TLRs cellular expression, binding ligands, signal adaptor & production [2].
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"6854",leadTitle:null,fullTitle:"Nanocomposites - Recent Evolutions",title:"Nanocomposites",subtitle:"Recent Evolutions",reviewType:"peer-reviewed",abstract:"To have unimaginably outstanding useful properties (physical, mechanical, electrical, optical, chemical, and magnetic) in a single material design is a highly challenging task in the material science community, which can be achieved through nanocomposites. These nanocomposites can be produced from all conventional materials, which include polymers, metals/alloys, and ceramics, by modifying their internal structures. Due to modification of the structures of all kinds of conventional materials, at either the nano or ultra-fine level, the materials exhibit superior performance, which is a boon for all fields of science. In general, nanocomposite materials can be manufactured by solid-state processing techniques, liquid metallurgy, ex-situ and in-situ powder metallurgy, and other basic science synthesis routes. Furthermore, the possibility of making environmentally friendly materials is also possible with nanotechnology. Therefore, to investigate and demonstrate developments in the field of nanocomposites, this book is targeted at all the scientific personnel working in this field.",isbn:"978-1-78985-012-3",printIsbn:"978-1-78985-011-6",pdfIsbn:"978-1-83881-737-4",doi:"10.5772/intechopen.73364",price:119,priceEur:129,priceUsd:155,slug:"nanocomposites-recent-evolutions",numberOfPages:230,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"fed595e75f84d3ab7e0817721acca1bd",bookSignature:"Subbarayan Sivasankaran",publishedDate:"January 23rd 2019",coverURL:"https://cdn.intechopen.com/books/images_new/6854.jpg",numberOfDownloads:14886,numberOfWosCitations:53,numberOfCrossrefCitations:33,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:85,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:171,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 22nd 2018",dateEndSecondStepPublish:"March 15th 2018",dateEndThirdStepPublish:"May 14th 2018",dateEndFourthStepPublish:"August 2nd 2018",dateEndFifthStepPublish:"October 1st 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"190989",title:"Dr.",name:"Subbarayan",middleName:null,surname:"Sivasankaran",slug:"subbarayan-sivasankaran",fullName:"Subbarayan Sivasankaran",profilePictureURL:"https://mts.intechopen.com/storage/users/190989/images/system/190989.jpeg",biography:"Dr. S. Sivasankaran is working as an associate professor in the Department of Mechanical Engineering, College of Engineering, Qassim University. He has received several Deanship of Scientific Research Grants in Qassim University towards research work in the fields of materials and manufacturing. He completed his PhD degree in Production Engineering (Manufacturing Technology—Nanocomposite Materials) from NIT Trichy, India. After his doctoral degree, he worked as an associate professor in the KPR Institute of Engineering and Technology (KPRIET), Coimbatore, Tamilnadu, India. He has established an advanced materials research laboratory and entrepreneurship development cell in KPRIET. He has received a number of research and seminar grants from government of India. Furthermore, he served as an associate professor in Hawassa University, East Africa, for 2 years where he was involved in curriculum development. He has published more than 75 research articles in refereed international journals, acts as a reviewer for more than 20 refereed international journals (Elsevier, Springer, ASME), and has edited two books. Finally, his research interests are nanocomposites, mechanical alloying;, powder metallurgy, stir casting, advanced welding, 3D printing, metal matrix composites, polymer matrix composites, mechanical behavior, machining behavior, advanced characterization techniques, optimization, and modeling.",institutionString:"Qassim University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Qassim University",institutionURL:null,country:{name:"Saudi Arabia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"206",title:"Composite Materials",slug:"nanotechnology-and-nanomaterials-composite-materials"}],chapters:[{id:"62955",title:"Nanocomposite for Space Charge Suppression in HVDC Cable Accessory",doi:"10.5772/intechopen.80217",slug:"nanocomposite-for-space-charge-suppression-in-hvdc-cable-accessory",totalDownloads:1135,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"HVDC cable accessories made of ethylene-vinyl acetate copolymer (EVA) by incorporation of specific fillers have to face the problem of space charge accumulation. The effects of doping contents on the space charge behaviors of EVA/ZnO composite are not completely clear. EVA composites are prepared with the fraction of 0, 1, 5 and 10 wt%, respectively, with which 5 wt% nano-sized plus 5 wt% micro-sized ZnO-doped samples are chosen for comparison. Obtained results show that the particles in EVA composite are in homodisperse. The permittivity is increased by ZnO doping and the dissipation factor of EVA composites with 1 and 5 wt% nanoparticles is lower at the lower frequencies. The homocharge injection occurs in cathode instead of anode when ZnO nanoparticles are introduced and 5 wt% nanoparticle doping performs well in suppressing space charge injection. The electric field in the 5 wt% nanoparticle-doped EVA distributes more uniformly under the high electric stress than that of others. During the depolarization procedure, the total remnant charges of 10 wt% doped samples are the least in the final. The above results are well explained by the DC conduction, apparent mobility and trap distribution characteristics.",signatures:"Boxue Du, Jin Li and Zhuoran Yang",downloadPdfUrl:"/chapter/pdf-download/62955",previewPdfUrl:"/chapter/pdf-preview/62955",authors:[{id:"27801",title:"Prof.",name:"Boxue",surname:"Du",slug:"boxue-du",fullName:"Boxue Du"},{id:"242178",title:"Dr.",name:"Jin",surname:"Li",slug:"jin-li",fullName:"Jin Li"},{id:"247739",title:"Dr.",name:"Zhuoran",surname:"Yang",slug:"zhuoran-yang",fullName:"Zhuoran Yang"}],corrections:null},{id:"63734",title:"Carbon Nanocomposites: Preparation and Its Application in Catalytic Organic Transformations",doi:"10.5772/intechopen.81109",slug:"carbon-nanocomposites-preparation-and-its-application-in-catalytic-organic-transformations",totalDownloads:1522,totalCrossrefCites:3,totalDimensionsCites:6,hasAltmetrics:0,abstract:"Carbon nanocomposites have gained huge interest in catalysis due to their small size and shape-dependent physicochemical properties. Particularly, metal nanostructures/carbon materials (mainly graphene and carbon nanotubes) based nanocomposites demonstrated extraordinary catalytic activity in organic reactions. The catalytic products prepared by using carbon nanocomposites are found to be highly valuable in various fields including pharmaceutical, biomedical, agricultural, and material sciences. Hence, the demand of carbon nanocomposites has been increasing rapidly, and the development of novel preparation methods also deserve a special concern. In this chapter, we discuss the main advances in the field over the last few years and explore the novel preparation methods of carbon nanocomposites (metal nanostructures/carbon materials) and their applications in various catalytic organic transformations.",signatures:"Mayakrishnan Gopiraman and Ick Soo Kim",downloadPdfUrl:"/chapter/pdf-download/63734",previewPdfUrl:"/chapter/pdf-preview/63734",authors:[{id:"247516",title:"Prof.",name:"Gopiraman",surname:"Mayakrishnan",slug:"gopiraman-mayakrishnan",fullName:"Gopiraman Mayakrishnan"},{id:"247532",title:"Prof.",name:"Kim",surname:"Ick Soo",slug:"kim-ick-soo",fullName:"Kim Ick Soo"}],corrections:null},{id:"62143",title:"Polymer/Noble Metal Nanocomposites",doi:"10.5772/intechopen.79016",slug:"polymer-noble-metal-nanocomposites",totalDownloads:865,totalCrossrefCites:3,totalDimensionsCites:11,hasAltmetrics:0,abstract:"Recently, the polymeric materials have extensive uses because of their amazing combination of properties, durability, light weight and simplicity of processing. However, these materials face some problems like their weak thermal stability and also poor mechanical stability. Therefore, a large number of additives especially metal nanoparticles were added to polymeric matrix to overcome these problems and designed polymer matrix nanocomposite. A composite is defined as the combination between two individuals or more than one material by physical or mechanical method to get a new material with unique and elegant structure and properties and carrying the feature of the two separated materials and distinguishable interface. Many approaches are used to prepare the polymer nanocomposites such as ex situ, in situ and radiolytic methods. The nanocomposites have important features such as excellent mechanical properties like high stiffness, strength, toughness; good chemical properties like corrosion resistance; and high physical properties like high optical, mechanical, thermal, low density and specific antibacterial properties. The nanocomposite materials with these higher properties have a wonderful and different range of functional applications. The deep view on the synthesis strategies and physical properties of the polymer/noble metal nanocomposites is offered in this book and also their applications in many fields.",signatures:"Ahmed Gamal Abed El-Azim Khalil El-Shamy",downloadPdfUrl:"/chapter/pdf-download/62143",previewPdfUrl:"/chapter/pdf-preview/62143",authors:[{id:"247670",title:"Dr.",name:"Ahmed",surname:"El-Shamy",slug:"ahmed-el-shamy",fullName:"Ahmed El-Shamy"}],corrections:null},{id:"62103",title:"Hybrid Nanocomposites Produced by Sputtering: Interaction with Eukaryotic and Prokaryotic Cells",doi:"10.5772/intechopen.79048",slug:"hybrid-nanocomposites-produced-by-sputtering-interaction-with-eukaryotic-and-prokaryotic-cells",totalDownloads:1e3,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The use of composite materials for different and diverse technological applications is a growing field. The development of this class of materials arises when it is required from a material a combination of properties that are impossible to co-exist, such as, for example, high hardness and good tenacity. However, in some applications the main focus of this combination of characteristics/properties is only required at the material surface; in this cases, the composite will be deposited onto the surface as a coating. Moreover, the introduction of reinforcements of nanometric size, where one of the dimensions is lower than 100 nm, may induce, in the deposited composite, particularly appealing properties due to the nanometric scale. This chapter presents the use of a particular deposition technique—sputtering—for the production of nanocomposites made of dissimilar materials such as ceramic/metal, ceramic/polymer and ceramic/polymer/metal. The application of these surfaces in interaction with both eukaryotic and prokaryotic cells will be given as an example of the broad range of applications of the developed surfaces.",signatures:"Ana Paula Piedade",downloadPdfUrl:"/chapter/pdf-download/62103",previewPdfUrl:"/chapter/pdf-preview/62103",authors:[{id:"250567",title:"Prof.",name:"Ana",surname:"Piedade",slug:"ana-piedade",fullName:"Ana Piedade"}],corrections:null},{id:"63128",title:"Conducting Polymers Incorporated with Related Graphene Compound Films for Use for Humidity and NH3 Gas Sensing",doi:"10.5772/intechopen.79060",slug:"conducting-polymers-incorporated-with-related-graphene-compound-films-for-use-for-humidity-and-nh3-g",totalDownloads:1106,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Using spin-coating technique, PEDOT:PSS + GQD + CNT (GPC), PEDOT:PSS + GQD + AgNW (GPA) films used for humidity sensors and P3HT + rGO + CNT (P3GC) films used for NH3 gas sensors were prepared. At room temperature and atmospheric pressure, all the sensing devices have extremely simple structure and they respond well to the humidity change (for GPC and GPA) and NH3 gas (for P3GC). The sensitivity of both the GPC and GPA humidity sensing devices was found to be dependent on the additives of CNT or AgNW. For the GPA sensors, the best sensitivity attained a value as large as 15.2% with a response time of 30 s. For the NH3 gas sensors made from P3GC films with a content of 20 wt.% of rGO and 10% of CNTs, the best performance parameters were obtained, such as responding time of ca. 30 s, sensing response of 0.8% at ammonia gas concentration of 10 ppm and a relative sensitivity of 0.05%/ppm. The fact that the P3HT + rGO + CNT sensors do not respond to humidity suggests useful applications in gas thin-film sensors for selectively sensing ammonia gas in a humid environment.",signatures:"Nguyen Nang Dinh",downloadPdfUrl:"/chapter/pdf-download/63128",previewPdfUrl:"/chapter/pdf-preview/63128",authors:[{id:"10661",title:"Prof.",name:"Nguyen",surname:"Dinh",slug:"nguyen-dinh",fullName:"Nguyen Dinh"}],corrections:null},{id:"64843",title:"Polymer Nanocomposites with Different Types of Nanofiller",doi:"10.5772/intechopen.81329",slug:"polymer-nanocomposites-with-different-types-of-nanofiller",totalDownloads:4054,totalCrossrefCites:19,totalDimensionsCites:55,hasAltmetrics:0,abstract:"The development of polymer nanocomposites has been an area of high scientific and industrial interest in the recent years, due to several improvements achieved in these materials, as a result of the combination of a polymeric matrix and, usually, an inorganic nanomaterial. The improved performance of those materials can include mechanical strength, toughness and stiffness, electrical and thermal conductivity, superior flame retardancy and higher barrier to moisture and gases. Nanocomposites can also show unique design possibilities, which offer excellent advantages in creating functional materials with desired properties for specific applications. The possibility of using natural resources and the fact of being environmentally friendly have also offered new opportunities for applications. This chapter aims to review the main topics and recent progresses related to polymer nanocomposites, such as techniques of characterization, methods of production, structures, compatibilization and applications. First, the most important concepts about nanocomposites will be presented. Additionally, an approach on the different types of filler that can be used as reinforcement in polymeric matrices will be made. After that, sections about methods of production and structures of nanocomposites will be detailed. Finally, some properties and potential applications that have been achieved in polymer nanocomposites will be highlighted.",signatures:"Amanda Dantas de Oliveira and Cesar Augusto Gonçalves Beatrice",downloadPdfUrl:"/chapter/pdf-download/64843",previewPdfUrl:"/chapter/pdf-preview/64843",authors:[{id:"249768",title:"Ph.D.",name:"Amanda",surname:"Oliveira",slug:"amanda-oliveira",fullName:"Amanda Oliveira"},{id:"254512",title:"Ph.D.",name:"Cesar",surname:"Beatrice",slug:"cesar-beatrice",fullName:"Cesar Beatrice"}],corrections:null},{id:"63653",title:"Perovskite Strontium Doped Rare Earth Manganites Nanocomposites and Their Photocatalytic Performances",doi:"10.5772/intechopen.79479",slug:"perovskite-strontium-doped-rare-earth-manganites-nanocomposites-and-their-photocatalytic-performance",totalDownloads:1247,totalCrossrefCites:3,totalDimensionsCites:3,hasAltmetrics:0,abstract:"Studying catalysts in situ is an important topic that helps us to understand their surface structure and electronic states in operation. Three types of materials are used in the degradation of organic matter, which has applications in the environmental remediation and self -cleaning surfaces. The technique is widely known but still hampered by one significant limitation. The materials generally absorb ultra violet UV light but we need to develop active materials for visible light. Utilizing the sunlight efficiently for solar energy conversion is an important demand in the present time. The research on visible-light active photocatalysts attracted a lot of interest. The perovskite-like compounds are found to be active catalysts for the oxidation of carbon monoxide. In the present chapter, we will focus on the application of the nano-sized strontium doped neodymium manganites within perovskite like structure as photocatalysis and studying their photocatalytic performance.",signatures:"Ihab A. Abdel-Latif",downloadPdfUrl:"/chapter/pdf-download/63653",previewPdfUrl:"/chapter/pdf-preview/63653",authors:[{id:"248894",title:"Dr.",name:"Ihab",surname:"Abdel-Latif",slug:"ihab-abdel-latif",fullName:"Ihab Abdel-Latif"}],corrections:null},{id:"63002",title:"Thermoreversible Polymeric Nanocomposites",doi:"10.5772/intechopen.80218",slug:"thermoreversible-polymeric-nanocomposites",totalDownloads:972,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Polymeric nanocomposites are widely used in applications such as structural materials, electronics, energy, and biomedical as they synergistically combine the desired properties of the filler and the polymer. The emergent properties can be designed and tuned based not only on the choice of filler and polymer but also on the type of bond and interface created between the two components. When the bond between the two is covalent, the nanocomposites have superior mechanical characteristics. When this covalent bond is reversible, a combination of high impact resistance and high tensile strength is achieved. A well-known approach to achieve these reversible covalent bonds is via the Diels-Alder reaction between a diene and a dienophile. At elevated temperatures, the retro Diels-Alder reaction is dominant resulting in bond cleavage. This chapter reviews the different strategies involving Diels-Alder reactions at the polymer-filler interface. Various fillers have been researched including silica, carbon nanotubes, and graphene, which impart different mechanical and conductive properties to the nanocomposite. A variety of polymer matrices have been reported by various researchers and are summarized here. The choice of diene and dienophile influences the rate of reversible reaction and thus the final properties as will be discussed.",signatures:"Ranjita K. Bose, Francesco Picchioni and Henky Muljana",downloadPdfUrl:"/chapter/pdf-download/63002",previewPdfUrl:"/chapter/pdf-preview/63002",authors:[{id:"249595",title:"Prof.",name:"Francesco",surname:"Picchioni",slug:"francesco-picchioni",fullName:"Francesco Picchioni"},{id:"249599",title:"Dr.",name:"Ranjita",surname:"Bose",slug:"ranjita-bose",fullName:"Ranjita Bose"},{id:"249600",title:"Dr.",name:"Henky",surname:"Muljana",slug:"henky-muljana",fullName:"Henky Muljana"}],corrections:null},{id:"63406",title:"Ultrasound-Assisted Melt Extrusion of Polymer Nanocomposites",doi:"10.5772/intechopen.80216",slug:"ultrasound-assisted-melt-extrusion-of-polymer-nanocomposites",totalDownloads:1372,totalCrossrefCites:5,totalDimensionsCites:5,hasAltmetrics:0,abstract:"A review of the latest developments in ultrasound-assisted melt extrusion of polymer nanocomposites is presented. In general, the application of ultrasound waves during melt extrusion of polymer in the presence of nanoparticles results in a more homogeneous dispersion of the nanoparticles in the polymer matrix. In spite of this, a lack of understanding in the field has hindered the development of this processing technique. Based on the analysis of literature on the field, key aspects are identified for a better understanding of the physical and chemical effects of ultrasound waves and the fabrication of polymer nanocomposites by means of melt extrusion.",signatures:"Carlos A. Ávila-Orta, Pablo González-Morones, Diana Agüero-\nValdez, Alain González-Sánchez, Juan G. Martínez-Colunga, José M.\nMata-Padilla and Víctor J. Cruz-Delgado",downloadPdfUrl:"/chapter/pdf-download/63406",previewPdfUrl:"/chapter/pdf-preview/63406",authors:[{id:"247436",title:"Dr.",name:"Carlos A.",surname:"Ávila-Orta",slug:"carlos-a.-avila-orta",fullName:"Carlos A. Ávila-Orta"},{id:"248815",title:"Dr.",name:"Pablo",surname:"Gonzalez-Morones",slug:"pablo-gonzalez-morones",fullName:"Pablo Gonzalez-Morones"},{id:"248816",title:"Dr.",name:"Víctor Javier",surname:"Cruz-Delgado",slug:"victor-javier-cruz-delgado",fullName:"Víctor Javier Cruz-Delgado"},{id:"248817",title:"Dr.",name:"Juan Guillermo",surname:"Martínez-Colunga",slug:"juan-guillermo-martinez-colunga",fullName:"Juan Guillermo Martínez-Colunga"},{id:"263932",title:"M.Sc.",name:"Diana",surname:"Agüero-Valdez",slug:"diana-aguero-valdez",fullName:"Diana Agüero-Valdez"},{id:"263933",title:"M.Sc.",name:"Alain",surname:"González-Sánchez",slug:"alain-gonzalez-sanchez",fullName:"Alain González-Sánchez"},{id:"263935",title:"Dr.",name:"José Manuel",surname:"Mata-Padilla",slug:"jose-manuel-mata-padilla",fullName:"José Manuel Mata-Padilla"}],corrections:null},{id:"63417",title:"Electrodeposited Zinc-Nickel Nanocomposite Coatings",doi:"10.5772/intechopen.80219",slug:"electrodeposited-zinc-nickel-nanocomposite-coatings",totalDownloads:1618,totalCrossrefCites:0,totalDimensionsCites:4,hasAltmetrics:0,abstract:"Composite coatings can demonstrate improved property performance as compared to metals and alloy materials. One category of composite coatings is composed of metal or metal alloys with a dispersed phase of nonmetallic nanoparticles. The addition of these nanoparticles has been found to improve corrosion, wear resistance, and hardness. Producing metal composite coatings using electrochemical techniques can be advantageous due to reduced production cost, lower working temperatures, and precise control of experimental parameters. Metal coatings such as zinc have been successfully co-deposited with TiO2, SiO2, CeO2 and mica particles and nickel has been co-deposited with a number of materials including TiO2, SiC, Al2O3, PTFE and silicates. Zinc-nickel alloys have long been studied for a number of properties, most notably corrosion resistance and recently their tribological properties. This chapter reviews the literature on electrodeposition of ZnNi nanocomposite coatings. Although there has been much work done on composite coatings, there is much less literature available on composite coatings with zinc-nickel alloys. So in this review, we look at the general trends for nanoparticle incorporation, deposition mechanisms, system stability, microstructures of the coatings and general corrosion trends.",signatures:"Heidi Conrad and Teresa D. 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Indeed, it appears in seas and oceans, lakes, rivers, harbors, and many other natural systems.
\r\n\tIn the last decades, particular attention to this field has been paid to the coastal erosion problem all over the world. Indeed, the deployment of artificial reservoirs, modification of the runoff characteristics of internal areas, sand extraction from rivers, and harbor siltation, caused a decrease of sediment input on the coastal environments, and, therefore, a generalized deficit in the sediment budget. Often, dredging activities are required to collect sediment finalized to “soft” techniques to restore beaches or to move the sand trapped in the harbor (clean or contaminated).
\r\n\tMoreover, the coastal protections induced hydrodynamics and morphodynamics modifications inducing sometimes strong variations to the sediment transport regime.
\r\n\tHistorically, all these aspects are related to specific research areas ranging from engineering, geology, geomorphology, biology, etc, but it is difficult to find a comprehensive overview of these topics.
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Every inflammation involves an immune response -innate and adaptive- that started with specific receptors called recognition receptors to identify stimuli/damage signal, activation of consequence inflammatory pathway/cascade, the release of inflammatory markers, and recruitment of inflammatory immune cells [1].
The innate immune response is initiated by either endogenous ligands acting as damage signals known as the damage-associated molecular pattern (DAMPs), or exogenous pathogenic ligands-that are accurately portion of the pathogenic microorganism- lead to the same fate; damage signals throughout pathogen-associated molecular patterns (PAMPs) [2]. These patterns alter the body of the cell and cause tissue injuries leading to massive necrosis that release intracellular component into surrounding, these components activate TLRs [3, 4]. These processes, which are both the mechanism and the net results of inflammations, infections, or ischemic injuries cause more, harm than the initial causes itself by improper stimulation of the immune response [3, 4].
TLRs are a family of pattern recognition receptors (PPR), which also involves nucleotide oligomerization domain (NOD)-like receptors (NLR) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLR). They are located on cell membrane/surface and nucleus, are responsible for the detection/recognition of the pathogen or intracellular damaged derived molecular signals to start immune response [1, 2].
These complicated inflammatory processes induced by the immune system are the “Classical typical scenario” involved in the majority of ischemic events, cancers, infectious and inflammatory diseases [4]. For further information about the immune system, Video 1 (https://youtu.be/8mEnyBdsrr8) can be shown on Armando Hasudungan YouTube channel [2] that would explain the innate immunity link with TLRs.
TLRs are PRR family involves 13 members that exist in mammals with 10 members detected in the human genome [5, 6], depending on their similar morphology with Toll. Toll is a gene product that participate in both embryonic polarity development and adult fly -antimicrobial response of the species
TLRs are expressed in almost all body tissues involved in immunologic response as well as those exposed to external environments like the spleen, blood, lung & gastrointestinal tract [4, 8]. The particular cellular expression involves innate and adaptive immunity as well as different nonimmune cells. TLRs cellular expression involves the white blood cells “the sentinel of the innate immune response”: microphages (MΦ) & mast cell (MC) “innate immune response keys”, dendritic cells (DCs) (primarily pathogenic detector of the adaptive immune response) [4, 6, 8, 9], endothelial cells, epithelial cells, fibroblast, glial cells, astrocytes, oligodendrocytes, etc. [1, 5, 8, 10].
Cellular expression of TLRs family members largely variable and mainly depends on the presence of active infections [8]; according to the same source, as ex., bacterial product & pro-inflammatory cytokines can induce the expression of TL3 while IL-10 blocks TLR4 expression. It has been found that TLR2 expression is more specifically involved in the gram-positive bacteria signaling [8]. TLRs are located either primarily to immune cell plasma membrane phospholipids including TLR 1, 2, 4, 5, 6, & 11 [3, 4, 8]; Or located at the endosomal and lysosomal phospholipids where their extracellular domain (ECD) and its ligand-binding site project into the interior of the organelles like TLR 3, 7, 8, 9, 10 and 13 [2, 3, 10, 11].
TLRs are a type I integral transmembrane glycoprotein family of very conserved structure [5, 7], consist of 700–1100 amino acids [2, 4]. Their structure, shown in Figure 1 consist of 2 domains: an ECD that recognize ligands, consist of repetitive motifs rich with leucine and an intracellular domain (ICD) –called cytoplasmic- that maintain inflammatory signal consequence, the last consist of interleukin (IL)-1 receptor region called Toll/IL receptor (TIR) domain [12, 13].
A representative structure of TLR. The conserved structural features of all TLRs consist of three critical components: (1) leucine-rich repeat (LRR) motif; (2) transmembrane helix; (3) intracellular TIR domain. The LRR structure is based on the model of TLR1-TLR2 heterodimer (Protein Data Bank, PDB, ID: 2z7x) interacting with six triacylated-lipopeptides, Pam3CysSerLys4 (Pam3CSK4), whereas the TIR domain homology model is based on TLR2-TIR structure (PDB ID: 1fyw) [
TLRs involves 13 family members that exist in mammals with 10 members detected in the human genome [5, 6]. Human TLRs amino acids sequence allow a subfamily classification into the TLR2, TLR3, TLR4, TLR5, and TLR9 subfamilies. The TLR2 subfamily involves TLR1, 2, 6, and 10; the TLR9 subfamily involves TLR7, 8, and 9 [14].
TLRs members can form homodimers/heterodimers among their same protein family or associates with an “outside TLR family” protein; both formations contribute to their structural and functional diversity [4]. Homodimers are formed by TLR4 while TLR members 1, 2, and 6 like TLR1/2 or TLR2/6 dimers form heterodimers [2, 3, 15, 16, 17]. TLRs members, their dimerization, cellular distribution, ligands, induced signaling pathway, and product are shown in Table 1; for further information about TLRs, Video 2 (https://youtu.be/8mEnyBdsrr8) about TLR overview can be shown at Armando Hasudungan YouTube channel [18].
TLRs | Immune Cell Expression | PAMPs | DAMPs | Signal Adaptor | Production |
---|---|---|---|---|---|
TLR1+ TLR2 | Cell surface Mo, MΦ, DC, B | Tri-acylated lipoproteins (Pam3CSK4) Peptidoglycans, Lipopolysaccharides | (TLR2 DAMPs listed below) | TIRAP, MyD88, Mal | IC |
TLR2+ TLR6 | Cell surface Mo, MΦ, MC, B | Diacylated lipoproteins (FSL-1) | Heat Shock Proteins (HSP 60, 70, Gp96) High mobility group proteins (HMGB1) Proteoglycans (Versican, Hyaluronic Acid fragments) | TIRAP, MyD88, Mal | IC |
TLR3 | Endosomes B, T, NK, DC | dsRNA (poly (I:C)) tRNA, siRNA | mRNA tRNA | TRIF | IC, type1 IFN |
TLR4 | Cell surface/ endosomes Mo, MΦ, DC, MC, IE | Lipopolysaccharides (LPS) Paclitaxel | Heat Shock Proteins (HSP22, 60, 70,72, Gp96) High mobility group proteins (HMGB1) Proteoglycans (Versican, Heparin sulfate, Hyaluronic Acid fragments) Fibronectin, Tenascin-C | TRAM, TRIF TIRAP, MyD88 Mal | IC, type1 IFN |
TLR5 | Cell surface Mo, MΦ, DC, IE | Flagellin | MyD88 | IC | |
TLR7 | Endosomes Mo, MΦ, DC. B | ssRNA Imidazoquinolin-es (R848) Guanosine analogues (Loxoribine) | ssRNA | MyD88 | IC, type1 IFN |
TLR8 | Endosomes Mo, MΦ, DC, MC | ssRNA, Imidazoquinolines (R848) | ssRNA | MyD88 | IC, type1 IFN |
TLR9 | Endosomes Mo, MΦ, DC, B, T | CpG DNA CpG ODNs | Chromatin IgG complex | MyD88 | IC, type1 IFN |
TLR10 | Endosomes Mo, MΦ, DC | profilin-like proteins | MyD88 | IC |
TLRs family members can recognize two types of associated molecular patterns as their ligands, derived from pathogens or damaged organelles damaged structures.
PAMPs derived from pathogen [5, 19]; like gram-negative bacterial lipopolysaccharides (LPS), gram-positive bacterial lipoteichoic acid (LTA) and peptidoglycan (PGN), mycobacterial lipopeptides, yeast zymosan, viral and bacterial ribonucleic acid (RNA), and unmethylated cytosine phosphate guanine containing- (CpG) deoxyribonucleic acid (DNA) [20, 21].
DAMPs damaged organelles structures, extracellular matrix, cytosolic and nuclear proteins, Heat shock protein-60 (HSP-60) and HSP-70, hyaluronic acid fragments, and free fatty acids (FFA) [5, 22, 23]. They cause activation of the innate and inflammatory immune responses, epithelial regeneration, and sterile inflammation control [6, 24].
Upon TLRs recognition and binding to their ligands, they undergo conformational changes, dimerization as well as interaction with adaptor molecules passing series of intracellular signal transduction pathways that involve transcription factors NF-κB, IRFs, and mitogen-activated protein kinase (MAPK) activation. These pathways finally resulting in the secretion of pro-inflammatory mediators including nitric oxide (NO), CK- like tumour necrosis factor-alpha (TNF-α), IL-6 & IL-1β, chemokines (CC), and type I IFN [15, 21, 25, 26]. As shown in Figure 2.
Signaling pathways of TLR. Surface and endosomal TLRs bind to adaptor molecules and co-receptors. Signal through Myd88 dependent/independent pathway ending with proinflammatory CK or type I IFN [
Co –receptors involved in TLRs signalling include Cluster differential 14 (CD14) and Lymphocyte antigen 96 (MD-2). Both have a major role in TLR4 activation after LPS recognition. CD14 is a glycophosphatidylinositol attached protein expressed on innate immune cells as macrophage and monocytes that function as co-receptor for both cell surface & endosomal expressed TLRs. Lymphocyte antigen 96 (MD-2), which is a cell membrane glycoprotein associated specifically with TLR4 ECD, and expressed at myeloid and endothelial cells [6, 13, 21, 26, 27].
TLRs signaling pathways involves four main adaptor protein molecules: MyD88, TIR domain-containing adaptor protein/MyD88 adaptor-like molecules (TIRAP) also called MAL, TIR domain-containing adaptor protein inducing interferon-β (TRIF), and TRIF related adaptor molecule (TRAM) [13, 21, 28]. TLRs signaling pathways involves activation of five TIR containing adaptor kinase molecules, like IL-1 receptor-associated kinase (IRAK) -1 and 4, TNF receptor-associated factor-6 (TRAF6), serine/threonine binding kinase (TBK)-1, MAPK, and inhibitor of kappa-B (IκB) kinase (IKK) [13, 28].
There are three transcription factors involved in the TLRs signalling pathway including NF-κB, AP1, and IRF. NF-κB is an intracellular pleiotropic protein complex; it is responsible for gene regulation of proinflammatory CK, CC, adhesion molecules, and cell cycle/survival regulating proteins as cyclin D1 and B cell lymphoma 2 (Bcl-2). AP1 is a dimer of both protein Jun and Fos families; that is associated with cell replication and survival regulation. Finally, the IRFs protein regulating IFNs, are responsible for signal stimulation via MyD88independent/TRIF pathway [6, 13].
There are two intracellular signalling pathways for TLRs involve MyD88-dependent/& MyD88-independent also called (TRIF-dependant) signal transduction pathway.
It is utilized by all TLRs but not TLR3 [21, 29]. This pathway activates the IRAKs, TRAF6, transforming growth factor (TGF)-β-activated kinase (TAK)-1 and the IKK complex [15]. It causes the nuclear translocation of NF-κB and adaptor protein-1 (AP1) [28, 30], and ends with the secretion of CK like IL-6, IL-10, IL-12 & TNF-α [16, 29]. MyD88 also stimulate the classical extracellular signal-regulated kinases (MAPK/ERK), phosphoinositide-3 (PI3), and Jun (N)terminal kinase (JNK) which stimulate the AP1 signalling pathway, and induce the interferon regulatory factor-7 (IRF7) ending with the release of type-I IFN or co-stimulatory molecules associated with the antimicrobial response by endosomal TLRs 3, 7, 8 and 9 [13, 29, 31, 32].
The main pathway of TLR3 and 4, involve TRIF signalling pathway activation which involves TRAF6 activation, results in inositol triphosphate-3 (IP3) phosphorylation and induction of IFN-β gene expression as well as activation of TRAF6 [21, 29].
Surprisingly the same outcome was obtained from plasmatoid dendritic cells (pDCs) stimulated by TLR 7& 9 throughout the activation of the MyD88/IRF7 dependent pathway [15, 33].
TLR4 further utilizes TIRAP to activate MyD88 and TRAM to bridge the TRIF activation, which means that TLR4 uniquely utilizes both the MYD88 dependent and independent pathways [11, 21, 29].
As stated by S. Kiziltas et al. “TLR stimulation product is dependent on the nature of PAMPs, the activated TLR, the activated cell and the level of CK. Moreover, the chronically activated signalling pathway would possibly induce transcription of oncogenic factor; adding further complexation to the intracellular signalling for these receptors” [5, 13].
TLRs play an important role in pathophysiological disorders due to their wide tissue distribution, their function as pattern recognition receptors that respond to variable bacterial and damage associated molecules, and involvement in multiple inflammatory signal pathways/& process all render TLRs being a major player in any inflammation-related disorder [4, 5, 6, 19, 22, 23, 34]. In addition, analysis of TLRs gene polymorphism in human disorders revealed an increased risk of bacterial infection and sepsis as an example [34]. This section is a shortcut or summary to TLR involvement in different pathophysiological disorders rather than a full description section.
Inflammation is a common etiology of many disorders and disease including ischemic injuries, microbial infections, diabetes, arthritis and cancer [3, 4, 35]; still, any inflammatory process is triggered by damage signal recognized by pattern receptors and induce activation of signaling pathways leading to the production of pro-inflammatory markers and activation of immune cells [35]. These processes also induce the release of free radicals (FR) such as reactive oxygen species (ROS) and the activation of hypoxia-inducible transcription factor-1 (HIF1), causing tissue stress and reduced tissue oxygen status, so-called tissue hypoxia. Hypoxia is believed to be a hallmark as well as a key trigger of inflammation itself [35, 36].
Under normal conditions HIF1-α subunit (the inducible form of the heterodimer protein HIF-1 transcription complex) [35], is controlled by hydroxylation of proline residue via prolyl hydroxylase enzyme, and breaking down via proteasome. However under inflammatory conditions LPS activate TLRs that stimulates nicotine amide adenine dinucleotide phosphate (NADPH) oxidase (Nox)-associated cross-talk with the MAPK signaling pathways [36, 37], that causes proinflammatory CK & markers production thus increasing mitochondrial FR release like ROS causing more and more tissue stress. That causes HIF1- α activation; here HIF1- α protein inactivation process will be inhibited due to proline consumption, leading to HIF1-α accumulation in MΦ, DCs and other non-immune cells that exposed to hypoxia/ & non-hypoxic damage signals [38]. Furthermore, this would induce metabolic reprogramming of mitochondrial respiration causing succinate release, and production of IL-1β [35, 38].
In dendritic cells, TLRs cause further stabilization of HIF1-α via release of NF-κB, which would further increase glucose uptake and render shifting of mitochondrial respiration to the anaerobic glycolytic pathway due to the increased oxygen demand versus the decreased supply [35, 36]. Finally result in disruption of the normal function of DCs, the primary pathogenic detector of the adaptive immune response; which undergo cellular maturation upon TLRS activation that results in further expression of co-stimulatory molecules, further production of pro-inflammatory CK & CC, and migration to lymph node so to present antigens to naïve T-cells [4, 35]. All these scenarios would further amplify the existing inflammation and tissue damage [35].
HIF1-α is a transcription factor that responsible for cellular adaptive responses after exposure to injury/stress environment, including maintenance like controlling angiogenesis to improve blood vessel formation, shifting cellular mitochondria respiration to anaerobic glycolysis through improving cellular survival and cellular adhesion in oxidative stress environment’s [36]. In addition, it is the major controller of phagocytes bactericidal capacity, and involved in myeloid cell-mediated inflammation, and is an essential factor for inhibition of myeloid cell apoptosis induced by LPS. The last point made it an important factor also in the TLR4 signaling pathway [36, 38]. HIF1-α function as a double-edged sword, that mediate cellular adaptive to stress but progress disease status by the same time [38].
TLRs are expressed in various central nervous system (CNS) cells predominantly in neurons, astrocytes, resident microglia, cerebral microvasculature, plexuses choroid, and leptomeninges. They are associated with the detection of- and regulated by central DAMPs [33]. TLR4 is further upregulated centrally by glutamate via N-methyl-D-aspartate (NMDA) dependent mechanism and peripherally by noradrenaline/β2 receptor, & corticotrophin-releasing factor. TLRs play an important role in restoring central homeostasis, physiology of stress-sensitive behaviour after injuries or diseases as multiple sclerosis, Alzheimer’s, and stroke [33].
In the experimental model of CNS, stress exposure revealed mRNA upregulation and activation of TLRs in the brain frontal cortex after the stress is involved in the loss of neuronal plasticity and survival depending on the activation of NF-κB induced ROS production. Also resultant bacterial translocation from the gut to the systemic circulation and other organs such as the liver, spleen, and mesenteric lymph nodes; These circulating gram-negative bacteria are the major source of LPS, which can activate brain TLR4 through multiple pathways, including a neuroinflammatory response. This is partially explained by the theory known as leaky gut [11, 33].
In another experimental model of neurogenesis, TLR3 & 4 were found to act as down regulators, TLR3 deletion/loss of function was also linked to improved cognitive function. The same reference state an opposed case in viral meningitis when TLR3 & 9 recruitment help to decrease neuronal injury and localize infection area and in Alzheimer disease where TLR2, 4, 5, 7 & 9 were suggested to improve disease progression by inhibiting amyloid plaque accumulation [1].
TLR is thought to play a considerable role in several respiratory disorders starting from allergic rhinitis ending with severe inflammatory disorders like acute respiratory distress syndrome (ARDS), through their activation by the causative inflammations derived by pulmonary oedema, trauma, sepsis & even drug overdose [9, 37]. In allergic rhinitis TLR2, 3, & 4 were found to be both upregulated by- and involved in-the causative inflammation [37].
TLR2 has the mainstay of involvement & determination in respiratory allergic disease due to considerable genetic variation. In asthma, an experimental study shows TLR2 induction by synthetic Pam3Cys triggers immune response & disease severity [37]. While in acute lung injury (ALI) & ARDS, TLR2 was found to be activated by Toll interacting protein (Tollip) [14]. TLR4 was found to increase asthmatics severity & prevalence in paediatrics. TLR4 genetic polymorphism affects cluster differentials (CD)41–251 regulatory T cells (Tregs) which are activated by LPS, the same ligand of TLR4 itself. [2, 3, 37].
An experimental model of doxorubicin and hydrogen peroxide-induced cardiac injury showed TLR2 to be involved in cardio myocytes apoptosis, besides TLR2 targeting suggested to be protective in septic cardiomyopathy [1]. In addition, murine models revealed cardiac tissue expression of TLR4 increased after hypertension, myocardial ischemia, maladaptive left ventricular hypertrophy, and angiotensin II (AngII) infusion participating in vascular remodelling & stiffness, endothelial dysfunction, increase myocardial infarction (MI) size & susceptibility. While Human studies revealed the same in patients with unstable angina, MI, heart failure, atherosclerosis & myocarditis [9, 27, 39, 40, 41].
TLR4 expression & signalling was increased in patients’ monocytes during attacks of unstable angina & MI [37]. In the experimental model & human vascular inflammation, TLR4 was found to increase the production of CK, CC as well as increase TLR2 expression. In the early stage of the atherosclerotic lesion, TLR4 mRNA protein was detected & MyD88 -the mainstay of TLR signalling pathway- gene deficiency was linked to decrement in CK, CC & lipid content production, as well as in atherosclerotic lesion size. The same reference stated that TLR2 genetic polymorphism was linked to increased coronary artery stenosis, while TLR7 & 8 was involved in cardiac inflammation caused by the Coxsackie virus [37].
The liver is the major organ that deals with gut-derived endotoxin, exposed by portal circulation [13, 42]. This continuous exposure would trigger frequent activation of the hepatic innate immune system; which contributes to the induction of inflammation in acute hepatic injuries, which means involvement of TLRs in the induction of inflammation [13]. Pathogenic suppression/& inhibition of TLRs found to mediates chronic hepatic injuries/disorders like hepatitis, fibrosis, alcoholic liver injuries, ischemia/reperfusion injury, and carcinoma [13, 28].
In Paracetamol human hepatotoxicity, endogenous chemical injury derives extracellular matrix (ECM) the ligand that activates TLR4 to release TNF-α, induce inducible nitric oxide synthase (iNOS), peroxynitrite, glutathione depletion, so that will amplify immune response, sequestering leukocytes, increase serum hyaluronic acid, causing steatosis, necrosis, and hepatic congestion [16].
Hepatitis viral nucleic acid & proteins are the ligands detected by TLR3, 7, 8, & 9. Starting with hepatitis B virus (HBV), in vitro activation of TLR1, 2, 3, 4, 5, 6, 7, 8, & 9 result in the release of IFN which inhibit HBV DNA replication and RNA transcription. Whilst HBV itself downregulates the expression of TLR1, 2, 4, & 6, this limits their antiviral effect or even renders them nugatory [28]. This downregulation of TLRs is attributed to the presence of HBV e antigen (HBeAg) during acute infection. About hepatitis C (HCV), its core protein activates TLR 1, 2, 4 & 6, which are supposed to produce antiviral IFNs as well as increased hepatic inflammation. The same effect is presumed by TLR 3 & 4 in HBV is achieved here to produce IFN-β [28].
In alcoholic liver disease (ALD), alcohol mainstay effects are to increase gut mucosal permeability to LPS, modification of gut flora, reducing endotoxin clearance rate, and increasing hepatic endotoxin level [16]. These scenarios lead to higher expression of TLR1, 2, 4, 6 & 9 by both parenchymal and non-parenchymal cells, activating their pathway and release of inflammatory mediators, this process observed in the chronic alcohol experimental model [28, 29]. While a patient with cirrhosis expresses a high level of TNF-α, IL-1β, & IL-6, as well as chronic endotoxemia, recurrent bacterial infection [16]. Finally, the process of hepatic regeneration depends on the interplay between the immune system and non-parenchymal cell, which involves activation of TLRs/MyD88 pathway, here the bulky activation of TLRs, would inversely affect the regeneration process, which indicates that the extent of such activation is essential for hepatic regeneration. TLR2, 4 & 9 reported no important role in liver regeneration process [28, 43].
Both human patients and experimental models of diabetes linked the active TLR to the progression of diabetes complication throughout the activation of NF-κB signalling in adipose tissue MΦ due to high level of plasma FFA associated with obesity & diabetes type 2 (T2DM) [44].
In vivo & in-vitro studies performed by Zhang N. et al. revealed that TLR 2 & 4 activation in insulin target tissues as the liver, adipose tissue & immune cells linked them with insulin resistance. The first suggests that high TLRs loss of function or genetic modification protects against high FFA level resulted from large mass adipose tissue secreting non-esterified free fatty acids & reduction of their clearance/oxidation which disturbs gut permeability to LPs [45].
TLR4 resultant inflammation associated with activation IKK, MAPK, JNK, and p38 pathways would further increase insulin receptor substrate-1 (IRS1) serine phosphorylation thus decrease insulin receptor’s signal transduction [31, 45]. Furthermore, TLR4-MyD88 signalling pathway activation was suggested throughout developmental researches for several anti-hyperlipidemic medications, while TLR1, 2, 3 & 7 were triggering both host immune defence and/autoimmune response that aggravate diabetic state [37].
TLRs expression in renal tube epithelial lining render their activation to be essential in renal vascular remodelling, endothelial dysfunction in multiple renal disorders like acute kidney injury (AKI), solid organ transplant, glomerulonephritis, ischemic/reperfusion injury (I/R injury) & diabetic renal disorders [27, 44]. Experimental streptozocin induced diabetic model revealed podcytopathy & fibrosis regression after TLR4 knocking out, as they are expressed by podocytes & decreased diabetic nephropathy after TLR2 knocking out [46, 47]. TLR4 gene polymorphism was linked to prostate cancer among gene clusters of TLR1, 6 & 10 [37].
TLRs, as the primary receptor for many ligands that trigger innate & adaptive immune response, with complex signaling pathways involving many adaptor molecules & co-receptors seem interesting for therapeutic target development. Synthetic agonist, antagonist and even naturalized antibodies could modify TLRs signaling to make them attractive targets for the management of different inflammatory disease. For example at 2013, Savva and Roger enlisted around 32 clinical trials at different phases for TLRs agonist/antagonist agent for the management of sepsis and infectious disease, these trials include even the antimalarial old agent chloroquine [28, 34].
TLR1/2 heterodimers were found to be increased in patients with atherosclerotic lesions, while administration of TLR1/2 agonist aggravates disease status, also TLR2 inhibition was suggested as diabetes and cardiovascular disorders therapy besides statins & thiazolidinedione by anti-inflammatory action [9]. Pam2/3CSK4 TLR2 ligands covalently linked to CD8+ or B-cell epitopes associated peptides were found to enhance therapeutic response in tumour models, by stimulating TLR2 induced T-cell activation [15]. A 3 component carbohydrate-based cancer vaccine involved TLR2 activator that mediates humoral immune response against tumour-induced glycopeptide antigens by affecting the maturation of cellular component of the innate immune system (DC & natural killer cells), furthermore cancer treatment with chimers of anti-tumour antibodies and small molecule agonist of TLR2 would alleviate disease progression [9].
Since high synovial expression of TLR3 in RA patients was found, one scenario for rheumatoid arthritis and possibly bone malignancy is to inhabit the TLR3 pathway via the RNA synthetic analogue Polyinosine-polycytidylic acid (poly (I:C) that affect monocyte –osteoclast cellular differentiation [9].
Various TLR4 antagonist was developed as a therapeutic agent, starting with the peptide P13- an inhibitor of TIR domain signalling pathway- that was found to ameliorate inflammatory response and improve surviving in a TLR4-mediated hepatic injury of murine model [16]. In addition, Lipid A mimetics E5564 and CRX526 bind to TLR4-MD2 complex showing valuable inhibition of pro-inflammatory cytokine IL-1 and TNF-α production in LPS treated animal models as well as septic shock patients in phase III clinical trial [9, 16, 29]. TLR4 inhibition was suggested as the scenario for treatment of thrombosis, atherosclerosis & vascular restenosis throughout coating TLR4 or MyD88 with inhibitory compound, small molecule antagonist, then by giving viral vectors that express antisense gene to TLR4 RNA [9], and finally TLR4/MD2/anti-Human IgG (Fc specific) (IgG-Fc) fusion protein inhibitor of NF-κB and JNK activation provides interesting biologic therapy for liver fibrosis, alcoholic and non-alcoholic steatohepatitis by decreasing IL-6 and monocyte Chemoattractant Protein-1(MCP-1) production [16].
Another TLR4-synergizer Fc/fusion protein and TL4 ligand α-1 acid glycoprotein were found to inhibit LPS-induced activation of hepatic MΦ by blocking the triggering receptor expressed on myeloid cells-1 (TREM1), and boosting the anti-inflammatory immune response. Other theoretically interesting scenarios involving the I.V administration of monophosphoryl lipid A derivatives as 2 adult HBV vaccine in treating viral hepatitis [13, 15, 16].
One possible scenario for cancer immunotherapy involved TLR5 binding to flagellin that can turn the tolerogenic DCs into active antigen-presenting cells (APC) [9].
Isatoribine, a TLR7 agonist administered I.V was found to decrease viral load with a moderate adverse effect profile in HCV patients. In addition, IGS-9620 that was experimentally assessed on the HBV animal model was found to decrease HBVs antigen (HBsAg) level in serum, HBV viral load as well as IFN-α in dose dependent-manner [15, 29]. Note that some TLR7 targeting therapies were approved by Food and Drug Administration (FDA) like imiquimod, TLR7-immune response modifier that was approved since 1997 for treatment of superficial skin malignant melanoma & genital warts by increasing cellular production of CK like IFN, IL-6 & TNF [9].
Selective TLR9 agonists like 1018 ISS (immunomodulatory sequences) that contain repeated CpG motifs were found to modulate the TLR9 signalling pathway involved in HBV infection and have been tested in phase III clinical trials. Another agonist IMO-2055 was under assessment in 2011 for oncologic disease as well as IMO-2125 which was found to maintain the high level of IFN was under assessment as a possible therapy to HCV patients. The TLR9 intracellular signalling inhibitors ST2825 and RO0884 designed to block IRAK1 &4/MyD88 singling pathway caused inhibition of the NF-κB, IL-1β, and TNF-α activation as well as decreased hepatic IL-6 secretion [9, 15, 29].
Medical and pharmacological development is focusing on the molecular level, in all aspects including analytical, physiological, pharmacological and even genetic aspects. Understanding immune response is thus important subject, furthermore, the target receptors which damage signals bind to, their signaling pathways end products will tell what possible immune response happened to human body. Toll-like receptors are those targets, the family of integral transmembrane glycoprotein expressed intracellularly or at cellular surface, considered main component and link between innate and adaptive immune response, which can induce signaling pathways involving four main adaptor molecules that initiate divaricated steps ending with inflammatory cytokines. These pathways could be involved in any inflammatory process/disorders and thus seems interesting targets for pharmacological intervention; all these steps bring us back to the bullet that explodes all these events in the body, the immune system.
The author declares no conflict of interest.
After precious Thanks to Almighty and Merciful GOD, I would like to express my thanks and gratitude to Professor G. H. Majeed who made it possible to me to accomplish this situation and reach you, my readers. Also to the magnificent group who introduced me to the world of toll-like receptors: professor Dr. Abduladheem Y. Abbood Al-Barrak, professor Dr. Bassim I. Mohammad, Dr. Samer Fadhel Hassan, Dr. Asma A. Swadi, and Dr. Huda J. Merza, and sure my own family.
Acute kidney injury Alcoholic liver disease Acute lung injury Angiotensin II Adaptor protein-1 Antigen-presenting cell Acute respiratory distress syndrome B cell lymphoma 2 Chemokine Cluster differential 14 Pro-inflammatory cytokines Cytosine phosphate guanine Damage-associated molecular pattern Dendritic cell Extracellular domain Extracellular matrix Free fatty acids Free radicals HBV e antigen HBV s antigen Hypoxia-inducible factor-1 Heat shock protein Ischemic/reperfusion injury Cytoplasmic domain Type-I interferon Anti-Human IgG (Fc specific) Inhibitor of kappa-B (IκB) kinase Interleukin Inducible nitric oxide synthase Inositol triphosphate-3 IL-1 receptor-associated kinase Interferon regulatory factor Inhibitor of kappa-B Jun (N)terminal kinase Lipopolysaccharides Leucine-rich repeat Lipoteichoic acid Mitogen-activated protein kinase Extracellular signal-regulated kinases Mast cell Monocyte Chemoattractant Protein-1 Lymphocyte antigen 96 Myocardial infarction Messenger ribonucleic acid Myeloid differential88 Macrophage nicotine amide adenine dinucleotide phosphate nucleotide oligomerization domain (NOD)-like receptors Nitric oxide nucleotide oligomerization domain NADPH oxidase Pam3CysSerLys4 Pathogen-associated molecular patterns Plasmatoid dendritic cells Peptidoglycan Phosphoinositide-3 Polyinosine-polycytidylic acid Pattern recognition receptors retinoic acid-inducible gene I retinoic acid-inducible gene I (RIG-I)-like receptors Reactive oxygen species Diabetes type 2 Transforming growth factor (TGF)-β-activated kinase Serine/threonine binding kinase Transcription factors Transforming growth factor Toll/IL-receptor TIR domain-containing adaptor protein/MyD88 adaptor like Toll-like receptors Tumour necrosis factor-alpha Toll interacting protein TNF receptor-associated factor-6 TRIF related adaptor molecule Regulatory T cells Triggering receptor expressed on myeloid cells-1 TIR domain-containing adaptor protein inducing interferon-β
YouTube video: [3] Armando Hasudungan, Immunology-Toll Like Receptors Overview [Internet. YouTube]. 2014. Available from: https://youtu.be/8mEnyBdsrr8
YouTube video: [18] Armando Hasudungan, Immunology - Toll Like Receptors Overview [Internet YouTube]. 2014. Available from: https://youtu.be/8mEnyBdsrr8
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Indeed, the resurgence of religions in all the continents is tangled in different ways to modernization processes. The main argument of this chapter is that this religious change toward pluralism can be fully understood in the context of multiple modernities theory, provided that it be revised and modified. The key understanding of changes must come from a better insight of popular religions worldwide. Latin American, Eastern Asia and Islam regions are good examples of popular forms of religious revitalization that contrasts with the Northern European case. New ways of producing sense and spiritual search in non-Western areas are framing specific relationships between religion and modernities and bringing about pluralisms. The interweaving of old and new religious traditions is accentuating interculturality and is generating great conditions for the emergence of new types of syncretism and/or sociocultural and even material (and violent) conflicts. 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There is a supposition therefore that heritage places or objects have intrinsic values that need to be discovered and assigned. This paper, using various examples from Africa, however, argues that values are not intrinsic to heritage but are a construct of heritage professionals/community, and therefore, a heritage place/object can have various values depending on who is making the judgment. It therefore follows that if values vary according to who is assigning them, then the significant/insignificant of a heritage place and object will also vary from one person/community to another. 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The chapter focuses on the development of the ideological interaction theory for connecting the discourse with language and personal thought. The concern criteria are ideology and the other social components like people, status, economy, media, and politics with their connectivity to the global situational trends. Therefore, the chapter surveys the personal traits as psychology, sociological surrounding, and cognitive efforts for the development of social as well as cultural interaction with the perspectives of individual influences.",book:{id:"6944",slug:"heritage",title:"Heritage",fullTitle:"Heritage"},signatures:"Yadu Prasad Gyawali",authors:null},{id:"58144",title:"Losing One’s Culture: The Narrative Identity of Nigerian Catholic Religious Sisters",slug:"losing-one-s-culture-the-narrative-identity-of-nigerian-catholic-religious-sisters",totalDownloads:880,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This chapter reports on part of the findings of a doctoral research focused on identity construction of Catholic religious sisters in the Church and in the wider Nigerian society. Primarily, the chapter interrogates how Catholic religious sisters negotiate their culture identity within the context of living religious life. Data were collected from 18 sister participants, who were purposefully recruited from two religious congregations across the different states of Nigeria. These included six temporary professed, six final professed and six leaders (including superiors/formators) representing the different categories of sisters that live religious life. The data were thematically analysed using the Dialogical Self Theory I-positions. The second sentence revealed tendencies for the participants to lose their cultural identity in terms of their struggles and sometimes compromises in identifying Western culture as the dominate culture of religious life. In this regard, the participants reported that their Nigerian communitarian culture of love, care and hospitality is regulated to the background. In response, this chapter calls for further research towards exploring the impact of culture on Catholic religious sisters’ expression of identity.",book:{id:"6169",slug:"culture-and-identity",title:"Culture and Identity",fullTitle:"Culture and Identity"},signatures:"Chika Eze, Graham C. Lindegger and Susan Rakoczy",authors:[{id:"216952",title:"Dr.",name:"Chika",middleName:null,surname:"Eze",slug:"chika-eze",fullName:"Chika Eze"}]},{id:"72251",title:"Public Diplomacy: Functions, Functional Boundaries and Measurement Methods",slug:"public-diplomacy-functions-functional-boundaries-and-measurement-methods",totalDownloads:842,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"It is common practice when evaluating the effect of public diplomacy to associate it with soft power. This chapter challenges this view. It holds that, rather than turning soft power resources into soft power, the fundamental function of public diplomacy is to transform a country’s assets into soft power resources that will attract the target country. This chapter also shows that although public diplomacy performs such functions, it is not necessarily effective, especially in ‘high politics’ such as territorial security. But even where its effectiveness can be exerted, public diplomacy is subject to other distractions. Therefore, in order to measure accurately the real effect of public diplomacy, it is necessary to exclude the potential influence of these interfering variables by strengthening the rigor of research design.",book:{id:"6944",slug:"heritage",title:"Heritage",fullTitle:"Heritage"},signatures:"Cao Wei",authors:null}],onlineFirstChaptersFilter:{topicId:"270",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:99,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:289,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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