\r\n\tSynthetic zeolites can be formed from different raw materials and among these many wastes represent some interesting sources due to their chemical and mineralogical composition. Today, a large number of different types of waste resulting from many human activities are produced in the world (e.g. industrial, municipal, agricultural waste) and most of them are deposed of in landfills thus determining a great environmental problem.
\r\n
\r\n\tThis book intends to provide the reader with a comprehensive overview of the current state-of-the-art on the possibility to transform the different types of waste materials into useful products, zeolites, through conventional processes and innovative methods. The aim is to demonstrate that waste can be a problem or a resource depending on how it is managed.
",isbn:"978-1-80356-426-5",printIsbn:"978-1-80356-425-8",pdfIsbn:"978-1-80356-427-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"3ed0dfd842de9cd1143212415903e6ad",bookSignature:"Dr. Claudia Belviso",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11561.jpg",keywords:"Structure, Properties, Natural Material, Synthetic Product, Type, Composition, Production, Disposal, Hydrothermal Method, Pre-fusion Process, Sonication, Multiple Steps",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 25th 2022",dateEndSecondStepPublish:"March 25th 2022",dateEndThirdStepPublish:"May 24th 2022",dateEndFourthStepPublish:"August 12th 2022",dateEndFifthStepPublish:"October 11th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"3 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Since 2002, Dr. Claudia Belviso has been carrying out research activity in the field of mineralogy and geochemistry aimed at environmental protection. She is responsible for the research activity on zeolite synthesis from waste materials and natural sources which has allowed her to be the inventor of an International Patent, publish numerous scientific articles in peer-reviewed journals, and carry out scientific research in national and international projects.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"61457",title:"Dr.",name:"Claudia",middleName:null,surname:"Belviso",slug:"claudia-belviso",fullName:"Claudia Belviso",profilePictureURL:"https://mts.intechopen.com/storage/users/61457/images/system/61457.jpg",biography:"Claudia Belviso is a researcher at the Institute of Methodologies of Environmental Analysis (IMAA) of CNR. After graduating in Geological Sciences and qualifying as a professional geologist, she earned a Ph.D. in Earth Sciences. Since 2002 has been carrying out her research activity in the field of mineralogy and geochemistry aimed at environmental protection. She is responsible for the research activity on zeolite synthesis from waste materials and natural sources as well as their application to solving environmental problems and as new raw material. These research activities have allowed her to be the inventor of an International Patent, publish numerous scientific articles in peer-reviewed journals, participate in national and international conferences, take part in the organization of international congresses, and carry out scientific research in national and international projects.",institutionString:"National Research Council",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"National Research Council",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"453622",firstName:"Tea",lastName:"Jurcic",middleName:null,title:"Ms.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"tea@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"5306",title:"Zeolites",subtitle:"Useful Minerals",isOpenForSubmission:!1,hash:"eec7f864baf093058440c0f56072a7cf",slug:"zeolites-useful-minerals",bookSignature:"Claudia Belviso",coverURL:"https://cdn.intechopen.com/books/images_new/5306.jpg",editedByType:"Edited by",editors:[{id:"61457",title:"Dr.",name:"Claudia",surname:"Belviso",slug:"claudia-belviso",fullName:"Claudia Belviso"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{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:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],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:"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:"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:"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:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],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:"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:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"21459",title:"Role of Fetuin-A in Injury and Infection",doi:"10.5772/18073",slug:"role-of-fetuin-a-in-injury-and-infection",body:'\n\t\t
\n\t\t\t
1. Introduction
\n\t\t\t
Injury and infection, seemingly unrelated conditions, converge on a common process - inflammation, which is mediated partly by innate immune cells including macrophages and monocytes. These innate immune cells are equipped with pattern recognition receptors (such as TLR2, TLR4, and TLR9) (Brightbill et al. 1999; Poltorak et al. 1998; Hemmi et al. 2000), and can recognize both damage- and pathogen-associated molecular patterns (DAMPs, such as HMGB1; and PAMPs, such as endotoxin) (Andersson et al. 2000; Chen et al. 2009;Krieg 2002;Wang et al. 1999;Ivanov et al. 2007). In response to various PAMPs or DAMPs, innate immune cells release proinflammatory cytokines (such as TNF, IL-1, IFN-γ or HMGB1) to mount inflammatory responses. If dysregulated, an uncontrolled inflammation may adversely lead to detrimental consequences. To orchestrate the inflammatory response to infection and injury, the liver strategically re-prioritizes the synthesis and systemic release of a group of proteins collectively termed “acute phase proteins” (APPs). For instance, fetuin-A, also called the alpha-2-HS-glycoprotein for the human homologue (Christie et al. 1987), has been implicated as an anti-inflammatory protein during injury or infections. In this book chapter, we summarize emerging evidence to support fetuin-A as an acute phase protein capable of attenuating injury- or infection-elicited inflammatory responses.
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2. Fetuin-A as a negative or positive APP
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Fetuin-A was first isolated by Pederson more than sixty years ago as a major plasma protein in the fetus (Pedersen 1944). During fetal development, it is expressed in most organs including the liver, kidney, gastrointestinal tract, skin and brain (Terkelsen et al. 1998; Kitchener et al. 1997; Dziegielewska et al. 2000; Kitchener et al. 1999). In adults however, fetuin-A is produced primarily by the liver, and its synthesis is divergently regulated during injury or infection, classifying it as a negative or positive APP.
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2.1. Regulators of hepatic Fetuin-A expression
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Although fetuin-A is constitutively expressed in hepatocytes, its expression is negatively regulated by several proinflammatory cytokines. For instance, the fetuin-A expression levels in human HepG2 hepatoma cells were reduced by proinflammatory cytokines such as TNF, IL-1, IL-6, and IFN-γ (Daveau et al. 1988;Li et al. 2011a). IFN-γ, at concentrations as low as 10-50 ng/ml, reduced fetuin-A expression levels by as much as 50-70% (Li et al. 2011a). In contrast, HMGB1 (1 μg/ml), a late proinflammatory mediator of lethal systemic inflammation (Wang et al. 1999; Yang et al. 2004; Wang et al. 2008), elevated fetuin-A expression levels by 2-3 folds in HepG2 cells, suggesting that different cytokines divergently regulate hepatic fetuin-A expression.
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2.2. Elevation of Fetuin-A Levels during ischemia
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In patients with cerebral ischemic injury (stroke), plasma fetuin-A levels were paradoxically elevated (Weikert et al. 2008;Tuttolomondo et al. 2010). The elevation of circulating fetuin-A levels correlated with an increase not only in LDL-cholesterol levels (Tuttolomondo et al. 2010) but also in risk of cardiovascular disorders (Weikert et al. 2008). Similarly, serum fetuin-A levels were increased up to 10-fold in cattle following traumatic injury (Dziegielewska et al. 1992), suggesting fetuin-A as a positive APP during ischemic or traumatic injury. Notably, HMGB1 can be passively leaked from injured cells (Peltz et al. 2009), and functions as an early mediator of traumatic or ischemic injury (Zhu et al. 2010; Wu et al. 2007; Liu et al. 2007b; Tsung et al. 2005; Tsung et al. 2007; Watanabe et al. 2005). It is thus plausible that HMGB1 participates in the up-regulation of hepatic fetuin-A expression during injury.
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In an animal model of focal cerebral ischemia (i.e., permanent middle cerebral artery occlusion, MCAo), fetuin-A levels in the ischemic brain tissue were also elevated in a time-dependent manner, starting between 2-6 h, peaking around 24-48 h, and returning towards base-line at 72 h post MCAo (Wang et al. 2010). This time-dependent increase in cerebral fetuin-A levels parallels with the transient elevation of the blood-brain barrier (BBB) permeability (Belayev et al. 1996), suggesting that circulating fetuin-A can gain entry across the BBB into the ischemic brain tissue. This possibility was supported by the observation that peripherally (intravenously) administered FITC-labeled fetuin-A was found in the ischemic brain region at 24 h after MCAo (Wang et al. 2010).
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2.3. Reduction of circulating Fetuin-A levels during infection
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In animal models of endotoxemia and sepsis (induced by cecal ligation and puncture, CLP), circulating fetuin-A levels were decreased in a time-dependent fashion, starting between 2-6 h, reaching a nadir (with maximal reduction by 50-60%) around 24-48 h. Afterwards, fetuin-A levels started to increase, returning towards basal levels approximately 72 h post endotoxemia or sepsis, supporting fetuin-A as a negative APP in animal models of lethal endotoxemia and sepsis (Li et al. 2011a). Interestingly, disruption of expression of early proinflammatory cytokines (such as IFN-γ) impaired bacterial endotoxin-mediated down-regulation of fetuin-A expression (Li et al. 2011a). It thus appears that early proinflammatory cytokines (such as TNF and IFN-γ) function as negative regulators to reduce circulating fetuin-A levels during an early stage of endotoxemia or sepsis; whereas late-acting proinflammatory mediators (e.g., HMGB1) stimulate fetuin-A expression to restore its circulating levels at a late stage.
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In patients with other inflammatory diseases such as pancreatitis (Kusnierz-Cabala et al. 2010), chronic kidney diseases (Metry et al. 2008), and rheumatoid arthritis (Sato et al. 2007), serum fetuin A levels were also decreased by 20-30%. In these patients, circulating fetuin-A levels were not only inversely correlated with levels of inflammatory cytokines (such as IL-6) (Kusnierz-Cabala et al. 2010), but also associated with increased mortality rates (Metry et al. 2008). Collectively, these observations classify fetuin-A as a negative APP during infection or other inflammatory illness.
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3. Biological functions of Fetuin-A
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Despite its abundance, the functions of fetuin-A remain poorly understood. A wide range of biological functions have been proposed for fetuin-A based on its structural similarities to other proteins or physical interactions with biogenic molecules.
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3.1. Inhibitor of insulin or TGF-β Signalling
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Fetuin-A shares sequence similarity to type II TGF-β receptors (Demetriou et al. 1996) and insulin receptor tyrosine kinases (Mathews et al. 1997;Haasemann et al. 1991), and has thus been proposed as an inhibitor of the TGF-β or insulin signaling pathways. After binding to to TGF-β1, fetuin-A prevents TGF-β1 from binding to its receptors, thereby antagonizing TGF-β1-mediated antiproliferative effects (Demetriou et al. 1996). Similarly, fetuin-A can also bind to the insulin receptor, and consequently inactivate (rather than activate, as in the case for insulin) the receptor tyrosine kinase (Goustin & Abou-Samra 2010). This may partly explain why higher fetuin-A levels were associated with insulin resistance in some patients with type 2 diabetes (Ix et al. 2008).
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3.2. Inhibition of pathological calcification
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As a glycoprotein, fetuin-A carries two N-linked and three O-linked oligosaccharide chains that terminate with sialic acid residues, and can bind cationic Ca2+ ions. Accordingly, fetuin-A has been proposed as an endogenous inhibitor of pathological mineralization or calcification in soft tissues (Jahnen-Dechent et al. 2001;Schinke et al. 1996;Szweras et al. 2002;Schafer et al. 2003;Ketteler et al. 2003). Specifically, fetuin-A forms protein-mineral colloids with calcium and phosphate (Heiss et al. 2003;Wu et al. 2009), thereby preventing uncontrolled mineralization that may otherwise occur under pathological conditions (Rochette et al. 2009).
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3.3. Inhibition of inflammation
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While investigating the mechanism underlying a cationic molecule spermine-mediated anti-inflammatory actions, we serendipitously discovered that macrophages lost their responsiveness to spermine when cultured under low serum conditions (Wang et al. 1997). That is, despite the addition of cytokine-suppressing concentrations of spermine, the bacterial lipopolysaccharide (LPS)-induced production of TNF by these serum-starved macrophages was uninhibited. Subsequently, we discovered that these serum-starved macrophages became deprived of fetuin-A that was required for spermine to inhibit TNF production (Wang et al. 1997). The involvement of fetuin-A in spermine-mediated immunosuppression was confirmed by adding highly purified fetuin-A or fetuin-specific antibodies, which respectively restored or impaired spermine-mediated TNF inhibition (Wang et al. 1997).
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It is plausible that fetuin-A functions as an opsonin for cationic spermine, and its availability to immune cells may be critical in regulating the innate immune response (Wang & Tracey 1999). Indeed, levels of fetuin-A in macrophage cultures could be altered by LPS stimulation or fetuin-A supplementation (Figure 1A). Intriguingly, the exogenously administered fetuin-A was predominantly localized in cytoplasmic punctate structures (Figure 1B), which co-localized with vesicles containing an autophagy marker (LC3) - possibly autophagosomes or amphisomes - in LPS-stimulated macrophages.
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When given at higher concentrations (e.g., 3.5 mg/ml), crude fetuin-A (> 98%, Sigma-Aldrich) abrogated endotoxin-induced release of IL-1 and nitric oxide (Dziegielewska et al. 1998). Upon purification by gel filtration and ion-exchange chromatography, the highly purified intact fetuin-A could effectively inhibit IFN-γ- or LPS-induced release of HMGB1 (Li et al. 2011a), a newly identified late mediator of lethal endotoxemia and sepsis (Wang et al. 2008;Wang et al.\n\t\t\t\t\t2009). However, even at the concentrations (e.g., 100 μg/ml) that abrogated LPS-induced HMGB1 release, fetuin-A only partly inhibited LPS-induced TNF secretion, suggesting fetuin-A as an effective inhibitor of HMGB1 release.
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Figure 1.
Exogenous fetuin-A was internalized into cytoplasmic vesicles in macrophage cultures. A). Supplementation of exogenous fetuin-A prevented endotoxin-induced fetuin-A depletion. Murine macrophage-like RAW 264.7 cells were stimulated with LPS (100 ng/ml) in the absence or presence of fetuin-A (100 μg/ml) for 2 h, and cellular fetuin-A levels were determined by Western blotting. The relative fetuin-A levels, as a ratio to β-actin, were expressed as the mean ± SD of three independent experiments. *, p < 0.05 versus control (“+LPS”); #, p < 0.01 vs control (“+LPS”). B) Exogenous fetuin-A was internalized into LC3-containing cytoplasmic vesicles. GFP-LC3-transfected RAW 264.7 cells were stimulated with LPS (200 ng/ml) in the presence of fetuin-A (100 μg/ml) overnight, and immunostained with fetuin-A-specific antibodies.
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4. Therapeutic potential of Fetuin-A in infection or injury
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4.1. Carrageenan-induced paw edema
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In an animal model of carrageenan-induced inflammation, intraperitoneal administration of fetuin-A (5 to 500 mg/kg) dose-dependently attenuated the development of paw edema (Ombrellino et al. 2001). The sialic acid moieties of fetuin-A might be required for its anti-inflammatory activities. When these sialic acid residues were removed by neuraminidase, the resultant asialofetuin-A failed to potentiate the anti-inflammatory activities of spermine (Wang et al. 1997) and failed to attenuate carrageenan-induced TNF production in vivo (Ombrellino et al. 2001). In contrast, administration of anti-fetuin-A neutralizing antibodies in combination with carrageenan led to significantly increased paw edema, indicating that fetuin-A plays an important role in counter-regulating inflammatory responses.
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4.2. Cerebral ischemic injury
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Cerebral ischemia is frequently caused by an obstruction of a cerebral artery. Despite advances in acute and prophylactic therapies, stroke represents the leading cause of long-term disability (500,000-700,000 cases per year), and the third most common cause of death (with a mortality rate of 20-25%) in the United States.
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4.2.1. Pathogenesis of cerebral ischemic injury
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Cerebral ischemic injury consists of two stages: primary tissue damage in the ischemic core and secondary tissue injury in the surrounding penumbra. The primary injury in the ischemic core is primarily mediated by tissue ion (Ca2+ and Na+) overload (Taylor & Meldrum 1995) and excitotoxicity (Lee et al. 1999); whereas the secondary injury in the surrounding penumbra is partly mediated by proinflammatory cytokines (Figure 2, Feuerstein et al. 1998).
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Figure 2.
Cascade of events leading to primary injury in the ischemic core and secondary injury in the surrounding penumbra.
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4.2.1.1. Primary early injury in the core
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Within seconds to minutes after cerebral ischemia, decreased ATP production leads to failure of the Na+/K+-ATPase pump, disruption of membrane potentials, influx of sodium and calcium, and subsequent release of excitatory amino acids (such as glutamate, Figure 2). Engagement of glutamate with the ionotropic N-methyl-D-aspartate receptor (NMDA) leads to Ca2+ influx and activation of damaging proteases (e.g., phospholipase A2, nitric oxide synthase, endonucleases, and calpain) that compromise the functional and structural integrity of neuronal cells within 20-60 minutes (Figure 2). Early-stage therapeutics that block ion (Na+ and Ca2+) channels (Taylor & Meldrum 1995) and glutamate receptors (Meldrum 1990) fail in clinical trials, partly because of the impracticalities of administering such drugs at a time when those mechanisms are already activated. These failures have prompted the search for downstream targets that also mediate ischemic injury.
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4.2.1.2. Secondary late injury in the penumbral zone
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Outside of the ischemic core where cells are destined to die lies a penumbral zone where brain cell death continues slowly for hours and even days after the onset of ischemia (Figure 2). This progressive expansion of cell death in the penumbra (i.e., secondary injury) is mediated by ischemia-elicited inflammatory responses. Within a few hours, microglia and neurons become activated to produce TNF and other cytokines (Kato et al. 1996;Botchkina et al. 1997). Subsequently, polymorphonuclear cells infiltrate into the ischemic brain tissue within 12-48 hours (Akopov et al. 1996), followed by an influx of monocytes and macrophages over a period of one to several days. Together, these centrally- and peripherally-derived cells orchestrate a potentially injurious inflammatory response by overproducing various proinflammatory cytokines (Figure 2).
During cerebral ischemia, brain spermine levels are decreased (Paschen et al. 1992), owing largely to an accompanying increase in the enzymatic activity of brain polyamine oxidase (Ivanova et al. 1998). The loss of spermine consequently tilts the balance towards neurotoxicity through activating the NMDA receptor, and increasing susceptibility to oxidative stress as well as excessive inflammatory response.
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Figure 3.
Divergent roles of spermine in cerebral ischemic injury.
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4.2.3. Peripheral administration of fetuin-A reduced cerebral ischemic injury
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As mentioned earlier, when given peripherally, exogenous fetuin-A gains entry across the BBB into the ischemic brain tissue (Figure 4). The time-course of fetuin-A extravasation in the ischemic brain tissue parallels with the time-dependent alteration of the BBB permeability (Belayev et al. 1996), which was transiently elevated (5 -25 h post MCAo) followed by a return towards baseline at 72 h post MCAo (Belayev et al. 1996). It is possible that the temporal breakdown of the BBB is required for circulating fetuin-A to transiently gain entry into the brain. Consistently, peripheral administration of fetuin-A (50 mg/kg) promoted a dose-dependent protection against cerebral ischemic injury during an early stage of cerebral ischemia (i.e., 24 h post MCAo) (Wang et al. 2010). However, the fetuin-A-mediated protection was not long-lasting, and gradually diminished at a later stage (e.g., 7 days post MCAo). It is possible that the restore of BBB function at a late stage (3 days after MCAo) limits subsequent fetuin-A extravasation, thereby diminishing fetuin-A-mediated long-lasting protective effects.
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Given the aforementioned pathogenic roles of Ca2+ and spermine in cerebral ischemia (in section 4.2.1 and 4.2.2), as well as the capacity of fetuin-A in binding Ca2+ and spermine (in secton 3.2 and 3.3) (Suzuki et al. 1994;Wang et al. 1997), it is plausible that fetuin-A confers protection by caging these toxic cationic molecules (Lee et al. 1999;Ivanova et al. 1998), thereby depriving them from damaging enzymes (such as Ca2+ -dependent proteases and polyamine oxidase). Furthermore, the fetuin-A-mediated protection is associated with a reduction of ischemia-elicited HMGB1 leakage from the ischemic core, and an inhibition of expression of proinflammatory cytokines (e.g., TNF) in the penumbra (Wang et al. 2010) (Figure 4), suggesting that fetuin-A confers protection partly by attenuating early inflammatory responses.
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Figure 4.
Protective roles of fetuin-A in cerebral ischemic injury and sepsis.
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4.3. Experimental sepsis
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Sepsis is the most common cause of death in intensive care units, claiming approximately 225,000 victims annually in the U.S. alone. The high mortality of sepsis is in part mediated by bacterial endotoxin, which activates macrophages and monocytes to sequentially release early (e.g., TNF and IL-1) (Dinarello 1996) and late (e.g., HMGB1) proinflammatory cytokines.
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4.3.1. Pathogenesis of sepsis
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The pathogenesis of sepsis is partly attributable to dysregulated systemic inflammatory responses that are initiated by early proinflammatory cytokines and sustained by late-acting proinflammatory mediators. For instance, excessive accumulation of early proinflammatory cytokines, including TNF (Tracey et al. 1987), interleukin (IL)-1 (Dinarello & Thompson 1991), interferon (IFN)-γ (Heinzel 1990), individually or in combination, contribute to the pathogenesis of lethal systemic inflammation. Because these early cytokines are difficult to target in clinical settings, we searched for other late proinflammatory mediators that may offer a wider therapeutic window.
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As aforementioned, HMGB1 is released from activated innate immune cells in response to microbial products (such as endotoxin or CpG-DNA) (Wang et al. 1999;Ivanov et al. 2007), or host cytokines (e.g., TNF or IFN-γ) (Wang et al. 1999;Rendon-Mitchell et al. 2003), and functions as a late mediator of endotoxemia and sepsis (Wang et al. 1999;Yang et al. 2004;Wang et al. 2008;Wang et al. 2009). In murine models of endotoxemia and sepsis, HMGB1 is first detectable in the circulation eight hours after the onset of diseases, subsequently increasing to plateau levels from 16 to 32 hours (Wang et al. 1999; Yang et al. 2004) (Figure 4). This late appearance of circulating HMGB1 parallels with the onset of animal lethality from endotoxemia or sepsis, and distinguishes itself from TNF and other early proinflammatory cytokines (Wang et al. 2001). Therefore, agents capable of selectively attenuating systemic HMGB1 accumulation at a late stage may hold potential in the treatment of lethal sepsis.
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4.3.2. Dual roles of spermine in experimental sepsis
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In light of the anti-inflammatory activities of spermine in vitro (Zhang et al. 1997;Zhu et al. 2009), we evaluated the effects of spermine on animal survival in animal models of sepsis. Intraperitoneal administration of spermine (1.0 -10 mg/kg, twice daily, for three days) did not protect mice against lethal endotoxemia, but confers a dose-dependent protection against lethal sepsis. This protection was associated with a significant attenuation of systemic accumulation of HMGB1 and other cytokines (e.g., IL-6, KC, MCP-1, MIP-2, TIMP-1, sTNFRI and sTNFRII) (Zhu et al. 2009). At a higher dose (100 mg/kg), however, spermine decreased animal survival rate from 58% to 38% at 48 h post CLP, and further decreasing it to 0% at 72 h post CLP. It is possible that spermine is enzymatically converted by polyamine oxidases into cytotoxic metabolites (e.g., 3-aminopropanal), thereby exerting these potentially toxic effects when given at higher doses.
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4.3.3. Protective role of Fetuin-A in sepsis
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To understand the role of fetuin-A in systemic inflammatory diseases, we determined the influence of fetuin-A disruption on endotoxemic and septic lethality. Although fetuin-A-deficient C57BL/6J mice were not more susceptible to cerebral ischemic insult than sex- and body-matched (male, 27-29 g) wild-type C57BL/6J mice (Wang et al. 2010), they were more susceptible to lethal endotoxemic or septic insult (Li et al. 2011a). It suggests that endogenous fetuin-A occupies an integral role in host defense against lethal systemic inflammation.
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The protective role of fetuin-A was further supported by the observations that supplementation with exogenous fetuin-A (20-100 mg/kg) provided a dose-dependent protection against lethal endotoxemia (Li et al. 2011a). In an animal model of sepsis, delayed administration of fetuin-A (20 - 100 mg/kg), beginning 24 h after the onset of sepsis and followed by an additional dose at 48 h post CLP, dose-dependently and significantly increased long-term animal survival rates from 45% to 90% (Li et al. 2011a).
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4.3.4. Protective mechanisms
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Supplementation of fetuin-A was associated with significant reduction of circulating HMGB1 levels, suggesting that fetuin-A confers protection by inhibiting late-acting proinflammatory mediators (Li et al. 2011a). The mechanisms underlying fetuin-A-mediated suppression of HMGB1 release may be complex. At the concentrations (100 μg/ml) that fetuin-A attenuated LPS-induced HMGB1 release in macrophage cultures, fetuin-A stimulated autophagy and impaired LPS-induced elevation of cytoplasmic and nuclear HMGB1 levels (Li et al. 2011a). It is presently unknown whether fetuin-A reduces cytoplasmic HMGB1 levels by stimulating its degradation in an autophagy-dependent fashion, as what has been shown for other HMGB1 inhibitors such as EGCG, the major catechin of Green tea (Camellia sinensis) (Li et al. 2011b).
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Accumulating evidence has suggested the possibility that fetuin-A functions as a negative regulator of HMGB1 release during lethal systemic inflammation (Figure 4). First, the time-dependent decrease of circulating fetuin-A levels was accompanied by parallel but opposite changes – a time-dependent increase - of circulating HMGB1 levels in animal models of endotoxemia (Wang et al. 1999) or sepsis (Yang et al. 2004). Second, disruption of fetuin-A expression led to elevation of serum HMGB1 levels in endotoxemia and sepsis (Li et al. 2011a). Lastly, supplementation of fetuin-A resulted in significant reduction of circulating HMGB1 levels during endotoxemia and sepsis (Li et al. 2011a).
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Nevertheless, the current study can not exclude other alternative mechanisms by which fetuin-A confers these protective effects. For instance, fetuin-A may be capable of binding bacteria (Chmiela et al. 1997;Dubreuil et al. 2002), thereby affecting macrophage-mediated pathogen elimination. Furthermore, fetuin-A may facilitate macrophages-mediated ingestion and elimination of apoptotic neutrophils (Lord 2003;Jersmann et al. 2003), thereby preventing secondary necrosis and passive leakage of injurious molecules (e.g., proteases, reactive oxygen species, and HMGB1) (Bell et al. 2006).
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5. Conclusions
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A liver-derived acute phase protein, fetuin-A, appears to be distinctly regulated by different proinflammatory mediators. A previously under-appreciated protective role for fetuin-A in injury and infection has been suggested by recent studies. Fetuin-A is capable of crossing the blood-brain barrier, inhibiting early inflammatory response in animal models of cerebral ischemia, thereby conferring a short-term neuroprotection against ischemic injury. Disruption of fetuin-A expression renders mice significantly more susceptible to lethal endotoxemia or sepsis; whereas repetitive administration of fetuin-A confers a dose-dependent and long-lasting protection in animal models of lethal endotoxemia and sepsis. Thus, fetuin-A occupies protective roles against injury- or infection-elicited inflammation.
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Acknowledgments
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We thank Arvin Jundoria for critical reading of the manuscript. Work in the author’s laboratory was supported by the National Institute of General Medical Sciences (R01GM063075 and R01GM070817 to HW) and the National Center of Complementary & Alternative Medicine (R01AT05076 to HW).
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\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/21459.pdf",chapterXML:"https://mts.intechopen.com/source/xml/21459.xml",downloadPdfUrl:"/chapter/pdf-download/21459",previewPdfUrl:"/chapter/pdf-preview/21459",totalDownloads:2418,totalViews:206,totalCrossrefCites:2,totalDimensionsCites:13,totalAltmetricsMentions:0,impactScore:9,impactScorePercentile:97,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"October 25th 2010",dateReviewed:"April 25th 2011",datePrePublished:null,datePublished:"October 5th 2011",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/21459",risUrl:"/chapter/ris/21459",book:{id:"234",slug:"acute-phase-proteins-regulation-and-functions-of-acute-phase-proteins"},signatures:"Haichao Wang, Wei Li, Shu Zhu, Ping Wang and Andrew E. Sama",authors:[{id:"30316",title:"Prof.",name:"Haichao",middleName:null,surname:"Wang",fullName:"Haichao Wang",slug:"haichao-wang",email:"hwang@nshs.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"85626",title:"Dr.",name:"Wei",middleName:null,surname:"Li",fullName:"Wei Li",slug:"wei-li",email:"wli2@nshs.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"North Shore University Hospital",institutionURL:null,country:{name:"United States of America"}}},{id:"85627",title:"Dr.",name:"Shu",middleName:null,surname:"Zhu",fullName:"Shu Zhu",slug:"shu-zhu",email:"szhu@nshs.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"North Shore University Hospital",institutionURL:null,country:{name:"United States of America"}}},{id:"85628",title:"Prof.",name:"Ping",middleName:null,surname:"Wang",fullName:"Ping Wang",slug:"ping-wang",email:"pwang@nshs.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"North Shore University Hospital",institutionURL:null,country:{name:"United States of America"}}},{id:"85629",title:"Prof.",name:"Andrew",middleName:null,surname:"Sama",fullName:"Andrew Sama",slug:"andrew-sama",email:"asama@nshs.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"North Shore University Hospital",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction ",level:"1"},{id:"sec_2",title:"2. Fetuin-A as a negative or positive APP",level:"1"},{id:"sec_2_2",title:"2.1. Regulators of hepatic Fetuin-A expression ",level:"2"},{id:"sec_3_2",title:"2.2. Elevation of Fetuin-A Levels during ischemia ",level:"2"},{id:"sec_4_2",title:"2.3. Reduction of circulating Fetuin-A levels during infection ",level:"2"},{id:"sec_6",title:"3. Biological functions of Fetuin-A",level:"1"},{id:"sec_6_2",title:"3.1. Inhibitor of insulin or TGF-β Signalling ",level:"2"},{id:"sec_7_2",title:"3.2. Inhibition of pathological calcification ",level:"2"},{id:"sec_8_2",title:"3.3. Inhibition of inflammation ",level:"2"},{id:"sec_10",title:"4. Therapeutic potential of Fetuin-A in infection or injury",level:"1"},{id:"sec_10_2",title:"4.1. Carrageenan-induced paw edema",level:"2"},{id:"sec_11_2",title:"4.2. Cerebral ischemic injury",level:"2"},{id:"sec_11_3",title:"4.2.1. Pathogenesis of cerebral ischemic injury",level:"3"},{id:"sec_11_4",title:"4.2.1.1. Primary early injury in the core",level:"4"},{id:"sec_12_4",title:"4.2.1.2. Secondary late injury in the penumbral zone",level:"4"},{id:"sec_14_3",title:"4.2.2. Divergent roles of spermine in cerebral ischemic injury",level:"3"},{id:"sec_15_3",title:"4.2.3. Peripheral administration of fetuin-A reduced cerebral ischemic injury",level:"3"},{id:"sec_17_2",title:"4.3. Experimental sepsis",level:"2"},{id:"sec_17_3",title:"4.3.1. Pathogenesis of sepsis",level:"3"},{id:"sec_18_3",title:"4.3.2. Dual roles of spermine in experimental sepsis",level:"3"},{id:"sec_19_3",title:"4.3.3. Protective role of Fetuin-A in sepsis",level:"3"},{id:"sec_20_3",title:"4.3.4. Protective mechanisms",level:"3"},{id:"sec_23",title:"5. Conclusions",level:"1"},{id:"sec_24",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAdibhatla\n\t\t\t\t\t\t\tR. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHatcher\n\t\t\t\t\t\t\tJ. 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R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShlipak\n\t\t\t\t\t\t\tM. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 Fetuin-A and incident diabetes mellitus in older persons. JAMA\n\t\t\t\t\t300\n\t\t\t\t\t182\n\t\t\t\t\t188\n\t\t\t\t\n\t\t\t'},{id:"B35",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJahnen-Dechent\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchafer\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHeiss\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGrotzinger\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tSystemic inhibition of spontaneous calcification by the serum protein alpha 2-HS glycoprotein/fetuin.\n\t\t\t\t\tZ Kardiol 90 Suppl 3\n\t\t\t\t\t47\n\t\t\t\t\t56\n\t\t\t\t\n\t\t\t'},{id:"B36",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJersmann\n\t\t\t\t\t\t\tH. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDransfield\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHart\n\t\t\t\t\t\t\tS. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003\n\t\t\t\t\tFetuin/alpha2-HS glycoprotein enhances phagocytosis of apoptotic cells and macropinocytosis by human macrophages.\n\t\t\t\t\tClin Sci (Lond)\n\t\t\t\t\t105\n\t\t\t\t\t273\n\t\t\t\t\t278\n\t\t\t\t\n\t\t\t'},{id:"B37",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKato\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKogure\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tX. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAraki\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tItoyama\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1996\n\t\t\t\t\tProgressive expression of immunomolecules on activated microglia and invading leukocytes following focal cerebral ischemia in the rat.\n\t\t\t\t\tBrain Res.\n\t\t\t\t\t734\n\t\t\t\t\t203\n\t\t\t\t\t212\n\t\t\t\t\n\t\t\t'},{id:"B38",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKetteler\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBongartz\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWestenfeld\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWildberger\n\t\t\t\t\t\t\tJ. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMahnken\n\t\t\t\t\t\t\tA. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBohm\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMetzger\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWanner\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJahnen-Dechent\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFloege\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003\n\t\t\t\t\tAssociation of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study.\n\t\t\t\t\tLancet\n\t\t\t\t\t361\n\t\t\t\t\t827\n\t\t\t\t\t833\n\t\t\t\t\n\t\t\t'},{id:"B39",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKitchener\n\t\t\t\t\t\t\tP. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDziegielewska\n\t\t\t\t\t\t\tK. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHutton\n\t\t\t\t\t\t\tE. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHinrichsen\n\t\t\t\t\t\t\tC. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaunders\n\t\t\t\t\t\t\tN. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999\n\t\t\t\t\tFetuin in neurons of the retina and cerebellum during fetal and postnatal development of the rat. Int J Dev Neurosci\n\t\t\t\t\t17\n\t\t\t\t\t21\n\t\t\t\t\t30\n\t\t\t\t\n\t\t\t'},{id:"B40",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKitchener\n\t\t\t\t\t\t\tP. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDziegielewska\n\t\t\t\t\t\t\tK. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKnott\n\t\t\t\t\t\t\tG. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiller\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNawratil\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPotter\n\t\t\t\t\t\t\tA. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSaunders\n\t\t\t\t\t\t\tN. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1997\n\t\t\t\t\tFetuin expression in the dorsal root ganglia and trigeminal ganglia of perinatal rats. Int J Dev Neurosci\n\t\t\t\t\t15\n\t\t\t\t\t717\n\t\t\t\t\t727\n\t\t\t\t\n\t\t\t'},{id:"B41",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKrieg\n\t\t\t\t\t\t\tA. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002 CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 20\n\t\t\t\t\t709\n\t\t\t\t\t760\n\t\t\t\t\n\t\t\t'},{id:"B42",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKusnierz-Cabala\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGurda-Duda\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPanek\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFedak\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDumnicka\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSolnica\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKulig\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Serum fetuin A concentrations in patients with acute pancreatitis. Clin Lab 56\n\t\t\t\t\t191\n\t\t\t\t\t195\n\t\t\t\t\n\t\t\t'},{id:"B43",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLee\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZipfel\n\t\t\t\t\t\t\tG. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChoi\n\t\t\t\t\t\t\tD. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999\n\t\t\t\t\tThe changing landscape of ischaemic brain injury mechanisms.\n\t\t\t\t\tNature 399 Supplement, A7 -A14\n\t\t\t'},{id:"B44",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhu\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHuang\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhou\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFan\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGong\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEissa\n\t\t\t\t\t\t\tN. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJahnen-Dechent\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTracey\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSama\n\t\t\t\t\t\t\tA. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011a A hepatic protein, fetuin-A, occupies a protective role in lethal systemic inflammation. PLoS ONE 6(2), e16945\n\t\t\t'},{id:"B45",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhu\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAssa\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tXu\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFan\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEissa\n\t\t\t\t\t\t\tN. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTracey\n\t\t\t\t\t\t\tK. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSama\n\t\t\t\t\t\t\tA. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011b EGCG induces autophagy and reduced cytoplasmic HMGB1 levels in endotoxin-stimulated macrophages. Biochem Pharmacol 81(9), 1152-1163.\n\t\t\t'},{id:"B46",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMori\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakahashi\n\t\t\t\t\t\t\tH. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTomono\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWake\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKanke\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSato\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHiraga\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAdachi\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYoshino\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNishibori\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007a Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats. FASEB J\n\t\t\t\t\t21\n\t\t\t\t\t3904\n\t\t\t\t\t3916\n\t\t\t\t\n\t\t\t'},{id:"B47",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMori\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTakahashi\n\t\t\t\t\t\t\tH. 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Eur J Clin Invest 38\n\t\t\t\t\t804\n\t\t\t\t\t811\n\t\t\t\t\n\t\t\t'},{id:"B54",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMuhammad\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBarakat\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStoyanov\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMurikinati\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTracey\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBendszus\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRossetti\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNawroth\n\t\t\t\t\t\t\tP. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBierhaus\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchwaninger\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 The HMGB1 receptor RAGE mediates ischemic brain damage. J Neurosci\n\t\t\t\t\t28\n\t\t\t\t\t12023\n\t\t\t\t\t12031\n\t\t\t\t\n\t\t\t'},{id:"B55",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOmbrellino\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVishnubhakat\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrazier\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tScher\n\t\t\t\t\t\t\tL. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFriedman\n\t\t\t\t\t\t\tS. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTracey\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tFetuin, a negative acute phase protein, attenuates TNF synthesis and the innate inflammatory response to carrageenan. Shock\n\t\t\t\t\t15\n\t\t\t\t\t181\n\t\t\t\t\t185\n\t\t\t\t\n\t\t\t'},{id:"B56",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPaschen\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1992\n\t\t\t\t\tPolyamine metabolism in reversible cerebral ischemia.\n\t\t\t\t\tCerebrovasc Brain Metab Rev\n\t\t\t\t\t4\n\t\t\t\t\t59\n\t\t\t\t\t88\n\t\t\t\t\n\t\t\t'},{id:"B57",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPaschen\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCsiba\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRohn\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBereczki\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1991\n\t\t\t\t\tPolyamine metabolism in transient focal ischemia of rat brain.\n\t\t\t\t\tBrain Res\n\t\t\t\t\t566\n\t\t\t\t\t354\n\t\t\t\t\t357\n\t\t\t\t\n\t\t\t'},{id:"B58",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPaschen\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWidmann\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWeber\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1992\n\t\t\t\t\tChanges in regional polyamine profiles in rat brains after transient cerebral ischemia (single versus repetitive ischemia): evidence for release of polyamines from injured neurons.\n\t\t\t\t\tNeurosci Lett\n\t\t\t\t\t135\n\t\t\t\t\t121\n\t\t\t\t\t124\n\t\t\t\t\n\t\t\t'},{id:"B59",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPedersen\n\t\t\t\t\t\t\tK. O.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1944 Fetuin, a new globulin isolated from serum. Nature 154\n\t\t\t\t\t575\n\t\t\t\t\t576\n\t\t\t\t\n\t\t\t'},{id:"B60",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPeltz\n\t\t\t\t\t\t\tE. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoore\n\t\t\t\t\t\t\tE. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEckels\n\t\t\t\t\t\t\tP. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDamle\n\t\t\t\t\t\t\tS. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTsuruta\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJohnson\n\t\t\t\t\t\t\tJ. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSauaia\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSilliman\n\t\t\t\t\t\t\tC. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBanerjee\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAbraham\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009 HMGB1 is markedly elevated within 6 hours of mechanical trauma in humans. Shock\n\t\t\t\t\t32\n\t\t\t\t\t17\n\t\t\t\t\t22\n\t\t\t\t\n\t\t\t'},{id:"B61",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPoltorak\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHe\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSmirnova\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tM. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHuffel\n\t\t\t\t\t\t\tC. V.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDu\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBirdwell\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlejos\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSilva\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGalanos\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFreudenberg\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRicciardi-Castagnoli\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLayton\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeutler\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1998 Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science\n\t\t\t\t\t282\n\t\t\t\t\t2085\n\t\t\t\t\t2088\n\t\t\t\t\n\t\t\t'},{id:"B62",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQin\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYuan\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOchani\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOchani\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRosas-Ballina\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCzura\n\t\t\t\t\t\t\tC. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHuston\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiller\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLin\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSherry\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKumar\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLarosa\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNewman\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTracey\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2006 Role of HMGB1 in apoptosis-mediated sepsis lethality. J Exp Med\n\t\t\t\t\t203\n\t\t\t\t\t1637\n\t\t\t\t\t1642\n\t\t\t\t\n\t\t\t'},{id:"B63",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQiu\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNishimura\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSims\n\t\t\t\t\t\t\tJ. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQiu\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSavitz\n\t\t\t\t\t\t\tS. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSalomone\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoskowitz\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tEarly release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab\n\t\t\t\t\t28\n\t\t\t\t\t927\n\t\t\t\t\t938\n\t\t\t\t\n\t\t\t'},{id:"B64",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRendon-Mitchell\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOchani\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHan\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSusarla\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCzura\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMitchell\n\t\t\t\t\t\t\tR. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSama\n\t\t\t\t\t\t\tA. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTracey\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2003 IFN-gamma Induces High Mobility Group Box 1 Protein Release Partly Through a TNF-Dependent Mechanism. J Immunol\n\t\t\t\t\t170\n\t\t\t\t\t3890\n\t\t\t\t\t3897\n\t\t\t\t\n\t\t\t'},{id:"B65",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRochette\n\t\t\t\t\t\t\tC. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRosenfeldt\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHeiss\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNarayanan\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBallauff\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJahnen-Dechent\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tA shielding topology stabilizes the early stage protein-mineral complexes of fetuin-A and calcium phosphate: a time-resolved small-angle X-ray study. Chembiochem\n\t\t\t\t\t10\n\t\t\t\t\t735\n\t\t\t\t\t740\n\t\t\t\t\n\t\t\t'},{id:"B66",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSato\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKazama\n\t\t\t\t\t\t\tJ. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWada\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKuroda\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNarita\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGejyo\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGao\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYamashita\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007 Decreased levels of circulating alpha2-Heremans-Schmid glycoprotein/Fetuin-A (AHSG) in patients with rheumatoid arthritis. 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R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJeyabalan\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCao\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPeng\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStolz\n\t\t\t\t\t\t\tD. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGeller\n\t\t\t\t\t\t\tD. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRosengart\n\t\t\t\t\t\t\tM. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBilliar\n\t\t\t\t\t\t\tT. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007 HMGB1 release induced by liver ischemia involves Toll-like receptor 4 dependent reactive oxygen species production and calcium-mediated signaling. J Exp Med 204\n\t\t\t\t\t2913\n\t\t\t\t\t2923\n\t\t\t\t\n\t\t\t'},{id:"B76",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTsung\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSahai\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTanaka\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakao\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFink\n\t\t\t\t\t\t\tM. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLotze\n\t\t\t\t\t\t\tM. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTracey\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGeller\n\t\t\t\t\t\t\tD. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBilliar\n\t\t\t\t\t\t\tT. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005 The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med 201\n\t\t\t\t\t1135\n\t\t\t\t\t1143\n\t\t\t\t\n\t\t\t'},{id:"B77",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTuttolomondo\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDi Raimondo\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDi Sciacca\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCasuccio\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBivona\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBellia\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBarreca\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSerio\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tD’Aguanno\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCiaccio\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLicata\n\t\t\t\t\t\t\tG.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPinto\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Fetuin-A and CD40 L plasma levels in acute ischemic stroke: differences in relation to TOAST subtype and correlation with clinical and laboratory variables. Atherosclerosis.\n\t\t\t\t\t208\n\t\t\t\t\t290\n\t\t\t\t\t296\n\t\t\t\t\n\t\t\t'},{id:"B78",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBloom\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVishnubhakat\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOmbrellino\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChe\n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFrazier\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIvanova\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBorovikova\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tManogue\n\t\t\t\t\t\t\tK. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFaist\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAbraham\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAndersson\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAndersson\n\t\t\t\t\t\t\tU.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMolina\n\t\t\t\t\t\t\tP. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAbumrad\n\t\t\t\t\t\t\tN. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSama\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTracey\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999 HMG-1 as a late mediator of endotoxin lethality in mice. Science\n\t\t\t\t\t285\n\t\t\t\t\t248\n\t\t\t\t\t251\n\t\t\t\t\n\t\t\t'},{id:"B79",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhu\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tD’Amore\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWard\n\t\t\t\t\t\t\tM. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJahnen-Dechent\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTracey\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSama\n\t\t\t\t\t\t\tA. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010 Peripheral administration of fetuin-A attenuates early cerebral ischemic injury in rats. J Cereb Blood Flow Metab 30\n\t\t\t\t\t493\n\t\t\t\t\t504\n\t\t\t\t\n\t\t\t'},{id:"B80",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiao\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOchani\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJustiniani\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLin\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAl\n\t\t\t\t\t\t\tAbed. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMetz\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiller\n\t\t\t\t\t\t\tE. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTracey\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tUlloa\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004 Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med\n\t\t\t\t\t10\n\t\t\t\t\t1216\n\t\t\t\t\t1221\n\t\t\t\t\n\t\t\t'},{id:"B81",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTracey\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999\n\t\t\t\t\tFetuin opsonizes macrophage-deactivating cations. In: Update in Intensive Care and Emergency Medicine: Immune Response in the Critically Ill (eds Marshall J.C. & Cohen J.), 155\n\t\t\t\t\t163 . SpringerVerlag Press.\n\t\t\t'},{id:"B82",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWard\n\t\t\t\t\t\t\tM. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSama\n\t\t\t\t\t\t\tA. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tNovel HMGB1-inhibiting therapeutic agents for experimental sepsis. Shock. 32\n\t\t\t\t\t348\n\t\t\t\t\t357\n\t\t\t\t\n\t\t\t'},{id:"B83",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCzura\n\t\t\t\t\t\t\tC. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSama\n\t\t\t\t\t\t\tA. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTracey\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2001\n\t\t\t\t\tHMGB1 as a Late Mediator of Lethal Systemic Inflammation.\n\t\t\t\t\tAm J Respir Crit Care Med\n\t\t\t\t\t164\n\t\t\t\t\t1768\n\t\t\t\t\t1773\n\t\t\t\t\n\t\t\t'},{id:"B84",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSoda\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSama\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTracey\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1997 Fetuin protects the fetus from TNF [letter]. Lancet\n\t\t\t\t\t350\n\t\t\t\t\t861\n\t\t\t\t\t862\n\t\t\t\t\n\t\t\t'},{id:"B85",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhu\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhou\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSama\n\t\t\t\t\t\t\tA. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008 Therapeutic potential of HMGB1 -targeting agents in sepsis. Expert Rev Mol Med 10:e32.\n\t\t\t'},{id:"B86",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWatanabe\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKubota\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNagaya\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOzaki\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNagafuchi\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAkashi\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTaira\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTsukikawa\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOowada\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNakano\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tThe role of HMGB-1 on the development of necrosis during hepatic ischemia and hepatic ischemia/reperfusion injury in mice.\n\t\t\t\t\tJ Surg Res\n\t\t\t\t\t124\n\t\t\t\t\t59\n\t\t\t\t\t66\n\t\t\t\t\n\t\t\t'},{id:"B87",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWeikert\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStefan\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchulze\n\t\t\t\t\t\t\tM. 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Circulation\n\t\t\t\t\t118\n\t\t\t\t\t2555\n\t\t\t\t\t2562\n\t\t\t\t\n\t\t\t'},{id:"B88",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWilliams\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1997\n\t\t\t\t\tModulation and block of ion channels: a new biology of polyamines.\n\t\t\t\t\tCell Signal\n\t\t\t\t\t9\n\t\t\t\t\t1\n\t\t\t\t\t13\n\t\t\t\t\n\t\t\t'},{id:"B89",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tC. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMartel\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYoung\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYoung\n\t\t\t\t\t\t\tJ. 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J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2007 TLR4 activation mediates kidney ischemia/reperfusion injury. J.Clin.Invest\n\t\t\t\t\t117\n\t\t\t\t\t2847\n\t\t\t\t\t2859\n\t\t\t\t\n\t\t\t'},{id:"B91",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tG. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGong\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQin\n\t\t\t\t\t\t\tZ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLiu\n\t\t\t\t\t\t\tX. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLorris\n\t\t\t\t\t\t\tB. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999\n\t\t\t\t\tTumor necrosis factor alpha expression produces increased blood-brain barrier permeability following temporary focal cerebral ischemia in mice.\n\t\t\t\t\tBrain Res Mol Brain Res\n\t\t\t\t\t69\n\t\t\t\t\t135\n\t\t\t\t\t143\n\t\t\t\t\n\t\t\t'},{id:"B92",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tOchani\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tQiang\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTanovic\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHarris\n\t\t\t\t\t\t\tH. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSusarla\n\t\t\t\t\t\t\tS. 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J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1997 Spermine inhibits proinflammatory cytokine synthesis in human mononuclear cells: a counterregulatory mechanism that restrains the immune response. J Exp Med\n\t\t\t\t\t185\n\t\t\t\t\t1759\n\t\t\t\t\t1768\n\t\t\t\t\n\t\t\t'},{id:"B96",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhang\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTracey\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tRegulation of macrophage activation and inflammation by spermine: a new chapter in an old story.\n\t\t\t\t\tCrit Care Med 28, N60 -N66\n\t\t\t'},{id:"B97",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhu\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAshok\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTracey\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSama\n\t\t\t\t\t\t\tA. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009a Spermine protects mice against lethal sepsis partly by attenuating surrogate inflammatory markers. Mol Med\n\t\t\t\t\t15\n\t\t\t\t\t275\n\t\t\t\t\t282\n\t\t\t\t\n\t\t\t'},{id:"B98",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZhu\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLi\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWard\n\t\t\t\t\t\t\tM. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSama\n\t\t\t\t\t\t\tA. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWang\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tHigh mobility group box 1 protein as a potential drug target for infection- and injury-elicited inflammation. Inflamm.Allergy Drug Targets.\n\t\t\t\t\t9\n\t\t\t\t\t60\n\t\t\t\t\t72\n\t\t\t\t\n\t\t\t'},{id:"B99",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZubrow\n\t\t\t\t\t\t\tA. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNumagami\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFritz\n\t\t\t\t\t\t\tK. I.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMishra\n\t\t\t\t\t\t\tO. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDelivoria-Papadopoulos\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tSpermine dependent activation of the N-methyl-D-aspartate receptor and the effect of nitric oxide synthase inhibition during hypoxia in the cerebral cortex of newborn piglets.\n\t\t\t\t\tBrain Res\n\t\t\t\t\t854\n\t\t\t\t\t11\n\t\t\t\t\t18\n\t\t\t\t\n\t\t\t'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Haichao Wang",address:null,affiliation:'
Departments of Emergency Medicine and Surgery, North Shore University Hospital,Hofstra North Shore – LIJ School of Medicine at the Hofstra UniversityLaboratories of Emergency Medicine and Surgical Research, The Feinstein Institute for Medical Research, NY, USA
Departments of Emergency Medicine and Surgery, North Shore University Hospital,Hofstra North Shore – LIJ School of Medicine at the Hofstra UniversityLaboratories of Emergency Medicine and Surgical Research, The Feinstein Institute for Medical Research, NY, USA
Departments of Emergency Medicine and Surgery, North Shore University Hospital,Hofstra North Shore – LIJ School of Medicine at the Hofstra UniversityLaboratories of Emergency Medicine and Surgical Research, The Feinstein Institute for Medical Research, NY, USA
Departments of Emergency Medicine and Surgery, North Shore University Hospital,Hofstra North Shore – LIJ School of Medicine at the Hofstra UniversityLaboratories of Emergency Medicine and Surgical Research, The Feinstein Institute for Medical Research, NY, USA
'},{corresp:null,contributorFullName:"Andrew E. Sama",address:null,affiliation:'
Departments of Emergency Medicine and Surgery, North Shore University Hospital,Hofstra North Shore – LIJ School of Medicine at the Hofstra UniversityLaboratories of Emergency Medicine and Surgical Research, The Feinstein Institute for Medical Research, NY, USA
'}],corrections:null},book:{id:"234",type:"book",title:"Acute Phase Proteins",subtitle:"Regulation and Functions of Acute Phase Proteins",fullTitle:"Acute Phase Proteins - Regulation and Functions of Acute Phase Proteins",slug:"acute-phase-proteins-regulation-and-functions-of-acute-phase-proteins",publishedDate:"October 5th 2011",bookSignature:"Francisco Veas",coverURL:"https://cdn.intechopen.com/books/images_new/234.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:null,printIsbn:"978-953-307-252-4",pdfIsbn:"978-953-51-4424-3",reviewType:"peer-reviewed",numberOfWosCitations:86,isAvailableForWebshopOrdering:!0,editors:[{id:"38691",title:"Prof.",name:"Francisco",middleName:null,surname:"Veas",slug:"francisco-veas",fullName:"Francisco Veas"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1040"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"21445",type:"chapter",title:"Transcriptional Regulation of Acute Phase Protein Genes",slug:"transcriptional-regulation-of-acute-phase-protein-genes",totalDownloads:3100,totalCrossrefCites:0,signatures:"Claude Asselin and Mylène Blais",reviewType:"peer-reviewed",authors:[{id:"38677",title:"Prof.",name:"Claude",middleName:null,surname:"Asselin",fullName:"Claude Asselin",slug:"claude-asselin"},{id:"49008",title:"Dr.",name:"Mylène",middleName:null,surname:"Blais",fullName:"Mylène Blais",slug:"mylene-blais"}]},{id:"21446",type:"chapter",title:"Acute Phase Proteins: Structure and Function Relationship",slug:"acute-phase-proteins-structure-and-function-relationship",totalDownloads:4219,totalCrossrefCites:7,signatures:"Sabina Janciauskiene, Tobias Welte and Ravi Mahadeva",reviewType:"peer-reviewed",authors:[{id:"30473",title:"Prof.",name:"Sabina",middleName:null,surname:"Janciauskiene",fullName:"Sabina Janciauskiene",slug:"sabina-janciauskiene"},{id:"47774",title:"Dr.",name:"Ravi",middleName:null,surname:"Mahadeva",fullName:"Ravi Mahadeva",slug:"ravi-mahadeva"},{id:"47775",title:"Prof.",name:"Tobias",middleName:null,surname:"Welte",fullName:"Tobias Welte",slug:"tobias-welte"}]},{id:"21447",type:"chapter",title:"Regulatory Mechanisms Controlling Inflammation and Synthesis of Acute Phase Proteins",slug:"regulatory-mechanisms-controlling-inflammation-and-synthesis-of-acute-phase-proteins",totalDownloads:3087,totalCrossrefCites:6,signatures:"Jolanta Jura and Aleksander Koj",reviewType:"peer-reviewed",authors:[{id:"30745",title:"Prof.",name:"Aleksander",middleName:null,surname:"Koj",fullName:"Aleksander Koj",slug:"aleksander-koj"},{id:"44986",title:"Mrs.",name:"Jolanta",middleName:null,surname:"Jura",fullName:"Jolanta Jura",slug:"jolanta-jura"}]},{id:"21448",type:"chapter",title:"IL-22 Induces an Acute-Phase Response Associated to a Cohort of Acute Phase Proteins and Antimicrobial Peptides as Players of Homeostasis",slug:"il-22-induces-an-acute-phase-response-associated-to-a-cohort-of-acute-phase-proteins-and-antimicrobi",totalDownloads:2832,totalCrossrefCites:0,signatures:"Francisco Veas and Gregor Dubois",reviewType:"peer-reviewed",authors:[{id:"38691",title:"Prof.",name:"Francisco",middleName:null,surname:"Veas",fullName:"Francisco Veas",slug:"francisco-veas"},{id:"135651",title:"Prof.",name:"Gregor",middleName:null,surname:"Dubois",fullName:"Gregor Dubois",slug:"gregor-dubois"}]},{id:"21449",type:"chapter",title:"Hemostatic Soluble Plasma Proteins During Acute-Phase Response and Chronic Inflammation",slug:"hemostatic-soluble-plasma-proteins-during-acute-phase-response-and-chronic-inflammation",totalDownloads:2311,totalCrossrefCites:1,signatures:"Irina I. 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1. Introduction
Epstein-Barr virus (EBV), a ubiquitous gamma-herpesvirus, infects the vast majority of the worldwide human population. This virus was initially discovered in cultured lymphoma cells from patients with Burkitt’s lymphoma (BL) in 1964 [1]. During the primary infection, EBV infects epithelial cells of the oropharynx where it actively replicates and also infects B cells where it establishes a life-long latency in the form of an episome located in the host cell nucleus. During latency, EBV may produce nine viral latency proteins, including six so-called “Epstein-Barr Nuclear Antigens” (EBNA1, -2, -3A, -3B, -3C, and -LP), involved in transcriptional regulation, and three “Latent Membrane Proteins” (LMP1, -2A, and -2B), mimicking signals needed for B cell maturation, as well as two small noncoding RNAs (EBER-1 and EBER-2), BamHI-A rightward transcripts (BARTs), and miRNAs. Four different latency programs can be identified, based on the proteins that are expressed (Table 1). EBV primary infection, which occurs more often in childhood, is usually asymptomatic in children, whereas it may be responsible for infectious mononucleosis (IM) in teenagers or young adults in western countries. In addition to this nonmalignant disease, EBV can also be associated with diverse malignant pathologies. In particular, EBV is involved in the development of several malignancies of lymphoid origin including endemic Burkitt’s lymphoma [2], nasal NK/T lymphoma [3], some Hodgkin’s lymphoma [4], and B- or T-cell lymphoproliferations in immunocompromised patients [5]. It is also implicated in epithelial malignancies such as undifferentiated nasopharyngeal carcinoma (NPC) [6] and 10% of cases of gastric carcinoma [7]. Although populations from all geographic areas are infected by the virus, the incidence of the pathologies in which it occurs varies significantly depending on the region [8]. For example, BL occurs mainly in children living in sub-Saharan Africa [9], and the prevalence of NPC is particularly high in adults living in Southern China, Southeast Asia, and Northern Africa [10]. The differences observed in the geographic distribution of these pathologies suggest that there could be various genetic variants of EBV, of different global distributions, and with different levels of transforming capacity. This question of a specific disease variant is raised by many authors and is still being debated. In this chapter, we wish to take inventory of the state of knowledge concerning the variability observed on the most mutated genes among all EBV genes and the possible implications in human pathology.
Program
EBV expressed proteins
Active promoters
B cell type
Latency III
Growth
EBNA-1, -2, -3A, -3B, -3C, -LP
Initially Wp
Naive B cells
LMP-1, -2A-, -2B
Then Cp
LMP promoters
EBER-1 and -2p
Latency II
Default
EBNA-1
Qp, EBER-1 and -2p
LMP-1, -2A, -2B
LMP promoters
Latency I
Latency
EBNA-1
Qp, EBER-1 and -2p
Resting B cells
Latency 0
No protein or LMP-2A
LMP-2Ap
Memory B cells
Table 1.
Proteins expressed during the different latency programs.
2. Evolving knowledge of the EBV genome
The fact that the viral genome is relatively large (175 kb), that it is made up of DNA, therefore less variable than if it was an RNA genome, and that it carries repetitive regions, limited its sequencing for a long time. The first published sequences were small fragments of the B95-8 genome; then, the entire B95-8 genome was sequenced in 1984 [11]. The B95-8 strain was the first cultured EBV cell line able to secrete large amounts of viral particles into the culture medium. It was originally obtained from a spontaneous human lymphoblastoid cell line (LCL) established from a North American case of infectious mononucleosis, the 883L cell line, whose virus was used to transform lymphocytes from a cotton top marmoset. Since it was the first strain with a fully published genome, B95-8 has been extensively studied and mapped for transcripts, promoters, and open reading frames.
This first EBV whole genome sequencing was followed by others, and complete viral genome sequences of the cell lines AG876, originating from a Ghanaian case of African BL [12] and GD1, obtained from cord B cells infected with EBV from saliva of an NPC patient in Guangzhou, China [13] were published. Sequences of some genes, mainly latency genes, were also studied, especially in lines established from patients [14, 15]. B95-8, GD1, and AG876 were sequenced by conventional shotgun sequencing (Sanger’s method). The comparison of sequences obtained for various cell lines revealed the existence of two types of EBV: type 1 or A, of which B95-8 can be considered as the prototype, and type 2 or B, exemplified by AG876. The main difference between the two types concerns the EBNA2 gene, with only 70% identity at the nucleotide level and 54% identity in the protein sequence [16]. Additional variations have also been observed in the EBNA3 genes, but to a lesser extent: 10, 12, and 19% of base pair differences for EBNA3A, 3B, and 3C, respectively [17]. The comparison of viral sequences also highlighted that the B95-8 cell line has a significant 11.8 kb deletion (positions 139,724–151,554) corresponding to some of the BART miRNA genes, one of the origins of lytic replication [11], the LF2 and LF3 genes, and a part of the LF1 gene. More complete sequence comprising the B95-8 sequence supplemented with a Raji fragment at the level of deletion has been constructed. It was annotated in 2010 as RefSeq HHV4 (EBV) sequence NC_007605 and is now used as a wild-type strain reference [18].
As adaptation of the virus to in vitro culture is possible, thus generating a bias in the results, some authors have preferred to sequence the viral genome directly in samples from patients. Therefore, the sequences GD2, from a Guangzhou NPC biopsy, and HKNPC1, from a Hong Kong NPC biopsy, were published [19, 20], both using a more recent sequencing technique, “next generation sequencing” (NGS). This technology can be used directly on samples or after enrichment, which avoids artifacts due to cellular DNA. Enrichment can be achieved by PCR or cloning into F-factor plasmids, but most frequently, it is carried out using target DNA capture by hybridization. NGS delivers a wealth of information and requires extensive bioinformatic analysis. This technology has made it possible to rapidly increase the number of fully sequenced viral genomes originating from healthy subjects or patients and thus obtain more information.
3. The most variable regions of the genome
Authors who sequenced the entire viral genome and analyzed the genomic variations came to the conclusion that the latent genes harbored the highest numbers of nonsynonymous mutations [20, 21, 22, 23, 24]. For example, Liu et al. [25] compared the sequences of nine strains of EBV to GD1, of which they were most closely related, and showed that latency genes were the most mutated. In this study, latent and tegument genes were found to harbor 58.4 to 84.3% of all nonsynonymous mutations detected for each genome. Santpere et al. [26] found that latent genes were twice as mutated as lytic genes. The observation that the latent genes harbor more nucleotide diversity than lytic genes was made regardless of the type of pathology: nasopharyngeal carcinoma [20, 21], NK/T lymphoma [27], endemic Burkitt’s lymphoma [22], Hodgkin’s lymphoma [22], posttransplant lymphoproliferative disease [22], gastric carcinoma [25], lung carcinoma [23], and also strains originating from infectious mononucleosis [22] or healthy subjects [26]. Why latent genes are the most variable is not clear today. By analyzing their data according to the Yang model [28], Santpere et al. [26] showed that the lytic genes had an evolutionary constraint close to that of the host: a strong purifying selection was objectified for 11 lytic genes. However, signatures of accelerated protein evolution rates were found in coding regions related to virus attachment and entry into host cells. The latency genes, on the other hand, show a positive selection, perhaps in relation to the MHC, which can be the cause of their large diversity. Changes in amino acids (aa) often occur in immune epitopes. Amino acid changes in CD8+ epitopes were described in all latent proteins, while changes in CD4+ epitopes were shown only for EBNA1 and -2 and LMP1 and -2 [20]. However, most codons of the EBNA3 gene under positive selection are not cytotoxic T-lymphocyte epitopes: either there are epitopes not described to date or the selection relates to other functionalities. The selection of mutants may depend on a difference in immunity in relation to the geography and/or capacity of a strain to infect and persist.
4. Variability of main latency proteins
After the virus enters a host cell, the genome circularizes through recombination of the terminal repeats (TRs) located at each end of the genome to form an episome that will be chromatinized and methylated in the same way as the human genome. Latent transcription programs in B cells are due to the differential activity of epigenetically regulated promoters and take place in three successive waves. The EBNA2 and EBNA-LP, as well as BHRF1, a bcl2 homolog, are the first viral proteins to be expressed, under the dependence of Wp promoter. The two expressed EBNAs and the cellular factor recombination signal-binding protein for immunoglobulin Kappa J region (RBP-Jk) activate then the Cp promoter, which drives the expression of all of the EBNA proteins, while Wp becomes progressively hypermethylated; the transcription will gradually be under Cp control. Subsequently, LMP1, LMP2A, and LMP2B proteins are expressed due to activation of their respective promoters. During latency I or II, Qp promoter controls EBNA1 expression, and Cp methylation is responsible for the five other EBNA silencing. Methylation does not control the Qp promoter, which is switched off by binding to a repressor protein.
As previously developed, latency proteins show the most sequence variations, and among them, EBNA1, EBNA2, EBNA-LP, and LMP1 are the most mutated. The main properties of these proteins are reported in Table 2.
4.1 EBNA1
EBNA1, expressed in both latent and lytic EBV infections, was the first EBV protein detected. EBNA1, whose structure (Figure 1) and functions have largely been studied [29, 30], is a 641 aa protein. However, EBNA1 proteins frequently exhibit size variations due to differing numbers of gly-ala repeats (aa 89–325). During latency, EBNA1 is the only protein expressed in all forms of latency in proliferating cells and also in all EBV associated malignancies. EBNA1, which acts as a homodimer, is essential for initiating EBV episome replication before mitosis, once per cell cycle, and mitotic segregation of EBV episomes, thus for the maintenance of EBV episome in latently infected cells [31]. The EBNA1 DNA-binding domain is essential but not sufficient for the replication function, and the N-terminal half of EBNA1 is also required. Two EBNA1 regions (aa 8–67 and aa 325–376) are particularly important for this activity, and the point mutations G81 or G425 enhance EBNA1-dependent DNA replication. Inversely, the EBNA1 aa 395–450 region mediates an interaction with the human ubiquitin-specific protease, USP7, which may negatively regulate replication. The partitioning of EBV episomes in two dividing cells requires two viral components: the ori P FR element and EBNA1, mainly the central Gly-Arg region aa 325–376 and secondarily the aa 8–67 sequence. EBNA1 also activates the expression of other latency genes participating in immortalization: the regions involved are the central Gly-Arg sequence and the 61–89 region. Interaction with the recognition sites located on FR, DS of ori P, and Bam-HI-Q takes place through binding sites located in the C-terminal of EBNA1 (aa 459-607), sequence which also mediates the dimerization of EBNA1 (aa 504–604). Through its interaction with both human casein kinase CK2 (aa 383–395) and cellular ubiquitin-specific protease USP7 (aa 442–448), EBNA1 is also able to disrupt promyelocytic leukemia protein (PML) bodies and degrade PML. In addition to its role in latent infection, EBNA1 can therefore participate in lytic infection by overcoming suppression by PML proteins [32]. Indeed, PML proteins and nuclear bodies were found to suppress lytic infection by EBV. Recently [33], organization in an oligomeric hexameric ring form was described for the EBNA1 DNA-binding domain, the oligomeric interface pivoting around residue T585. Mutations occurring on this residue had both positive and negative effects on EBNA1-dependent DNA replication and episome maintenance.
Figure 1.
Schematic representation of basic structure of EBNA1 protein with the different motifs and their position. Gly-Arg: region rich in Gly-Arg; Gly-Ala: Gly-Ala repeats; CK2: interaction with human casein kinase, CK2; USP7: interaction with the human ubiquitin specific protease, USP7; DNA binding: DNA-binding domain; Dimerization: region that mediates the dimerization of EBNA1. The different mutations discussed are noted.
Based on polymorphisms observed at 15 codons, Bhatia et al. [14] reported two strains named P (prototype) and V (variant), each having two subtypes defined by the aa at position 487 (P-ala, P-thr, V-pro, and V-leu). They detected mostly the P-thr and the V-leu variants, respectively, in African and American BL tumors, but these findings were not confirmed by another group who reported different spectra of EBNA1 subtypes according to different geographical areas in both healthy patients and BL tumors [34]. A fifth subtype, V-val, was later recognized in South-East Asia and was found to be prevalent in NPC samples by numerous authors [20, 35, 36, 37]. These findings suggest that the V-val variant might adapt particularly well to the nasopharyngeal epithelium or that this strain possesses an increased oncogenic potential. Indeed, most of the variant codons, localized in the DNA-binding domain, may have an impact on the EBV phenotype resulting in impaired ability to transform B-lymphocytes [30]. However, other reports observed that this subtype had no tumor-specific expression [38], and it is likely that it probably represents a dominant EBNA1 subtype in Asian regions, not found in other areas of the world [8, 23, 25]. The P-thr subtype is the most commonly observed in peripheral blood of American and African subjects as well as in African tumors. In our experience, P-thr is also the most prevalent in France and particularly in the course of lymphoproliferative diseases.
Apart from these mutations, others have been reported. For example, Borozan et al. [39] looked at gastric carcinomas and mainly found two mutations already described in NPC, H418L and A439T, located outside the DNA-binding domain and common in both NPC and GC but uncommon in other EBV isolates, from lymphomas or healthy subjects. They also described a new mutation, T85A, positioned in the region required for transcriptional activation of other latency genes and thus able to modify this function. Wang et al. [23] described the substitution T585I. T585 is subject to substitutions, and T585 polymorphism is found frequently in NPC tumors and Burkitt’s lymphoma. T585I was previously found, and this strain was defective in replication and maintenance of the viral episome [40], as well as deficient in suppressing lytic cycle gene transcription and lytic DNA replication.
In summary, EBNA1 V-val variant seems to be a geographic variant almost exclusively present in South-East Asia. Conversely, mutations T85 and T585, which occur in functional regions of the protein, could have biological consequences and especially the substitution T585I, which promotes lytic replication and is found in NPC.
4.2 EBNA2
EBNA2, a 487 aa protein, is expressed in vivo during latency III shortly after infection of B cells or in lymphomas occurring in immunocompromised patients and in LCL. As mentioned above, the variations in EBNA2 make it possible to classify EBV as types 1 and 2 (or A and B) since only 70% identity at the nucleotide level and 54% homology in the protein sequence were observed. The overall structure of the EBNA2 protein (Figure 2) is characterized by poly-P and poly-RG areas, this last one being a protein-protein and protein-nucleic acid interaction domain important for efficient cell growth transformation, and nine regions conserved throughout the gene [41]. EBNA2 acts principally as a transcription factor and contains three categories of domains critical for its transcription regulation function: transactivation domains (TAD), self-association domains (SAD), and nuclear localization signals (NLS). EBNA2 does not bind directly to DNA. It uses cell proteins as adapters to access viral or cellular enhancer and promoter sites. The C-terminal TAD (aa 448–471) is able to recruit components of basic transcriptional machinery as well as chromatin modifiers and can bind to the viral coactivator EBNA-LP, while the N-terminal TAD (aa 1–58) cannot bind EBNA-LP, although its activity can be enhanced by this protein. Two SADs (aa 1–58 and 97–121), separated by the poly-proline stretch, were identified in the N-terminal region [42]. An additional third one has been reported, localized in a nonconserved region, and flanked by the second SAD and the adapter region [43]. EBNA2 contributes to B-cell immortalization, and it has been demonstrated that type 1 EBV, which is predominantly found in EBV-associated diseases, immortalizes B cells in vitro much more efficiently than type 2 [44], which is predominantly determined by sequence variation in the C-terminus of EBNA2 [45]. During the early events of EBV infection in resting B cells, EBNA2 initiates the transcription of a cascade of primary and secondary viral and cellular target genes and therefore is responsible for the initiation of immortalization by reprogramming the resting state into a proliferative state. For this, EBNA2 interacts with chromatin remodelers and as a transcription factor cofactor [46]. Mühe et al. [47] demonstrated that the first 150 N-terminal aa of EBNA2 are important for the initiation of immortalization. EBNA2 is also involved in immortalization maintenance; the region implicated here (aa 295–378) includes the conserved regions CR5 (aa 295–307) and CR6 (aa 320–326), particularly important for this function. CR5 mediates the contact between EBNA2 and SKIP (Ski-interacting protein), and CR6 is the CBF1 (C promoter-binding factor 1) or RBP-Jk targeting domain. Mechanisms to initiate and maintain B cell immortalization are not completely understood today.
Figure 2.
Schematic representation of basic structure of EBNA2 protein with the different motifs and their position. The two transactivation domains (TADs), the three self-association domains (SADs), and the two nuclear localization signals (NLSs) are mentioned. Poly P: area rich in P; PolyRG: area rich in RG; CR5: conserved region 5, which interacts with SKIP (Ski-interacting protein); CR6: conserved region 6, which interacts with CBF1 (C promoter-binding factor 1). The different mutations discussed are mentioned.
Wang et al. [41], working on 25 EBV-associated GCs, 56 NPCs, and 32 throat washings from healthy donors in Northern China, described 4 EBNA2 subtypes according to the presence of a deletion, namely subtypes E2-A (no aa deletion), E2-B (aa 294Q deletion), E2-C (aa 357K and 358G deletion), and E2-D (aa 357K, 358G, and 294Q deletion). The E2-A subtype exhibited six nonsilent mutations, P291T, R413G, I438L, E476G, P484H, and I486T; the substitution P291T was present in six NPC E2-D and six NPC E2-C. The substitution R413G was detected in E2-C for one patient. They found that E2-A and E2-C were dominant in the samples they analyzed and that the E2-D pattern was detected only in the NPC specimens. The mutation R163M was detected in all samples. This mutation has previously been described worldwide and in different diseases.
Mutations 357 and 358 occurred in the RG domain (aa 335–362), a downregulator of EBNA2 activation of the LMP1 promoter [48]. Moreover, aa 357–363 (KGKSRDK) constitutes the PKC phosphorylation site, which can reduce the amounts of EBNA2/CBF1 complex formed. EBNA2 is suspected to be involved in the development of malignancies as a result of sequence variations most frequently affecting its regulation function.
Interestingly, EBNA2 entire-gene deletion has been shown in some endemic BL cell lines such as P3HR1, Daudi, Sav, Oku, and Ava [49]; it remains to determine if this deletion occurs classically in vivo in African BL.
In short, geographic variants were not formally demonstrated for EBNA2. Among the described mutations, the most interesting are those occurring in the PKC phosphorylation site because they can activate the Cp and/or LMP1p and thus increase the production of latency proteins.
4.3 EBNA-LP (EBNA-leader protein)
EBNA-LP, like EBNA2 and concomitantly with EBNA2, is expressed shortly after the infection of B cells in healthy individuals as well as in EBV-related malignant diseases in immunodeficient patients and LCLs. EBNA-LP acts mostly as a coactivator of the transcriptional activator EBNA2, thus inducing the expression of some cellular genes, including cyclin D2 [50], or viral genes, that is, LMP1 [51], LMP2b, and Cp and therefore having an important role in B cell immortalization. EBNA-LP also can directly interact with several cell proteins such as tumor suppressors or proteins involved in apoptosis or cell cycle regulation.
EBNA-LP is comprised of a variable number of 66 aa repetitive units, corresponding to the variable number of W1 and W2 exons located in the EBV internal repeat IR1, followed by a unique 45 aa domain, encoded by two unique 3′ exons Y1 and Y2 (Figure 3). Therefore, EBNA-LP protein may vary in size according to the number of W1–W2 repeats contained in each EBV isolate. By convention, the protein annotation is based on a single W repeat isoform (Figure 4). In this configuration, the protein has 110 aa. Conserved regions were identified in the N extremity of the protein (CR1 to CR3, respectively, aa 11–33, 45–52, and 55–62, implicated in EBNA2 binding), and in the C-terminal region (CR4 and CR5, respectively, aa 76–82 and 101–110). CR3 and a serine within W2 (S35) were demonstrated to be important for EBNA2 coactivation. EBV-mediated B cell immortalization maps to the W1W2 repeated domains and requires at least two IR1 repetitions to be effective, but a number greater than or equal to 5 is optimal [53]. Some interactions with cell proteins are mediated by the repeated W1W2 N-terminus [54]. EBNA-LP gene transcription initiates from the W promoter (Wp) residing in each IR1 repeat during the early stages of infection, and multiple EBNA-LP protein isoforms are produced. During the later stages of infection and in LCLs, transcription initiates from the C promotor (Cp) [55]. The level of transcription initiated by Cp compared to Wp varies according to different circumstances [56].
Figure 3.
Schematic representation of the IR1 region of EBV genome (according to Ref. [52]). The promoters Wp, Cp, and Qp are represented, as well as the different proteins expressed according to the stage of infection.
Figure 4.
Sequence of EBNA-LP protein, with the position of the corresponding exons opposite. Conserved regions are represented as well as the key positions. Phosphorylated serins are mentioned by an asterisk.
About 15% of BL tumors host a virus, which uses exclusively the W promoter, expressing an EBV atypical latency program [49], harboring EBNA1, EBNA3A, 3B, 3C, and a truncated form of EBNA-LP. In these cases, EBV genome lacks the EBNA2gene and the unique Y1Y2 exons of EBNA-LP. This was firstly described in P3HR1 and Daudi BL cell lines [57]. Subsequently, these cells were shown to be more resistant to apoptosis than cells infected by wild-type virus, what would be related to the truncated shape of EBNA-LP.
Given the difficulty of sequencing repetitive regions, only few authors have sequenced the IR1 region, including the EBNA-LP coding region. Previous studies identified two EBNA-LP distinct isoforms, type 1 and type 2 variants, based on the presence of G8/T12 or V8/A12 in exon W1 [58]. The Q54R substitution was also described in exon W2 from an African type 2 spontaneous lymphoblastoid cell line LCL [59]. Despite this, a high degree of conservation was reported for the Wp promoter and the W1-W2 intron, while the most diversity was observed for the BWRF1 ORF, which only shows 80% homology between various strains, and for Y exons [60]. The sequence variations in the Y exons, and especially the Y2 exon, made it possible to define four main subgroups, called A, B, C, and Z. The Akata strain belongs to subgroup A and B95-8 to subgroup B. Subgroup Z is found in type 2 EBVs, and the C subtype is characterized by V95E and V102I. Finally, it has been reported that tumor-derived strains are more prone to interstrain genetic exchange in IR1 [60].
4.4 LMP1
LMP1 is considered to be the main oncogenic protein in EBV. LMP1 is a multifunctional self-aggregating protein essential for the transformation of human B cells and rodent fibroblasts [61]. It is a 386 aa protein comprising a 24 aa cytosolic N-terminal (NT) segment, a 162 aa portion consisting of six transmembrane (TM) domains, and a 200 aa cytosolic C-terminal (CT) domain (Figure 5) [62]. The NT domain plays an important role in the orientation and anchoring of LMP1 to the membrane and its constitutive aggregation, thus contributing to the transforming function of LMP1 [63]. The TM region is involved in the localization of LMP1 at the level of lipid rafts in the membrane, thus inducing its clustering to activate signaling from the CT tail. It is remarkable that the F38LWY41 pattern in the first transmembrane fragment (TM1) and a second pattern consisting of aa W98 in TM3 are essential for the association of TM domains (1–2) with TM domains (3–6) as well as for the oligomerization and signaling of LMP1 [64]. The CT part is involved in the activation of LMP1-induced cell signaling pathways, including two important regions, CTAR1/TES1 and CTAR2/TES2 (Carboxyl-Terminal Activating Region/Transformation Effector Site) critical for EBV-mediated B-cell growth transformation [65]. Together, these regions mimic CD40, a member of the tumor necrosis factor (TNF) receptor family and key B-cell costimulatory receptor, thus enabling the recruitment of cell adapters associated with the TNF receptor family, TNF receptor-associated factors (TRAFs). The CTAR1 region includes the P204-X-Q206-X-T208 consensus pattern necessary for the attachment of TRAF adapters, specifically TRAF1, TRAF2, TRAF3, and TRAF5 [66]. Within the CTAR2 region, the Y384-Y385-D386 pattern is essential for binding the TNF receptor-associated death domain (TRADD) adapter. There is a third region, CTAR3 (aa 232–350), that is not essential for in vitro B cell immortalization and is less well known [67]. In this region located between CTAR1 and CTAR2 (aa 253–302), a variable number of repeat 11 aa elements (4 repeats for B95-8) exist.
Figure 5.
Schematic representation of basic structure of LMP1 protein with the different motifs and their position. TM1–6: transmembrane domains 1–6. The FWLY pattern in TM1 and W98 in TM3 are essential for the association of TM1–2 with TM3–6 and oligomerization signaling. CTAR1–3: carboxyl-terminal activating regions 1–3. PQQAT pattern is necessary for the attachment of TRAF adapters. YYD pattern is essential for binding the TNF receptor-associated death domain (TRADD) adapter.
LMP1 acts principally as a viral pseudoreceptor, which regulates host cell signal transduction by constitutive activation of cell pathways as mitogen-activated protein kinase (MAPK) pathways and principally the extracellular regulated kinases 1 and 2 (ERK1/2), c-Jun amino-terminal kinases 1–3 (JNK1–3), and p38 isoform pathways. LMP1 also induces the phosphatidylinositol 3-kinase (PI3K) pathway, which contributes to survival signals [68] and transcription of activator protein 1 (AP1) [69], PI3K, and AP1 pathways, therefore playing a major role in proliferation and cell cycle control. LMP1 is also responsible for the activation of JAK/STAT and interferon regulatory factor 7 (IRF7) pathways and for aberrant constitutive NF-kB activation. Indeed, the CTAR1 PXQXT pattern is able to engage TRAFs, leading finally to the activation of noncanonical NF-kB pathway that controls processing of the NF-kB2/p100 precursor [70]. The CTAR2 YYD pattern is in turn implicated in the activation of the canonical NF-kB pathway [71] after binding of tumor necrosis factor receptor superfamily member 1A (TNFRSF1A)-associated via TRADD and receptor-inter-acting protein 1 (RIP1). A wider region of LMP1 seems to be responsible for binding RIP1 (aa 351–386), compared to TRADD (aa 375–386) [72]. NF-kB is considered to be the principal factor by which LMP1 regulates gene expression and modifies cell behavior [73]. Activation of NF-kB is associated with upregulation of anti-apoptotic genes [32, 74] and downregulation of pro-apoptotic factors, as well as induction of tumorigenesis-associated B-cell activation markers [75, 76]. CTAR3, less well defined, seems to activate SUMOylation pathways and participate in the maintenance of EBV latency and control of cell migration, a hallmark of oncogenesis [77, 78].
Besides its ability to transform B cells, during the latency state, LMP1 seems also to be able to facilitate the release of virions from B cells during lytic replication [32].
Variations in the LMP1 sequence have been widely studied, particularly in the context of its impact on clinical occurrence or evolution. A 30 bp deletion (del30), resulting in a 10 aa loss in the C-terminal (aa 343–352), was first described in the Cao cell isolate from a Chinese NPC [79]. In addition, this isolate harbored numerous substitutions. A high prevalence of the same deletion, as reviewed by Chang et al. [8], was found in Asian NPC biopsy tissues [80, 81], in lymphomas and EBV-related gastric cancers from Eastern Asia [82] and in Asian nasal NK/T-cell lymphomas [83, 84]. Del30 was shown to be often associated with the G335D mutation in NPC, and such strains were reported to have a greater transforming activity in vitro than the reference LMP1 [85, 86]. If the 30 bp deletion is partly localized to CTAR2, it does not alter NF-kB activation [87] and finally does not modify signaling properties [88]. However, it is clear that strains bearing del30 are selected over the wt-LMP1 variants in NK/T-cell lymphomas [83] and NPC tumors [89]. Given that del30 strains have been currently detected in normal carriers [90] or in various EBV-associated diseases [91], and, because of a low prevalence of del30 strains in samples from Africa, North America, and Europe [8, 92], it is generally admitted that LMP1 del30 may represent a geographic polymorphism rather than a disease-associated polymorphism [93]. In a study, we carried out in France in patients with NK/T lymphoma, we found a del30 EBV in 4/4 biopsies studied and in 46.1% of total blood samples analyzed, while in a control population, the deletion was present in 4.8% of cases [94]. Other deletions were also described, such as the rare C terminal 69 bp deletion reported to weakly activate the AP1 transcription factor [95], or the 15 bp deletion (aa 275–279) frequently encountered in Western Europe [94].
Otherwise, numerous substitutions have been described in LMP1 (Table 3), particularly in the N-terminal extremity. Some authors have made attempts to classify viral strains by taking into account these substitutions with the aim of highlighting a viral implication in certain pathologies [99]. Thus, Mainou and Raab-Traub [88] classified EBV into seven variants, namely Alaskan, China 1, China 2, Med+, Med-, NC, and B95-8, all having the same in vitro transforming potential and signaling properties. Zuercher et al. [98] mentioned two polymorphisms, I124V/I152L and F144I/D150A/L151I, which seem to be markers of increased NF-kB activation in vitro. Lei et al. [96] distinguished four models according to the substitutions occurring in both the LMP1 gene and its promoter. The patients suffering from NPC that they studied all carried a strain belonging to pattern B, while the BLs were distributed among the four patterns. Many authors recognize two evolutionarily distinct clusters, Asian-derived EBV strains including GD2, HKNPC1, and Akata strains and non-Asian and African/American strains including AG876, B95-8, and Mutu strains, suggesting that the LMP1 gene could be used as a geographic marker [25, 97].
Protein
Role/localization
Main properties
EBNA1
Latency
Initiation of viral episome replication before mitosis
Mitotic segregation of EBV episomes
Transcription of other latency genes (Cp and LMPp enhancer)
Degradation of promyelocytic leukemia protein (PML) bodies
Cellular transcription regulation
EBNA2
Latency
Viral and cellular transcription factor
Initiation and maintenance of B cell immortalization
Blocking of methylation sites for BZLF-1 binding
EBNA-LP
Latency
Coactivator of the transcriptional activator EBNA2
LMP1
Latency
Similarity to constitutively activated CD40
Constitutive activation of cell pathways
Maintenance of EBV latency and control of cell migration
BNRF1
Tegument
Establishment of latency and cell immortalization
Increase in the number of cellular centrioles
BPLF1
Tegument
Downregulation of viral ribonucleotide reductase (RR)
Disruption of damaged DNA repair
Decreasing of innate immunity
BKRF3
Tegument
DNA replication and repair—viral DNA mutagenesis prevention
Table 2.
Main properties of proteins developed in this chapter.
Finally, it should be noted that LMP1 carries a molecular signature of accelerated evolution rate probably due to positive selection as deduced from a significant proportion of nonsignificant variations [26].
So, regarding LMP1, which is the most oncogenic latency protein, two geographic clusters appear to exist corresponding to an Asian variant and a non-Asiatic variant. The described 30 bp deletion is mainly present on Asian strains, and it shows an obvious tropism for nasopharynx. Although many substitutions have been described, little work is done to analyze changes in LMP1 properties based on these substitutions. NPC could be associated with a particular strain, but this remains to be confirmed.
5. Variability of tegument proteins
After the latency proteins, the tegument proteins carry the most changes, and among them, the most mutated are BNRF1, BPLF1, and BKRF3, which will be detailed, as well as BBRF2. This latter protein appears to play an important role in viral infectivity [100], but its structure and function are poorly known today. For this reason, BBRF2 will not be developed here.
5.1 BNRF1
EBV major tegument protein BNRF1 contains 1318 aa, and its structure is shown schematically in Figure 6. BNRF1 is a member of a protein family with homology to the cellular purine biosynthesis enzyme FGARAT. BNRF1 is involved in the establishment of latency and cell immortalization by hijacking the antiviral DAXX (death domain-associated protein-6) histone chaperone [101]. BNRF1 seems to have lost conventional purine biosynthesis activity. It forms a stable quaternary complex with DAXX histone-binding domain (HBD), H3.3 and H4 [102], responsible for BNRF1 localization to PML nuclear bodies involved in antiviral intrinsic resistance and transcriptional repression of host cells. In the presence of BNFR1, DAXX can no longer collaborate with ATRX to assemble histone variant H3.3 into repressive chromatin at GC-rich repetitive DNA. Binding to DAXX, histone H3.3 and histone H4 occur, respectively, via the BNRF1 DAXX interaction domain (DID) (aa 360–600) and BNRF1 residues 40–52 and 99–102. Huang et al. [102] demonstrated that the quaternary complex formation is abrogated when dual mutations V546D/L548D and D568A/D569A occurred on BRNF1 DID and is partially diminished in vitro in case of dual mutations Y390A/K461A and V546S/L548S on BNRF1 DID. BNRF1 mutations at K461A, Y390A/K461A, V546S/L548S or Y390A, V546A/L548A, and D568A/569A moderately or severely reduced BNRF1 colocalization at PML nuclear bodies, respectively. A PurM-like domain (610–976) and a GATase domain (1037–1318) were defined. It has also recently been shown that BNRF1 can cause an abnormal increase in the number of cellular centrioles [103]. This phenomenon can lead to aneuploidy or structural chromosome abnormalities and, possibly, to carcinogenesis. The gene regions concerned have not been described.
Figure 6.
Schematic representation of basic structure of BNRF1 protein with the different motifs and their position. H3.3 and H4 regions, respectively, involved in binding to H3.3 and H4. DID: DAXX-interaction domain, domain implicated in binding to DAXX (death-domain associated protein-6) histone chaperone. PurM-like domain and GATase domain were noted, as well as the different mutations discussed.
BNRF1 is reported to be one of the most frequently mutated tegument proteins. It is interesting to note that a nonsense mutation was described in C666–1, an EBV-positive NPC cell line, with no major structural alterations in the BNRF1-deleted virus [92].
So, the mutations described for BNRF1 do not appear to correspond to a particular geographical distribution. On the other hand, some mutations seem to be able to modify DNA chromatinization, thus affecting the transcription, and therefore have important consequences on cell functioning.
5.2 BPLF1
BPLF1, the largest EBV protein (3149 aa), is a late lytic tegument protein. BPLF1 possesses a deubiquitinating (DUB) activity. BPLF1 is able to downregulate viral ribonucleotide reductase (RR) activity, by deubiquitination of the large subunit RR1 [104], and to specifically deubiquitinate proliferating cell nuclear antigen (PCNA), a DNA polymerase processivity factor, thus disrupting the repair of damaged DNA [105]. By triggering activation of repair pathways and co-opting DNA repair and replication factors, the virus could create genomic instability. The DUB activity is carried by the first 246 aa of the N-terminal region, and the C61 residue of the catalytic triad (Cys-His-Asp) is essential for activity [104]. BPLF1 relocalizes Pol 𝜼 to nuclear sites of viral DNA production, thereby bypassing DNA damage [106]. This mechanism contributes to efficient production of infectious virus.
BPLF1 is also able to deubiquinate cell factors, such as TRAF6, NEMO, and IkBα, leading to TLR signaling inhibition through both MyD88- and TRIF-dependent pathways, thus decreasing innate immune responses by reduced NF-kB activation and proinflammatory cytokine production [107]. It is noteworthy that the same catalytic active site also carries a deneddylating activity shown to target cullin ring ligases, potentially affecting viral replication and infectivity [108]. The role of BPLF1 to help drive human B-cell immortalization and lymphoma formation has also been discussed [109].
Sequencing of various viral strains has shown that BPLF1 is one of the proteins with the greatest number of changes [20, 24, 110]. Most of these mutations are not analyzed in detail, but Kwok et al. [21], working on the sequences of eight NPC biopsy specimens, reported two nonsynonymous mutations in the N-terminal region of the protein that exhibit deubiquitinating activity. The same finding was reported by Simbiri et al. [110], who also described 3 C-terminal mutations (L2935P, P2987L, and R3005Q). A single-nucleotide deletion coupled with a single-nucleotide insertion three nucleotides away was reported by Zeng et al. [13] in a NPC strain. As a result, two aa substitutions (GA/EG) were predicted to occur. Tu et al. [24] undertook phylogenetic analysis based on several reported EBV genome sequences and some major genes as BPLF1. They observed that EBV Asian subtypes clustered as a separate branch from the non-Asian ones.
So, as with other proteins, it seems that the Asian strains carry a protein different from the other strains. Substitutions occurring in the region carrying the deubiquitinase activity could have biological consequences.
5.3 BKRF3
BKRF3 is a small protein (255 aa), which belongs to the early lytic gene family, and encodes an uracil-DNA glycosylase (UDG), which removes inappropriate uracil residues from DNA. BKRF3 excises uracil bases incorporated in double-stranded DNA due to uracil misincorporation or more often cytosine deamination [111, 112]. BKRF3 participates in DNA replication and repair and prevents viral DNA mutagenesis. BKRF3 shares substantial similarity in overall structure with the one UDG family. Four of the five catalytic motifs are completely conserved (aa 90–94, 110–114, 146–149, 191–192), whereas the fifth domain (aa 213–229) carries a seven-residue insertion in the leucine loop [113]. In addition, the 29 N-terminal aa carry a nuclear localization signal (sequence KRKQ). Only changes in BKRF3 that do not severely affect viral replication can be retained, but it may be considered that these mutations cause a change in virus-cell interrelations.
6. Conclusion
The aim of this chapter was to take stock of the most frequently observed variations in the EBV genome and more particularly to see if some of these variations are considered to be involved in tumor pathology. The candidate viral genes concerned are numerous; those developed here are the most affected, and the mutations reported in the literature have been identified. Some mutations have been well studied, in particular as regards their impact on the structure or functionality of the protein or the cellular consequences of these modifications. However, most mutations have only been described. If a tumorigenic impact of viral mutations is not yet certain, many authors agree that geographic variants exist, and it seems clear that Asian strains have different characteristics from non-Asian strains. Further work is necessary to complete the mass of information and analysis, not at the level of one or several genes, but at the level of the entire genome.
\n',keywords:"Epstein-Barr virus, lymphoma, carcinoma, mutation, sequence, next generation sequencing",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/73024.pdf",chapterXML:"https://mts.intechopen.com/source/xml/73024.xml",downloadPdfUrl:"/chapter/pdf-download/73024",previewPdfUrl:"/chapter/pdf-preview/73024",totalDownloads:426,totalViews:0,totalCrossrefCites:0,dateSubmitted:"May 1st 2020",dateReviewed:"June 16th 2020",datePrePublished:"August 19th 2020",datePublished:"December 22nd 2021",dateFinished:"August 19th 2020",readingETA:"0",abstract:"The Epstein-Barr virus (EBV) is a DNA virus with a relatively stable genome. Indeed, genomic variability is reported to be around 0.002%. However, some regions are more variable such as those carrying latency genes and specially EBNA1, -2, -LP, and LMP1. Tegument genes, particularly BNRF1, BPLF1, and BKRF3, are also quite mutated. For a long time, it has been considered for this ubiquitous virus, which infects a very large part of the population, that particular strains could be the cause of certain diseases. However, the mutations found, in some cases, are more geographically restricted rather than associated with proliferation. In other cases, they appear to be involved in oncogenesis. The objective of this chapter is to provide an update on changes in viral genome sequences in malignancies associated with EBV. We focused on describing the structure and function of the proteins corresponding to the genes mentioned above in order to understand how certain mutations of these proteins could increase the tumorigenic character of this virus. Mutations described in the literature for these proteins were identified by reporting viral and/or cellular functional changes as they were described.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/73024",risUrl:"/chapter/ris/73024",signatures:"Sylvie Ranger-Rogez",book:{id:"9619",type:"book",title:"Epstein-Barr Virus",subtitle:"New Trends",fullTitle:"Epstein-Barr Virus - New Trends",slug:"epstein-barr-virus-new-trends",publishedDate:"December 22nd 2021",bookSignature:"Emmanuel Drouet",coverURL:"https://cdn.intechopen.com/books/images_new/9619.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83968-490-6",printIsbn:"978-1-83968-489-0",pdfIsbn:"978-1-83968-491-3",isAvailableForWebshopOrdering:!0,editors:[{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"317161",title:"Prof.",name:"Sylvie",middleName:null,surname:"Ranger-Rogez",fullName:"Sylvie Ranger-Rogez",slug:"sylvie-ranger-rogez",email:"sylvie.rogez@unilim.fr",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Evolving knowledge of the EBV genome",level:"1"},{id:"sec_3",title:"3. The most variable regions of the genome",level:"1"},{id:"sec_4",title:"4. Variability of main latency proteins",level:"1"},{id:"sec_4_2",title:"4.1 EBNA1",level:"2"},{id:"sec_5_2",title:"4.2 EBNA2",level:"2"},{id:"sec_6_2",title:"4.3 EBNA-LP (EBNA-leader protein)",level:"2"},{id:"sec_7_2",title:"4.4 LMP1",level:"2"},{id:"sec_9",title:"5. Variability of tegument proteins",level:"1"},{id:"sec_9_2",title:"5.1 BNRF1",level:"2"},{id:"sec_10_2",title:"5.2 BPLF1",level:"2"},{id:"sec_11_2",title:"5.3 BKRF3",level:"2"},{id:"sec_13",title:"6. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from BURKITT’S lymphoma. Lancet. 1964;1:702-703. DOI: 10.1016/s0140-6736(64)91524-7'},{id:"B2",body:'Zur Hausen H, Schulte-Holthausen H. 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DOI: 10.1002/(sici)1097-0215(19990129)80:3<356::aid-ijc4>3.0.co;2-d'},{id:"B84",body:'Nagamine M, Takahara M, Kishibe K, Nagato T, Ishii H, Bandoh N, et al. Sequence variations of Epstein-Barr virus LMP1 gene in nasal NK/T-cell lymphoma. Virus Genes. 2007;34:47-54. DOI: 10.1007/s11262-006-0008-5'},{id:"B85",body:'Li SN, Chang YS, Liu ST. Effect of a 10-amino acid deletion on the oncogenic activity of latent membrane protein 1 of Epstein-Barr virus. Oncogene. 1996;12:2129-2135'},{id:"B86",body:'Cheung ST, Leung SF, Lo KW, Chiu KW, Tam JS, Fok TF, et al. Specific latent membrane protein 1 gene sequences in type 1 and type 2 Epstein-Barr virus from nasopharyngeal carcinoma in Hong Kong. International Journal of Cancer. 1998;76:399-406. DOI: 10.1002/(sici)1097-0215(19980504)76:3<399::aid-ijc18>3.0.co;2-6'},{id:"B87",body:'Farrell PJ. Signal transduction from the Epstein-Barr virus LMP-1 transforming protein. Trends in Microbiology. 1998;6:175-177; discussion 177-178. DOI: 10.1016/s0966-842x(98)01262-1'},{id:"B88",body:'Mainou BA, Raab-Traub N. LMP1 strain variants: Biological and molecular properties. Journal of Virology. 2006;80:6458-6468. DOI: 10.1128/JVI.00135-06'},{id:"B89",body:'Edwards RH, Sitki-Green D, Moore DT, Raab-Traub N. Potential selection of LMP1 variants in nasopharyngeal carcinoma. Journal of Virology. 2004;78:868-881. DOI: 10.1128/jvi.78.2.868-881.2004'},{id:"B90",body:'Correa RM, Fellner MD, Alonio LV, Durand K, Teyssié AR, Picconi MA. Epstein-Barr virus (EBV) in healthy carriers: Distribution of genotypes and 30 bp deletion in latent membrane protein-1 (LMP-1) oncogene. Journal of Medical Virology. 2004;73:583-588. DOI: 10.1002/jmv.20129'},{id:"B91",body:'Lorenzetti MA, Gantuz M, Altcheh J, De Matteo E, Chabay PA, Preciado MV. Distinctive Epstein-Barr virus variants associated with benign and malignant pediatric pathologies: LMP1 sequence characterization and linkage with other viral gene polymorphisms. 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DOI: 10.1002/ijc.30128'},{id:"B95",body:'Larcher C, Bernhard D, Schaadt E, Adler B, Ausserlechner MJ, Mitterer M, et al. Functional analysis of the mutated Epstein-Barr virus oncoprotein LMP1(69del): Implications for a new role of naturally occurring LMP1 variants. Haematologica. 2003;88:1324-1335'},{id:"B96",body:'Lei H, Li T, Li B, Tsai S, Biggar RJ, Nkrumah F, et al. Epstein-Barr virus from Burkitt lymphoma biopsies from Africa and South America share novel LMP-1 promoter and gene variations. Scientific Reports. 2015;5:16706. DOI: 10.1038/srep16706'},{id:"B97",body:'Lin Z, Wang X, Strong MJ, Concha M, Baddoo M, Xu G, et al. Whole-genome sequencing of the Akata and Mutu Epstein-Barr virus strains. Journal of Virology. 2013;87:1172-1182. DOI: 10.1128/JVI.02517-12'},{id:"B98",body:'Zuercher E, Butticaz C, Wyniger J, Martinez R, Battegay M, Boffi El Amari E, et al. Genetic diversity of EBV-encoded LMP1 in the Swiss HIV Cohort Study and implication for NF-κb activation. PLoS One. 2012;7:e32168. DOI: 10.1371/journal.pone.0032168'},{id:"B99",body:'Edwards RH, Seillier-Moiseiwitsch F, Raab-Traub N. Signature amino acid changes in latent membrane protein 1 distinguish Epstein-Barr virus strains. Virology. 1999;261:79-95. DOI: 10.1006/viro.1999.9855'},{id:"B100",body:'Masud HMAA, Yanagi Y, Watanabe T, Sato Y, Kimura H, Murata T. Epstein-Barr virus BBRF2 is required for maximum infectivity. Microorganisms. 2019;7(705):14 pages. DOI: 10.3390/microorganisms7120705'},{id:"B101",body:'Tsai K, Thikmyanova N, Wojcechowskyj JA, Delecluse H-J, Lieberman PM. EBV tegument protein BNRF1 disrupts DAXX-ATRX to activate viral early gene transcription. PLoS Pathogens. 2011;7:e1002376. DOI: 10.1371/journal.ppat.1002376'},{id:"B102",body:'Huang H, Deng Z, Vladimirova O, Wiedmer A, Lu F, Lieberman PM, et al. Structural basis underlying viral hijacking of a histone chaperone complex. Nature Communications. 2016;7:12707. DOI: 10.1038/ncomms12707'},{id:"B103",body:'Shumilov A, Tsai M-H, Schlosser YT, Kratz A-S, Bernhardt K, Fink S, et al. Epstein-Barr virus particles induce centrosome amplification and chromosomal instability. Nature Communications. 2017;8:14257. DOI: 10.1038/ncomms14257'},{id:"B104",body:'Whitehurst CB, Ning S, Bentz GL, Dufour F, Gershburg E, Shackelford J, et al. The Epstein-Barr virus (EBV) deubiquitinating enzyme BPLF1 reduces EBV ribonucleotide reductase activity. Journal of Virology. 2009;83:4345-4353. DOI: 10.1128/JVI.02195-08'},{id:"B105",body:'Whitehurst CB, Vaziri C, Shackelford J, Pagano JS. Epstein-Barr virus BPLF1 deubiquitinates PCNA and attenuates polymerase η recruitment to DNA damage sites. Journal of Virology. 2012;86:8097-8106. DOI: 10.1128/JVI.00588-12'},{id:"B106",body:'Dyson OF, Pagano JS, Whitehurst CB. The translesion polymerase pol η is required for efficient Epstein-Barr virus infectivity and is regulated by the viral deubiquitinating enzyme BPLF1. Journal of Virology. 2017;91(19):14 pages. DOI: 10.1128/JVI.00600-17'},{id:"B107",body:'van Gent M, Braem SGE, de Jong A, Delagic N, Peeters JGC, Boer IGJ, et al. Epstein-Barr virus large tegument protein BPLF1 contributes to innate immune evasion through interference with toll-like receptor signaling. PLoS Pathogens. 2014;10:e1003960. DOI: 10.1371/journal.ppat.1003960'},{id:"B108",body:'Gastaldello S, Hildebrand S, Faridani O, Callegari S, Palmkvist M, Guglielmo CD, et al. A deneddylase encoded by Epstein–Barr virus promotes viral DNA replication by regulating the activity of cullin-RING ligases. Nature Cell Biology. 2010;12:351-361. DOI: 10.1038/ncb2035'},{id:"B109",body:'Whitehurst CB, Li G, Montgomery SA, Montgomery ND, Su L, Pagano JS. Knockout of Epstein-Barr virus BPLF1 retards B-cell transformation and lymphoma formation in humanized mice. MBio. 2015;6(5):11 pages. DOI: 10.1128/mBio.01574-15'},{id:"B110",body:'Simbiri KO, Smith NA, Otieno R, Wohlford EEM, Daud II, Odada SP, et al. Epstein-Barr virus genetic variation in lymphoblastoid cell lines derived from Kenyan pediatric population. PLoS One. 2015;10:e0125420. DOI: 10.1371/journal.pone.0125420'},{id:"B111",body:'Lu C-C, Huang H-T, Wang J-T, Slupphaug G, Li T-K, Wu M-C, et al. Characterization of the uracil-DNA glycosylase activity of Epstein-Barr virus BKRF3 and its role in lytic viral DNA replication. Journal of Virology. 2007;81:1195-1208. DOI: 10.1128/JVI.01518-06'},{id:"B112",body:'Su M-T, Liu I-H, Wu C-W, Chang S-M, Tsai C-H, Yang P-W, et al. Uracil DNA glycosylase BKRF3 contributes to Epstein-Barr virus DNA replication through physical interactions with proteins in viral DNA replication complex. Journal of Virology. 2014;88:8883-8899. DOI: 10.1128/JVI.00950-14'},{id:"B113",body:'Géoui T, Buisson M, Tarbouriech N, Burmeister WP. New insights on the role of the gamma-herpesvirus uracil-DNA glycosylase leucine loop revealed by the structure of the Epstein-Barr virus enzyme in complex with an inhibitor protein. Journal of Molecular Biology. 2007;366:117-131. DOI: 10.1016/j.jmb.2006.11.007'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Sylvie Ranger-Rogez",address:"sylvie.rogez@unilim.fr",affiliation:'
Department of Virology, University Hospital Dupuytren, France
Faculty of Pharmacy, UMR CNRS 7276, UMR INSERM 1262, France
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IntechOpen’s Academic Editors and Authors have received funding for their work through many well-known funders, including: the European Commission, Bill and Melinda Gates Foundation, Wellcome Trust, Chinese Academy of Sciences, Natural Science Foundation of China (NSFC), CGIAR Consortium of International Agricultural Research Centers, National Institute of Health (NIH), National Science Foundation (NSF), National Aeronautics and Space Administration (NASA), National Institute of Standards and Technology (NIST), German Research Foundation (DFG), Research Councils United Kingdom (RCUK), Oswaldo Cruz Foundation, Austrian Science Fund (FWF), Foundation for Science and Technology (FCT), Australian Research Council (ARC).
Open Access publication costs can often be designated directly in the grants or in specific budgets allocated for that purpose. Many of the most important funding organisations encourage, and even request, that the projects they fund are made available at no cost to the wider public. IntechOpen strives to maintain excellent relationships with these funders and ensures compliance with mandates.
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In order to help Authors identify appropriate funding agencies and institutions, we have created a list, based on extensive research on various OA resources (including ROARMAP and SHERPA/JULIET) of organizations that have funds available. Before consulting our list we encourage you to petition your own institution or organization for Open Access funds or check the specifications of your grant with your funder to ascertain if publication costs are included. Where you are in receipt of a grant you should clarify:
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Does your institution already have a budget for covering Open Access publication costs?
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Does your grant list Open Access publication fees as legitimate direct/indirect costs?
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Please be aware that you must be a member, or grantee, of the institutions/funders listed in order to apply for their Open Access publication funds.
Open Access publication costs can often be designated directly in the grants or in specific budgets allocated for that purpose. Many of the most important funding organisations encourage, and even request, that the projects they fund are made available at no cost to the wider public. IntechOpen strives to maintain excellent relationships with these funders and ensures compliance with mandates.
\n\n
In order to help Authors identify appropriate funding agencies and institutions, we have created a list, based on extensive research on various OA resources (including ROARMAP and SHERPA/JULIET) of organizations that have funds available. Before consulting our list we encourage you to petition your own institution or organization for Open Access funds or check the specifications of your grant with your funder to ascertain if publication costs are included. Where you are in receipt of a grant you should clarify:
\n\n
\n\t
Does your institution already have a budget for covering Open Access publication costs?
\n\t
Does your grant list Open Access publication fees as legitimate direct/indirect costs?
\n
\n\n
If you are associated with any of the institutions in our list below, you can apply to receive OA publication funds by following the instructions provided in the links. Please consult the Open Access policies or grant Terms and Conditions of any institution with which you are linked to explore ways to cover your publication costs (also accessible by clicking on the link in their title).
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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. 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The understanding was included to the literature as personnel management at the beginning of the twentieth century and it turned into an approach as human resources management in the 1980s. It could be observed that many organizations, which deem the human as the most critical stakeholder, adopt a traditional way of personnel management in operating human resources. The employees play a key role in the success of an organization. For this reason, subjects such as recruitment, training, development, career management, performance appraisal, occupational health, and safety are the fundamental functions of human resources management. The study examines to what extent these roles are evaluated through a case study. The subject matter of the study is the most powerful culture and art foundation in Turkey. Compared to many other nonprofit organizations, the foundation actively performs a variety of services within a year worldwide. 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Social marketing strategies can also be used to promote behavioral change and help individuals transform their lives, achieve well-being, and adopt prosocial behaviors. In this chapter, we seek to analyze with a netnographic study, how SNS are being employed by nonprofits and nongovernment organizations (NGOs) to enable citizens and consumers to participate in different programs and activities that promote social transformation and well-being. A particular interest is to identify how organizations are using behavioral economic tactics to nudge individuals and motivate them to engage in prosocial actions. 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This study uses a case study approach, financial data, and website methodologies to collect and analyze the research data. The case study is Tesla, Inc., which is a US electric vehicle and clean energy company based in Austin, Texas. Tesla is a green technology company that produces and designs electric cars, battery energy storage from home to grid-scale, solar roof tiles and solar panels, and related products and services. Tesla is growing fastly by introducing new green products, and it is now one of the world’s most valuable enterprises. It has a high market capitalization of almost US$1 trillion to become the world’s most valuable automaker. This study concludes that Tesla has changed their strategy to become the most worldwide sales of purely battery electric vehicles, capturing 23% of the market and 16% of the plug-in electric battery in the market for 2020. It has also developed a significant installer of photovoltaic systems through its subsidiary Tesla Energy in the United States. One of the largest global battery energy-storage systems suppliers is Tesla Energy, with 3.99 gigawatt-hours installed in 2021.",book:{id:"11251",title:"Banking and Accounting",coverURL:"https://cdn.intechopen.com/books/images_new/11251.jpg"},signatures:"Nizar Mohammad Alsharari"},{id:"82427",title:"Our Globalization Era among Success, Obstacles and Doubts",slug:"our-globalization-era-among-success-obstacles-and-doubts",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.105545",abstract:"In the last decades, the never-ending and unlimited expanding of both international economies and operations became globalization. Among its main features, one could recall the enormous increase of world macro-economic quantities (Gross World Product, Inter-continental Trade, FDI), as well as financial values (public debts and currency printing). The chapter tries to quantify them, by a statistical analysis of historical data (Section 1). Section 2 is dedicated to the strategic problems of firms, in particular the threats and opportunities for (inter) national firms willing to become global, and obstacles are included in Section 3. This given, it deals with the behavior of countries from the political and juridical points of view, and those ones passed form initial perplexities, distaste, or even hostility to a favorable behavior. Conclusions (Section 4) recall both the problematic alternative for globalized companies between “the world as our next door” and their social responsibilities and the similar problem for host countries, between socioeconomic advantages and protection of local workers, resources, and environment.",book:{id:"11476",title:"Globalization and Sustainability - Recent Advances, New Perspectives and Emerging Issues",coverURL:"https://cdn.intechopen.com/books/images_new/11476.jpg"},signatures:"Arnaldo Canziani, Annalisa Baldissera and Ahmad Kahwaji"},{id:"82289",title:"Consumer Culture and Abundance of Choices: Having More, Feeling Blue",slug:"consumer-culture-and-abundance-of-choices-having-more-feeling-blue",totalDownloads:2,totalDimensionsCites:0,doi:"10.5772/intechopen.105607",abstract:"The defining feature of contemporary consumer culture is the escalation of consumption opportunities and the expanding space for choice. An unbridled and unrestricted range of products is part of material prosperity, rising living standards, and emancipation of human freedoms. The growing demands for constant consumer decision-making in an increasingly opaque environment of potential targets of choice exposes consumers to the risk of procrastination, passivity, and resignation, as well as psychological discomfort. The goal here is to contribute to theories of consumer behavior in the context of the psychological experience of choice under the conditions of the accelerated quantity of consumption volumes against the backdrop of the COVID-19 pandemic. While conventional offline shopping was drastically curtailed during the coronavirus crisis, freedom of consumer choice was maintained despite many proclamations to the contrary. I seek to provide support to the claim that freedom of consumer choice was maintained and often amplified during the pandemic in the online virtual environment of digital commerce formats. Freedom of consumer choice has merely been transformed into a horizontal level of application by the relatively rapid and fluid conversion of market activities into the cyberspace of a growing number of e-stores and online supermarkets, unconstrained by the physical space of shelves and counters.",book:{id:"11581",title:"A New Era of Consumer Behavior - Beyond the Pandemic",coverURL:"https://cdn.intechopen.com/books/images_new/11581.jpg"},signatures:"Ondřej Roubal"},{id:"82405",title:"Does Board Structure Matter in CSR Spending of Commercial Banks? Empirical Evidence from an Emerging Economy",slug:"does-board-structure-matter-in-csr-spending-of-commercial-banks-empirical-evidence-from-an-emerging-",totalDownloads:7,totalDimensionsCites:0,doi:"10.5772/intechopen.105589",abstract:"This chapter examines the impact of board elements on CSR spending by private commercial banks in an emerging economy, considering Bangladesh as a case. In doing so, we collected necessary data from the annual reports of 30 commercial banks listed on the Dhaka Stock Exchange, covering the period 2007–2020. In addition, we reviewed the patterns of CSR spending by commercial banks to understand the CSR universe in Bangladesh. We adopted the OLS model with two-way clustering to measure the effects of board elements on CSR spending. Our results confirm that factors, such as independent directors and board size, have a significant and positive relationship with CSR expenditures, while board gender deters the same. Also, board meetings do not have any significant connection with CSR spending. For control variables, factors, such as firm size and leverage, tend to promote the CSR spending of commercial banks, while profitability has no such relationship. As for the sectoral distribution of CSR funds, we found that although the absolute amount of CSR expenditures by banks has increased substantially over the years, they are primarily limited to health, education, natural disasters, and humanitarian activities. These findings are expected to have significant policy implications.",book:{id:"11602",title:"Corporate Social Responsibility",coverURL:"https://cdn.intechopen.com/books/images_new/11602.jpg"},signatures:"Bishnu Kumar Adhikary and Ranjan Kumar Mitra"},{id:"82395",title:"Toward a Better Understanding of Green Human Resource Management’s Impact on Green Competitive Advantage: A Conceptual Model",slug:"toward-a-better-understanding-of-green-human-resource-management-s-impact-on-green-competitive-advan",totalDownloads:11,totalDimensionsCites:0,doi:"10.5772/intechopen.105528",abstract:"Today, green human resource management (GHRM) has become a key business strategy where HRM plays an active role in the ongoing green movement. Thus, the topic of GHRM is of growing interest among management scholars. However, despite the theoretically important role of GHRM, relatively small number of research has been discovered so far about how GHRM, in companies striving to achieve environmental sustainability, could help them gain a green competitive advantage (GCA). Thus, based on the resource-based view (RBV) arguments, the main objective of this paper is to develop a conceptual model of the relationship between GHRM and green competitive advantage through green knowledge, green values, and green commitment. This model is expected to provide a strategic map that could be utilized by the practitioners and managers so that GHRM implementation can be more effective in contributing to green competitive advantage. Overall, the present article extends knowledge on the resource-based view by contributing to the literature on GHRM and its interactions with the main assets that lead to green competitive advantage.",book:{id:"11602",title:"Corporate Social Responsibility",coverURL:"https://cdn.intechopen.com/books/images_new/11602.jpg"},signatures:"Hosna Hossari and Kaoutar Elfahli"},{id:"82248",title:"Sustainability and Excellence: Pillars for Business Survival",slug:"sustainability-and-excellence-pillars-for-business-survival",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.105420",abstract:"The chapter presents an overview of management models starting with self-assessment (ISO 9004) and continuing with the European Foundation for Quality Management (EFQM) Excellence Model. Stakeholders’ analysis and their needs and expectations diagnostic are the baseline for building sustainable businesses. Sustainability and excellence are connected, and particular details of these approaches’ implementation are presented. Partnership development appears a key principle in the EFQM model. Based on companies’ strategies analysis, a simplified model may be proposed in order to support business survival in changing environments. Some guidelines to allow assessment of excellence fundamentals implementation are given. Based on experience and without seeing as exhaustive, a summary sheet of possible approaches and deployments is given. This may be used as a practical tool to connect actions implemented in organizations with the excellence model enablers, so as to facilitate assessment to explore the performance maturity level. The same sequence of Plan-Do-Check-Act relates approaches stated by ISO 26000 and sustainability initiatives. Embedding excellence and sustainability into business strategic objectives allows the management to define the framework for competitive continuous improvement.",book:{id:"11476",title:"Globalization and Sustainability - Recent Advances, New Perspectives and Emerging Issues",coverURL:"https://cdn.intechopen.com/books/images_new/11476.jpg"},signatures:"Irina Severin, Maria Cristina Dijmarescu and Mihai Caramihai"}],onlineFirstChaptersTotal:75},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[],lsSeriesList:[],hsSeriesList:[],sshSeriesList:[],testimonialsList:[]},series:{item:{id:"22",title:"Business, Management and Economics",doi:"10.5772/intechopen.100359",issn:"2753-894X",scope:"
\r\n\tThis series will provide a comprehensive overview of recent research trends in business and management, economics, and marketing. Topics will include asset liability management, financial consequences of the financial crisis and covid-19, financial accounting, mergers and acquisitions, management accounting, SMEs, financial markets, corporate finance and governance, managerial technology and innovation, resource management and sustainable development, social entrepreneurship, corporate responsibility, ethics and accountability, microeconomics, labour economics, macroeconomics, public economics, financial economics, econometrics, direct marketing, creative marketing, internet marketing, market planning and forecasting, brand management, market segmentation and targeting and other topics under business and management. This book series will focus on various aspects of business and management whose in-depth understanding is critical for business and company management to function effectively during this uncertain time of financial crisis, Covid-19 pandemic, and military activity in Europe.
",coverUrl:"https://cdn.intechopen.com/series/covers/22.jpg",latestPublicationDate:"June 27th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:1,editor:{id:"356540",title:"Prof.",name:"Taufiq",middleName:null,surname:"Choudhry",slug:"taufiq-choudhry",fullName:"Taufiq Choudhry",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000036X2hvQAC/Profile_Picture_2022-03-14T08:58:03.jpg",biography:"Prof. Choudhry holds a BSc degree in Economics from the University of Iowa, as well as a Masters and Ph.D. in Applied Economics from Clemson University, USA. In January 2006, he became a Professor of Finance at the University of Southampton Business School. He was previously a Professor of Finance at the University of Bradford Management School. He has over 80 articles published in international finance and economics journals. His research interests and specialties include financial econometrics, financial economics, international economics and finance, housing markets, financial markets, among others.",institutionString:null,institution:{name:"University of Southampton",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:3,paginationItems:[{id:"86",title:"Business and Management",coverUrl:"https://cdn.intechopen.com/series_topics/covers/86.jpg",isOpenForSubmission:!0,editor:{id:"128342",title:"Prof.",name:"Vito",middleName:null,surname:"Bobek",slug:"vito-bobek",fullName:"Vito Bobek",profilePictureURL:"https://mts.intechopen.com/storage/users/128342/images/system/128342.jpg",biography:"Dr. Vito Bobek works as an international management professor at the University of Applied Sciences FH Joanneum, Graz, Austria. He has published more than 400 works in his academic career and visited twenty-two universities worldwide as a visiting professor. Dr. Bobek is a member of the editorial boards of six international journals and a member of the Strategic Council of the Minister of Foreign Affairs of the Republic of Slovenia. He has a long history in academia, consulting, and entrepreneurship. His own consulting firm, Palemid, has managed twenty significant projects, such as Cooperation Program Interreg V-A (Slovenia-Austria) and Capacity Building for the Serbian Chamber of Enforcement Agents. He has also participated in many international projects in Italy, Germany, Great Britain, the United States, Spain, Turkey, France, Romania, Croatia, Montenegro, Malaysia, and China. Dr. Bobek is also a co-founder of the Academy of Regional Management in Slovenia.",institutionString:"Universities of Applied Sciences FH Joanneum, Austria",institution:null},editorTwo:{id:"293992",title:"Dr.",name:"Tatjana",middleName:null,surname:"Horvat",slug:"tatjana-horvat",fullName:"Tatjana Horvat",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hXb0hQAC/Profile_Picture_1642419002203",biography:"Tatjana Horvat works as a professor for accountant and auditing at the University of Primorska, Slovenia. She is a Certified State Internal Auditor (licensed by Ministry of Finance RS) and Certified Internal Auditor for Business Sector and Certified accountant (licensed by Slovenian Institute of Auditors). At the Ministry of Justice of Slovenia, she is a member of examination boards for court expert candidates and judicial appraisers in the following areas: economy/finance, valuation of companies, banking, and forensic investigation of economic operations/accounting. At the leading business newspaper Finance in Slovenia (Swedish ownership), she is the editor and head of the area for business, finance, tax-related articles, and educational programs.",institutionString:null,institution:{name:"University of Primorska",institutionURL:null,country:{name:"Slovenia"}}},editorThree:null},{id:"87",title:"Economics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/87.jpg",isOpenForSubmission:!0,editor:{id:"327730",title:"Prof.",name:"Jaime",middleName:null,surname:"Ortiz",slug:"jaime-ortiz",fullName:"Jaime Ortiz",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002zaOKZQA2/Profile_Picture_1642145584421",biography:"Dr. Jaime Ortiz holds degrees from Chile, the Netherlands, and the United States. He has held tenured faculty, distinguished professorship, and executive leadership appointments in several universities around the world. Dr. Ortiz has previously worked for international organizations and non-government entities in economic and business matters, and he has university-wide globalization engagement in more than thirty-six countries. He has advised, among others, the United Nations Development Program, Inter-American Development Bank, Organization of American States, Pre-investment Organization of Latin America and the Caribbean, Technical Cooperation of the Suisse Government, and the World Bank. Dr. Ortiz is the author, co-author, or editor of books, book chapters, textbooks, research monographs and technical reports, and refereed journal articles. He is listed in Who’s Who in the World, Who’s Who in America, Who’s Who in Finance and Business, Who’s Who in Business Higher Education, Who’s Who in American Education, and Who’s Who Directory of Economists. Dr. Ortiz has been a Fulbright Scholar and an MSI Leadership Fellow with the W.K. Kellogg Foundation. His teaching interests revolve around global economies and markets while his research focuses on topics related to development and growth, global business decisions, and the economics of technical innovation.",institutionString:null,institution:{name:"University of Houston",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},{id:"88",title:"Marketing",coverUrl:"https://cdn.intechopen.com/series_topics/covers/88.jpg",isOpenForSubmission:!0,editor:{id:"203609",title:"Associate Prof.",name:"Hanna",middleName:null,surname:"Gorska-Warsewicz",slug:"hanna-gorska-warsewicz",fullName:"Hanna Gorska-Warsewicz",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSD9pQAG/Profile_Picture_2022-06-14T11:58:32.jpeg",biography:"Hanna Górska-Warsewicz, Ph.D. is Associate Professor at Warsaw University of Life Sciences and Head of Department of Food Market and Consumption Research. She specializes in the subject of brands, brand equity, and brand management in production, service, and trade enterprises. She combines this subject with marketing and marketing management in both theoretical and practical aspects. Prof. Hanna Górska-Warsewicz also analyzes brands in the context of trademarks, legal regulations and the protection of intangible. She is an author or co-author of over 200 publications in this field, including 8 books. 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