Examples of commercially available drug discovery softwares.
\r\n\tThe applications are those related to intelligent monitoring activities such as the quality assessment of the environmental matrices through the use of innovative approaches, case studies, best practices with bottom-up approaches, machine learning techniques, systems development (for example algorithms, sensors, etc.) to predict alterations of environmental matrices. The goal is also to be able to protect natural resources by making their use increasingly sustainable.
\r\n\r\n\tContributions related to the development of prototypes and software with an open-source component are very welcome.
\r\n\r\n\tThis book is intended to provide the reader with a comprehensive overview of the current state of the art in the field of Ambient Intelligence. A format rich in figures, tables, diagrams, and graphical abstracts is strongly encouraged.
",isbn:"978-1-83969-069-3",printIsbn:"978-1-83969-068-6",pdfIsbn:"978-1-83969-070-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"3fbf8f0bcc5cdff72aaf0949d7cbc12e",bookSignature:"Dr. Carmine Massarelli",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10391.jpg",keywords:"Embedded Systems, Technologies, Sensors, Remote Sensing, Smart Homes, Smart Cities, Integrated Monitoring Techniques, Agroecosystem, Smart Public Spaces, Computer Vision, Image Processing, Open-Source",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 12th 2020",dateEndSecondStepPublish:"November 9th 2020",dateEndThirdStepPublish:"January 8th 2021",dateEndFourthStepPublish:"March 29th 2021",dateEndFifthStepPublish:"May 28th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Environmental technologist expert in the development of Smart Technologies for water management and environmental monitoring, characterization, and monitoring of contaminated and degraded sites, integration of spatial data such as standard methodologies, interoperability, spectral data infrastructures.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"315689",title:"Dr.",name:"Carmine",middleName:null,surname:"Massarelli",slug:"carmine-massarelli",fullName:"Carmine Massarelli",profilePictureURL:"https://mts.intechopen.com/storage/users/315689/images/system/315689.jpg",biography:"Main activities:\n-development of Smart Technologies for water management and environmental monitoring;\n-characterization and monitoring of contaminated and degraded sites;\n-implementation of early warning systems and impact assessment systems also from multitemporal monitoring;\n-integration of spatial data: methodologies, standards, interoperability, spatial data infrastructures;\n-use of open source IT systems for the processing, analysis, and integration of remote sensing data with airborne and satellite sensors for thematic purposes such as characterization, control, and analysis of the territory in support of environmental policies relating to contaminated sites;\n-evaluation of the contamination of environmental matrices with specific tests and chemical analyses;\n-installation of airborne sensors and definition of flight parameters for Earth observation, CASI-1500 hyperspectral and TABI-320 thermal sensors;\n-acquisition of spectral signatures of objects through Fieldspec portable spectroradiometer and creation of databases in SQL language;\n-use of tools such as Ground Penetrating Radar for the advanced investigation of the subsoil with law enforcement agencies.",institutionString:"National Research Council",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Research Council",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"9",title:"Computer and Information Science",slug:"computer-and-information-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"297737",firstName:"Mateo",lastName:"Pulko",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/297737/images/8492_n.png",email:"mateo.p@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"42297",title:"Structure-Based Approaches Targeting Oncogene Promoter G-Quadruplexes",doi:"10.5772/54809",slug:"structure-based-approaches-targeting-oncogene-promoter-g-quadruplexes",body:'The genetic information stored in DNA can be transcribed and translated into functional proteins with various biological roles, and the control of gene expression and cell division is tightly controlled under normal physiological conditions. However, genetic mutations arising during DNA replication can trigger uncontrolled cell growth, leading to the development of various types of cancers (Croce 2008). The cellular transformational events associated with cancer have been linked with mutations in particular genes, termed proto-oncogenes. These genes are necessary for the normal development and differentiation of cells, but when mutated into oncogenes they can lead to the overexpression of proteins involved in signal transduction and mitosis, ultimately resulting in cancer development. Blocking oncogenic translation using siRNAs has attracted intense attention in the literature (Heidenreich 2009; Ventura et al. 2009), but inhibiting oncogenic transcription through targeting DNA itself has been less explored.While DNA is a well-established biomolecular target for anti-cancer therapy, most DNA-binding drugs such as cisplatin (Alderden et al. 2006) and its analogues interact with DNA non-selectively, resulting in adverse side effects (Jung et al. 2007). Consequently, this has driven interest in the targeting of unusual, non-canonical structures in DNA, in order to achieve selectivity for particular (onco)genes while potentially reducing adverse side effects. One such DNA structure that has attracted significant attention in the recent literature as an anti-cancer target is the G-quadruplex. While G-quadruplexes were initially regarded as somewhat of a structural curiosity when they were first discovered, accumulating evidence over the past decade have suggested that these non-canonical DNA structures may play important roles in modulating various biological processes (Lipps et al. 2009).
G-quadruplexes are four-stranded guanine-rich DNA structures that were first found at the ends of eukaryotic telomeres, and the role of telomeric G-quadruplexes for inhibiting telomerase activity has been intensely studied since the early 1990s (Blackburn 1991). Human telomeric DNA is usually 4–14 kilobases long, and is comprised of TTAGGG tandem repeats. Up-regulated telomerase activity in cancer cells maintains the length of telomeres after cell division, conferring immortality. Hurley and co-workers demonstrated that the activity of telomerase can be inhibited by small molecule-induced stabilization of telomeric G-quadruplex (Wheelhouse et al. 1998).
A few years later, Hurley and co-workers reported the seminal discovery of a potential G-quadruplex structure in the nuclease hypersensitive element III1 (NHEIII1) of the promoter region of the c-myc oncogene, and they further demonstrated that the transcriptional repression of c-myc can be achieved by induction of putative G-quadruplex formation by a small molecule (Siddiqui-Jain et al. 2002). Evidently, c-myc transcription was inhibited by the putative formation of the G-quadruplex structure in the promoter region, thus suppressing oncogenic expression. Later, other studies identified the presence of G-quadruplex-forming sequences in the promoter regions of other oncogenes such as c-kit (Rankin et al. 2005), KRAS (Cogoi et al. 2006), bcl-2 (Dai et al. 2006) and VEGF (Jiang et al. 1991). In 2007, Huppert and Balasubramanian conducted a large-scale bioinformatics analysis throughout the human genome, and found that G-quadruplex-forming sequences are enriched in the promoter regions of genes, and that >40% of annotated genes bears at least one potential G-quadruplex sequence within 1kb of the transcription start site (Huppert et al. 2007). Recent evidence has suggested that G-quadruplexes may exist in vivo and may play putative roles in various biological processes, such as the regulation of gene expression (Dexheimer et al. 2009; Gonzalez et al. 2009). Consequently, targeting the oncogenic G-quadruplexes using small molecules has emerged as an alternative strategy for the potential treatment of cancers (Balasubramanian et al. 2009).
Since the discovery of the first c-myc G-quadruplex stabilizer TMPyP4 and inhibitor of c-myc oncogenic expression by Hurley and co-workers, many other c-myc interactive small molecule ligands have been identified. For example, cationic porphyrins (Grand et al. 2002), quindoline and berberine derivatives (Ou et al. 2007; Lu et al. 2008; Ma et al. 2008), and trisubstituted isoalloxazines (Bejugam et al. 2007) have been demonstrated to interfere with the oncogenic transcription in vitro. Quarfloxin, developed by Cylene Pharmaceuticals, entered clinical trials due to its ability to interact with G-quadruplexes in vivo (Duan et al. 2001). Interestingly, quarfloxin concentrates in the nucleus and disrupts the G-quadruplex-nucleolin interaction, leading to the redistribution of nucleolin in the nucleoplasm which ultimately triggers the apoptosis and inhibition of cancer cell growth.
With advances in computer processing power and in the development of algorithms for molecular stimulation and docking, the use of high-throughput virtual screening for drug discovery has become increasingly popular (McInnes 2007). The rapid screening of a large chemical library using computational programs can efficiently weed out non-binding ligands in silico, thus dramatically reducing the number of compounds to be tested in vitro. While the use of computer-aided virtual screening for discovering enzyme antagonists has been widely employed, the use of computational analysis for identifying G-quadruplex ligands has been comparatively less explored (Ma et al. 2012). In this chapter, we first describe the general structure of G-quadruplexes and their involvement in transcriptional events, particularly those relevant to oncogenic expression. We then discuss the use of in silico methods to identify small molecule ligands of oncogenic promoter G-quadruplexes, and identify features or limitations of each method. Finally, we highlight recent, representative, examples of promoter G-quadruplex targeting by small molecules discovered using in silico methods.
G-quadruplexes are constructed from stacks of G-tetrads, which consist of four guanine bases aligned in a co-planar arrangement stabilized by Hoogsteen hydrogen-bonding and monovalent cations (e.g. K+ and Na+) in the central cavity (Figure 1) (Mergny et al. 1998; Parkinson et al. 2002; Huppert et al. 2007). G-quadruplexes exhibit a high degree of structural polymorphism, contributing to the wide variety of distinct G-quadruplex topologies that differ in strand orientation, loop size, surface and groove dimensions (Burge et al. 2006). Consequently, G-quadruplexes formed from different DNA sequences may exhibit unique structural features that can be specifically targeted by small molecule ligands (Monchaud et al. 2008).
The structure of a G-tetrad stabilized by Hoogsteen hydrogen bonding and a monovalent cation resided in the central channel (left). Some possible topologies for an intramolecular G-quadruplex (right).
As previously mentioned, the occurrence of G-quadruplex-forming regions in the promoter region of oncogenes offers an alternative therapeutic avenue for the treatment of cancer. The induction of the G-quadruplex structure in the promoter region of the target gene could inhibit transcription of the oncogene, thus suppressing the production of the resultant oncoprotein. The potential to repress oncogenic expression by G-quadruplex formation can be illuminated by considering the history of the efforts targeted against well-studied oncogene c-myc.
Transcription regulation of oncogenes by promoter G-quadruplex formation mediated by small molecules (circle).
MYC protein is a transcription factor that controls cell proliferation, differentiation and apoptosis (Marcu et al. 1992), and its cellular level is strictly regulated in normal cells. Mutation of c-myc and the overexpression of the MYC protein are observed in around 80% of solid tumors, including cervical carcinoma, myeloid leukemias and osteosarcomas (Lutz et al. 2002; Meyer et al. 2008; Wierstra et al. 2008). Accumulating evidence has revealed that the c-myc promoter region plays a pivotal role in the regulation of c-myc transcriptional activity. In particular, the nuclear hypersensitivity element III1 (NHE III1), a 27 bp guanine rich sequence located upstream of the c-myc protein, has been reported to control around 90% of c-myc transcription (Davis et al. 1989). In vitro experiments suggested that this sequence is able to fold into an intramolecular parallel G-quadruplex with predominant 1:2:1 and 2:1:1 loop topologies (Seenisamy et al. 2004). Hurley and co-workers showed the basal transcription activity of c-myc can be significantly enhanced by destabilizing the c-myc G-quadruplex through a guanine-to-thymine mutation in the quadruplex-forming sequence (Siddiqui-Jain et al. 2002). In the same report, they demonstrated the suppression of oncogenic c-myc transcription activity by a cationic porphyrin that can stabilize the G-quadruplex structure (Siddiqui-Jain et al. 2002). These results demonstrated that the c-myc promoter G-quadruplex may act as a regulator of oncogenic transcription, and that small molecule stabilizers of the G-quadruplex could potentially down-regulate the expression of oncogenes (Figure 2).
These promoter G-quadruplex-stabilizing ligands have potential advantages as alternative anti-cancer compounds compared to conventional protein or enzyme inhibitors (Balasubramanian et al. 2011). Firstly, since the availability of G-quadruplexes in cells is generally limited, a lower concentration of inhibitor could theoretically be used to achieve the desired biological effect. Secondly, due to the unique structural diversity of G-quadruplex motifs, superior selectivity towards a particular G-quadruplex may be potentially achieved by the rational design and modification of the lead compound. Thirdly, a number of oncogenes such as c-kit, BRAF and c-myc, which have been reported to contain G-quadruplex-forming motifs in their promoter regions, encode kinase or protein products that have been clinically validated as targets for the treatment of cancer. However, a number of issues remain for the development of effective promoter G-quadruplex ligands for the treatment of human diseases. These include acquiring more detailed and comprehensive structural information on the relevant topologies of G-quadruplexes in living systems, as well as developing ligands with sufficient G-quadruplex selectivity and affinity for potential in vivo application. Leading experts Balasubramanian, Hurley and Neidle have recently reviewed the targeting of oncogenic promoter G-quadruplexes as a potential anti-cancer strategy (Balasubramanian et al. 2011).
Virtual screening techniques have recently emerged as a complementary technique to traditional high-throughput screening technologies employed in the pharmaceutical industry (Shoichet 2004; Ghosh et al. 2006; Cavasotto et al. 2007). Using computer-aided methodologies, large numbers of compounds can be rapidly screened in order to efficiently eliminate non-binding compounds in silico, thus dramatically reducing the costs associated with preliminary testing in a drug discovery project. However, while the application of in silico techniques for discovering enzyme inhibitors has been well-established, the targeting of DNA structures using virtual screening has been comparatively less explored. Broadly speaking, virtual screening can be sub-divided into pharmacophore modelling and molecular docking. A representative list of commercially available molecular docking softwares for both pharmacophore modelling and molecular docking (receptor-ligand modelling) is given in Table 1.
Pharmacophore modelling can be further classified into structure-based and ligand-based methods. In structure-based pharmacophore modelling, the structure of receptor must be first determined using techniques such as X-ray crystallography and nuclear magnetic resonance (NMR). Alternatively, if the structure of particular target is not known, a model can be constructed by homology with closely-related structures. In general, a structure containing the biomolecular target complexed with its ligand is advantageous for virtual screening since the key features of the interaction between the ligand and the binding pocket can be directly examined. Some commercially available computational software programs such as LIGANDSCOUT (Wolber et al. 2004) and POCKET v.2 (Chen et al. 2006) are able to analyse the binding interaction and calculate the relevant contributions of each feature to the specificity and inhibitory potency of the ligand. Ligand–target interactions can include hydrogen bonding, ionic interactions and hydrophobic interactions, and this information can be harnessed to generate a three-dimensional (3D) pharmacophore model.
Company/Institution | Software | Uses |
Accelrys | Discovery Studio, Insight II | Pharmacophore modelling, receptor-ligand docking, de novo drug design, molecular stimulation |
MolSoft | ICM-Pro | Pharmacophore modelling, receptor-ligand docking, 3D QSAR model constructions |
Tripos | Sybyl | Receptor-ligand docking, chemoinformatics, 3D QSAR model constructions |
Scripps Research Institute | Autodock | Receptor-ligand docking |
Schrodinger | Phase | Receptor-ligand docking, pharmacophore modelling |
Examples of commercially available drug discovery softwares.
In contrast, a prior knowledge of the biomolecular target is not needed in ligand based pharmacophore modelling, but instead a library of compounds with known potencies towards the biomolecular target is required for the construction of a training set. In silico techniques are then employed to generate a 3D pharmacophore that bears the representative electronic and steric features of the compounds from the training set. To obtain a reliable 3D pharmacophore, the training set should include structurally diverse compounds with in vitro potencies spanning a few orders of magnitude.
To confirm the validity of the 3D pharmacophore generated from either structure-based or ligand-based pharmacophore modelling, cost analysis techniques can be carried out based on statistical calculations in order to generate the “best” hypothetical structure. The validated pharmacophore is then subjected to virtual screening from chemical libraries to identify molecules that possess similar steric and electronic features with the pharmacophore. However, a drawback of pharmacophore modelling is that since the affinity calculation only involves the matching of geometry and functional groups of the potential ligand with the 3D pharmacophore, the screening process will tend to reveal ligands that structurally and electronically resemble the training set of compounds, rather than uncovering novel hit scaffolds.
On the other hand, molecular docking represents a totally different approach for virtual screening of bioactive compounds. Molecular docking involves stimulating the interactions between biomolecules and the ligands by computational algorithms. Molecular modelling has been gaining in popularity due to the increasing availability of biomolecular structures determined by either X-ray crystallography or NMR. In addition, advances in computational power and the continual development of more refined docking algorithms help to mitigate the relatively high computational strain demanded by molecular docking. In molecular docking, knowledge of the 3D biomolecular structure is essential, with or without the binding ligand. As previously described, the use of a biomolecular structure co-crystallized with a ligand is preferred as the binding pocket of the ligand can be easily identified and the subsequent docking analysis can then be restricted to the areas around the binding pocket in order to avoid wastage of computational resources and to eliminate false positives that interact outside of the binding site.
After completion of a virtual screening campaign, the resulting hit list of compounds can be subjected to experimental assays for hit validation (Figure 3). Alternatively, the hit structures can be used to construct analogues that can be screened in silico to potentially generate more potent ligands before chemical synthesis and biological testing.
Pipeline of computer-aided drug discovery and lead optimization processes.
In order to drive the development of more potent and selective ligands targeting promoter G-quadruplexes, it is important to understand the detailed interactions between the G-quadruplex and the ligand at the molecular scale. Molecular modelling can provide a tool for visualizing the three-dimensional interactions of the G-quadruplex-ligand complex in order to better understand the structural or functional features required for effective binding. Compared to pharmacophore-based methods, molecular docking can potentially make more effective use of the structural information of the receptor for the discovery of novel G-quadruplex-targeting compounds. In particular, high-quality structural data on the distinctive features of different promoter G-quadruplexes may aid the design and optimization of bioactive ligands that are able to discriminate between related G-quadruplex topologies. In this section, we give a general overview for the in silico structure-based discovery of oncogenic promoter G-quadruplex stabilizing ligands.
Computer-aided high-throughput molecular docking and hit validation usually involves three stages (Tang et al. 2006). The first stage is the construction and preparation/selection of the chemical library, and the preparation of the biomolecular model for molecular docking. The second stage is the docking of the individual compounds of the chemical library against the biomolecule, followed by score calculation. In the third stage, the high-scoring compounds can be selected for in vitro biological assays to validate their activities towards the biomolecular target.
A poorly-designed chemical library can result a high rate of false positives, or otherwise poor-quality hits. Therefore, the careful selection of a chemical library containing members possessing favourable pharmacokinetic properties (absorption, distribution, metabolism, excretion, and toxicity; ADMET) or structural diversity could improve the hit rate of a single docking campaign. Today, most chemical libraries are focused in some way by applying a manually selected pre-filter. For example, the Lipinski rule-of-five is a common filter that represents a collection of structural properties correlated with desirable solubility and bioavailability of small molecules (Lipinski et al. 2001). Screening compounds libraries with a pre-filter reduces the likelihood of identifying hit compounds with undesirable ADMET properties, therefore minimizing any loss of investment in chemical synthesis or biological assays. Two types of chemical libraries commonly chosen for virtual screening campaigns are drug/drug-like databases and natural product libraries.
Name | Company | Size of library | URL |
ChEMBL | European Bioinformatics Institute (EBI) | "/>1.1 million | https://www.ebi.ac.uk/chembl/ |
ZINC | Bioinfomatics and Chemical Informatics Research Center (BCIRC) | "/>21 million | http://zinc.docking.org/ |
IBS Database | InterBioScreen Ltd | "/>45000 | http://www.ibscreen.com/natural.shtml |
NatDiverse | Analyticon Discovery | "/>20000 | http://www.ac-discovery.com |
Super Drug Database | Humboldt-University | ~3000 | http://bioinf.charite.de/superdrug/ |
DrugBank | University of Alberta | 6711 | http://www.drugbank.ca/ |
Examples of commercially available chemical libraries used in computer-aided drug discovery.
Approved drugs usually have favourable or validated pharmacokinetic properties and toxicological profiles, which can improve the hit rate of the screening campaign, and could allow promising hit compounds to potentially bypass early-stage testing, thus streamlining the hit-to-lead optimization process. However, the use of an existing drug library for virtual screening cannot uncover novel bioactive compounds against the biological target. On the other hand, natural products represent the largest class of compounds in the chemical world. The interactions of natural products with biomolecules have been refined throughout evolutionary timescales, and these unique interactions can be harnessed by medicinal chemists to discover potential drugs. Since most natural products do not strictly adhere to Lipinski rule-of-fives, the virtual screening of natural product libraries can yield novel bioactive scaffolds that could not be obtained from drug-like or combinatorial libraries. Examples of commercially available drug databases and natural product libraries that can be used in high-throughput virtual screening are shown in Table 2.
To construct the receptor model for molecular docking, the atomic coordinates of G-quadruplex solved by the X-ray crystallography and NMR studies with or without bound ligand can usually be retrieved from the Protein Data Bank (Berman et al. 2000) or Nucleic Acid Database (Berman et al. 1996). Generally, structural data obtained from X-ray crystallography is considered more advantageous compared to those from solution NMR studies, as more detailed structural information can be obtained at the atomic scale. For G-quadruplexes lacking hard structural data, a model can be constructed by homology by modification of known, related G-quadruplex structures determined by X-ray crystallography. Commercially available software such as Discovery Studio (Accelrys Inc.) or ICM-Pro (Molsoft) can perform modification of the G-quadruplex conformation or topology through the addition or deletion of nucleobases, addition of monovalent cations in the central ion channel, or modification of the loop length and/or addition of nucleotides in the loop region (Lee et al. 2010).
The receptor model prepared can then be subjected to local energy minimization to generate the most suitable conformer for subsequent molecular docking analysis. While the small molecule ligands are usually assumed to be flexible so that the binding geometry of the ligand can be corrected predicted, the target is usually assumed to be mostly rigid, as the explicit treatment of receptor flexibility in the docking calculations would be too computationally expensive. Several approaches have been proposed to account for receptor flexibility in virtual screening campaigns. In the case of the G-quadruplex, the flexibility of the loop regions could be important especially for G-quadruplex groove-binding ligands.
An early approach tackling the problem of receptor flexibility was the “soft-docking” method (Jiang et al. 1991). In this approach, the compounds need not fit perfectly to the binding pocket of receptor and a certain degree of steric crash is allowed. During the docking process, the ligand and the receptor adjust their conformations continuously in order to achieve the most suitable conformation with maximum interaction. However, this method only utilizes a single receptor conformation, and thus the choice of receptor model for docking is of the utmost importance.
An alternative strategy that may be useful in G-quadruplex ligand discovery is the use of multiple receptor conformations (MRC) to probe the receptor flexibility (Totrov et al. 2008). This could involve a combination of multiple structures experimentally determined by X-ray crystallography or NMR, or could be generated by molecular stimulation (MD). By considering the different receptor features from multiple conformations, a more representative receptor conformation could be generated for virtual screening. Some modern docking algorithms are able to explicitly model receptor flexibility, but this is usually constrained to the ligand binding domain in order to conserve computing resources. A more thorough discussion of the common approaches used to model receptor flexibility can be found in review articles by Kavraki and co-worker (Teodoro et al. 2003), and Durrant and co-worker (Durrant et al. 2010).
The compounds from the chemical libraries are docked to the receptor structure individually. Generally, assigning the docking site across the entire G-quadruplex structure yields end-stacking compounds as the highest-scoring hits. For discovering groove-binders, which typically display weaker binding affinities, the search area for docking can be limited to the groove or loop regions of the G-quadruplex. Once the compound has been docked into the receptor, most computer algorithms will perform global energy optimization of the small molecule inside the binding pocket to find the most favourable orientation of the small molecule (Abagyan et al. 1994). For example, ICM-Pro (Molsoft) docking software (Abagyan et al. 1997) includes the following steps for global energy optimization:
After the global energy optimization, score assignment is then performed to rank the compounds according to their predicted binding affinities. The score is a qualitative parameter that reflects the binding strength of the compound to the receptor and is composed a collection of factors such as hydrophobic interactions, van der Waal interactions, hydrogen bonding, and electrostatic interactions. However, the accuracy of the docking score will necessarily be limited by the assumptions and approximations of the scoring function. Other factors which may not be explicitly predicted by the computational algorithms, such as solvent environment and binding pocket availability, could also influence the actual binding affinity of the ligand.
Different docking programs may employ different scoring functions, which are generally classified into the following types: 1) force-field functions; 2) knowledge-based scoring functions; and 3) empirical scoring functions (Kitchen et al. 2004). These scoring functions perform calculations that involve different parameters such as statistical potential and weighted interaction terms to rank the apparent potency of the compounds. To improve the accuracy of the scoring assignment, the consensus scoring approach has been investigated. This strategy involves the combination of the weighted scores obtained for a single ligand from different score functions, to improve the hit rate of a docking campaign (Charifson et al. 1999; Clark et al. 2002; Baber et al. 2005; Yang et al. 2005).
In the conventional drug discovery, validation of a screening hit by in vitro assays is usually followed by the synthesis of a range of structurally related analogues in order to optimize the binding and selectivity of the ligand towards the target. However, this approach necessarily entails a significant investment into manpower and materials, and can be very time-consuming. An alternative strategy utilizes the principles of computer-aided structure-based design in order to achieve the more efficient allocation of resources towards analogues with higher predicted binding affinities. By analysis of the receptor-ligand complex determined using X-ray crystallography or molecular modelling, a library of derivatives can be generated in silico that retain the important features of hit ligand that contribute to high binding affinity. This focused library can then undergo a second round of molecular docking procedure to identify the most promising derivatives for synthesis and evaluation.. The application of in silico structure-based optimization has also been applied for the development of oncogenic promoter G-quadruplex stabilizing ligands.
The use of in silico virtual screening to discover promoter G-quadruplex-stabilizing ligands has only been recently reported. Tang and co-workers utilized ligand-based pharmacophore modelling techniques to identify two non-planar alkaloids as groove binders of the parallel G-quadruplex (Li et al. 2009). In their report, the representative pharmacophore was constructed using the CATALYST software package (version 4.11, Accelrys Inc.) (Nicklaus et al. 1997). A total of 38 1,4-disubstituted anthraquinone derivatives comprised the training set, with IC50 values against rat glioma C6 cells spanning three orders of magnitudes (from 0.07 mM to 103 mM). Ten hypothetical models were constructed using the HypoGen hypothesis process, with the best pharmacophore containing one hydrogen bond receptor, one hydrogen bond donor, one positive ionizable group and two hydrophobic sites. The best pharmacophore model was selected for virtual screening and was mapped against a natural product database containing ca. 10,000 compounds derived from Chinese herbal medicines. A total of 176 hit compounds were identified with a diversity of scaffolds different to those of the training set, and 20 compounds were chosen for further evaluation based on compound availability. Intriguingly, the hit compounds included two neutral non-planar compounds, peimine (1) and peimimine (2). In UV melting experiments, peimine (2) and peimimine (3) were found to stabilize the tetramolecular G-quadruplex motif with significant increases in Tm. Further experiments indicated that both compounds were selective for parallel G-quadruplexes, and did not stabilize other G-quadruplex topologies or duplex DNA. Circular dichroism (CD) experiments found that compound 1 was able to enhance the characteristic parallel G-quadruplex CD signal at 262 nm of all the parallel G-quadruplexes examined, including c-kit oncogenic promoter G-quadruplex. The study from Tang and co-workers demonstrated the feasibility of employing ligand-based pharmacophore modelling to identity novel oncogenic promoter G-quadruplex-stabilizing compounds. However, further research would be required to fully characterize the possible biological effects of the compound in living cells.
In 2010, our group has employed high-throughput virtual screening techniques to identify fonsecin B (3) as a c-myc G-quadruplex stabilizer (Lee et al. 2010). Since no X-ray structure of the c-myc G-quadruplex was available, a molecular model of the predominant 1:2:1 loop isomer of c-myc G-quadruplex was constructed using the X-ray crystal structure of the related intramolecular human telomeric G-quadruplex. The model was built by the insertion or deletion of nucleobases and modification of the loop size to correspond to the 1:2:1 loop isomer of the c-myc G-quadruplex (Ou et al. 2007) using ICM-Pro (Molsoft). After the preparation of the receptor model, over 20,000 compounds from a natural product library were docked against the molecular model using the Molsoft ICM-Pro (3.6.1 d) docking protocol. Since most G-quadruplex stabilizing ligands possess a large polyaromatic scaffold for end-stacking, the docking area to the termini of the G-quadruplex was restricted to avoid the wastage of computational time. From the results of the virtual screening campaign, four hits were identified and tested in a preliminary in vitro PCR stop assay to assess their abilities to stabilize the c-myc G-quadruplex, and fonsecin B (3) emerged as the top candidate.
A variety of experiments were performed to analyze the interaction and selectivity of fonsecin B towards the c-myc G-quadruplex. UV-visible absorption spectroscopy revealed that compound 3 displayed 5.5-fold and 16.5-fold higher binding affinities for the c-myc G-quadruplex over duplex and single-stranded DNA, respectively. We then performed a detailed molecular modelling experiment in order to investigate the binding mode of the compound to the c-myc G-quadruplex. The modelling results revealed that 3 was stacked against the 3ʹ-terminal of G-quadruplex with a binding energy of –48 kcal mol–1. The phenolic and carbonyl oxygen atoms were predicted to orientate towards the central ionic channel, where the two oxygen atoms could possibly be stabilized by electrostatic interactions with the potassium ion. By comparison, intercalation of 3 into the G-quadruplex was calculated to be extremely unfavourable, with a binding energy of ca. 25 kcal mol–1. PCR stop assays showed that 3 was able to stabilize the c-myc G-quadruplex with the similar potency to the well-known G-quadruplex ligand TmPyP4.
Apart from the high-throughput virtual screening of chemical libraries, structure-based optimization by in silico approaches have also been employed to improve the potency of the lead compounds to a particular oncogenic promoter G-quadruplex target. In 2009, Che and co-workers developed a series of Pt(II) complexes as c-myc G-quadruplex stabilizing ligands using an in silico structure-based optimization strategy (Wu et al. 2009). Among a series of Pt(II)-salphen complexes tested in preliminary in vitro assays, complex 4 was found to be most potent and was chosen for in silico structural modification. Over 60 derivatives of complex 4 were designed that contained side chains with various lengths and functional groups to interact with the grooves of the G-quadruplex, and these compounds were docked to the c-myc G-quadruplex using the ICM program. In the molecular docking analysis, the highest scoring compound 5 was found to bind more favorably to the c-myc G-quadruplex compared to the parent complex 4 due to the additional interactions between the side chains of 5 with the G-quadruplex grooves regions. Compound 5 was then synthesized for biological evaluation, and the PCR stop assay results showed 5 could stabilize the formation of the c-myc G-quadruplex with an IC50 value of 4.4 µM, which was an order lower than that of parent compound 4. In this report, Che and co-workers successfully demonstrate the use of structure-based optimization of a Pt(II)-salphen complex to devise a more promising scaffold for stabilization of the c-myc oncogenic promoter G-quadruplex.
Structures of promoter G-quadruplex-targeting compounds discovered via high-throughput virtual screening.
Later, the Che group reported another successful application of computer-based lead optimization of Pt(II) metal complexes to discover efficient c-myc G-quadruplex stabilizing ligands (Wang et al. 2010). Based on hit complex 6, over 550 derivatives were designed by attaching side chains of various lengths and functionality to the parent scaffold, the library of compounds were rapidly screened in silico. Three of the highest scoring complexes 7–9 were then synthesized and subjected to comprehensive in vitro assays to evaluate their ability to stabilize the c-myc G-quadruplex. In the UV-Vis absorption experiments, all three complexes showed at least 10-fold higher binding affinities towards the c-myc G-quadruplex over duplex DNA. Furthermore, the complexes increased the Tm of the c-myc G-quadruplex by over 9 °C, and displayed improved potency at stabilizing the c-myc G-quadruplex in the PCR stop assay when compared to the parent compound. Subsequent reverse transcriptase PCR (RT-PCR) experiments showed that the mRNA level of the c-myc gene could be significantly diminished in the presence of complexes 7–9, suggesting that these compounds could be used as suppressors of oncogenic expressing in living cells. This report by Che and co-workers again demonstrated the feasibility of in silico structure-based lead optimization of metal complexes, and suggested that the use of a larger chemical library of derivatives could generate a larger diversity of hits with potentially improved potencies.
Chemical structures of the platinum(II) complexes discovered through in silico structure-based optimization as c-myc oncogenic G-quadruplex stabilizing ligands.
Our group has recently reported the structural-based optimization of FDA-approved drug methylene blue (MB) to generate more potent analogues as c-myc G-quadruplex stabilizers (Chan et al. 2011). Over 3,000 FDA-approved drugs were screened in silico against the 1:2:1 loop isomer model of the c-myc G-quadruplex developed by our group, and MB emerged as the top candidate. Although the MB is a well-known DNA intercalator and has been previously reported to bind the G-quadruplex, its application as a c-myc oncogenic promoter G-quadruplex stabilizer was first discovered by our group. 50 MB derivatives were designed in silico and were docked against the c-myc G-quadruplex using ICM-Pro software. Compounds 10a–c bearing a bromophenyl pendant linked by an aliphatic side chain showed the greatest binding energy from the virtual screening, and they were synthesized for biological evaluation. In the fluorescence intercalator displacement (FID) assay, compound 10b was found to effectively displace thiazole orange (TO) from the c-myc G-quadruplex with a DC50 value of 0.75 µM, while compounds 10a and 10c displayed higher DC50 values of ca. 6 and 2 µM, respectively. Furthermore, compound 10b could inhibit Taq polymerase mediated-extension of the c-myc sequence through induction of the G-quadruplex structure in the PCR stop assay with superior potency compared to the parent compound MB. Detailed molecular docking analysis revealed that compound 10b was predicted to form strong end-stacking interactions with the terminal of c-myc G-quadruplex with groove interactions, whereas the parent compound MB was predicted to interact with the G-quadruplex via a mostly intercalative mode. In living cells, compound 10b was shown to be effectively down-regulate the c-myc promoter activity with an IC50 value of ca. 1 µM as revealed by a luciferase assay. The increased activity of the 10b compared to MB against c-myc promoter activity could be potentially attributed, at least in part, to the stabilization of c-myc G-quadruplex structure. This report demonstrated the structure-based lead optimization approach effectively generate novel analogues of existing drug as oncogenic G-quadruplex stabilizing ligands.
Chemical structures of the FDA-approved drug methylene blue and its analogues designed by a structural-based optimization strategy as c-myc oncogenic G-quadruplex stabilizing ligands.
The identification of oncogenes involved in the progression of various types of tumours has stimulated the development of various anti-cancer strategies targeting oncogenic expression. The discovery of G-quadruplex motifs in the promoter regions of oncogenes and the elucidation of their putative roles in the regulation of oncogenic transcription has opened a new potential therapeutic avenue for the treatment of cancer. However, it should be noted that the application of G-quadruplex-stabilizing ligands for the modulation of oncogenic activity in living systems is still in its infancy. Most promoter quadruplex ligands discovered thus far have not yet progressed past pre-clinical investigation. To advance further, several important criteria have to be addressed. These include the bioavailability of G-quadruplex-binding compounds as well their conformational rigidity and promiscuity for other physiological targets. In particular, the action of the lead candidates against the large number of other gene promoters and G-quadruplex structures that are likely to be present in normal cells should be rigorously assessed. These factors would aid in the determination of the permissible dosage and therapeutic window of the G-quadruplex-targeting compounds for the potential treatment of cancer. With continual advances in computational technologies and modelling techniques, as well as the concurrent development of more focused yet diverse chemical libraries, we envisage that the discovery and investigation of novel promoter G-quadruplex-stabilizing ligands would continue to thrive in the near future. Furthermore, in silico hit-to-lead optimization allows the chemical space around hit compounds to be explored without necessitating the actual synthesis of analogue molecules, thus significantly reducing expenses associated with materials and manpower.
This work is supported by Hong Kong Baptist University (FRG2/11-12/009), Environment and Conservation Fund (ECF Project 3/2010), Centre for Cancer and Inflammation Research, School of Chinese Medicine (CCIR-SCM, HKBU), the Health and Medical Research Fund (HMRF/11101212), the Research Grants Council (HKBU/201811 and HKBU/204612), the Science and Technology Development Fund, Macao SAR (001/2012/A) and the University of Macau (SRG013-ICMS12-LCH, MYRG091(Y1-L2)-ICMS12-LCH and MYRG121(Y1-L2)-ICMS12-LCH).
The patient requiring extracorporeal membrane oxygenation (ECMO) for any etiology is almost always managed in the intensive care unit (ICU) and requires care around the clock, which is delivered by a collaboration of physicians, nurses (RNs), respiratory therapists, perfusionists, and many others. Close collaboration between care providers is crucial, particularly between the RN managing hemodynamic medication infusions and the ECMO specialist managing the pump. RNs provide extensive, holistic care for ICU patients and their families, much of it geared toward traditional, clinical care with the additional implications of ECMO therapy, which requires additional specialized training. Acuity, unpredictability, and heavy resource requirements of the ECMO patient, especially when initiating therapy, can necessitate unusual and innovative staffing models, which rely on flexibility and often extra hours and shifts to accommodate individual patient and unit needs.
\nRNs are essential to the delivery of optimal healthcare and play an integral role in the care of patients admitted to the ICU, so it is important that, when staffed well, RNs reduce the risk of inhospital mortality anywhere from 14 to 36% [10, 29]. A recent expert consensus suggests RN-to-ECMO patient ratios should be at least 1:1 or 1:2 to deliver safe and quality patient care [33]. A recent survey found that RNs were allocated 1:1 in nearly 60% of ECMO centers internationally when also monitoring and intervening on the ECMO circuit [9]. This chapter will further discuss the nursing implications involved in the care of the ECMO patient, the RN’s role in prevention of associated complications, and the importance of the holistic approach required at the bedside.
\nNursing care should include monitoring of the ECMO circuit as nurses and associated staff, such as respiratory therapists and perfusionists, are at the bedside with the patient continually. ECMO cannulae require the same, if not more, attention that any peripheral or central venous catheter would, including assessment for erythema, purulence, adequacy of securement, and dressing integrity. It is significantly important to monitor for fixation of the ECMO cannulae. Initial placement of ECMO cannulae is usually confirmed by echocardiography and the position reaffirmed by radiographs [19]. Thus, ensuring the securement and stability of the cannulae by routine and repeated physical assessment is integral, as misplaced cannulae, loose sutures, or distant lashing straps can lead to specific complications such as inadequate flows or cannula dislodgment [28]. Ideal placement of lashing straps and appropriate securement of cannulae can be seen in Figure 1.
\nAppropriate lashing strap distance demonstrating safe securement and appropriate tension on the ECMO cannulae.
It is particularly important for the nurse and other bedside clinicians to be mindful of the integrity of the pump, as mispositioning of cannulae or hypovolemia can result in end-organ injury [11]. Suction events involve disruption of flow secondary to venous collapse onto the drainage cannula and can result in thrombus formation [11]. The occurrence of thrombi in the pump or oxygenator can be recognized by a visible thrombus, an increasing pressure decrease across the oxygenator, or a low post-oxygenator pCO2 [11].
\nThere are additional considerations that the nurse caring for the ECMO patient will need to exercise specific to the therapy. Disruption of innate circulatory flow secondary to ECMO can result in limb ischemia. Thus, it is important to monitor limbs, especially those distal from cannulation sites. Clinical judgment, pulse palpation, and Doppler sonography of limb vessels are effective tools for this purpose [28]. Another modern tool for monitoring tissue oxygenation in lower extremities in ECMO patients is near-infrared spectroscopy [28]. The nurse may also note that clinicians will often place distal perfusion catheters to help prevent or treat distal limb ischemia, as demonstrated in Figure 2 [28]. Harlequin syndrome can present in patients with venoarterial (VA) cannulation, where the heart has recovered but the lungs are still poorly functioning. The hallmark assessment finding for this is upper extremity cyanosis [28].
\nLeft femoral artery perfusion catheter in place providing flow from the arterial ECMO cannula to the left lower extremity.
Vessel perforation may take place on insertion; but, symptoms may not present immediately [28]. The most serious complication is a large retroperitoneal hematoma; but, considerable local bleeding at the insertion site is also possible, and site assessment, as well as assessment of the abdomen, flanks, and inguinal areas for ecchymosis, hypotension, and acutely worsening anemia, is necessary [28]. Additional assessment findings may include bulging or swelling at the insertion site, most consistent with pseudoaneurysm. Mild insertional hematomas may be mitigated and controlled by application of manual pressure, with subsequent monitoring of flows and distal pulses, both of which are imperative for clinical safety.
\nInfection is an associated risk of ECMO therapy as well and linked to greater likelihood of mortality. In one study, patients on ECMO experienced an overall mortality of 68.3:75.6% in patients with infections and 67.1% in patients without infections [30]. The use of steroids in acute respiratory distress syndrome (ARDS) or adrenal insufficiency, body temperature control, and multiple blood transfusions after cardiac operations for coagulopathy during ECMO can interfere with the presentation of infection in patients undergoing ECMO [30]. Thus, routine inspection and care of all invasive lines, including ECMO catheters, become integral. Implementing standard decolonization practices set forth by the nurse’s institution is appropriate for ECMO catheters, such as antimicrobial scrubs and occlusive dressings.
\nHospital-acquired pressure ulcers (HAPUs) are seen often in the intensive care setting and continue to be a significant financial burden within the healthcare system. The costs range anywhere from $500 to $70,000 per pressure ulcer and can cause length of stay (LOS) to increase by as much as 11 days [26]. While incidence of pressure ulcer development ranges per hospital and patient population, in a database of 710,626 patients, an estimated 3.6% of all patients within the adult critical care and step-down units developed a HAPU [31]. In the acute care setting, a range from 0.4 to 12% has been found [31]. Within the cardiac surgery patients which comprise a portion of patients on ECMO, pressure ulcer incidence as high as 29.5% occurs [26]. The consequences of these pressure ulcers often include infection leading to sepsis, increased pain, further disability, and sometimes death [26]. Although general risk factors such as age, immobility, poor nutritional status, altered sensory perception, moisture, diabetes mellitus, vascular disease, and other comorbidities have been identified, patients receiving ECMO support are also at an increased risk for pressure ulcer development due to multiple factors unique to this population [7, 26]. If patients do undergo cardiothoracic surgery, factors that increase the likelihood of a HAPU include cardiopulmonary bypass time, vasopressor therapy, and body temperature while in the operating room [26]. While on ECMO support, hemodynamic instability related to turning can inhibit appropriate prevention measures, leading to higher incidence of skin breakdown. Nurses can experience apprehension related to routine turning due to the potential of accidental decannulation or risk of worsening hemodynamic instability. High doses of multiple vasopressors that are utilized in patients newly placed on ECMO can lead to decreased peripheral perfusion and have also been shown to increase risk of HAPU. These risk factors make it essential to establish a dedicated skin care regimen for patients receiving ECMO support to prevent HAPU.
\nSkin care goals for patients receiving ECMO support should largely be similar to any patient that is in the intensive care setting. “At-risk” patients are identified by using a standardized risk screening tool such as the Braden Scale score and treated with stratified skin care interventions implemented based on severity of risk. Patients with a Braden Scale score of 14 or less (moderate to high risk) receive maximum interventions [31]. Patients need to be turned and repositioned every 2 h as tolerated. Turns should be scheduled and require a multidisciplinary team to ensure patient safety (perfusionist or respiratory therapist to hold ECMO cannulas, nurse for lines, etc.). For patients who do not tolerate a full turn, such as those who are hemodynamically unstable on ECMO, specialty beds have been shown to be very effective in reducing HAPU [20]. These rotation and pressure redistribution beds can be set to rotate every 30 min to different ranges as patients tolerate. Even subtle and small frequent position changes have been shown to reduce HAPUs [7]. Many facilities also use fluidized repositioning devices to offload pressure [31]. Silicone gel adhesive dressings should be utilized when possible and can be applied on the sacrum, elbows, and heels. Specialized heel-protective boots can also be used if available. Nutritional status also has a significant impact on the body’s ability to repair wounds. This makes dietitians an essential part of the treatment team to ensure these patients receive adequate nutrition in order to prevent skin breakdown and promote healing.
\nThere are multiple factors all contributing to this patient population’s increased risk of HAPU. Staff education, awareness, and motivation are essential in delivering the proper skin care measures in ECMO patients. When possible, a multidisciplinary skin care team can address each of the challenges present in this population to ensure that adequate prevention measures are being implemented.
\nEarly physical rehabilitation and mobility implemented in patients receiving ECMO support have been shown to significantly improve patient outcomes, including decreased LOS in the ICU and hospital, decreased rate of delirium, shorter durations of mechanical ventilation, decreased time to ambulation, increased function, and increased likelihood of returning home to family versus a rehabilitation facility [1, 36]. In spite of the obvious importance of early mobility in ECMO patients, there are limitations to this, particularly hemodynamic instability. The first 24–48 h after the initiation of ECMO are typically the most critical and often do not allow for aggressive physical therapy regardless of the type of ECMO. Most patients during this time are requiring the maximum amount of ventilatory and circulatory support. Eligibility for physical therapy is based upon hemodynamic stability and degree of mechanical and pharmacological support and is specific to each patient case.
\nHistorically, a dual-lumen ECMO catheter would occupy one vessel, usually the internal jugular vein, and provide veno-venous (VV)-ECMO through one cannulation site, allowing bridge-to-transplant patients to participate in early mobility more easily. This was optimal for ambulation because both lower extremities were free and the patients were seen as less high risk for accidental decannulation. However, recently there has been a significant push to mobilize all types of ECMO patients whether they are bridge-to-transplant patients or bridge-to-recovery patients, despite the location and type of cannulation. Whatever the level of physical therapy the patient can tolerate, whether this is passive range of motion or ambulation in the hallway has been shown to improve patient outcomes [1]. Typically, VV-ECMO patients are more stable than VA-ECMO patients, and thus bedside nurses are more comfortable with early mobility in these patients. Patients on VA-ECMO with bi-femoral cannulation are some of the most difficult to ambulate. Fear of accidental decannulation, risk of hemodynamic instability, and lack of training in the physical rehabilitation of these patients have all been barriers to early mobilization. However, the study at the University of Maryland demonstrates that physical mobility is safely possible regardless of the type of ECMO or cannulation site [36].
\nMany institutions who have an established ECMO program have developed a dedicated multidisciplinary team highly trained in the initiation of physical therapy for ECMO patients [36]. These teams typically include a physical therapist, one to two critical care nurses, a perfusionist or respiratory therapist, and a critical care attending physician. When assessing for eligibility, it is helpful to have a standardized screening tool [36]. The University of Maryland developed a protocol for the initiation of ECMO physical therapy [36]. The initial screening was composed of two parts: a medical screening and a physical therapy assessment [36]. The medical screening criteria included hemodynamic stability specific for each patient, coagulopathy: no bleeding at the cannulation site, stable ECMO flows with RN activities, a RASS goal of −1 to 0 with a range (−2 to +2), and stability of cannulation position [36]. The physical therapy assessment included vital signs, assessment of mental status, ECMO flow remaining stable (hip flexion with femoral cannulated lower extremities), and documented ECMO cannulation position [36]. If both of these screens were passed, then the patient met the criteria for further rehabilitation as tolerated [36]. The common physical therapy progression included bed activities/bed mobility such as passive range of motion and resistive training [36]. If that was well tolerated, then patients progressed to the edge of bed activities including balance training and pre-transfer activities [36]. Following this were sit-to-stand transfers, standing and pre-gait activities, and lastly ambulation [36]. Stabilization devices to secure the ECMO cannulas are recommended before physical therapy is initiated [1]. Adjustments on the sweep gas flow rates and increased oxygenation settings can be used during physical therapy based on clinician assessment [1].
\nIn the aforementioned study, 167 of the 254 patients supported on ECMO received physical therapy [36]. One hundred and thirty-four of those patients had at least one femoral cannula, while 66 patients had two, 44 of which were on VA-ECMO and 39 of whom were on VA-ECMO with bi-femoral cannulas. Only five patients had a dual-lumen catheter. Only three minor events were recorded during physical therapy: one episode of hypotension and two episodes of arrhythmias. Of the patients who received physical therapy, 109 patients survived hospital discharge, and 26 of those patients were discharged home. The patients who received physical therapy while on ECMO scored higher on their ICU mobility scale (IMS) than the ones who only received physical therapy after decannulation [36]. It is important to note that this was only possible due to a dedicated team of individuals specifically trained for the initiation and completion of physical therapy and mobility in ECMO patients and that the resources necessary to develop this type of team may not exist at all institutions who utilize ECMO support [36].
\nThe Society of Critical Care Medicine developed the ABCDEF (Assess, prevent, and manage pain; Both spontaneous awakening and breathing trials; Choice of analgesia and Sedation; Delirium assess, prevent, and manage; Early mobility and exercise; Family engagement/empowerment) bundle as an ICU Liberation Collaborative [25]. A recent study measured the success of this bundle on over 15,000 patients spread across 68 academic, community and federal intensive care units. Patients who received more of the ABCDEF bundle each day showed lower delirium rates, less use of physical restraints, decreased length of mechanical ventilation, avoidance of ICU readmission, increased instances of being discharged to home, and ultimately decreased mortality rates [25]. The significance of this bundle is that it can be applied to every ICU patient regardless of their diagnosis, including the ECMO patient population. Implementing the ABCDEF bundle on ECMO patients potentially increases the likelihood of returning to their baseline function sooner.
\nThe use of ECMO is accompanied by a myriad of potential complications across multiple body systems that are considered calculated risks upon initiation of therapy; however, without it, mortality may increase in conditions like severe acute heart failure [32]. A recent, international, randomized controlled trial (RCT) also suggests a potential mortality benefit with the use of ECMO in severe acute respiratory distress syndrome (ARDS); however, it was found to not be statistically significant [8]. There is abundant literature surrounding the complications of ECMO; but, despite these risks, survival to hospital discharge is greater than 50% [4, 12]. In one recent meta-analysis, the most frequently reported complications associated with ECMO include acute kidney injury (AKI), bleeding, and infection [6]. Specialized RNs have knowledge and understanding of potential complications related to ECMO therapy and can assist with early detection through critical thinking, performing frequent assessments, and reporting them through an open dialog with the team of providers involved.
\nThe incidence of acute kidney injury (AKI) has been reported as high as 80% of ECMO patients and is associated with a quadrupled mortality risk [13, 34]. Severe fluid overload is one of the major reasons that renal replacement therapy (RRT) is initiated in this population and is often performed through the ECMO circuit but can also be performed after the pump, which could lower the risk of air embolism not trapped by the oxygenator [34]. Fluid overload is independently associated with increased mortality, prolonged LOS, prolonged ventilator time, and prolonged ECMO time [13, 34].
\nThis consideration can lead providers to assume earlier RRT for therapeutic fluid removal would reduce these comorbidities; however, there is little data to suggest the efficacy of this. In fact, studies suggest increased mortality in ECMO patients who require RRT during their time on pump [16, 37]. Of ECMO patients who suffer AKI, an estimated 46% of survivors require RRT after ECMO is completed [6]. The bedside RN can assist in early identification of AKI by monitoring urine output; measuring strict fluid intake and output; assessing serial serum chemistry values, particularly serum creatinine and trends of electrolyte dyscrasias; and identifying physical exam findings consistent with fluid overload.
\nAbdominal compartment syndrome (ACS) is a known complication of ECMO [3]. This can be caused by massive fluid overload, which can be necessary to keep ECMO flows appropriate (read aforementioned suction events) [3]. This significantly positive fluid balance is associated with generalized edema, pleural effusions, and ascites, all of which are known to be causes of ACS. ACS can also compress femoral cannulas, thus diminishing the effectiveness of the ECMO therapy [28]. Clinical assessments significant for the monitoring of abdominal compartment syndrome include physical monitoring of abdomen for tension, distention (diameter), discoloration, and, if the technology is readily available, measurement of intraabdominal pressure.
\nBleeding is the most frequent complication associated with ECMO and affects approximately 30% of the patients receiving the therapy [2]. Bleeding may occur secondary to primary injury such as trauma and surgery or as a result of ECMO itself. Disruption of the red blood cell membrane leads to hemolysis, which is a common complication of patients on ECMO [11]. SIRS and contact between the patient’s blood and the ECMO circuit lead to activation of the coagulation cascade, affecting fibrinolysis, thrombin formation, and platelet function [2].
\nLarge amounts of bleeding will cause losses and consumption of coagulation factors and platelets, leading providers to believe that a heparin overdose may be occurring, thus decreasing the heparin, leading to acute thrombosis of the ECMO circuit or in other places where blood flow may be stagnant [22]. Thrombosis is mainly associated with VA-ECMO and can occur in the atria, ventricles, upper and lower extremity deep vein thrombosis (DVT), pulmonary vasculature, brain, or the ECMO circuit [22]. Unfractionated heparin (UFH) is well known, easily monitored, and easily reversible, allowing its frequent use managing hypercoagulability in the ECMO patient. Institutional guidelines vary; but, systemic anticoagulation with UFH infusion to target aPTT between 50 and 70, with some variations [2]. Despite ease of use, UFH can be associated with complications such as heparin-induced thrombocytopenia (HIT), further contributing to bleeding [22]. Alternatives such as warfarin, lepirudin, or argatroban may also be used in lieu of UFH for anticoagulation in the event of HIT [2]. The ECMO patient provides a unique challenge for providers, who must balance hypercoagulability with coagulopathy with careful but aggressive, administration of blood product transfusions and anticoagulants.
\nIt is clear that there is a litany of reasons the patient on ECMO may experience bleeding and bleeding often results in the need for transfusion. Adult patients on ECMO may require 2–3 units of packed red blood cells (PRBCs) and up to 14 units of plasma or cryoprecipitate daily [11]. Additionally, platelet counts of 45,000–60,000 count/μL are associated with mild to moderate bleeding [11]. Demands on bedside clinicians can be burdensome, as transfusion requirements have been reported to average 45 units of packed red blood cells transfused per adult ECMO patient [11].
\nLarge transfusion volumes are independently associated with increased mortality [11]; despite this, anticoagulation remains the standard practice in patients undergoing ECMO due to thrombotic complications [2]. With the significant risk for bleeding and the subsequent need for anticoagulation, nursing can expect regular and repeated blood draws, transfusions, and anticoagulant titration to be a part of their daily practice in the care of the ECMO patient.
\nA prospective, 1-day study identified approximately 50% of adult patients in over 1200 ICUs internationally whom were thought to have some form of infection, increasing ICU, and hospital mortality rates by over double that of patients without infection [35]. The literature suggests that from anywhere 13–26% of reported nosocomial infection rate in adults receiving ECMO (particularly VA-ECMO) is significantly associated with infection before initiation of ECMO, prolonged LOS, ECMO duration (particularly >10 days), and prolonged ventilator days [5, 14, 15, 30]. In the ICU patient, respiratory infections are most common; however, with the addition of ECMO, blood stream infections become most prominent [17, 35]. Other reported nosocomial events in ECMO patients include respiratory, urinary, and surgical site infections [17].
\nCare provided by the specialized RN remains inherently important in the prevention of infection, particularly when caring for lines and their cannulation sites with thorough hand, cannulation site, and patient hygiene and the application of impermeable site dressings. Protocols preventing ventilator-acquired pneumonia (VAP) are common practice and include interventions like hand hygiene, meticulous oral care with chlorhexidine gluconate solution, endotracheal tube cuff pressure control, and control of sedation [27]. Further management of routine line and cannulation site management are further discussed earlier in this chapter under Section 2.
\nCardiopulmonary complications are often resultant of high left ventricular (LV) afterload, especially on prolonged ECMO (particularly VA-ECMO), which can lead to pulmonary edema [21]. Other cardiac sequelae include aortic valve regurgitation, biventricular failure, and LV thrombus which have been treated with a variety of modalities including intra-aortic balloon pump (IABP) and other percutaneous and surgical procedures to shunt elevated LV pressures [24]. Additional lung complications significantly associated with ECMO include pulmonary hemorrhage, hemorrhagic pulmonary infarct, pulmonary calcifications, and fibrinous pleuritis [18]. The bedside RN can assist with early detection of these complications by close assessment of vasopressor and inotrope requirements, endotracheal secretions, monitoring the ventilator for peak and plateau pressures, and ensuring daily chest radiographs and frequent echocardiograms which are ordered to monitor progression of cardiopulmonary disease.
\nA study reviewing nearly 24,000 patients on ECMO revealed 10.9% of incidence of nearly equal prevalence of seizure, stroke, or intracranial hemorrhage (ICH) [23]. These patients who suffered ICH while on ECMO had increased mortality, while strokes and ICH alike both demonstrated increased LOS and increased likelihood of requiring placement in a skilled nursing facility (SNF) or long-term acute care hospital (LTACH) upon discharge [23]. Other sources suggest up to 50% of patients on ECMO demonstrate severe neurological sequelae [19]. Intracranial hemorrhage has been identified in as high as 40% of non-survivors of ECMO, and thrombotic events have been identified in approximately 15% of ECMO courses [2].
\nThe clinical suspicion for stroke may be obscured in ECMO patients given the multitude of other systemic or metabolic derangements usually encountered in ICU patients [19]. The bedside RN becomes integral to monitoring subtle neurologic indicators such as pupilometer and bi-spectral index, which can read zero in the event of catastrophic neurologic injury.
\nWith the advent of advancing ECMO technology comes an expanded library for indications of use. VA and VV support are commonly being utilized for bridge-to-transplant and respiratory or cardiac failure. Additionally, ECMO therapy is being utilized as bridge to support the body through a medical emergency in the form of extracorporeal cardiopulmonary resuscitation (ECPR). With the introduction of high-tech innovation, critical care nursing frequently encounters stressors due to resource scarcity, increased workloads, and moral distress related to carrying out aggressive life-sustaining treatments that may conflict with the patient’s best interests or maybe even personal preferences.
\nECMO is a costly, resource-intensive therapy requiring commitment from the patient, family, and multiple disciplines. The impact of caring for an ECMO patient puts a mental and physical strain, not only on the patient and family but the entire medical team involved in the patient’s care. Providing the intense, complex nursing care impacts not only the nursing staff or ECMO provider but the entire nursing unit caring for the patient. Institutions employing the use of ECMO in treating complex, critically ill patients as one of their only means of survival must have a process that addresses the moral and ethical dilemmas that arise from caring for the critically ill. Common questions are “Who receives ECMO treatment?”, “When should support cease?”, and “What is the goal of therapy, quantity or quality of life?”
\nAllocation of nursing resources has become undoubtedly one of the most challenging aspects in caring for patients and families. Nursing staff ratios, complexity of patients, and the mental and physical impact on the bedside nurse become compounded when one critically ill patient draws a majority of a unit’s resources. ECMO patients can begin their treatment with significantly unstable hemodynamic parameters requiring multiple blood transfusions, circulatory support with several vasoactive medications, and frequent lab draws pulling a majority of the nursing unit’s resources for the care of one patient. This places an enormous burden on the nursing staff to be creative and flexible with patient care assignments. RN:patient ratios may be less than desirable, ultimately impacting the care provided to other patients on the unit as well. Everyone, from the unit manger to housekeeping, plays a hands-on role in supporting the entire unit as well as the ECMO care team.
\nHow do we reduce some of the ethical or moral dilemmas nurses experience caring for complex, critically ill patients? Communication is the key in healthcare. An integral part of communication is developing and maintaining a team not isolated to healthcare workers but also including the patient and family. Early involvement of the palliative care team and social work is crucial to providing consistent support to the patient and family. Interdisciplinary daily rounds including the bedside nurse, family members, palliative care team, and social work are integral to find commonalities for all regarding goals of care. If conflict arises about treatment benefits or burden and the patient’s best interest is no longer being served, support from the ethics committee can be beneficial to the family and healthcare team. These are just the foundation. In critical care nursing, it is important that the nursing staff’s voice be heard. It is vital to recognize the nursing assessment of not just the patient but the situation and to be included in the decision-making that nurses are ultimately responsible for performing.
\nUnfortunately, despite a team’s best efforts, an ECMO patient may continue to decline, with multiple organ systems failing or a devastating systemic event. In such cases, withdrawing care may be imminent, and the question must be asked of the patient and family should be “is the patient’s preference quantity or quality of life?” Can the patient make their wishes known? In the case of bridge-to-transplant, patients may be able to make their wishes known to their families and healthcare team. For the critically ill patient who is dependent on their family or the healthcare team for their medical decisions, is this truly representative of what the patient’s wishes would be? Does conflict arise between the healthcare team and family regarding withdrawal of care? These questions are applicable in any situation involving ECMO; however, they cannot be answered algorithmically or methodically, as they need to be answered uniquely to each situation.
\nNurses are in a unique position in healthcare. They are at the bedside for 8- or 12-hour shifts as most consistent patient advocate. They support and inform family members and build personal and emotional bonds with them. Although valuable, this rapport can be morally taxing to the bedside RN. As nurses witness a patient and families suffering during clinical decline, they begin to question the continued aggressiveness of care that likely will not benefit from treatment, thus causing moral distress to the nursing staff. Sadness, frustration, and anxiety felt by the nursing staff for prolonged periods of time can lead to staff burnout, job dissatisfaction, and decreased staff retention.
\nThe ECMO patient is often the most critically ill within the hospital at any given moment, prompting highly trained bedside RNs as well as other healthcare providers, familiar with the therapy, to be readily available to provide the multifaceted care this population requires. In addition to routine ICU care, the ECMO patient necessitates additional monitoring due to associated risk factors assumed when being placed on pump. Medical, ethical, and emotional considerations exist and must be addressed regularly in order to provide the best care of this unique patient population. Despite high mortality associated with ECMO, the survivability continues to increase as time progresses and the bedside RN will continue to be responsible for vital functions in continuing that trend.
\nSupporting women in scientific research and encouraging more women to pursue careers in STEM fields has been an issue on the global agenda for many years. But there is still much to be done. And IntechOpen wants to help.
",metaTitle:"IntechOpen Women in Science Program",metaDescription:"Supporting women in scientific research and encouraging more women to pursue careers in STEM fields has been an issue on the global agenda for many years. But there is still much to be done. And IntechOpen wants to help.",metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"At IntechOpen, we’re laying the foundations for the future by publishing the best research by women in STEM – Open Access and available to all. Our Women in Science program already includes six books in progress by award-winning women scientists on topics ranging from physics to robotics, medicine to environmental science. Our editors come from all over the globe and include L’Oreal–UNESCO For Women in Science award-winners and National Science Foundation and European Commission grant recipients.
\\n\\nWe aim to publish 100 books in our Women in Science program over the next three years. We are looking for books written, edited, or co-edited by women. Contributing chapters by men are welcome. As always, the quality of the research we publish is paramount.
\\n\\nAll project proposals go through a two-stage peer review process and are selected based on the following criteria:
\\n\\nPlus, we want this project to have an impact beyond scientific circles. We will publicize the research in the Women in Science program for a wider general audience through:
\\n\\nInterested? If you have an idea for an edited volume or a monograph, we’d love to hear from you! Contact Ana Pantar at book.idea@intechopen.com.
\\n\\n“My scientific path has given me the opportunity to work with colleagues all over Europe, including Germany, France, and Norway. Editing the book Graph Theory: Advanced Algorithms and Applications with IntechOpen emphasized for me the importance of providing valuable, Open Access literature to our scientific colleagues around the world. So I am highly enthusiastic about the Women in Science book collection, which will highlight the outstanding accomplishments of women scientists and encourage others to walk the challenging path to becoming a recognized scientist." Beril Sirmacek, TU Delft, The Netherlands
\\n\\nAdvantages of Publishing with IntechOpen
\\n\\n\\n"}]'},components:[{type:"htmlEditorComponent",content:'At IntechOpen, we’re laying the foundations for the future by publishing the best research by women in STEM – Open Access and available to all. Our Women in Science program already includes six books in progress by award-winning women scientists on topics ranging from physics to robotics, medicine to environmental science. Our editors come from all over the globe and include L’Oreal–UNESCO For Women in Science award-winners and National Science Foundation and European Commission grant recipients.
\n\nWe aim to publish 100 books in our Women in Science program over the next three years. We are looking for books written, edited, or co-edited by women. Contributing chapters by men are welcome. As always, the quality of the research we publish is paramount.
\n\nAll project proposals go through a two-stage peer review process and are selected based on the following criteria:
\n\nPlus, we want this project to have an impact beyond scientific circles. We will publicize the research in the Women in Science program for a wider general audience through:
\n\nInterested? If you have an idea for an edited volume or a monograph, we’d love to hear from you! Contact Ana Pantar at book.idea@intechopen.com.
\n\n“My scientific path has given me the opportunity to work with colleagues all over Europe, including Germany, France, and Norway. Editing the book Graph Theory: Advanced Algorithms and Applications with IntechOpen emphasized for me the importance of providing valuable, Open Access literature to our scientific colleagues around the world. So I am highly enthusiastic about the Women in Science book collection, which will highlight the outstanding accomplishments of women scientists and encourage others to walk the challenging path to becoming a recognized scientist." Beril Sirmacek, TU Delft, The Netherlands
\n\n\n\n\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5698},{group:"region",caption:"Middle and South America",value:2,count:5172},{group:"region",caption:"Africa",value:3,count:1689},{group:"region",caption:"Asia",value:4,count:10244},{group:"region",caption:"Australia and Oceania",value:5,count:888},{group:"region",caption:"Europe",value:6,count:15650}],offset:12,limit:12,total:117315},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{topicId:"23"},books:[{type:"book",id:"9538",title:"Demographic Analysis - Selected Concepts, Tools, and Applications",subtitle:null,isOpenForSubmission:!0,hash:"f335c5d0a39e8631d8627546e14ce61f",slug:null,bookSignature:"Ph.D. Andrzej Klimczuk",coverURL:"https://cdn.intechopen.com/books/images_new/9538.jpg",editedByType:null,editors:[{id:"320017",title:"Ph.D.",name:"Andrzej",surname:"Klimczuk",slug:"andrzej-klimczuk",fullName:"Andrzej Klimczuk"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10207",title:"Sexual Abuse - an Interdisciplinary Approach",subtitle:null,isOpenForSubmission:!0,hash:"e1ec1d5a7093490df314d7887e0b3809",slug:null,bookSignature:"Dr. Ersi Abaci Kalfoglou and Dr. Sotirios Kalfoglou",coverURL:"https://cdn.intechopen.com/books/images_new/10207.jpg",editedByType:null,editors:[{id:"68678",title:"Dr.",name:"Ersi Abaci",surname:"Kalfoglou",slug:"ersi-abaci-kalfoglou",fullName:"Ersi Abaci Kalfoglou"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10660",title:"Heritage",subtitle:null,isOpenForSubmission:!0,hash:"14096773aa1e3635ec6ceec6dd5b47a4",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10660.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10662",title:"Pedagogy",subtitle:null,isOpenForSubmission:!0,hash:"c858e1c6fb878d3b895acbacec624576",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10662.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10811",title:"Urban Transition - Perspectives on Urban Systems and Environments",subtitle:null,isOpenForSubmission:!0,hash:"4885cfa30ba6184b0da9f575aee65998",slug:null,bookSignature:"Ph.D. Marita Wallhagen and Dr. Mathias Cehlin",coverURL:"https://cdn.intechopen.com/books/images_new/10811.jpg",editedByType:null,editors:[{id:"337569",title:"Ph.D.",name:"Marita",surname:"Wallhagen",slug:"marita-wallhagen",fullName:"Marita Wallhagen"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10911",title:"Higher Education",subtitle:null,isOpenForSubmission:!0,hash:"c76f86ebdc949d57e4a7bdbec100e66b",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10911.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10913",title:"Indigenous Populations",subtitle:null,isOpenForSubmission:!0,hash:"c5e8cd4e3ec004d0479494ca190db4cb",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10913.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10914",title:"Racism",subtitle:null,isOpenForSubmission:!0,hash:"0737383fcc202641f59e4a5df02eb509",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10914.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:9},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:18},{group:"topic",caption:"Business, Management and Economics",value:7,count:2},{group:"topic",caption:"Chemistry",value:8,count:7},{group:"topic",caption:"Computer and Information Science",value:9,count:11},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:5},{group:"topic",caption:"Engineering",value:11,count:15},{group:"topic",caption:"Environmental Sciences",value:12,count:2},{group:"topic",caption:"Immunology and Microbiology",value:13,count:5},{group:"topic",caption:"Materials Science",value:14,count:4},{group:"topic",caption:"Mathematics",value:15,count:1},{group:"topic",caption:"Medicine",value:16,count:62},{group:"topic",caption:"Nanotechnology and Nanomaterials",value:17,count:1},{group:"topic",caption:"Neuroscience",value:18,count:1},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:6},{group:"topic",caption:"Physics",value:20,count:2},{group:"topic",caption:"Psychology",value:21,count:3},{group:"topic",caption:"Robotics",value:22,count:1},{group:"topic",caption:"Social Sciences",value:23,count:3},{group:"topic",caption:"Technology",value:24,count:1},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:2}],offset:12,limit:12,total:8},popularBooks:{featuredBooks:[{type:"book",id:"7802",title:"Modern Slavery and Human Trafficking",subtitle:null,isOpenForSubmission:!1,hash:"587a0b7fb765f31cc98de33c6c07c2e0",slug:"modern-slavery-and-human-trafficking",bookSignature:"Jane Reeves",coverURL:"https://cdn.intechopen.com/books/images_new/7802.jpg",editors:[{id:"211328",title:"Prof.",name:"Jane",middleName:null,surname:"Reeves",slug:"jane-reeves",fullName:"Jane Reeves"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8545",title:"Animal Reproduction in Veterinary Medicine",subtitle:null,isOpenForSubmission:!1,hash:"13aaddf5fdbbc78387e77a7da2388bf6",slug:"animal-reproduction-in-veterinary-medicine",bookSignature:"Faruk Aral, Rita Payan-Carreira and Miguel Quaresma",coverURL:"https://cdn.intechopen.com/books/images_new/8545.jpg",editors:[{id:"25600",title:"Prof.",name:"Faruk",middleName:null,surname:"Aral",slug:"faruk-aral",fullName:"Faruk Aral"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9961",title:"Data Mining",subtitle:"Methods, Applications and Systems",isOpenForSubmission:!1,hash:"ed79fb6364f2caf464079f94a0387146",slug:"data-mining-methods-applications-and-systems",bookSignature:"Derya Birant",coverURL:"https://cdn.intechopen.com/books/images_new/9961.jpg",editors:[{id:"15609",title:"Dr.",name:"Derya",middleName:null,surname:"Birant",slug:"derya-birant",fullName:"Derya Birant"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9157",title:"Neurodegenerative Diseases",subtitle:"Molecular Mechanisms and Current Therapeutic Approaches",isOpenForSubmission:!1,hash:"bc8be577966ef88735677d7e1e92ed28",slug:"neurodegenerative-diseases-molecular-mechanisms-and-current-therapeutic-approaches",bookSignature:"Nagehan Ersoy Tunalı",coverURL:"https://cdn.intechopen.com/books/images_new/9157.jpg",editors:[{id:"82778",title:"Ph.D.",name:"Nagehan",middleName:null,surname:"Ersoy Tunalı",slug:"nagehan-ersoy-tunali",fullName:"Nagehan Ersoy Tunalı"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8686",title:"Direct Torque Control Strategies of Electrical Machines",subtitle:null,isOpenForSubmission:!1,hash:"b6ad22b14db2b8450228545d3d4f6b1a",slug:"direct-torque-control-strategies-of-electrical-machines",bookSignature:"Fatma Ben Salem",coverURL:"https://cdn.intechopen.com/books/images_new/8686.jpg",editors:[{id:"295623",title:"Associate Prof.",name:"Fatma",middleName:null,surname:"Ben Salem",slug:"fatma-ben-salem",fullName:"Fatma Ben Salem"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7434",title:"Molecular Biotechnology",subtitle:null,isOpenForSubmission:!1,hash:"eceede809920e1ec7ecadd4691ede2ec",slug:"molecular-biotechnology",bookSignature:"Sergey Sedykh",coverURL:"https://cdn.intechopen.com/books/images_new/7434.jpg",editors:[{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",slug:"sergey-sedykh",fullName:"Sergey Sedykh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9839",title:"Outdoor Recreation",subtitle:"Physiological and Psychological Effects on Health",isOpenForSubmission:!1,hash:"5f5a0d64267e32567daffa5b0c6a6972",slug:"outdoor-recreation-physiological-and-psychological-effects-on-health",bookSignature:"Hilde G. Nielsen",coverURL:"https://cdn.intechopen.com/books/images_new/9839.jpg",editors:[{id:"158692",title:"Ph.D.",name:"Hilde G.",middleName:null,surname:"Nielsen",slug:"hilde-g.-nielsen",fullName:"Hilde G. Nielsen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9208",title:"Welding",subtitle:"Modern Topics",isOpenForSubmission:!1,hash:"7d6be076ccf3a3f8bd2ca52d86d4506b",slug:"welding-modern-topics",bookSignature:"Sadek Crisóstomo Absi Alfaro, Wojciech Borek and Błażej Tomiczek",coverURL:"https://cdn.intechopen.com/books/images_new/9208.jpg",editors:[{id:"65292",title:"Prof.",name:"Sadek Crisostomo Absi",middleName:"C. Absi",surname:"Alfaro",slug:"sadek-crisostomo-absi-alfaro",fullName:"Sadek Crisostomo Absi Alfaro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9139",title:"Topics in Primary Care Medicine",subtitle:null,isOpenForSubmission:!1,hash:"ea774a4d4c1179da92a782e0ae9cde92",slug:"topics-in-primary-care-medicine",bookSignature:"Thomas F. Heston",coverURL:"https://cdn.intechopen.com/books/images_new/9139.jpg",editors:[{id:"217926",title:"Dr.",name:"Thomas F.",middleName:null,surname:"Heston",slug:"thomas-f.-heston",fullName:"Thomas F. Heston"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9343",title:"Trace Metals in the Environment",subtitle:"New Approaches and Recent Advances",isOpenForSubmission:!1,hash:"ae07e345bc2ce1ebbda9f70c5cd12141",slug:"trace-metals-in-the-environment-new-approaches-and-recent-advances",bookSignature:"Mario Alfonso Murillo-Tovar, Hugo Saldarriaga-Noreña and Agnieszka Saeid",coverURL:"https://cdn.intechopen.com/books/images_new/9343.jpg",editors:[{id:"255959",title:"Dr.",name:"Mario Alfonso",middleName:null,surname:"Murillo-Tovar",slug:"mario-alfonso-murillo-tovar",fullName:"Mario Alfonso Murillo-Tovar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8697",title:"Virtual Reality and Its Application in Education",subtitle:null,isOpenForSubmission:!1,hash:"ee01b5e387ba0062c6b0d1e9227bda05",slug:"virtual-reality-and-its-application-in-education",bookSignature:"Dragan Cvetković",coverURL:"https://cdn.intechopen.com/books/images_new/8697.jpg",editors:[{id:"101330",title:"Dr.",name:"Dragan",middleName:"Mladen",surname:"Cvetković",slug:"dragan-cvetkovic",fullName:"Dragan Cvetković"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7831",title:"Sustainability in Urban Planning and Design",subtitle:null,isOpenForSubmission:!1,hash:"c924420492c8c2c9751e178d025f4066",slug:"sustainability-in-urban-planning-and-design",bookSignature:"Amjad Almusaed, Asaad Almssad and Linh Truong - Hong",coverURL:"https://cdn.intechopen.com/books/images_new/7831.jpg",editors:[{id:"110471",title:"Dr.",name:"Amjad",middleName:"Zaki",surname:"Almusaed",slug:"amjad-almusaed",fullName:"Amjad Almusaed"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5141},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"9208",title:"Welding",subtitle:"Modern Topics",isOpenForSubmission:!1,hash:"7d6be076ccf3a3f8bd2ca52d86d4506b",slug:"welding-modern-topics",bookSignature:"Sadek Crisóstomo Absi Alfaro, Wojciech Borek and Błażej Tomiczek",coverURL:"https://cdn.intechopen.com/books/images_new/9208.jpg",editors:[{id:"65292",title:"Prof.",name:"Sadek Crisostomo Absi",middleName:"C. Absi",surname:"Alfaro",slug:"sadek-crisostomo-absi-alfaro",fullName:"Sadek Crisostomo Absi Alfaro"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9139",title:"Topics in Primary Care Medicine",subtitle:null,isOpenForSubmission:!1,hash:"ea774a4d4c1179da92a782e0ae9cde92",slug:"topics-in-primary-care-medicine",bookSignature:"Thomas F. Heston",coverURL:"https://cdn.intechopen.com/books/images_new/9139.jpg",editors:[{id:"217926",title:"Dr.",name:"Thomas F.",middleName:null,surname:"Heston",slug:"thomas-f.-heston",fullName:"Thomas F. Heston"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8697",title:"Virtual Reality and Its Application in Education",subtitle:null,isOpenForSubmission:!1,hash:"ee01b5e387ba0062c6b0d1e9227bda05",slug:"virtual-reality-and-its-application-in-education",bookSignature:"Dragan Cvetković",coverURL:"https://cdn.intechopen.com/books/images_new/8697.jpg",editors:[{id:"101330",title:"Dr.",name:"Dragan",middleName:"Mladen",surname:"Cvetković",slug:"dragan-cvetkovic",fullName:"Dragan Cvetković"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9343",title:"Trace Metals in the Environment",subtitle:"New Approaches and Recent Advances",isOpenForSubmission:!1,hash:"ae07e345bc2ce1ebbda9f70c5cd12141",slug:"trace-metals-in-the-environment-new-approaches-and-recent-advances",bookSignature:"Mario Alfonso Murillo-Tovar, Hugo Saldarriaga-Noreña and Agnieszka Saeid",coverURL:"https://cdn.intechopen.com/books/images_new/9343.jpg",editors:[{id:"255959",title:"Dr.",name:"Mario Alfonso",middleName:null,surname:"Murillo-Tovar",slug:"mario-alfonso-murillo-tovar",fullName:"Mario Alfonso Murillo-Tovar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9785",title:"Endometriosis",subtitle:null,isOpenForSubmission:!1,hash:"f457ca61f29cf7e8bc191732c50bb0ce",slug:"endometriosis",bookSignature:"Courtney Marsh",coverURL:"https://cdn.intechopen.com/books/images_new/9785.jpg",editors:[{id:"255491",title:"Dr.",name:"Courtney",middleName:null,surname:"Marsh",slug:"courtney-marsh",fullName:"Courtney Marsh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7831",title:"Sustainability in Urban Planning and Design",subtitle:null,isOpenForSubmission:!1,hash:"c924420492c8c2c9751e178d025f4066",slug:"sustainability-in-urban-planning-and-design",bookSignature:"Amjad Almusaed, Asaad Almssad and Linh Truong - Hong",coverURL:"https://cdn.intechopen.com/books/images_new/7831.jpg",editors:[{id:"110471",title:"Dr.",name:"Amjad",middleName:"Zaki",surname:"Almusaed",slug:"amjad-almusaed",fullName:"Amjad Almusaed"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9376",title:"Contemporary Developments and Perspectives in International Health Security",subtitle:"Volume 1",isOpenForSubmission:!1,hash:"b9a00b84cd04aae458fb1d6c65795601",slug:"contemporary-developments-and-perspectives-in-international-health-security-volume-1",bookSignature:"Stanislaw P. Stawicki, Michael S. Firstenberg, Sagar C. Galwankar, Ricardo Izurieta and Thomas Papadimos",coverURL:"https://cdn.intechopen.com/books/images_new/9376.jpg",editors:[{id:"181694",title:"Dr.",name:"Stanislaw P.",middleName:null,surname:"Stawicki",slug:"stanislaw-p.-stawicki",fullName:"Stanislaw P. Stawicki"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7769",title:"Medical Isotopes",subtitle:null,isOpenForSubmission:!1,hash:"f8d3c5a6c9a42398e56b4e82264753f7",slug:"medical-isotopes",bookSignature:"Syed Ali Raza Naqvi and Muhammad Babar Imrani",coverURL:"https://cdn.intechopen.com/books/images_new/7769.jpg",editors:[{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9279",title:"Concepts, Applications and Emerging Opportunities in Industrial Engineering",subtitle:null,isOpenForSubmission:!1,hash:"9bfa87f9b627a5468b7c1e30b0eea07a",slug:"concepts-applications-and-emerging-opportunities-in-industrial-engineering",bookSignature:"Gary Moynihan",coverURL:"https://cdn.intechopen.com/books/images_new/9279.jpg",editors:[{id:"16974",title:"Dr.",name:"Gary",middleName:null,surname:"Moynihan",slug:"gary-moynihan",fullName:"Gary Moynihan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7807",title:"A Closer Look at Organizational Culture in Action",subtitle:null,isOpenForSubmission:!1,hash:"05c608b9271cc2bc711f4b28748b247b",slug:"a-closer-look-at-organizational-culture-in-action",bookSignature:"Süleyman Davut Göker",coverURL:"https://cdn.intechopen.com/books/images_new/7807.jpg",editors:[{id:"190035",title:"Associate Prof.",name:"Süleyman Davut",middleName:null,surname:"Göker",slug:"suleyman-davut-goker",fullName:"Süleyman Davut Göker"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"7434",title:"Molecular Biotechnology",subtitle:null,isOpenForSubmission:!1,hash:"eceede809920e1ec7ecadd4691ede2ec",slug:"molecular-biotechnology",bookSignature:"Sergey Sedykh",coverURL:"https://cdn.intechopen.com/books/images_new/7434.jpg",editedByType:"Edited by",editors:[{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",slug:"sergey-sedykh",fullName:"Sergey Sedykh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8545",title:"Animal Reproduction in Veterinary Medicine",subtitle:null,isOpenForSubmission:!1,hash:"13aaddf5fdbbc78387e77a7da2388bf6",slug:"animal-reproduction-in-veterinary-medicine",bookSignature:"Faruk Aral, Rita Payan-Carreira and Miguel Quaresma",coverURL:"https://cdn.intechopen.com/books/images_new/8545.jpg",editedByType:"Edited by",editors:[{id:"25600",title:"Prof.",name:"Faruk",middleName:null,surname:"Aral",slug:"faruk-aral",fullName:"Faruk Aral"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9569",title:"Methods in Molecular Medicine",subtitle:null,isOpenForSubmission:!1,hash:"691d3f3c4ac25a8093414e9b270d2843",slug:"methods-in-molecular-medicine",bookSignature:"Yusuf Tutar",coverURL:"https://cdn.intechopen.com/books/images_new/9569.jpg",editedByType:"Edited by",editors:[{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9839",title:"Outdoor Recreation",subtitle:"Physiological and Psychological Effects on Health",isOpenForSubmission:!1,hash:"5f5a0d64267e32567daffa5b0c6a6972",slug:"outdoor-recreation-physiological-and-psychological-effects-on-health",bookSignature:"Hilde G. Nielsen",coverURL:"https://cdn.intechopen.com/books/images_new/9839.jpg",editedByType:"Edited by",editors:[{id:"158692",title:"Ph.D.",name:"Hilde G.",middleName:null,surname:"Nielsen",slug:"hilde-g.-nielsen",fullName:"Hilde G. Nielsen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7802",title:"Modern Slavery and Human Trafficking",subtitle:null,isOpenForSubmission:!1,hash:"587a0b7fb765f31cc98de33c6c07c2e0",slug:"modern-slavery-and-human-trafficking",bookSignature:"Jane Reeves",coverURL:"https://cdn.intechopen.com/books/images_new/7802.jpg",editedByType:"Edited by",editors:[{id:"211328",title:"Prof.",name:"Jane",middleName:null,surname:"Reeves",slug:"jane-reeves",fullName:"Jane Reeves"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8063",title:"Food Security in Africa",subtitle:null,isOpenForSubmission:!1,hash:"8cbf3d662b104d19db2efc9d59249efc",slug:"food-security-in-africa",bookSignature:"Barakat Mahmoud",coverURL:"https://cdn.intechopen.com/books/images_new/8063.jpg",editedByType:"Edited by",editors:[{id:"92016",title:"Dr.",name:"Barakat",middleName:null,surname:"Mahmoud",slug:"barakat-mahmoud",fullName:"Barakat Mahmoud"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10118",title:"Plant Stress Physiology",subtitle:null,isOpenForSubmission:!1,hash:"c68b09d2d2634fc719ae3b9a64a27839",slug:"plant-stress-physiology",bookSignature:"Akbar Hossain",coverURL:"https://cdn.intechopen.com/books/images_new/10118.jpg",editedByType:"Edited by",editors:[{id:"280755",title:"Dr.",name:"Akbar",middleName:null,surname:"Hossain",slug:"akbar-hossain",fullName:"Akbar Hossain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9157",title:"Neurodegenerative Diseases",subtitle:"Molecular Mechanisms and Current Therapeutic Approaches",isOpenForSubmission:!1,hash:"bc8be577966ef88735677d7e1e92ed28",slug:"neurodegenerative-diseases-molecular-mechanisms-and-current-therapeutic-approaches",bookSignature:"Nagehan Ersoy Tunalı",coverURL:"https://cdn.intechopen.com/books/images_new/9157.jpg",editedByType:"Edited by",editors:[{id:"82778",title:"Ph.D.",name:"Nagehan",middleName:null,surname:"Ersoy Tunalı",slug:"nagehan-ersoy-tunali",fullName:"Nagehan Ersoy Tunalı"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9961",title:"Data Mining",subtitle:"Methods, Applications and Systems",isOpenForSubmission:!1,hash:"ed79fb6364f2caf464079f94a0387146",slug:"data-mining-methods-applications-and-systems",bookSignature:"Derya Birant",coverURL:"https://cdn.intechopen.com/books/images_new/9961.jpg",editedByType:"Edited by",editors:[{id:"15609",title:"Dr.",name:"Derya",middleName:null,surname:"Birant",slug:"derya-birant",fullName:"Derya Birant"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8686",title:"Direct Torque Control Strategies of Electrical Machines",subtitle:null,isOpenForSubmission:!1,hash:"b6ad22b14db2b8450228545d3d4f6b1a",slug:"direct-torque-control-strategies-of-electrical-machines",bookSignature:"Fatma Ben Salem",coverURL:"https://cdn.intechopen.com/books/images_new/8686.jpg",editedByType:"Edited by",editors:[{id:"295623",title:"Associate Prof.",name:"Fatma",middleName:null,surname:"Ben Salem",slug:"fatma-ben-salem",fullName:"Fatma Ben Salem"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"1175",title:"Neuroplasticity",slug:"neuroplasticity",parent:{title:"Neurobiology",slug:"life-sciences-neuroscience-neurobiology"},numberOfBooks:3,numberOfAuthorsAndEditors:70,numberOfWosCitations:10,numberOfCrossrefCitations:14,numberOfDimensionsCitations:40,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"neuroplasticity",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"6250",title:"The Hippocampus",subtitle:"Plasticity and Functions",isOpenForSubmission:!1,hash:"78f1e57726307f003f39510c175c3102",slug:"the-hippocampus-plasticity-and-functions",bookSignature:"Ales Stuchlik",coverURL:"https://cdn.intechopen.com/books/images_new/6250.jpg",editedByType:"Edited by",editors:[{id:"207908",title:"Dr.",name:"Ales",middleName:null,surname:"Stuchlik",slug:"ales-stuchlik",fullName:"Ales Stuchlik"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6092",title:"Neuroplasticity",subtitle:"Insights of Neural Reorganization",isOpenForSubmission:!1,hash:"1003fc63680b1c04e9135f3dea18a8c3",slug:"neuroplasticity-insights-of-neural-reorganization",bookSignature:"Victor V. Chaban",coverURL:"https://cdn.intechopen.com/books/images_new/6092.jpg",editedByType:"Edited by",editors:[{id:"83427",title:"Prof.",name:"Victor",middleName:null,surname:"Chaban",slug:"victor-chaban",fullName:"Victor Chaban"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5521",title:"Synaptic Plasticity",subtitle:null,isOpenForSubmission:!1,hash:"9eea3c7f926cd466ddd14ab777b663d8",slug:"synaptic-plasticity",bookSignature:"Thomas Heinbockel",coverURL:"https://cdn.intechopen.com/books/images_new/5521.jpg",editedByType:"Edited by",editors:[{id:"70569",title:"Dr.",name:"Thomas",middleName:null,surname:"Heinbockel",slug:"thomas-heinbockel",fullName:"Thomas Heinbockel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:3,mostCitedChapters:[{id:"57827",doi:"10.5772/intechopen.71165",title:"A Role for the Longitudinal Axis of the Hippocampus in Multiscale Representations of Large and Complex Spatial Environments and Mnemonic Hierarchies",slug:"a-role-for-the-longitudinal-axis-of-the-hippocampus-in-multiscale-representations-of-large-and-compl",totalDownloads:680,totalCrossrefCites:3,totalDimensionsCites:6,book:{slug:"the-hippocampus-plasticity-and-functions",title:"The Hippocampus",fullTitle:"The Hippocampus - Plasticity and Functions"},signatures:"Bruce Harland, Marcos Contreras and Jean-Marc Fellous",authors:[{id:"210681",title:"Dr.",name:"Bruce",middleName:null,surname:"Harland",slug:"bruce-harland",fullName:"Bruce Harland"},{id:"210682",title:"Dr.",name:"Marco",middleName:null,surname:"Contreras",slug:"marco-contreras",fullName:"Marco Contreras"},{id:"210683",title:"Prof.",name:"Jean-Marc",middleName:null,surname:"Fellous",slug:"jean-marc-fellous",fullName:"Jean-Marc Fellous"}]},{id:"54143",doi:"10.5772/67127",title:"Plasticity of Dendritic Spines. Not Only for Cognitive Processes",slug:"plasticity-of-dendritic-spines-not-only-for-cognitive-processes",totalDownloads:928,totalCrossrefCites:0,totalDimensionsCites:6,book:{slug:"synaptic-plasticity",title:"Synaptic Plasticity",fullTitle:"Synaptic Plasticity"},signatures:"Ignacio González-Burgos, Dulce A. Velázquez-Zamora, David\nGonzález-Tapia, Nallely Vázquez-Hernández and Néstor I. Martínez-\nTorres",authors:[{id:"190521",title:"Dr.",name:"Ignacio",middleName:null,surname:"Gonzalez-Burgos",slug:"ignacio-gonzalez-burgos",fullName:"Ignacio Gonzalez-Burgos"},{id:"196267",title:"Dr.",name:"Dulce A",middleName:null,surname:"Velázquez-Zamora",slug:"dulce-a-velazquez-zamora",fullName:"Dulce A Velázquez-Zamora"},{id:"196269",title:"MSc.",name:"David",middleName:null,surname:"González-Tapia",slug:"david-gonzalez-tapia",fullName:"David González-Tapia"},{id:"196270",title:"MSc.",name:"Nallely",middleName:null,surname:"Vázquez-Hernández",slug:"nallely-vazquez-hernandez",fullName:"Nallely Vázquez-Hernández"},{id:"196271",title:"MSc.",name:"Nestor I",middleName:null,surname:"Martínez-Torres",slug:"nestor-i-martinez-torres",fullName:"Nestor I Martínez-Torres"}]},{id:"57312",doi:"10.5772/intechopen.70854",title:"The Hippocampus as a Neural Link between Negative Affect and Vulnerability for Psychostimulant Relapse",slug:"the-hippocampus-as-a-neural-link-between-negative-affect-and-vulnerability-for-psychostimulant-relap",totalDownloads:876,totalCrossrefCites:1,totalDimensionsCites:4,book:{slug:"the-hippocampus-plasticity-and-functions",title:"The Hippocampus",fullTitle:"The Hippocampus - Plasticity and Functions"},signatures:"Jeffrey L. Barr, Brenna Bray and Gina L. Forster",authors:[{id:"145620",title:"Dr.",name:"Gina",middleName:null,surname:"Forster",slug:"gina-forster",fullName:"Gina Forster"},{id:"219827",title:"Dr.",name:"Jeffrey",middleName:null,surname:"Barr",slug:"jeffrey-barr",fullName:"Jeffrey Barr"},{id:"219828",title:"BSc.",name:"Brenna",middleName:null,surname:"Bray",slug:"brenna-bray",fullName:"Brenna Bray"}]}],mostDownloadedChaptersLast30Days:[{id:"59437",title:"Music and Brain Plasticity: How Sounds Trigger Neurogenerative Adaptations",slug:"music-and-brain-plasticity-how-sounds-trigger-neurogenerative-adaptations",totalDownloads:1321,totalCrossrefCites:2,totalDimensionsCites:3,book:{slug:"neuroplasticity-insights-of-neural-reorganization",title:"Neuroplasticity",fullTitle:"Neuroplasticity - Insights of Neural Reorganization"},signatures:"Mark Reybrouck, Peter Vuust and Elvira Brattico",authors:[{id:"196698",title:"Prof.",name:"Mark",middleName:null,surname:"Reybrouck",slug:"mark-reybrouck",fullName:"Mark Reybrouck"},{id:"209976",title:"Prof.",name:"Elvira",middleName:null,surname:"Brattico",slug:"elvira-brattico",fullName:"Elvira Brattico"},{id:"209977",title:"Prof.",name:"Peter",middleName:null,surname:"Vuust",slug:"peter-vuust",fullName:"Peter Vuust"}]},{id:"54566",title:"Introductory Chapter: Mechanisms and Function of Synaptic Plasticity",slug:"introductory-chapter-mechanisms-and-function-of-synaptic-plasticity",totalDownloads:1594,totalCrossrefCites:3,totalDimensionsCites:3,book:{slug:"synaptic-plasticity",title:"Synaptic Plasticity",fullTitle:"Synaptic Plasticity"},signatures:"Thomas Heinbockel",authors:[{id:"70569",title:"Dr.",name:"Thomas",middleName:null,surname:"Heinbockel",slug:"thomas-heinbockel",fullName:"Thomas Heinbockel"}]},{id:"57312",title:"The Hippocampus as a Neural Link between Negative Affect and Vulnerability for Psychostimulant Relapse",slug:"the-hippocampus-as-a-neural-link-between-negative-affect-and-vulnerability-for-psychostimulant-relap",totalDownloads:876,totalCrossrefCites:1,totalDimensionsCites:4,book:{slug:"the-hippocampus-plasticity-and-functions",title:"The Hippocampus",fullTitle:"The Hippocampus - Plasticity and Functions"},signatures:"Jeffrey L. Barr, Brenna Bray and Gina L. Forster",authors:[{id:"145620",title:"Dr.",name:"Gina",middleName:null,surname:"Forster",slug:"gina-forster",fullName:"Gina Forster"},{id:"219827",title:"Dr.",name:"Jeffrey",middleName:null,surname:"Barr",slug:"jeffrey-barr",fullName:"Jeffrey Barr"},{id:"219828",title:"BSc.",name:"Brenna",middleName:null,surname:"Bray",slug:"brenna-bray",fullName:"Brenna Bray"}]},{id:"53848",title:"Plasticity in Damaged Multisensory Networks",slug:"plasticity-in-damaged-multisensory-networks",totalDownloads:933,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"synaptic-plasticity",title:"Synaptic Plasticity",fullTitle:"Synaptic Plasticity"},signatures:"Karolina A Bearss and Joseph FX DeSouza",authors:[{id:"192667",title:"Prof.",name:"Joseph",middleName:null,surname:"DeSouza",slug:"joseph-desouza",fullName:"Joseph DeSouza"},{id:"192780",title:"Ph.D.",name:"Karolina",middleName:"Anna",surname:"Bearss",slug:"karolina-bearss",fullName:"Karolina Bearss"}]},{id:"53929",title:"Mitochondrial Regulators of Synaptic Plasticity in the Ischemic Brain",slug:"mitochondrial-regulators-of-synaptic-plasticity-in-the-ischemic-brain",totalDownloads:1061,totalCrossrefCites:0,totalDimensionsCites:2,book:{slug:"synaptic-plasticity",title:"Synaptic Plasticity",fullTitle:"Synaptic Plasticity"},signatures:"Han-A Park and Elizabeth A. Jonas",authors:[{id:"192869",title:"Prof.",name:"Elizabeth",middleName:null,surname:"Jonas",slug:"elizabeth-jonas",fullName:"Elizabeth Jonas"},{id:"194069",title:"Dr.",name:"Han-A",middleName:null,surname:"Park",slug:"han-a-park",fullName:"Han-A Park"}]},{id:"55453",title:"Synaptic Plasticity by Afferent Electrical Stimulation",slug:"synaptic-plasticity-by-afferent-electrical-stimulation",totalDownloads:983,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"synaptic-plasticity",title:"Synaptic Plasticity",fullTitle:"Synaptic Plasticity"},signatures:"Stefan Golaszewski",authors:[{id:"54888",title:"Prof.",name:"Stefan",middleName:null,surname:"Golaszewski",slug:"stefan-golaszewski",fullName:"Stefan Golaszewski"}]},{id:"53927",title:"GABAergic Synapse Dysfunction and Repair in Temporal Lobe Epilepsy",slug:"gabaergic-synapse-dysfunction-and-repair-in-temporal-lobe-epilepsy",totalDownloads:1087,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"synaptic-plasticity",title:"Synaptic Plasticity",fullTitle:"Synaptic Plasticity"},signatures:"Meghan A. Van Zandt and Janice R. Naegele",authors:[{id:"154904",title:"Prof.",name:"Janice",middleName:null,surname:"Naegele",slug:"janice-naegele",fullName:"Janice Naegele"},{id:"194530",title:"Ph.D. Student",name:"Meghan",middleName:null,surname:"Van Zandt",slug:"meghan-van-zandt",fullName:"Meghan Van Zandt"}]},{id:"54067",title:"Neuroplasticity in Bipolar Disorder: Insights from Neuroimaging",slug:"neuroplasticity-in-bipolar-disorder-insights-from-neuroimaging",totalDownloads:1001,totalCrossrefCites:1,totalDimensionsCites:2,book:{slug:"synaptic-plasticity",title:"Synaptic Plasticity",fullTitle:"Synaptic Plasticity"},signatures:"Marlos Vasconcelos Rocha, Fabiana Nery, Amanda Galvão-de-\nAlmeida, Lucas de Castro Quarantini and Ângela Miranda-Scippa",authors:[{id:"192139",title:"Ph.D.",name:"Marlos",middleName:"Vasconcelos",surname:"Rocha",slug:"marlos-rocha",fullName:"Marlos Rocha"},{id:"192876",title:"Dr.",name:"Fabiana",middleName:null,surname:"Nery-Fernandes",slug:"fabiana-nery-fernandes",fullName:"Fabiana Nery-Fernandes"},{id:"192877",title:"Prof.",name:"Ângela",middleName:null,surname:"Miranda-Scippa",slug:"angela-miranda-scippa",fullName:"Ângela Miranda-Scippa"},{id:"192878",title:"Prof.",name:"Lucas",middleName:null,surname:"De Castro Quarantini",slug:"lucas-de-castro-quarantini",fullName:"Lucas De Castro Quarantini"},{id:"192879",title:"Dr.",name:"Giovanna",middleName:null,surname:"Ladeia-Rocha",slug:"giovanna-ladeia-rocha",fullName:"Giovanna Ladeia-Rocha"},{id:"192880",title:"Prof.",name:"Amanda",middleName:null,surname:"Galvão-de Almeida",slug:"amanda-galvao-de-almeida",fullName:"Amanda Galvão-de Almeida"}]},{id:"54143",title:"Plasticity of Dendritic Spines. Not Only for Cognitive Processes",slug:"plasticity-of-dendritic-spines-not-only-for-cognitive-processes",totalDownloads:928,totalCrossrefCites:0,totalDimensionsCites:6,book:{slug:"synaptic-plasticity",title:"Synaptic Plasticity",fullTitle:"Synaptic Plasticity"},signatures:"Ignacio González-Burgos, Dulce A. Velázquez-Zamora, David\nGonzález-Tapia, Nallely Vázquez-Hernández and Néstor I. Martínez-\nTorres",authors:[{id:"190521",title:"Dr.",name:"Ignacio",middleName:null,surname:"Gonzalez-Burgos",slug:"ignacio-gonzalez-burgos",fullName:"Ignacio Gonzalez-Burgos"},{id:"196267",title:"Dr.",name:"Dulce A",middleName:null,surname:"Velázquez-Zamora",slug:"dulce-a-velazquez-zamora",fullName:"Dulce A Velázquez-Zamora"},{id:"196269",title:"MSc.",name:"David",middleName:null,surname:"González-Tapia",slug:"david-gonzalez-tapia",fullName:"David González-Tapia"},{id:"196270",title:"MSc.",name:"Nallely",middleName:null,surname:"Vázquez-Hernández",slug:"nallely-vazquez-hernandez",fullName:"Nallely Vázquez-Hernández"},{id:"196271",title:"MSc.",name:"Nestor I",middleName:null,surname:"Martínez-Torres",slug:"nestor-i-martinez-torres",fullName:"Nestor I Martínez-Torres"}]},{id:"57301",title:"Neuroplasticity in Young Age: Computer-Based Early Neurodevelopment Classifier",slug:"neuroplasticity-in-young-age-computer-based-early-neurodevelopment-classifier",totalDownloads:497,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"neuroplasticity-insights-of-neural-reorganization",title:"Neuroplasticity",fullTitle:"Neuroplasticity - Insights of Neural Reorganization"},signatures:"Hagit Friedman, Marina Soloveichick, Shai Barak, Omer Bar-Yosef,\nSaab Raunak and Smolkin Tatiana",authors:[{id:"206485",title:"Dr.",name:"Hagit",middleName:null,surname:"Friedman",slug:"hagit-friedman",fullName:"Hagit Friedman"},{id:"217798",title:"BSc.",name:"Moran",middleName:null,surname:"Moskovich",slug:"moran-moskovich",fullName:"Moran Moskovich"},{id:"217799",title:"Dr.",name:"Omer",middleName:null,surname:"Bar-Yosef",slug:"omer-bar-yosef",fullName:"Omer Bar-Yosef"},{id:"217800",title:"Dr.",name:"Shai",middleName:null,surname:"Barak",slug:"shai-barak",fullName:"Shai Barak"},{id:"217802",title:"Dr.",name:"Tatiana",middleName:null,surname:"Smolkin",slug:"tatiana-smolkin",fullName:"Tatiana Smolkin"},{id:"217803",title:"Dr.",name:"Rawnak",middleName:null,surname:"Saab",slug:"rawnak-saab",fullName:"Rawnak Saab"},{id:"217804",title:"Dr.",name:"Marina",middleName:null,surname:"Soloveichick",slug:"marina-soloveichick",fullName:"Marina Soloveichick"}]}],onlineFirstChaptersFilter:{topicSlug:"neuroplasticity",limit:3,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",middleName:null,surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:1},route:{name:"book.detail",path:"/books/new-trends-and-developments-in-metrology",hash:"",query:{},params:{book:"new-trends-and-developments-in-metrology"},fullPath:"/books/new-trends-and-developments-in-metrology",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()