleep disorders in pregnancy. 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The development of the limb bud is often taken as a paradigm for a cellular and molecular comprehension of the common principles of organogenesis and pattern formation. Embryonic patterning implies that cells acquire positional information, usually by interpreting concentration gradient of signalling molecules. Accordingly, limb pattern is specified along three principal axes: anterior-posterior (A-P) (e.g., thumb to little finger), dorsal-ventral (D-V) (e.g., back of hand to palm) and proximal-distal (P-D) (e.g., shoulder to nails). Digit pattern across the A-P axis is a classic example of a signalling gradient that specifies positional values, linked to a gradient of Sonic-Hedgehog (SHH). D-V patterning is less studied and involves signals from dorsal and ventral ectoderm. The specification of P-D positional values has long been considered to involve a timing mechanism, under the control of ligands of the fibroblast growth factor (FGF) family. A concentration gradient of molecules can also give cells polarity information, recently shown to be critical for patterning and morphogenesis.
The limbs are not essential for life, thus a large number of mutant strains are available for studies on the genetic determinants of limb development, in normal and pathological conditions. Manipulation of chicken limb buds has been widely used in the past, mainly because of the ease of examination and manipulation, to postulate the first models of limb bud development leading to the identification of important regulatory genes and interactions. In addition to the chicken model, functional genetics has made great advances thanks to spontaneous and engineered loss- and gain-of-function mutant mouse strains, and recently with the advent of the zebrafish embryos as animal models.
In this chapter, we illustrate the pathways centred on the master transcription factor p63, and discuss the mechanisms by which these pathways impact on the regulation of signalling molecules controlling growth and patterning of the normal limb bud. Based on available knowledge, we propose how signalling networks are misregulated in the split hand foot malformation (SHFM) and related developmental conditions, and indicate emerging functions of the FGF8 and Wnt5a diffusible molecules.
Around the embryonic age E8.0 in the mouse, limb buds are initiated as four lumps of mesenchymal cells covered by ectoderm, protruding from the main body axis at approximately the position of somites 6–11 (the forelimbs, FL) and somites 24–27 (the hindlimbs, HL). The limb buds are paired along the cephalo-caudal axis and develop at the same fixed locations on this body axis (Figure 1A). How are their positions defined?
Schematic representation of limb development with embryonic timeline for chick wing and mouse forelimb. A) Representation of the prospective limb territories in a stage 14/8 chick (Hamburger-Hamilton stages, HH))/mouse embryo. The forelimbs (FL) and hindlimbs (HL) derive from discrete regions of the lateral plate mesoderm (LPM).
It has been proposed that the position of several dorsal organs along the cephalo-caudal axis, their identity and timing of appearance depend on the expression of specific sets of
A key signalling molecule for limb initiation is FGF10, a member of the FGF family of diffusible peptides. The
The expression of
The current model considers that, shortly after gastrulation, a re-epithelization of mesodermal cells occurs so that the entire embryo is essentially epithelial, including also the notochord, the somites, the intermediate mesoderm and the lateral plate mesoderm (LPM). At stage HH 13 in the chick, before limb initiation, the somatopleure displays epithelial rather than mesenchymal features. The LPM of the limb field starts out as an epithelium and ultimately generates limb-bud mesenchyme through a process termed epithelial-mesenchymal transition (EMT) [7] (Figure 1B). In embryos null for
The FL and HL of all vertebrate species are evidently different (e.g., wing vs. leg in the chick embryo, pectoral vs. pelvic fins in fish embryos, arms vs. legs in primates, etc.). The specification of limb-type identity and morphology is established before overt limb initiation. A large body of evidence indicates that two transcription factors of the T-box family participate in the early definition of limb-type identity:
However, although only expressed in FL and HL, respectively,
A signalling molecule known to act upstream of
The mechanism through which RA controls limb development has been widely debated [21], but clear results have only been produced in recent years [17, 19, 22, 24 - 27]. Mouse and zebrafish embryos null for the gene
The limb skeleton is laid down as five cartilage skeletal elements, not just the three referred to as stylopod (humerus/femur), zeugopod (radius-ulna/tibia-fibula), and autopod (digits); in fact two carpal regions between zeugopod and autopod are present, that initially have the same size as the other segments but then grow substantially less.
P-D extension and patterning is strictly linked to the signalling activity of the apical ectodermal ridge (AER), a morphologically distinct ectodermal thickening, extending along the entire A-P length, and lining the D-V border. The AER is present between E9 and E11 in the mouse embryo, consists of a pseudo-stratified epithelium in the chick and pluri-stratified epithelium in the mouse, and is a dynamic structure constantly undergoing morphogenetic changes [30 - 32].
The AER plays a fundamental role in promoting and regulating the outgrowth and patterning of the P-D limb axis. Experimental removal of the AER in chicken limb buds, causes a developmental arrest, and truncation of wing skeleton [33], meanwhile grafts of an AER to a recipient limb bud induces ectopic P-D outgrowth [34]. In 1993, Niswander identified FGFs as the relevant signals produced by the AER to induce P-D limb axis formation and extension. P-D extension and outgrowth is rescued by exogenous application of FGFs on AER removal [35]. This study provided the first molecular insights into how AER-FGF signalling controls in P–D extension and patterning. Four FGF ligands (4, -8, -9 and -17), are expressed by the AER cells with redundant functions during P–D patterning of mouse limb buds. Inactivation of the three FGFs expressed predominantly by the posterior AER (FGF4, -9, -17) does not alter limb-bud development [36]. In contrast, loss of
Other AER-expressed FGFs, in particular
The AER is first induced by the expression of
Old experiments showed that removing the AER at progressively earlier stages resulted in truncations of the limb skeleton at progressively more proximal levels [33]. Thus, the acquisition of a P-D positional identity seemed to depend on the time that proliferating/unspecified cells spend near the AER (the progress zone, PZ) under the influence of AER signals. According to the model proposed by Summerbell and Wolpert [45] the mesenchymal progenitor cells leaving the PZ early would acquire proximal identities, whereas the same cells leaving the PZ later would acquire progressively more distal identities (Figure 1D).
The great merit of this model has been to introduce the notion of time as an important factor in morphogenetic signalling; however, as a result of extensive molecular and cellular analyses, the original PZ model has been largely abandoned. First, the loss of proximal but not distal skeletal elements in
A third model has been proposed, in which P-D patterning is controlled by opposing diffusible signals, with RA functioning as a proximal signal and FGF acting as a distal signal [26]. Chick FL or HL ectopically exposed to RA or FGF8, or to antagonists of RAR or FGF receptor, display P-D fate changes that either expand or contract expression of proximal limb markers [23]. Further evidence has been recently provided, indicating that RA is needed for P–D patterning of both FL and HL [47, 48]. Using recombinant heterotopic chick limb transplantations they propose that the exposure to the activities of Wnt3a, FGF8 (distal molecule), and RA (proximal molecule) maintains the potential to form both proximal and distal structures. While these studies report the ability of RA treatment to reprogram distal limb mesenchyme to a proximal fate and to maintain early limb mesenchyme in a
Recently, Cunningham and colleagues [29] provide convincing evidence that RA is not required for limb patterning and that RA-FGF antagonism does not occur along the limb P-D axis, as originally proposed [26]. They suggest that both the initial expression of
The mammalian limb bud is typically pentadactylous, for example, the autopodium gives rise to five skeletal elements. The digit organization, from anterior (pre-axial, the thumbs) to posterior (post-axial, the little finger) is referred to as the A-P pattern. It has long been recognized that the embryonic tissue mainly implicated in the regulation of the A-P pattern is the zone of polarizing activity (ZPA) (Figure 1E). In 1956, a region within the posterior-proximal limb mesenchyme was identified, that when grafted in the anterior margin of host chicken wing buds results in mirror image duplications of all digits [49, 50]. The ZPA acts as a signalling centre and specifies positional information in the limb-bud mesenchyme by secreting the diffusible molecule Sonic Hedgehog (SHH). Within the limb bud mesenchyme, SHH is present in a posterior (high) to anterior (low) gradient [51, 52]. Genetic studies indicate that the time spent expressing
SHH signalling is translated into an intracellular, anterior (high) to posterior (low), gradient of the transcriptional repressor Gli3R within the limb mesenchyme [67]. Upon binding to the receptor Patched, SHH counteracts the conversion of Gli3 full-length into its cleaved repressor form. The Gli3R gradient is then required to establish the polarized expression of other genes involved in A-P patterning, and ultimately is translated into digit pattern, in ways not fully clarified [24, 57 - 61].
Further genetic studies in mouse and zebrafish embryos have implicated also HAND2 in the activation of
An exhaustive illustration of this topic is beyond the scope of this chapter. Digit patterning has commonly been interpreted in the context of a gradient of expression of
Thus, a SHH gradient is translated into an inverse Gli3R gradient [24, 67]. However, between
This observation, rather than supporting the SHH gradient model, is consistent with a Turing-type model of digit patterning [68 - 70]. According to this model, dynamic interactions between activator and inhibitor molecules produce periodic patterns of spots or stripes, serving as a molecular pre-pattern for chondrogenesis. Although the core molecules of a self-organizing mechanism remain poorly known, potential candidates for molecular modulators of the system include the
The Turing’s model implies the activity of two diffusing and interacting molecules; however,
Finally, in spite of the major role played by posterior
The maintenance and propagation of
Dorsal-ventral (D-V) patterning is mainly organized via signalling by Wnt7a, a diffusible molecule of the Wnt-family expressed in the dorsal ectoderm. Wnt7a is both necessary and sufficient to dorsalize the limb, indeed the loss of
Wnt7a induces the expression of
Congenital limb malformations are relatively common, and are genetically and clinically heterogeneous, with a diverse spectrum in their epidemiology, aetiology and anatomy. They are often difficult to diagnose and categorize, because of their complex phenotypes and their association with other malformations and clinical symptoms. Many etiological factors have been suggested for limb anomalies, including inheritance of mutated genes, teratogenic drugs, environmental chemicals, ionizing radiation (atomic weapons, radioiodine and radiation therapy), infections, metabolic imbalance (e.g., maternal diabetes), or mechanical factors like amniotic band syndrome. With the advent of functional genetics, molecular pathways centred on disease genes are being unravelled.
A wide set of human congenital limb malformations can be attributed to defects in P-D development. In this chapter, we will attempt to link known disease-causing genes with their known or presumed function in the maintenance of the AER. We will focus on the genes for which more functional data are available: namely
P-D defect refer to absence or hypoplasia of distal structure of the limb with more or less normal proximal structures. The spectrum of P-D limb reduction anomalies ranges from very mild disorders, such as syndactyly, to very severe forms, such as phocomelia or amelia. The most frequent congenital limb malformations are syndactylies, characterized by the fusion of the soft tissues of fingers and toes with or without bone fusion. Syndactylies are due to the lack of apoptosis in the interdigital mesenchyme and may also occur isolated or with other symptoms in a syndrome [93].
Polydactylies are distinguished by the appearance of supernumerary digits or parts of them, which may be present as a complete duplication of a whole limb or as a duplication of single digits [94]. Pre-axial polydactyly with extra digits located on the side of the hand or of the thumb or postaxial polydactyly where the extra digit is found on the side of the hand or foot of the fifth digit are common isolated limb malformation traits. On molecular level, many forms of polydactyly have been shown to be more or less directly linked to the SHH signal transduction pathway, which play a major role in A-P patterning of the limb [95, 96].
Brachydactylies are defined by shortened digits and are classified on an anatomic and genetic background into five groups from A to E [93]. Isolated brachydactylies are often inherited in an autosomal dominant manner and are characterized by a high degree of phenotypic variability. Type-B brachydactylies are associated to mutation in the
A severe P-D arrest of the developing limb bud gives rise to phocomelia, characterized by undeveloped limbs [102]. Usually the upper limbs are not fully formed and sections of the “hands and arms may be missing”. Short arm bones, fused fingers and missing thumbs will often occur. Legs and feet are also affected. Individuals with phocomelia will often lack thigh bones, and the hands or feet may be abnormally small or appear as stumps due to their close attachment to the body. Phocomelia is a known negative effect of the administration of thalidomide to pregnant women, in use in the late 1950s/early 1960s, to treat morning sickness, although the mechanism of action of this teratogen remains controversial [103, 104].
Failure of formation of limb buds gives rise to amelia, the complete absence of one or more limbs. The most severe form of amelia is the tetra-amelia, characterized by the absence of all four limbs, associated with craniofacial, pulmonary and urogenital defects. This autosomal recessive disorder has been linked to mutations of the
SHFM, also known as ectrodactyly or lobster-claw malformation, is a congenital defect affecting predominantly the central rays of hands and/or feet. It may manifest either as an isolated trait or as part of syndromic conditions comprising other developmental disorders [105]. SHFM occurs with the incidence of about 1 in 18,000 live born infants and accounts for 8–17% of all limb malformations [106, 107]. SHFM is clinically heterogeneous, ranging from a relatively mild defect, such as hypoplasia of a single phalanx or syndactyly, to aplasia of one or more central digits (i.e., classical cleft, also known as lobster-claw anomaly).
Inter-individual and intra-familial variability of the SHFM is very high. Furthermore, variable expressivity of this feature can be so significant, that a different pattern of anomaly is seen in each limb of the same individual patient [93]. SHFM is mostly sporadic, although familial forms are known: in these cases an autosomal dominant transmission with reduced penetrance is the most common mode, but autosomal recessive and X-linked forms have been reported.
SHFM has been linked to (at least) six distinct loci [106] (Table 1). SHFM-I (MIM #183600) is the most frequent type and is linked to mutations and/or deletions/rearrangements of the
SHFM type-III (MIM# 600095) is associated with duplications/rearrangements around the
Mutations of p63 are associated to SHFM type-IV (MIM #605289), a condition in which ectrodactyly appears as an isolated non-syndromic disorder linked to mutations or chromosomal anomalies in the DBD or in the C-terminal domain of p63
SHFM type-VI (MIM #225300) is the only autosomal recessive form of this malformation, and is due to homozygous point mutations of the
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\tRearrangements 7q21.3-q22.1 | \n\t\t\t1 family | \n\t\t\tAutosomal dominant Autosomal recessive | \n\t\t\tSHFM | \n\t\t\tEEC, mental retardation, sensorineural deafness | \n\t\t\tCrackower et al. (1996) Marinoni et al. (1995) Shamseldin et al. (2012) | \n\t\t
\n\t\t\t\t | \n\t\t\tXq26 | \n\t\t\t1 family | \n\t\t\tX-linked recessive | \n\t\t\tSHFM, syndactyly, metacarpalhypoplasia, phalangeal hypoplasia | \n\t\t\t\n\t\t\t | Faiyaz ul Haque et al. (2005) | \n\t\t
\n\t\t\t\t | \n\t\t\tDuplication 10q24 | \n\t\t\t20% | \n\t\t\tAutosomal dominant | \n\t\t\tSHFM, triphalangeal and/ orduplicated thumbs | \n\t\t\t\n\t\t\t | de Mollerat et al. (2003) | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t10% non syndromic93% EEC syndromes | \n\t\t\tAutosomal dominant | \n\t\t\tSHFM | \n\t\t\tEEC, ADULT, LADD, CHARGE,VATER/mental retardation | \n\t\t\tvan Bokhoven et al. (2001) Ianakiev et al. (2000) | \n\t\t
\n\t\t\t\t | \n\t\t\tDeletion 2q31 | \n\t\t\t\n\t\t\t | Autosomal dominant | \n\t\t\tSHFM | \n\t\t\tMental retardation, ectodermal and craniofacialfindings, orofacial clefting | \n\t\t\tGoodman et al. (2002) Del Campo et al. (1999) | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t3 family1 sporadic case | \n\t\t\tAutosomal recessive | \n\t\t\tSHFM, tibial aplasia/ hypoplasia | \n\t\t\t\n\t\t\t | Ugur and Tolun (2008) Blattner et al. (2012) Khan et al. (2012) | \n\t\t
Genetic alterations and SHFM-related phenotypes
SHFM – Split Hand/Foot Malformation, EEC – Ectrodactyly-Ectodermal dysplasia-Cleft lip/palate, ADULT – Acro-Dermato-Ungual-Lacrimal-Tooth syndrome, LADD – Lacrimo-Auriculo-Dento-Digital syndrome,
CHARGE syndrome (Coloboma of the eye, Heart defects, atresia of the nasal choanae, Retardation of growth and/or development, Genital and/or urinary abnormalities, Ear abnormalities and deafness), VATER association - vertebral anomalies, anal atresia, cardiovascular anomalies, tracheoesophageal fistula, renal and/or radial anomalies, limb defects.
SHFM type-IV and EEC are caused by mutations in the
p63 is expressed in the basal or progenitor layers of many epithelial tissues [138, 139], and is able to promote the epithelial stratification program typical of the mammalian skin, as well as to control proliferation and exit from the cell cycle of epidermal stem cells. For these activities p63 has been proposed as a master regulator of epidermal stem cell maintenance, proliferation and stratification [140]. The
Attempts to establish genotype–phenotype correlations are hampered by the variable clinical expressivity observed within families: SHFM type-IV and the EEC syndromes are due to mutations in the DNA-binding domain of p63 [129]. In these cases, all p63 isoforms are affected by the mutations. DBD mutants usually act as dominant-negative effectors and render the WT protein unable to bind DNA [129], explaining the dominant transmission of EEC. In contrast, the Hay Wells or ankyloblepharon-ectodermal dysplasia-cleft palate syndrome (AEC, MIM #106260) manifests with normal limbs but severe skin defects, and is typically associated with heterozygous missense mutations in the SAM domain of p63. The acro-dermato-ungual lacrimal tooth (ADULT, MIM #103285) syndrome is associated with a specific gain-of-function mutation R298Q/G in exon 8, affecting the DNA-binding domain of p63. Finally, both limb-mammary syndrome (LMS, MIM #603543), very similar to ADULT and EEC syndromes, and Rapp-Hodgkin syndrome (RHS, MIM #129400), resembling AEC, are due to p63 mutations.
Mice null for
Mouse models of the AEC syndrome have also been generated. Compared to EEC patients, AEC patients suffer of extreme skin fragility but have normal limbs. The AEC-mutant p63 proteins appear to act in a dominant-negative fashion. Mice were generated in which either ∆Np63a is down regulated in the skin, as a way to mimic the dominant negative action of mutant p63 in the AEC patients, or an AEC-mutant p63 was introduced [151 - 153]. These mice show severe skin erosion resembling the AEC phenotype, characterized by suprabasal epidermal proliferation, delayed terminal differentiation and altered basement membrane.
p63 mutations cause limb congenital phenotypes due to their impact on the AER Animal models show p63 is essential for epidermal stratification [90, 139, 154 - 156]. Considering that the AER is one of the earliest attempt of the embryonic (non-neural) ectoderm to organize into a multilayered epithelial tissue [157], it is not surprising that in
p63 is expected to control AER functions via transcriptional regulation of AER-restricted target genes [122, 154 - 156], indeed failure of AER stratification has also been associated with loss of expression of key morphogens for limb development, such as
In vitro, ∆Np63α induces transcription from the
Sp8 is a transcription factor of the Sp1 zinc-finger family [168, 169], homologous to the Drosophila
A number of observations suggest that p63 and Dlx proteins may regulate
Considering that the AER of
In further support of this, genome-wide CNV analyses on a Chinese family with SHFM type-III revealed a micro-duplication on chromosome 10q24 co-segregating with the SHFM phenotype [174]. This novel duplication contains two discontinuous DNA fragments: the minimal centromeric duplicated segment involves
Another pathway that links p63 and Dlx5 in the regulation of the
From the above considerations, it appears that numerous players in the p63-Dlx5 cascade may contribute to regulate
Several biochemical observations indicate that the ∆N- and TAp63 proteins are tightly regulated at post-translational level, via protein modification (phosphorylation, sumoylation and ubiquitination) and protein-protein interactions [126, 158, 179, 180]. Such modifications modulate the stability of the p63 protein, regulate its transcriptional activity and ultimately modulate its ability to orchestrate the timing of exit from the cell cycle and the dynamic of stratification of mammalian ectoderm [156, 181, 182].
Among the interacting or modifying proteins, MDM2 and p53 have been previously recognized [179, 180]. Recently we have shown that the peptidyl-prolyl
Another modification is acetylation, catalyzed by histone acetyl-transferase on lysine residues, and known to finely regulate p53 and p73 stability and transcriptional activity [184 - 189]. p73 is acetylated by p300 on lysine residues in the DBD and Oligomerization Domain [190] enhancing p73 ability to bind and activate proapototic target genes [191]. The p73-p300 interaction requires the prolyl-isomerase Pin1, which induces conformational changes following phosphorylation by the tyrosine kinase c-Abl [192]. Acetylation of p53 correlates with its stabilization and activation by antagonizing the activity of the MDM2 ubiquitin-ligase. It is interesting to note that a naturally occurring p63 mutation found in SHFM type-IV patients changes lysine 193 into glutamic acid (K193E) [125, 146, 147, 193]. Our unpublished data show that ∆Np63α is acetylated by p300 on the K193 residue, and that the K193E mutation prevents this modification (Guerrini and Restelli, unpublished) (Figure 2).
Schematic representation of the molecules and their interactions that regulate the stability of ΔNp63 during the AER stratification. p63 regulates its own stability via to the expression of
Expression of
An emerging role of FGF8 is the control of p63 stability in the AER cells. The AER of
p63 stability might also be regulated by another post-translational modification, namely acetylation by the p300 histone acetylase. c-Abl is a key regulator of the p53 family members and is known to be activated by treatment with FGF2 [192, 195 - 198]. Recently we have collected new data showing that FGF8 is able to stabilize ∆Np63α also via a novel pathway that requires the c-Abl tyrosine kinase and the protein acetylation by p300 (Guerrini and Restelli, unpublished). Thus, Dlx5, p63, Pin1, p300 and FGF8 participate in a time- and location-restricted regulatory loop that seems to be able to self-maintain and whose normal functioning is necessary for AER stratification, hence for normal extension and patterning of the limb buds. These results shed new light on the general molecular mechanisms at the basis of the SHFM and EEC limb malformations (Figure 2).
In an interesting set of experiments using cultured embryonic limbs, it was recently shown that the FGF/MAPK pathway establishes a high-distal to low-proximal gradient that controls the migration velocity of mesenchymal cells [199]. These cell movements enable continuous rearrangement of the cells at the distal tip of the limb bud. The effect of FGF/MAPK signalling emanating from the AER is different than the effect induced by Wnt5a in the limb bud. While Wnt5a induces directional movement of cells, FGF8 acts to induce rapid, yet disorganized, movements. Ultimately, the activity of both Wnt5a and FGF results in distal elongation (Figure 3). These observations suggest that FGF8 acts by inducing random movements, but with a higher velocity as cells move close to the source. A study proposes that the FGF pathway drives tail-bud elongation in the chick embryo by promoting random cell movements [200]. According to these authors FGF creates a gradient of cell motility and that the tail bud elongates by mass action of random cell movement at the posterior end of the embryo. Although this data indicate a similar mode of FGF action, cells in the limb bud additionally undergo oriented processes of cell division and directional movements under the influence of Wnt5a. This study indicates that it is the combined action of non-canonical WNT and FGF that integrates orientation and movement, consequently driving limb-bud elongation and thereby establishing a progenitor field of the proper dimensions for the subsequent patterning and morphogenesis of limb anatomy.
Schematic representation of the mesenchymal cells orientation and organization in the early limb bud. These cellular events are regulated by the combined activities of the WNT and FGF pathways. Wnt5A/Jnk/PCP pathway is necessary for the proper orientation of cell movements and cell division. In contrast, the FGF/MAPK signaling pathway, emanating from the AER establishes a gradient of cell velocity. The combination of oriented cell divisions and movements drives the P-D extension of the limb bud necessary for subsequent morphogenesis.
Wnt molecules are the vertebrate homologs of the Drosophila
Several members of the Wnt family of ligands are expressed in the ectoderm and mesenchyme of the developing limbs. At early stages,
Wnt ligands signal through the Frizzled (Fz) seven-pass trans-membrane receptors. In the “canonical” pathway, binding of Wnt ligands to Fz receptors represses the axin/glycogen synthase kinase-3β (GSK3β) complex, which in the absence of the ligand promotes the degradation of β-catenin via the ubiquitin pathway (reviewed in reference [204]). In Wnt-activated cells, cytoplasmic β-catenin accumulates and translocates to the nucleus where, in conjunction with T cell-specific factor/lymphoid enhancer binding factor-1 (Tcf/Lef1) transcription factors, activates transcription of target genes.
A role of “canonical” Wnt signalling in limb development has long been recognized [205]. In the chick limb bud, the Wnt/β-catenin pathway is essential for the induction and maintenance of the AER. Indeed, ectopic expression of Wnts in the interflank region prior to limb outgrowth induces ectopic
In the chick embryo
Wnt signalling has been implicated in removing “excess” tissue by programmed cell death and sculpting the limb shape. Indeed, the ability of BMP4 to induce cell death in the developing limb appears to be mediated by Dkk1 [213]. Loss of function of Dkk1 in mice results in the downregulation of
Wnt ligands can also activate two other branches of “non-canonical” pathways; one of these is known as the planar cell polarity (PCP) pathway, involves Fz receptors and dishevelled (Dvl), which interact with a distinct set of “PCP proteins” such as Van Gogh (Vang) and Prickle [217]. The PCP pathway recruits the small GTPases Rho and Cdc42 and the c-Jun N-terminal kinase (JNK) [218 - 220]. Initially identified in Drosophila, PCP establishes cellular polarity in the plane of an epithelium, perpendicular to the apical-basal orientation [217]. Studies in vertebrate model systems, including Xenopus and zebrafish, indicate that the PCP pathway also regulates a morphogenetic process known as convergent extension (CE). CE was first demonstrated in gastrulating
A role of “non-canonical” Wnt signalling during limb development has been recognized, although the cellular and molecular mechanisms are not fully clarified. The vertebrate
In addition to the PCP pathway, Wnt5a has been shown to activate at least two other non-canonical pathways. The first is known as the Wnt–Ca2+ pathway, in which Wnt5a stimulation induces Ca2+ release and subsequent activation of the Ca2+-sensitive kinases protein kinase C and Ca2+/calmodulin-dependent kinase [226, 227, 237, 238]. Over-expression of the core PCP proteins, Dvl and Pk, can also activate the Wnt–Ca2+ cascade in zebrafish and
Wnt5a can signal through different Fz receptors and co-receptors, but also via non-conventional tyrosine-kinase like receptors (Ror2 and Ryk) and can activate both the canonical and the non-canonical Wnt pathways [241, 242]. Activation of the canonical pathway entails the Lrp5 and Lrp6 co-receptors, which through cytoplasmic Dvl promote stabilization of β-catenin, its nuclear translocation and the activation of gene transcription [243, 244]. However, the distinct phenotypes observed between
In human, missense mutations in
In mice, the disruption of
Recent data [199] shed light on the cellular functions of Wnt5a during limb development. Inspired by the CE process and the PCP pathway, first described in lower organisms, the authors examined the proliferative expansion and migration of mesenchymal cells of the mouse limb bud; in particular, they examined the orientation of cell division and movements in response to Wnt5a. The combination of oriented cell divisions and movements drives the P-D elongation of the limb bud necessary to set the stage for subsequent morphogenesis. They show that Wnt5a via the JNK PCP pathway is needed for the proper orientation of mesenchymal cell movements and cell division reminiscent of CE in
Although these recent studies implicate Wnt5a in the oriented migration and cell division of the mesenchymal cells, little is known about the ectoderm cells, and in particular the AER cells, in which
Proposed model of regulation of the AER cell orientation. Dlx5 is known to regulate the transcription of both
An emerging theme in developmental biology is the importance of gene dosage and dynamic gene expression for correct morphogenesis [56]. Several
We propose that the portion of the p63 network that (direct or indirect) regulates
A gene-dosage effect combined with the co-expression of functionally redundant genes implies the existence of a threshold level to be maintained to assure AER stratification and signalling functions. Indeed, we have noted that the expression of
p63 is a master regulator of ectodermal cell proliferation, differentiation and stratification, and has a key role in the establishment of a positive loop that maintains
We illustrate that the p63-Dlx5 transcriptional regulation is at the centre of a pathway relevant for the SHFM malformation. The stability of p63 and the activation of the pathway appear to be under the regulation of FGF8, which in turn is regulated by the pathway. In addition to decipher this positive regulatory loop, these data support a model to attempt to explain the SHFM-III pathogenesis in terms of genome positional effects on the
FGF8 and Wnt5a provide instructions for mesoderm cells as to which direction and orientation to take, at the basis of AER formation and proper migration of mesenchymal cells. This instruction adopts molecules of the PCP pathway, most likely inducing convergent extension. While this has been recently demonstrated for the mesenchymal cells, the possibility that a Wnt5a-dependent PCP pathway is also functional for the organization and stratification of the AER cells remains to be addressed. Notably, data from the human malformation diseases and the corresponding animal models clearly suggest so.
The study of animal models of EEC and SHFM diseases has provided much of this knowledge, and will continue to do so. The big hope is that, once the pathways will be elucidated, we might be able to exploit diffusible molecules and attempt to correct the limb malformation defects. Preliminary attempts are being conducted on whole-organ cultured limbs.
A-P, anterior-posterior
D-V, dorsal-ventral
P-D, proximal-distal
SHH, sonic hedgehog
FGF, fibroblast growth factor
FL, forelimb
HL, hindlimb
ZPA, zone of polarizing activity
AER, apical ectodermal ridge
PZ, progress zone
KO, knock-out
PCP, planar cell polarity
CE, convergent extension
LPM, lateral plate mesoderm
Obesity is defined as a chronic disease that results in an increase in adipose tissue (AT) in the body as a result of the energy intake being more than the energy spent. Today, it has become a common and important health problem in both developed and developing countries due to various reasons such as changes in eating habits and inactivity [1, 2]. Obesity directly or indirectly affects national economies. Obesity causes an increase in the rates of noncommunicable diseases, damage to various organs, shortens the life span, and negatively affects the quality of life [3, 4, 5]. In the case of obesity, which is so important, the level of leptin increases. Leptin is an adipokine secreted in fat cells [6]. After leptin is released from the fat cell, it reaches the central nervous system via the blood, binds to its receptor, and reduces food intake through this receptor [7, 8]. Leptin is produced by the obese
Leptin (a fat tissue hormone), the
The mouse leptin gene size is 4.5 kilobases long containing 167 amino acids [15]. Regulation of the leptin gene initiator that controls leptin production, is mediated by glucocorticoid response elements, CCAAT/enhancers, cyclic adenosine monophosphate (cAMP), and specificity protein 1 (SP1) binding sites [17]. Studies have shown that human leptin is 84% similar to mouse leptin and 83% to rat leptin [18]. Besides, a positive correlation was found between plasma leptin concentrations and AT leptin mRNA levels. Therefore, as leptin mRNA increases, plasma leptin concentrations also increase [19].
Human leptin is produced from a gene on chromosome 7. The structure of human leptin, a 16 kilodalton protein, is in the form of a 4 α helical bundle coil, like class-I helical cytokines [20]. The most highly conserved amino acid extension is the GLDFIP sequence [21, 22]. Leptin, synthesized by adipocytes, is a hormone that notifies the brain of energy reserves and affects metabolism, reproduction, growth, and development processes [16, 22]. Circulating leptin levels act at the hypothalamic central level to increase energy expenditure and reduce food intake when the body is well nourished [23]. It induces the storage of triglycerides in AT and has an effect on appetite [7]. When plasma leptin levels increase, it sends a signal of satiety to the brain in the short term, while it sends information about the energy status in the long term [24]. It also influences hypothalamic neuropeptide signaling [25]. The main physiological role of leptin during periods of hunger is to regulate the neuroendocrine system. With regard to obesity, leptin levels rise with increasing adiposity [26]. Circulating leptin levels are high in obese, pointing to the importance of leptin resistance in the obese [24]. Leptin-deficient mice have been found to show neuroendocrine abnormalities similar to starving mice. Leptin supplementation causes neuroendocrine normalization and reduced food intake in leptin-deficient obese rodents and humans, thereby reversing obesity [10]. Mutations of the
It has been reported that leptin plays a proinflammatory role by increasing the inflammatory immune response, and this is associated with the pathogenesis of many complications of obesity [28]. It is noted that leptin can affect both adaptive and innate immunity by inducing proinflammatory response and thus playing a key role in regulating the pathogenesis of various autoimmune/inflammatory diseases [29]. It has been shown that as the degree of obesity increases in adults, the levels of plasminogen activator inhibitor-1 (PAI-1) and leptin, which is a proinflammatory marker, increase. It has been reported that it is responsible for the proinflammatory process, which is associated with an increased level of obesity [30]. Leptin regulates the functions of immune cells, such as natural killer cells, dendritic cells, neutrophils, eosinophils, macrophages, and basophils [23].
Effector systems that control energy intake and energy expenditure, hypothalamic control centers where leptin signals from different sources are received, and the size of AT mass are the regulatory steps of leptin synthesis [31]. The major sites of leptin mRNA expression are in the stomach, liver, and AT [32]. Leptin mRNA is also expressed at minor levels in the fetal tissue, placenta, heart, brain, and pituitary gland [18]. Leptin synthesized is generally related to the degree of adiposity. Larger adipocytes express more leptin genes than smaller adipocytes [33]. Mechanical stretching of the fat cell, determined by the amount of stored triglycerides, can generate signals to increase leptin synthesis [24]. In addition, in humans, uridine diphosphate N-acetylglucosamine (UDPGlcNAc) and hexosamine act as potential links between cell size and leptin content. Body mass index is positively correlated with the amount of UDPGlcNAc in subcutaneous AT [34].
The composition of the food, not the amount, affects leptin production [35]. The composition of a meal affects leptin levels; for example, low-fat and high-carb food causes increased leptin levels [36]. Compared to high-carbohydrate meals, high-fat meals lower circulating plasma leptin levels 24 hours after a meal [37]. It has been reported that meals rich in ω-6 polyunsaturated fatty acids (PUFA) increase leptin production [35]. It has been reported that the protein composition of a meal does not affect leptin production [38].
Gender differences have an effect on leptin production. Although there is no difference in leptin levels between girls and boys in the prepubertal period, leptin levels increase in girls and decrease in boys with puberty development [39, 40]. This is explained by the fact that with puberty, the amount of body fat in girls increases more than in boys, and testosterone suppresses leptin levels in boys [41]. In addition, the fact that the subcutaneous AT mass is significantly larger than the omental fat mass of women is also among the factors [39]. Reproductive hormones greatly affect leptin production. Androgenic hormones inhibit leptin synthesis, while estrogens stimulate leptin synthesis [42]. In one study, it was thought that increased estrogen concentrations caused an increase in leptin concentration, which may have been caused by leptin stimulating gonadotrophin releasing hormone (GnRH) synthesis and thus increasing estrogen synthesis [43]. In addition, chronic insomnia and an increase in melatonin concentrations have been reported to decrease plasma leptin concentrations [44].
The immune system has a role in regulating energy expenditure and AT lipolysis [45]. White adipose tissue (WAT) is the primary energy store; brown adipose tissue (BAT) is associated with heat production. Sympathetic activity in WAT is increased in conditions associated with decreased leptin synthesis/secretion, such as cold exposure and starvation. By the way, catecholamine and β-adrenoceptor agonists inhibit leptin production; this suppressive effect is mediated by β3-adrenoceptor agonists, which actively reduce leptin levels [46]. Leptin also causes sympathetic nervous system activation, resulting in regulatory feedback inhibition [47]. Intracerebroventricular injections of leptin have been noted to increase metabolic rates through increased norepinephrine release from sympathetic nerve terminals innervating BAT [48].
After a meal, plasma insulin and amino acid levels initiate the mammalian target of rapamycin (mTOR) pathway, which stimulates leptin biosynthesis via mechanisms involving the 5′/3′ untranslated region (UTR) [49]. Cyclic AMP activates cyclic AMP-activated exchange proteins (EPACs). Deletion of
Leptin antagonizes orexigenic pathways and stimulates anorexigenic pathways. Leptin exerts its general effects on the nervous system through these pathways [7]. Orexigenic neuropeptides that are down-regulated by leptin are orexins, agouti-related peptides, neuropeptide Y, and melanin-concentrating hormone. By the way, the anorexigenic neuropeptides upregulated by leptin are alpha-melanocyte-stimulating hormone, which acts on corticotropin-releasing hormone, cocaine and amphetamine-regulated transcript, and melanocortin-4 receptor (Figure 1) [31].
The leptin/Melanocortin pathway. ARC; the arcuate nucleus of the hypothalamus, POMC; proopiomelanocortin, Ob-R; leptin receptor, PVN; paraventricular nucleus, MSH; melanocyte-stimulating hormone (α-MSH,β-MSH,γ-MSH), MC4R; melanocortin-4 receptor, SIM1; single-minded 1 [
Glucocorticoids are long-term regulators of leptin expression [52, 53]. They increase leptin mRNA levels by acting on adipocytes;
Lactates and hexoses also increase leptin secretion [56]. Because leptin secretion requires ATP, suppressing glucose uptake suppresses leptin secretion. When the energy supply is low, food is needed to increase it. Glucose, the cellular sensor of energy stock, stimulates leptin gene expression and secretion in both muscle and AT via hexosamine biosynthetic [57]. Insulin lowers blood sugar when glucose levels rise above normal and also increases leptin promoter activity [58]. No increase in leptin mRNA levels was observed after adipocytes were incubated with insulin for 1–2 hours, but an increase in leptin release was observed [54].
Regulation of tumor necrosis factor-alpha(TNFα) and leptin may be interdependent and similar as they have comparable functions such as suppressing lipid synthesis, reducing food intake, and stimulating lipolysis [59]. Leptin limits AT mass. TNFα has the role of stimulating leptin secretion from mature human adipocytes. TNFα therapy has been shown to cause increased leptin levels in humans [60].
Leptin receptors are in the family of cytokine receptors. There are six isoforms encoded by the
In gastric chief cells (also known as zymogenic cell or peptic cell), leptin is released upon sensing gastrin and secretin and it is actively inhibited by cholecystokinin [68]. The binding of leptin to its receptor activates the Janus kinase (JAK) signal transducer and activator of the transcription 3 (STAT3) signal transduction pathway, inducing cellular anti-apoptotic events, angiogenesis, and proliferation [69, 70]. The gene product also interacts with IL-1 and Notch cascade, which are involved in promoting tumor growth. Some other pathways activated are mitogen-activated protein kinases/extracellular signal-regulated kinases pathway (MAPK/ERK), phosphatidylinositol 3 kinase (PI3K), 5′AMP activated protein kinase (AMPK), and mTOR [71].
After leptin binds to its receptor on the cell membrane, it acts by stimulating the following signaling pathways in the cell.
In the activation of this signaling pathway, leptin is activated by phosphorylation of its receptor, binding of STAT3, and phosphorylated by JAK2 [72]. Activated STAT3 enters the nucleus and binds to target sites on DNA; and so cellular activity takes place (Figure 2).
Leptin signaling pathways. POMC;pro-opiomelanocortin, SOCS3; intracellular suppressor of cytokine signal 3, PTP1B; protein tyrosine phosphatase 1B, SHP2; tyrosine phosphatase 2, IRS; (insulin receptor substrate)/PI3K; (phosphoinositol 3 kinase), FoxO1; (forkhead box O1) and mTOR; (mammalian target of rapamycin), S6K; ribosomal S6 kinase, ERK; extracellular signal-regulated kinase [
Stimulation of the leptin receptor activates the protein tyrosine phosphatase 2 (SHP2), contributing to the activation of the ERK signaling pathway, resulting in a cellular response [72, 74].
As a result of the stimulation of the receptor, it provides activation of STAT5 by JAK2. Activated STAT5 acts by binding to the target region in the nucleus [75].
Leptin also activates the IRS (insulin receptor substrate)/PI3K (phosphoinositol 3 kinase) pathway [76, 77] (Figure 2). The SH2B1 adapter protein mediates activation of the PI3K pathway by linking the JAK2 and IRS protein via the SH2 domain [78]. In addition, the IRS/PI3K pathway proceeds in two substeps, FoxO1 (forkhead box O1) and mTOR (the mammalian target of rapamycin) (Figure 2).
Oxidative stress results from an imbalance between reactive oxygen species (ROS) and the organism’s antioxidant defense. Due to oxidative stress, peroxidative damage to macromolecules and membranes of cells occurs in organisms. Moreover, their metabolic activities in cell components are impaired. Known to tissue and organ pathologies occur in the presence of oxidative stress in the organism [79, 80, 81, 82, 83, 84, 85, 86]. It has been reported that high leptin levels can induce the formation of ROS, mainly due to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation [87, 88]. However, leptin replacement therapy has also been shown to significantly downregulate NADPH oxidase expression in AT of leptin-deficient
Free radical-mediated peroxidation of membrane lipids loses its integrity, increasing membrane fluidity and permeability. The lipid peroxidation process is one of the oxidative conversions of PUFAs to products known as malondialdehyde (MDA). MDA is a highly toxic molecule and its secondary products such as thiobarbituric acid reactive agent are commonly used to assess lipid peroxidation [90, 91, 92, 93, 94]. Glutathione (GSH) is an important nonenzymatic component of the cellular antioxidant system and plays an important role in ROS antioxidation [95, 96, 97]. It has been suggested that leptin modulates the activity of various antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) in patients with leptin gene mutations [98]. Leptin production is increased by overexpression of the endogenous antioxidant enzyme catalase and correlates with markers of oxidative stress and inflammatory in
Hyperleptinemia is the most prominent feature of obesity and is likely to be involved in the pathogenesis of obesity-related pathologies [19]. Studies in obese individuals have shown a correlation between leptin levels and oxidative stress parameters such as nitric oxide (NO), superoxide anion (O2−.), peroxynitrite, MDA, hydroperoxides, protein carbonyl (PC) contents, GSH, and SOD [106, 107, 108]. Studies in which hyperleptinemia was induced by the administration of exogenous leptin in nonobese animals suggest that leptin increases the level of systemic oxidative stress [109, 110]. In addition, some
Recently, some studies have shown that there is an important relationship between leptin and apoptosis; such as in a study, it was determined that there is a leptin receptor (Ob-R) on the surface of breast cancer cells. Leptin is thought to stimulate these cancer cells with various effects, such as migration and spread. It has been determined that the expression of Ob-R increases as the tumor grows [117]. Another study reported that leptin may affect the risk of breast cancer by increasing estrogen synthesis [118, 119]. It is believed that leptin, which is associated with breast cancer, exerts this effect by affecting the JAK/STAT and MAPK pathways, as well as increasing the transcriptional expression of vascular endothelial growth factor receptor-2 (VEGFR-2) and VEGF [120]. In another study, it was determined that the ratio between leptin and adiponectin is important in regulating the development of breast cancer [121]. Again, in some studies, it has been determined that leptin triggers cell proliferation by stimulating the MAPK pathway in breast cancer cells [122]. It has been observed that leptin also stimulates estrogen receptors via MAPK in breast cancer cells [123].
It has also been reported that leptin is associated with lung cancer. Ob-Ra and Ob-Rb were expressed on the surface of lung cancer cells. It has been determined that leptin plays a role in the development and progression of lung cancer as well as its migration [124, 125]. It has been reported that leptin also increases cytokine production by stimulating JAK/STAT3, PI3K/AKT, and MEK1/2 signaling pathways [126]. In a study, it was determined that the removal of leptin from the medium in non-small cell lung cancer cell lines inactivates the JAK/STAT3 and Notch signaling pathways, thus stopping cell proliferation and stimulating apoptosis (Figure 3) [128].
Leptin signaling. AKT; protein kinase B, GRB2; growth factor receptor-bound protein 2, JAK; Janus kinase, Ob-R; leptin receptor, MAPK; mitogen-activated protein kinase, FOS, JUN, JUNB; GENES PI3K; phosphatidylinositol 3 kinase, SHP2; Src homology 2-containing tyrosine phosphatase, STAT3; signal transducer and activator of transcription 3 [
In some studies, leptin has been shown to stimulate cell proliferation and prevent apoptosis by activation of the PI3K/AKT signaling pathway in thyroid cancer cells [129, 130].
Leptin has been reported to be associated with liver cancer [131]. In one study, they reported elevated leptin levels in patients with hepatocellular carcinoma [132]. It has been determined that leptin increases liver fibrosis by stimulating transforming growth factor-β (TGF-β) synthesis and release. It has also been reported that leptin stimulates the production of a tissue inhibitor of metalloproteinase1 through the JAK/STAT pathway in hepatic stellate cells [133]. Leptin has also been reported to cause the proliferation of hepatocellular cancer cells by altering cyclin D1,
Another study demonstrated the presence of leptin receptors on the surface of human colon tumor cells [135]. In colorectal cancer, leptin acts as a very potent mitogen and antiapoptotic cytokine. It has been determined that leptin plays a role in many stages of this type of cancer [136, 137]. It has been reported that leptin increase is proportional to tumor development and tumor metastasis [138]. It has been determined that leptin exerts this effect via JAK and the extracellular signal-regulating kinase (ERK) pathway [139]. In another study, they found that leptin prevented apoptosis and stimulated cell proliferation via PI3K/AKT/mTOR pathways in colon cancer cells (Figure 4) [141].
Intracellular signaling pathways of leptin in connection with cellular proliferation. AKT: Protein kinase B/serine–threonine kinase, ERK: Extracellular signal-regulated kinase, JAK: Janus kinases, MAPK: Mitogen-activated protein kinase, MEK: Mitogen-activated protein kinase, mTOR: Mechanistic/mammalian target of rapamycin, Ob-R: Leptin receptor, PI3K: Phosphatidylinositol3-kinase, STAT: Signal transducer and activator of transcription [
In a study conducted in ovarian cancer, it was determined that leptin is directly related to PI3K/AKT signaling pathways, antiapoptotic proteins XIAP (X-linked inhibitor of apoptosis), and Bcl-XL. By activating these pathways, leptin has been reported to suppress cell proliferation and apoptosis [142]. In another study, it was determined that leptin administration to epithelial ovarian cancer cells increases cancer cell proliferation in a dose-dependent manner, and this increase is done by suppressing genes that inhibit cell proliferation [143].
An increase in leptin levels has been found to be associated with the development of prostate cancer [144]. It has been determined that leptin suppresses apoptosis in prostate cancer cells. Leptin has been reported to exert this effect via the MAPK and PI3K pathways [145]. It has also been reported that leptin stimulates the increase of (hypoxia-inducible factor 1), which is known to play an important role in carcinogenesis in prostate cancer cell culture and stimulates the spread and adhesion of these cells [146].
In conclusion, leptin is adiponectin released from AT. As a result of studies, it has been reported that leptin is associated with oxidative stress and apoptosis, as well as regulating body energy metabolism and food intake. Knowing the release of leptin, its receptor, cellular effects, and especially the relationship between oxidative stress and apoptosis will guide various studies on this subject.
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Cárdenas-Aguayo, M. del C. Silva-Lucero, M. Cortes-Ortiz,\nB. Jiménez-Ramos, L. Gómez-Virgilio, G. Ramírez-Rodríguez, E. Vera-\nArroyo, R. Fiorentino-Pérez, U. García, J. Luna-Muñoz and M.A.\nMeraz-Ríos",authors:[{id:"42225",title:"Dr.",name:"Jose",middleName:null,surname:"Luna-Muñoz",slug:"jose-luna-munoz",fullName:"Jose Luna-Muñoz"},{id:"114746",title:"Dr.",name:"Marco",middleName:null,surname:"Meraz-Ríos",slug:"marco-meraz-rios",fullName:"Marco Meraz-Ríos"},{id:"169616",title:"Dr.",name:"Maria del Carmen",middleName:null,surname:"Cardenas-Aguayo",slug:"maria-del-carmen-cardenas-aguayo",fullName:"Maria del Carmen Cardenas-Aguayo"},{id:"169857",title:"Dr.",name:"Maria del Carmen",middleName:null,surname:"Silva-Lucero",slug:"maria-del-carmen-silva-lucero",fullName:"Maria del Carmen Silva-Lucero"},{id:"169858",title:"Dr.",name:"Maribel",middleName:null,surname:"Cortes-Ortiz",slug:"maribel-cortes-ortiz",fullName:"Maribel Cortes-Ortiz"},{id:"169859",title:"Dr.",name:"Berenice",middleName:null,surname:"Jimenez-Ramos",slug:"berenice-jimenez-ramos",fullName:"Berenice Jimenez-Ramos"},{id:"169860",title:"Dr.",name:"Laura",middleName:null,surname:"Gomez-Virgilio",slug:"laura-gomez-virgilio",fullName:"Laura Gomez-Virgilio"},{id:"169861",title:"Dr.",name:"Gerardo",middleName:null,surname:"Ramirez-Rodriguez",slug:"gerardo-ramirez-rodriguez",fullName:"Gerardo Ramirez-Rodriguez"},{id:"169862",title:"Dr.",name:"Eduardo",middleName:null,surname:"Vera-Arroyo",slug:"eduardo-vera-arroyo",fullName:"Eduardo Vera-Arroyo"},{id:"169863",title:"Dr.",name:"Rosana Sofia",middleName:null,surname:"Fiorentino-Perez",slug:"rosana-sofia-fiorentino-perez",fullName:"Rosana Sofia Fiorentino-Perez"},{id:"169864",title:"Dr.",name:"Ubaldo",middleName:null,surname:"Garcia",slug:"ubaldo-garcia",fullName:"Ubaldo Garcia"}]},{id:"58070",doi:"10.5772/intechopen.72427",title:"MRI Medical Image Denoising by Fundamental Filters",slug:"mri-medical-image-denoising-by-fundamental-filters",totalDownloads:2564,totalCrossrefCites:17,totalDimensionsCites:30,abstract:"Nowadays Medical imaging technique Magnetic Resonance Imaging (MRI) plays an important role in medical setting to form high standard images contained in the human brain. MRI is commonly used once treating brain, prostate cancers, ankle and foot. The Magnetic Resonance Imaging (MRI) images are usually liable to suffer from noises such as Gaussian noise, salt and pepper noise and speckle noise. So getting of brain image with accuracy is very extremely task. An accurate brain image is very necessary for further diagnosis process. During this chapter, a median filter algorithm will be modified. Gaussian noise and Salt and pepper noise will be added to MRI image. A proposed Median filter (MF), Adaptive Median filter (AMF) and Adaptive Wiener filter (AWF) will be implemented. The filters will be used to remove the additive noises present in the MRI images. The noise density will be added gradually to MRI image to compare performance of the filters evaluation. The performance of these filters will be compared exploitation the applied mathematics parameter Peak Signal-to-Noise Ratio (PSNR).",book:{id:"6144",slug:"high-resolution-neuroimaging-basic-physical-principles-and-clinical-applications",title:"High-Resolution Neuroimaging",fullTitle:"High-Resolution Neuroimaging - Basic Physical Principles and Clinical Applications"},signatures:"Hanafy M. Ali",authors:[{id:"213318",title:"Dr.",name:"Hanafy",middleName:"M.",surname:"Ali",slug:"hanafy-ali",fullName:"Hanafy Ali"}]},{id:"41589",doi:"10.5772/50323",title:"The Role of the Amygdala in Anxiety Disorders",slug:"the-role-of-the-amygdala-in-anxiety-disorders",totalDownloads:9671,totalCrossrefCites:4,totalDimensionsCites:28,abstract:null,book:{id:"2599",slug:"the-amygdala-a-discrete-multitasking-manager",title:"The Amygdala",fullTitle:"The Amygdala - A Discrete Multitasking Manager"},signatures:"Gina L. Forster, Andrew M. Novick, Jamie L. Scholl and Michael J. Watt",authors:[{id:"145620",title:"Dr.",name:"Gina",middleName:null,surname:"Forster",slug:"gina-forster",fullName:"Gina Forster"},{id:"146553",title:"BSc.",name:"Andrew",middleName:null,surname:"Novick",slug:"andrew-novick",fullName:"Andrew Novick"},{id:"146554",title:"MSc.",name:"Jamie",middleName:null,surname:"Scholl",slug:"jamie-scholl",fullName:"Jamie Scholl"},{id:"146555",title:"Dr.",name:"Michael",middleName:null,surname:"Watt",slug:"michael-watt",fullName:"Michael Watt"}]},{id:"26258",doi:"10.5772/28300",title:"Excitotoxicity and Oxidative Stress in Acute Ischemic Stroke",slug:"excitotoxicity-and-oxidative-stress-in-acute-ischemic-stroke",totalDownloads:7157,totalCrossrefCites:6,totalDimensionsCites:25,abstract:null,book:{id:"931",slug:"acute-ischemic-stroke",title:"Acute Ischemic Stroke",fullTitle:"Acute Ischemic Stroke"},signatures:"Ramón Rama Bretón and Julio César García Rodríguez",authors:[{id:"73430",title:"Prof.",name:"Ramon",middleName:null,surname:"Rama",slug:"ramon-rama",fullName:"Ramon Rama"},{id:"124643",title:"Prof.",name:"Julio Cesar",middleName:null,surname:"García",slug:"julio-cesar-garcia",fullName:"Julio Cesar García"}]},{id:"62072",doi:"10.5772/intechopen.78695",title:"Brain-Computer Interface and Motor Imagery Training: The Role of Visual Feedback and Embodiment",slug:"brain-computer-interface-and-motor-imagery-training-the-role-of-visual-feedback-and-embodiment",totalDownloads:1439,totalCrossrefCites:13,totalDimensionsCites:23,abstract:"Controlling a brain-computer interface (BCI) is a difficult task that requires extensive training. Particularly in the case of motor imagery BCIs, users may need several training sessions before they learn how to generate desired brain activity and reach an acceptable performance. A typical training protocol for such BCIs includes execution of a motor imagery task by the user, followed by presentation of an extending bar or a moving object on a computer screen. In this chapter, we discuss the importance of a visual feedback that resembles human actions, the effect of human factors such as confidence and motivation, and the role of embodiment in the learning process of a motor imagery task. Our results from a series of experiments in which users BCI-operated a humanlike android robot confirm that realistic visual feedback can induce a sense of embodiment, which promotes a significant learning of the motor imagery task in a short amount of time. We review the impact of humanlike visual feedback in optimized modulation of brain activity by the BCI users.",book:{id:"6610",slug:"evolving-bci-therapy-engaging-brain-state-dynamics",title:"Evolving BCI Therapy",fullTitle:"Evolving BCI Therapy - Engaging Brain State Dynamics"},signatures:"Maryam Alimardani, Shuichi Nishio and Hiroshi Ishiguro",authors:[{id:"11981",title:"Prof.",name:"Hiroshi",middleName:null,surname:"Ishiguro",slug:"hiroshi-ishiguro",fullName:"Hiroshi Ishiguro"},{id:"231131",title:"Dr.",name:"Maryam",middleName:null,surname:"Alimardani",slug:"maryam-alimardani",fullName:"Maryam Alimardani"},{id:"231134",title:"Dr.",name:"Shuichi",middleName:null,surname:"Nishio",slug:"shuichi-nishio",fullName:"Shuichi Nishio"}]}],mostDownloadedChaptersLast30Days:[{id:"29764",title:"Underlying Causes of Paresthesia",slug:"underlying-causes-of-paresthesia",totalDownloads:192666,totalCrossrefCites:3,totalDimensionsCites:7,abstract:null,book:{id:"1069",slug:"paresthesia",title:"Paresthesia",fullTitle:"Paresthesia"},signatures:"Mahdi Sharif-Alhoseini, Vafa Rahimi-Movaghar and Alexander R. 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Precise anatomical description along with a correct characterization of the component structures is essential for understanding its functions.",book:{id:"6331",slug:"hypothalamus-in-health-and-diseases",title:"Hypothalamus in Health and Diseases",fullTitle:"Hypothalamus in Health and Diseases"},signatures:"Miana Gabriela Pop, Carmen Crivii and Iulian Opincariu",authors:null},{id:"57103",title:"GABA and Glutamate: Their Transmitter Role in the CNS and Pancreatic Islets",slug:"gaba-and-glutamate-their-transmitter-role-in-the-cns-and-pancreatic-islets",totalDownloads:3478,totalCrossrefCites:3,totalDimensionsCites:9,abstract:"Glutamate and gamma-aminobutyric acid (GABA) are the major neurotransmitters in the mammalian brain. Inhibitory GABA and excitatory glutamate work together to control many processes, including the brain’s overall level of excitation. The contributions of GABA and glutamate in extra-neuronal signaling are by far less widely recognized. In this chapter, we first discuss the role of both neurotransmitters during development, emphasizing the importance of the shift from excitatory to inhibitory GABAergic neurotransmission. The second part summarizes the biosynthesis and role of GABA and glutamate in neurotransmission in the mature brain, and major neurological disorders associated with glutamate and GABA receptors and GABA release mechanisms. The final part focuses on extra-neuronal glutamatergic and GABAergic signaling in pancreatic islets of Langerhans, and possible associations with type 1 diabetes mellitus.",book:{id:"6237",slug:"gaba-and-glutamate-new-developments-in-neurotransmission-research",title:"GABA And Glutamate",fullTitle:"GABA And Glutamate - New Developments In Neurotransmission Research"},signatures:"Christiane S. Hampe, Hiroshi Mitoma and Mario Manto",authors:[{id:"210220",title:"Prof.",name:"Christiane",middleName:null,surname:"Hampe",slug:"christiane-hampe",fullName:"Christiane Hampe"},{id:"210485",title:"Prof.",name:"Mario",middleName:null,surname:"Manto",slug:"mario-manto",fullName:"Mario Manto"},{id:"210486",title:"Prof.",name:"Hiroshi",middleName:null,surname:"Mitoma",slug:"hiroshi-mitoma",fullName:"Hiroshi Mitoma"}]},{id:"35802",title:"Cross-Cultural/Linguistic Differences in the Prevalence of Developmental Dyslexia and the Hypothesis of Granularity and Transparency",slug:"cross-cultural-linguistic-differences-in-the-prevalence-of-developmental-dyslexia-and-the-hypothesis",totalDownloads:3601,totalCrossrefCites:2,totalDimensionsCites:7,abstract:null,book:{id:"673",slug:"dyslexia-a-comprehensive-and-international-approach",title:"Dyslexia",fullTitle:"Dyslexia - A Comprehensive and International Approach"},signatures:"Taeko N. 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Testosterone affects nitric oxide (NO) production and phosphodiesterase type 5 (PDE-5) expression in the corpus cavernosum through molecular pathways, preserves smooth muscle contractility by regulating both contraction and relaxation, and maintains the structure of the corpus cavernosum. Interestingly, testosterone deficiency has relationship to neurological diseases, which leads to ED. Testosterone replacement therapy is widely used to treat patients with testosterone deficiency; however, this treatment might also induce some problems. Basic research suggests that PDE-5 inhibitors, L-citrulline, and/or resveratrol therapy might be effective therapeutic options for testosterone deficiency-induced ED. Future research should confirm these findings through more specific experiments using molecular tools and may shed more light on endocrine-related ED and its possible treatments.",book:{id:"5994",slug:"sex-hormones-in-neurodegenerative-processes-and-diseases",title:"Sex Hormones in Neurodegenerative Processes and Diseases",fullTitle:"Sex Hormones in Neurodegenerative Processes and Diseases"},signatures:"Tomoya Kataoka and Kazunori Kimura",authors:[{id:"219042",title:"Ph.D.",name:"Tomoya",middleName:null,surname:"Kataoka",slug:"tomoya-kataoka",fullName:"Tomoya Kataoka"},{id:"229066",title:"Prof.",name:"Kazunori",middleName:null,surname:"Kimura",slug:"kazunori-kimura",fullName:"Kazunori Kimura"}]}],onlineFirstChaptersFilter:{topicId:"18",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81998",title:"Understanding the Neuropathophysiology of Psychiatry Disorder Using Transcranial Magnetic Stimulation",slug:"understanding-the-neuropathophysiology-of-psychiatry-disorder-using-transcranial-magnetic-stimulatio",totalDownloads:0,totalDimensionsCites:null,doi:"10.5772/intechopen.103748",abstract:"Transcranial magnetic stimulation (TMS) is a safe and non-invasive tool that allows researchers to probe and modulate intracortical circuits. The most important aspect of TMS is its ability to directly stimulate the cortical neurons, generating action potentials, without much effect on intervening tissue. This property can be leveraged to provide insight into the pathophysiology of various neuropsychiatric disorders. Using multiple patterns of stimulations (single, paired, or repetitive), different neurophysiological parameters can be elicited. Various TMS protocol helps in understanding the neurobiological basis of disorder and specific behaviors by allowing direct probing of the cortical areas and their interconnected networks. While single-pulse TMS can provide insight into the excitability and integrity of the corticospinal tract, paired-pulse TMS (ppTMS) can provide further insight into cortico-cortical connections and repetitive TMS (rTMS) into cortical mapping and modulating plasticity.",book:{id:"11742",title:"Neurophysiology",coverURL:"https://cdn.intechopen.com/books/images_new/11742.jpg"},signatures:"Jitender Jakhar, Manish Sarkar and Nand Kumar"},{id:"81646",title:"Cortical Plasticity under Ketamine: From Synapse to Map",slug:"cortical-plasticity-under-ketamine-from-synapse-to-map",totalDownloads:15,totalDimensionsCites:0,doi:"10.5772/intechopen.104787",abstract:"Sensory systems need to process signals in a highly dynamic way to efficiently respond to variations in the animal’s environment. For instance, several studies showed that the visual system is subject to neuroplasticity since the neurons’ firing changes according to stimulus properties. This dynamic information processing might be supported by a network reorganization. Since antidepressants influence neurotransmission, they can be used to explore synaptic plasticity sustaining cortical map reorganization. To this goal, we investigated in the primary visual cortex (V1 of mouse and cat), the impact of ketamine on neuroplasticity through changes in neuronal orientation selectivity and the functional connectivity between V1 cells, using cross correlation analyses. We found that ketamine affects cortical orientation selectivity and alters the functional connectivity within an assembly. These data clearly highlight the role of the antidepressant drugs in inducing or modeling short-term plasticity in V1 which suggests that cortical processing is optimized and adapted to the properties of the stimulus.",book:{id:"11374",title:"Sensory Nervous System - Computational Neuroimaging Investigations of Topographical Organization in Human Sensory Cortex",coverURL:"https://cdn.intechopen.com/books/images_new/11374.jpg"},signatures:"Ouelhazi Afef, Rudy Lussiez and Molotchnikoff Stephane"},{id:"81582",title:"The Role of Cognitive Reserve in Executive Functioning and Its Relationship to Cognitive Decline and Dementia",slug:"the-role-of-cognitive-reserve-in-executive-functioning-and-its-relationship-to-cognitive-decline-and",totalDownloads:24,totalDimensionsCites:0,doi:"10.5772/intechopen.104646",abstract:"In this chapter, we explore how cognitive reserve is implicated in coping with the negative consequences of brain pathology and age-related cognitive decline. Individual differences in cognitive performance are based on different brain mechanisms (neural reserve and neural compensation), and reflect, among others, the effect of education, occupational attainment, leisure activities, and social involvement. These cognitive reserve proxies have been extensively associated with efficient executive functioning. We discuss and focus particularly on the compensation mechanisms related to the frontal lobe and its protective role, in maintaining cognitive performance in old age or even mitigating the clinical expression of dementia.",book:{id:"11742",title:"Neurophysiology",coverURL:"https://cdn.intechopen.com/books/images_new/11742.jpg"},signatures:"Gabriela Álvares-Pereira, Carolina Maruta and Maria Vânia Silva-Nunes"},{id:"81488",title:"Aggression and Sexual Behavior: Overlapping or Distinct Roles of 5-HT1A and 5-HT1B Receptors",slug:"aggression-and-sexual-behavior-overlapping-or-distinct-roles-of-5-ht1a-and-5-ht1b-receptors",totalDownloads:20,totalDimensionsCites:0,doi:"10.5772/intechopen.104872",abstract:"Distinct brain mechanisms for male aggressive and sexual behavior are present in mammalian species, including man. However, recent evidence suggests a strong connection and even overlap in the central nervous system (CNS) circuitry involved in aggressive and sexual behavior. The serotonergic system in the CNS is strongly involved in male aggressive and sexual behavior. In particular, 5-HT1A and 5-HT1B receptors seem to play a critical role in the modulation of these behaviors. The present chapter focuses on the effects of 5-HT1A- and 5-HT1B-receptor ligands in male rodent aggression and sexual behavior. Results indicate that 5-HT1B-heteroreceptors play a critical role in the modulation of male offensive behavior, although a definite role of 5-HT1A-auto- or heteroreceptors cannot be ruled out. 5-HT1A receptors are clearly involved in male sexual behavior, although it has to be yet unraveled whether 5-HT1A-auto- or heteroreceptors are important. Although several key nodes in the complex circuitry of aggression and sexual behavior are known, in particular in the medial hypothalamus, a clear link or connection to these critical structures and the serotonergic key receptors is yet to be determined. This information is urgently needed to detect and develop new selective anti-aggressive (serenic) and pro-sexual drugs for human applications.",book:{id:"10195",title:"Serotonin and the CNS - New Developments in Pharmacology and Therapeutics",coverURL:"https://cdn.intechopen.com/books/images_new/10195.jpg"},signatures:"Berend Olivier and Jocelien D.A. Olivier"},{id:"81093",title:"Prehospital and Emergency Room Airway Management in Traumatic Brain Injury",slug:"prehospital-and-emergency-room-airway-management-in-traumatic-brain-injury",totalDownloads:49,totalDimensionsCites:0,doi:"10.5772/intechopen.104173",abstract:"Airway management in trauma is critical and may impact patient outcomes. Particularly in traumatic brain injury (TBI), depressed level of consciousness may be associated with compromised protective airway reflexes or apnea, which can increase the risk of aspiration or result in hypoxemia and worsen the secondary brain damage. Therefore, patients with TBI and Glasgow Coma Scale (GCS) ≤ 8 have been traditionally managed by prehospital or emergency room (ER) endotracheal intubation. However, recent evidence challenged this practice and even suggested that routine intubation may be harmful. This chapter will address the indications and optimal method of securing the airway, prehospital and in the ER, in patients with traumatic brain injury.",book:{id:"11367",title:"Traumatic Brain Injury",coverURL:"https://cdn.intechopen.com/books/images_new/11367.jpg"},signatures:"Dominik A. Jakob, Jean-Cyrille Pitteloud and Demetrios Demetriades"},{id:"81011",title:"Amino Acids as Neurotransmitters. 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In the current chapter, a comparison of the crosstalk between these two systems, which are responsible for excitation and inhibition in neurons, is presented. The interactions are discussed at the metabolic, receptor, and transport levels. Reaction-diffusion and a convectional flow into the interstitial fluid create a balanced distribution of glycine and glutamate. Indeed, the neurons’ final physiological state is a result of a balance between the excitatory and inhibitory influences. However, changes to the glycine and/or glutamate pools under pathological conditions can alter the state of nervous tissue. Thus, new therapies for various diseases may be developed on the basis of amino acid medication.",book:{id:"10890",title:"Recent Advances in Neurochemistry",coverURL:"https://cdn.intechopen.com/books/images_new/10890.jpg"},signatures:"Yaroslav R. 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Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:3,paginationItems:[{id:"7",title:"Bioinformatics and Medical Informatics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",isOpenForSubmission:!0,editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",slug:"slawomir-wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",biography:"Professor Sławomir Wilczyński, Head of the Chair of Department of Basic Biomedical Sciences, Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Poland. 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Editor-in-chief of the journal in the field of aesthetic medicine and dermatology - Aesthetica.",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},{id:"8",title:"Bioinspired Technology and Biomechanics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",isOpenForSubmission:!0,editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",slug:"adriano-andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",biography:"Dr. Adriano de Oliveira Andrade graduated in Electrical Engineering at the Federal University of Goiás (Brazil) in 1997. He received his MSc and PhD in Biomedical Engineering respectively from the Federal University of Uberlândia (UFU, Brazil) in 2000 and from the University of Reading (UK) in 2005. He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. His research interests include Biomedical Signal Processing and Modelling, Assistive Technology, Rehabilitation Engineering, Neuroengineering and Parkinson's Disease.",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",isOpenForSubmission:!0,editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",slug:"luis-villarreal-gomez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",biography:"Dr. Luis Villarreal is a research professor from the Facultad de Ciencias de la Ingeniería y Tecnología, Universidad Autónoma de Baja California, Tijuana, Baja California, México. Dr. Villarreal is the editor in chief and founder of the Revista de Ciencias Tecnológicas (RECIT) (https://recit.uabc.mx/) and is a member of several editorial and reviewer boards for numerous international journals. He has published more than thirty international papers and reviewed more than ninety-two manuscripts. His research interests include biomaterials, nanomaterials, bioengineering, biosensors, drug delivery systems, and tissue engineering.",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:18,paginationItems:[{id:"81778",title:"Influence of Mechanical Properties of Biomaterials on the Reconstruction of Biomedical Parts via Additive Manufacturing Techniques: An Overview",doi:"10.5772/intechopen.104465",signatures:"Babatunde Olamide Omiyale, Akeem Abiodun Rasheed, Robinson Omoboyode Akinnusi and Temitope Olumide Olugbade",slug:"influence-of-mechanical-properties-of-biomaterials-on-the-reconstruction-of-biomedical-parts-via-add",totalDownloads:2,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering - Annual Volume 2022",coverURL:"https://cdn.intechopen.com/books/images_new/11405.jpg",subseries:{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering"}}},{id:"81751",title:"NanoBioSensors: From Electrochemical Sensors Improvement to Theranostic Applications",doi:"10.5772/intechopen.102552",signatures:"Anielle C.A. Silva, Eliete A. Alvin, Lais S. de Jesus, Caio C.L. de França, Marílya P.G. da Silva, Samaysa L. Lins, Diógenes Meneses, Marcela R. Lemes, Rhanoica O. Guerra, Marcos V. da Silva, Carlo J.F. de Oliveira, Virmondes Rodrigues Junior, Renata M. Etchebehere, Fabiane C. de Abreu, Bruno G. Lucca, Sanívia A.L. Pereira, Rodrigo C. Rosa and Noelio O. 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For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}}]},{type:"book",id:"7218",title:"OCT",subtitle:"Applications in Ophthalmology",coverURL:"https://cdn.intechopen.com/books/images_new/7218.jpg",slug:"oct-applications-in-ophthalmology",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Michele Lanza",hash:"e3a3430cdfd6999caccac933e4613885",volumeInSeries:2,fullTitle:"OCT - Applications in Ophthalmology",editors:[{id:"240088",title:"Prof.",name:"Michele",middleName:null,surname:"Lanza",slug:"michele-lanza",fullName:"Michele Lanza",profilePictureURL:"https://mts.intechopen.com/storage/users/240088/images/system/240088.png",biography:"Michele Lanza is Associate Professor of Ophthalmology at Università della Campania, Luigi Vanvitelli, Napoli, Italy. His fields of interest are anterior segment disease, keratoconus, glaucoma, corneal dystrophies, and cataracts. His research topics include\nintraocular lens power calculation, eye modification induced by refractive surgery, glaucoma progression, and validation of new diagnostic devices in ophthalmology. \nHe has published more than 100 papers in international and Italian scientific journals, more than 60 in journals with impact factors, and chapters in international and Italian books. He has also edited two international books and authored more than 150 communications or posters for the most important international and Italian ophthalmology conferences.",institutionString:'University of Campania "Luigi Vanvitelli"',institution:{name:'University of Campania "Luigi Vanvitelli"',institutionURL:null,country:{name:"Italy"}}}]},{type:"book",id:"7560",title:"Non-Invasive Diagnostic Methods",subtitle:"Image Processing",coverURL:"https://cdn.intechopen.com/books/images_new/7560.jpg",slug:"non-invasive-diagnostic-methods-image-processing",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Mariusz Marzec and Robert Koprowski",hash:"d92fd8cf5a90a47f2b8a310837a5600e",volumeInSeries:3,fullTitle:"Non-Invasive Diagnostic Methods - Image Processing",editors:[{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",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. 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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. 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Science",numberOfPublishedBooks:11,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:12,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],subseriesList:[{id:"22",title:"Applied Intelligence",scope:"This field is the key in the current industrial revolution (Industry 4.0), where the new models and developments are based on the knowledge generation on applied intelligence. The motor of the society is the industry and the research of this topic has to be empowered in order to increase and improve the quality of our lives.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",keywords:"Machine Learning, Intelligence Algorithms, Data Science, Artificial Intelligence, Applications on Applied Intelligence"},{id:"23",title:"Computational Neuroscience",scope:"Computational neuroscience focuses on biologically realistic abstractions and models validated and solved through computational simulations to understand principles for the development, structure, physiology, and ability of the nervous system. This topic is dedicated to biologically plausible descriptions and computational models - at various abstraction levels - of neurons and neural systems. 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. Particularly interesting are models of various types of more compound functions and abilities, various and more general fundamental principles (e.g., regarding architecture, organization, learning, development, etc.) found at various spatial and temporal levels.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",keywords:"Single-Neuron Modeling, Sensory Processing, Motor Control, Memory and Synaptic Pasticity, Attention, Identification, Categorization, Discrimination, Learning, Development, Axonal Patterning and Guidance, Neural Architecture, Behaviours and Dynamics of Networks, Cognition and the Neuroscientific Basis of Consciousness"},{id:"24",title:"Computer Vision",scope:"The scope of this topic is to disseminate the recent advances in the rapidly growing field of computer vision from both the theoretical and practical points of view. Novel computational algorithms for image analysis, scene understanding, biometrics, deep learning and their software or hardware implementations for natural and medical images, robotics, VR/AR, applications are some research directions relevant to this topic.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",keywords:"Image Analysis, Scene Understanding, Biometrics, Deep Learning, Software Implementation, Hardware Implementation, Natural Images, Medical Images, Robotics, VR/AR"},{id:"25",title:"Evolutionary Computation",scope:"Evolutionary computing is a paradigm that has grown dramatically in recent years. This group of bio-inspired metaheuristics solves multiple optimization problems by applying the metaphor of natural selection. It so far has solved problems such as resource allocation, routing, schedule planning, and engineering design. Moreover, in the field of machine learning, evolutionary computation has carved out a significant niche both in the generation of learning models and in the automatic design and optimization of hyperparameters in deep learning models. This collection aims to include quality volumes on various topics related to evolutionary algorithms and, alternatively, other metaheuristics of interest inspired by nature. For example, some of the issues of interest could be the following: Advances in evolutionary computation (Genetic algorithms, Genetic programming, Bio-inspired metaheuristics, Hybrid metaheuristics, Parallel ECs); Applications of evolutionary algorithms (Machine learning and Data Mining with EAs, Search-Based Software Engineering, Scheduling, and Planning Applications, Smart Transport Applications, Applications to Games, Image Analysis, Signal Processing and Pattern Recognition, Applications to Sustainability).",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",keywords:"Genetic Algorithms, Genetic Programming, Evolutionary Programming, Evolution Strategies, Hybrid Algorithms, Bioinspired Metaheuristics, Ant Colony Optimization, Evolutionary Learning, Hyperparameter Optimization"},{id:"26",title:"Machine Learning and Data Mining",scope:"The scope of machine learning and data mining is immense and is growing every day. It has become a massive part of our daily lives, making predictions based on experience, making this a fascinating area that solves problems that otherwise would not be possible or easy to solve. This topic aims to encompass algorithms that learn from experience (supervised and unsupervised), improve their performance over time and enable machines to make data-driven decisions. It is not limited to any particular applications, but contributions are encouraged from all disciplines.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",keywords:"Intelligent Systems, Machine Learning, Data Science, Data Mining, Artificial Intelligence"},{id:"27",title:"Multi-Agent Systems",scope:"Multi-agent systems are recognised as a state of the art field in Artificial Intelligence studies, which is popular due to the usefulness in facilitation capabilities to handle real-world problem-solving in a distributed fashion. The area covers many techniques that offer solutions to emerging problems in robotics and enterprise-level software systems. Collaborative intelligence is highly and effectively achieved with multi-agent systems. Areas of application include swarms of robots, flocks of UAVs, collaborative software management. Given the level of technological enhancements, the popularity of machine learning in use has opened a new chapter in multi-agent studies alongside the practical challenges and long-lasting collaboration issues in the field. It has increased the urgency and the need for further studies in this field. We welcome chapters presenting research on the many applications of multi-agent studies including, but not limited to, the following key areas: machine learning for multi-agent systems; modeling swarms robots and flocks of UAVs with multi-agent systems; decision science and multi-agent systems; software engineering for and with multi-agent systems; tools and technologies of multi-agent systems.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",keywords:"Collaborative Intelligence, Learning, Distributed Control System, Swarm Robotics, Decision Science, Software Engineering"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:{id:"25",title:"Environmental Sciences",doi:"10.5772/intechopen.100362",issn:"2754-6713",scope:"\r\n\tScientists have long researched to understand the environment and man’s place in it. The search for this knowledge grows in importance as rapid increases in population and economic development intensify humans’ stresses on ecosystems. Fortunately, rapid increases in multiple scientific areas are advancing our understanding of environmental sciences. Breakthroughs in computing, molecular biology, ecology, and sustainability science are enhancing our ability to utilize environmental sciences to address real-world problems.
\r\n\tThe four topics of this book series - Pollution; Environmental Resilience and Management; Ecosystems and Biodiversity; and Water Science - will address important areas of advancement in the environmental sciences. They will represent an excellent initial grouping of published works on these critical topics.
\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
",annualVolume:11966,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",editor:{id:"110740",title:"Dr.",name:"Ismail M.M.",middleName:null,surname:"Rahman",fullName:"Ismail M.M. Rahman",profilePictureURL:"https://mts.intechopen.com/storage/users/110740/images/2319_n.jpg",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"201020",title:"Dr.",name:"Zinnat Ara",middleName:null,surname:"Begum",fullName:"Zinnat Ara Begum",profilePictureURL:"https://mts.intechopen.com/storage/users/201020/images/system/201020.jpeg",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorThree:null,editorialBoard:[{id:"252368",title:"Dr.",name:"Meng-Chuan",middleName:null,surname:"Ong",fullName:"Meng-Chuan Ong",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRVotQAG/Profile_Picture_2022-05-20T12:04:28.jpg",institutionString:null,institution:{name:"Universiti Malaysia Terengganu",institutionURL:null,country:{name:"Malaysia"}}},{id:"63465",title:"Prof.",name:"Mohamed Nageeb",middleName:null,surname:"Rashed",fullName:"Mohamed Nageeb Rashed",profilePictureURL:"https://mts.intechopen.com/storage/users/63465/images/system/63465.gif",institutionString:null,institution:{name:"Aswan University",institutionURL:null,country:{name:"Egypt"}}},{id:"187907",title:"Dr.",name:"Olga",middleName:null,surname:"Anne",fullName:"Olga Anne",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBE5QAO/Profile_Picture_2022-04-07T09:42:13.png",institutionString:null,institution:{name:"Klaipeda State University of Applied Sciences",institutionURL:null,country:{name:"Lithuania"}}}]},{id:"39",title:"Environmental Resilience and Management",keywords:"Anthropic effects, Overexploitation, Biodiversity loss, Degradation, Inadequate Management, SDGs adequate practices",scope:"\r\n\tThe environment is subject to severe anthropic effects. Among them are those associated with pollution, resource extraction and overexploitation, loss of biodiversity, soil degradation, disorderly land occupation and planning, and many others. These anthropic effects could potentially be caused by any inadequate management of the environment. However, ecosystems have a resilience that makes them react to disturbances which mitigate the negative effects. It is critical to understand how ecosystems, natural and anthropized, including urban environments, respond to actions that have a negative influence and how they are managed. It is also important to establish when the limits marked by the resilience and the breaking point are achieved and when no return is possible. The main focus for the chapters is to cover the subjects such as understanding how the environment resilience works, the mechanisms involved, and how to manage them in order to improve our interactions with the environment and promote the use of adequate management practices such as those outlined in the United Nations’ Sustainable Development Goals.
",annualVolume:11967,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/39.jpg",editor:{id:"137040",title:"Prof.",name:"Jose",middleName:null,surname:"Navarro-Pedreño",fullName:"Jose Navarro-Pedreño",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRAXrQAO/Profile_Picture_2022-03-09T15:50:19.jpg",institutionString:"Miguel Hernández University of Elche, Spain",institution:null},editorTwo:null,editorThree:null,editorialBoard:[{id:"177015",title:"Prof.",name:"Elke Jurandy",middleName:null,surname:"Bran Nogueira Cardoso",fullName:"Elke Jurandy Bran Nogueira Cardoso",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRGxzQAG/Profile_Picture_2022-03-25T08:32:33.jpg",institutionString:"Universidade de São Paulo, Brazil",institution:null},{id:"211260",title:"Dr.",name:"Sandra",middleName:null,surname:"Ricart",fullName:"Sandra Ricart",profilePictureURL:"https://mts.intechopen.com/storage/users/211260/images/system/211260.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}}]},{id:"40",title:"Ecosystems and Biodiversity",keywords:"Ecosystems, Biodiversity, Fauna, Taxonomy, Invasive species, Destruction of habitats, Overexploitation of natural resources, Pollution, Global warming, Conservation of natural spaces, Bioremediation",scope:"