Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
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We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
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Throughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
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1. Introduction
West Nile virus (WNV) was first isolated in Uganda (West Nile district) in 1937 from the blood of a native Ugandan woman [1] and until the end of the 20th century was considered a cause of viral encephalitis limited only in Africa and Asia. It became a global public health concern after the virus introduction in North America and especially New York in 1999 [2]. Before that, Romania had recorded the first large outbreak of West Nile neuroinvasive disease (WNND) in Europe in 1996, with 393 confirmed cases [3]. Since then, major outbreaks of WNV fever and encephalitis took place in regions throughout the world including America, Europe and Middle East, causing human and animal deaths. In the last decade, lineage 2 strains, considered of low virulence, have been introduced in Central and South Eastern Europe and were incriminated as causative agents of major human and animal disease outbreaks. A great number of WNV infections in humans occurred in 2010 and 2011 in Greece, with 363 laboratory confirmed cases and 44 deaths [4]. WNV lineage 2 strains were first detected from pools of Culex mosquitoes (strain Nea Santa-Greece-2010) [5] and a Eurasian magpie (strain magpie-Greece/10) [6] at the epicenter of the outbreak.
The unexpected high virulence of lineage 2 strains creates major concerns regarding the pathogenic potential of evolving and mutating WNV strains. The basic properties of WNV function will be presented focusing especially on the replication cycle, the pathogenicity mechanism as well as some important genetic determinants of virulence that have been recognized so far and can pose serious public health risks when present at various WNV strains.
2. Classification
West Nile Virus (WNV) is a member of the Flaviviridae family of single-stranded RNA viruses with linear non-segmented genomes. More than 58 members belong to the Flaviviridae family, whose name comes from the word “flavi”, Latin for “yellow”, because one of the most famous flaviviruses is the Yellow Fever Virus. Flaviviridae family is further divided in 3 genera: flaviviruses, pestiviruses and hepaciviruses. Pestivirus genus consists of 4 viral species that cause important animal diseases: Bovine Viral Diarrhea Virus type 1 and 2, Border Disease Virus and Classical Swine Fever Virus. The only member of the Hepacivirus genus is Hepatitis C virus. The Flavivirus genus is the largest with at least 53 species divided into 12 serologically related groups. Of these, the Japanese Encephalitis Virus (JEV) group (8 species) is the one with the most human-associated disease viruses; Japanese Encephalitis Virus, St. Louis Encephalitis Virus, Murray Valley Encephalitis Virus and West Nile Virus are four members of the JEV group that have been associated with widespread human and animal disease outbreaks [7]. The International Committee of Taxonomy of Viruses can be consulted for the most accurate update regarding nomenclature and taxonomy of all viruses at the species level [8].
3. Structure and genome
The WNV genome is a positive single stranded RNA of approximately 11000 nucleotides surrounded by an icosahedral nucleocapsid which is contained in a lipid bi-layered envelope, of approximately 50 nm in diameter (Figure 1). The genome is transcribed as a single polyprotein that is cleaved by host and viral proteases into three structural (C, prM/M, and E) and seven nonstructural (NS1, xlinkA, xlinkB, NS3, NS4A, NS4B, and NS5) proteins [9] (Figure 2). Recent studies also reported that a larger NS1-like (NS1\') viral protein, which is often detected during infection, is the possible result of ribosomal frameshifting [10].
Figure 1.
Structure of West Nile virus determined by cryo-EM. (A) A surface shaded view of the virion, one asymmetric unit of the icosahedron is indicated by the triangle. The 5-fold and 3-fold icosahedral symmetry axes are labeled. (B) A central cross section showing the concentric layers of density. Virion core, lipid bilayer and proteins E and M are indicated. Reprinted with permission from Science, 10 October 2003:248.DOI:10.1126/science.1089316.
The viral capsid is approximately 30 nm in diameter and consists of C protein dimers, the basic component of nucleocapsids, with the RNA binding domains located at the C- and N- termini separated by a hydrophobic region [11]. The hydrophobic regions of the C dimers form an apolar surface which binds to the inner side of the viral lipid membrane [12]. In immature virions, the lipid bi-layered envelope that coats the nucleocapsid contains 180 molecules each of E and prM proteins organized into 60 asymmetric trimeric spikes consisting of prM-E heterodimers [13]. The transition from immature to mature virions starts with the release of the N-terminal prepeptide from the prM protein after cleavage by a furin-like protease in the trans-Golgi compartment of the infected cell [14].
Figure 2.
RNA genome of West Nile virus and site sites cleaved by host proteases and virus-encoded xlinkB/NS3 protease.
Mature virions are characterized by the structural change, rotation and rearrangement of the 60 trimeric prM-E heterodimers to form 90 antiparallel homodimers with quasi-icosahedral symmetry that cover the lipid membrane [15, 16]. The E proteins are organized in 3 domains connected by flexible hinges [17]. Domain I (DI) is positioned at the central portion of the protein, linking together the other two domains. Domain II (DII) is a long domain containing a 13 residues long, glycine-rich, hydrophobic sequence that forms an internal fusion loop which is necessary for flaviviral fusion. Domain III (DIII) is an Ig-like fold that is thought to participate in interactions between virions and host factors associated with virus entry [18] (Figure 3).
Figure 3.
Diagram showing the structural rearrangement required for immature particles to become mature particles. The three independent E molecules per icosahedral asymmetric unit are colored green, red, and blue. The three domains in each E molecule are labeled I, II, and III. Reprinted with permission from EMBO J. 22(11):2604-13.
The viral nonstructural proteins are responsible for regulating viral mechanisms of transcription, translation and replication and attenuate host antiviral responses (Table 1). NS1 protein functions as a cofactor for viral RNA replication and is the only nonstructural protein that is secreted in high levels (up to 50 μg/ml) in the serum of WNV infected patients and has been connected with severe disease [19]. Many theories have been proposed regarding the contribution of NS1 to the pathogenic mechanism of WNV: it has been proposed to elicit hazardous autoantibodies [20], to contribute to the formation of various immune complexes circulating in the host organism [21], antibodies against NS1 to cause endothelial cell damage [22], or to minimize immune response targeting of WNV by decreasing recognition of infected cells by the complement system [23].
xlinkA is a hydrophobic, multifunctional membrane-associated protein which plays an important role in RNA replication [24] and viral particles assembly [25, 26]. xlinkA is also the major suppressor of beta interferon (IFN-β) transcription, thus inhibiting interferon response, one of the first lines of defense of the host [27].
xlinkB is a cofactor required for NS3 proteolytic activity. NS3 is a multifunctional protein, with two distinct functional domains. The protease comprises the N-terminal amino acid residues of NS3, while the carboxylated terminus contains a helicase, a nucleoside triphosphatase and a RNA triphosphatase [28 - 31]. The NS3 trypsin-like serine protease is only active as a heterodimeric complex with its cofactor, xlinkB. In the cytoplasm of infected host cells, this heterodimeric complex (xlinkB-NS3pro) is responsible for post-translational cleavage of the viral polyprotein to release structural and non-structural viral proteins that are essential in viral replication mechanism and virions assembly. Cleavage takes place at the C-terminal side of two basic residues (e.g., RR, KK, and RK), a sequence motif that occurs at the junctions of xlinkA/B, xlinkB/3, NS3/4A, and NS4B/5. It also cleaves the viral polyprotein within the C-terminal region of protein C and protein NS4A as a necessary precursor to cleavage of prM and NS4B, respectively, by cell signalase in the lumen of the endoplasmic reticulum [28, 32]. The C-terminal of NS3 is characterized by the presence of motifs with homology to supergroup II RNA helicases, to a RNA-stimulated nucleoside triphosphatase (NTPase) and to a RNA triphosphatase (RTPase) [30, 33, 34]. The NTPase activity provides the chemical energy which is necessary to unwind RNA replication intermediates into forms that can be amplified by the NS5 RNA-dependent RNA polymerase [35, 36]. The RTPase dephosphorylates the 5’ end of viral RNA, before cap addition by the N-terminal methyl transferase region of NS5 [37]. RNA helicases travel along RNA in a 3’ to 5’ direction fueled by ATP hydrolysis; this movement opens secondary structures and displaces proteins bound to RNA [38]. Thus, together with the NS5 polymerase, with which NS3 is in tight association and interaction, the NS3hel plays an important role in flavivirus replication. However, a complete picture of the mechanism by which NS3hel associates with RNA template is not yet completely known.
NS4A, along with NS4B and xlinkA, are the least known flavivirus proteins. The NS4A precise functional role has not been sufficiently characterized, although evidence suggests a role of “organizer” of the replication complex of flaviviruses. Its N-terminal is generated in the cytoplasm after cleavage by the xlinkB-NS3 protease complex, whereas the C-terminal region (frequently designated 2K fragment) serves as a signal sequence for the translocation of the adjacent NS4B into the endoplasmic reticulum lumen. The 2K fragment is removed from the N terminus of NS4B by the host signalase, however a prior xlinkB-NS3 protease complex activity at the NS4A/2K site is required [39]. Proteolytic removal of the 2K peptide also induces membrane alterations [40]. Recently NS4A was proven to act as a cofactor for NS3 helicase allowing the helicase to sustain the unwinding rate of the viral RNA under conditions of ATP deficiency [41]. NS4B colocalizes with viral replication complexes and proved to dissociate NS3 from single-stranded RNA, thereby enabling it to bind to a new dsRNA duplex, consequently enhancing the helicase activity and modulating viral replication [42, 43]. In addition, NS4A and NS4B, along with xlinkA, as has already been referred, and NS5 proteins appear to inhibit the interferon-α/β response of the host [44-46].
Finally, NS5 is the C-terminal protein of the viral polyprotein and is the largest and most conserved of flaviviruses proteins. The N-terminal region of NS5 contains an S-adenosyl methionine methyltransferase (MTase) domain, part of the viral RNA capping machinery. The cap is a unique structure found at the 5’ end of viral and cellular eukaryotic mRNA, critical for both mRNA stability and binding to the ribosome during translation [47, 48]. The C-terminal region of NS5 contains a RNA-dependent RNA polymerase which is required for the synthesis of the viral RNA genome [49]. It was already mentioned that NS5 is in close interaction with NS3, constituting the major enzymatic components of the viral replication complex, which promotes efficient viral replication in close association with cellular host factors.
Non structural Protein
Function
NS1
Cofactor for viral RNA replication, pathogenic mechanism in early infection (decrease complement recognition)
xlinkA
Viral RNA replication and virions assembly, Major suppressor of IFN-β transcription
xlinkB
Cofactor for NS3pro activity, interferons antagonist
NS3
Serine protease, RNA helicase, RTPase, NTPase
NS4A
“Organizer” of replication complex, inhibitor of interferon α/β host response
NS4B
Inhibitor of interferon α/β host response, enhancer of NS3hel activity
Functions of West Nile virus nonstructural proteins.
4. Replication cycle
WNV has the ability to replicate in various types of cell cultures from a wide variety of species (mammal, avian, amphibian and insect) (Figure 4). The first step in the infectious cell entry involves the binding of E protein to a cellular molecule-receptor [50]. Several cell molecules have been proven to function as co-receptors for in-vitro virion attachment: WNV interacts with DC-SIGN and DC-SIGN-R in dendritic cells [51]. It has been documented to attach to the integrin αvb3, through DIII RGD/RGE sequence, which is an integrin recognition motif [52]. However a recent study showed that WNV entry does not require integrin αvb3 in certain cell types suggesting that receptor molecule usage is strain-specific and/or cell type-dependent [53].Rab 5 GTPase was found to be a requirement for WNV and Dengue Virus cellular entrance [54]. Laminin binding protein is also a putative receptor for the WNV, with proved high specificity and efficiency between LBP and DII of E protein [55, 56]. Many other attachment factors have been identified for flaviviruses, including CD14 [57], GRP78/BiP [58], 37-kDa/67-kDa laminin binding protein [58], heat-shock proteins 90 and 70 [59], and even negatively charged lycoaminoglycans, such as heparan sulfate, which are expressed in various cell types, though, for the latter, recent studies did not reveal specific binding of WNV with heparan sulfate [60].
After the viral attachment via the cellular receptors, WNV enters the cell through clathrin-mediated endocytosis [61]. It is characteristic that it was possible to inhibit WNV infection by treating cells with chemical inhibitors like chloropromazine [62] that prevent the formation of clathrin-coated pits, or by expressing negative mutants of Eps15 in cells. Eps15 is a protein involved in clathrin-coated pit formation [63]. The endosome environment is characterized by acidic PH, which triggers conformational changes of the E glycoprotein. The first step involves the disruption of the E protein rafts and dissociation of the E homodimers to monomers. An outward projection of DII takes place, and the fusion loop of DII is exposed to the target membrane. The E proteins insert their fusion loops into the outer leaflet of the cell membrane. Three E monomers interact with one another via their fusion loops to form an unstable trimer which is stabilized through additional interactions between the DI domains of the three E proteins [50, 64]. Next, DIII is believed to fold back against the trimer to form a hairpin-like configuration. The energy released by these conformational changes induces the formation of a hemifusion intermediate, in which the monolayers of the interacting membranes are merged. Finally, a fusion pore is formed and after enlargement of the pore, the nucleocapsid is released into the host cell. The viral RNA is released by the nucleocapsid with a yet unknown mechanism and is translated. The produced polyprotein is cleaved at multiple sites by the NS3 serine protease and the host signal peptidase within the lumen of the endoplasmic reticulum. At the same time, the viral RNA-dependent RNA polymerase copies complementary negative polarity (–) strands from the positive polarity genomic (+) RNA template, and these negative strands serve as templates for the synthesis of new positive viral RNAs. Studies showed that RNA replication can continue without protein synthesis, and that from a (+) strand RNA only one (-) strand RNA can be synthesized at a time, while from a (-) strand RNA multiple (+) strand RNAs can be simultaneously copied [65,66]. However virion assembly cannot take place if sufficient protein synthesis has not been performed: Each virion contains 180 copies each of E and prM structure proteins and only one genomic copy.
Figure 4.
West Nile virus replication cycle. The virion is attached to the cellular membrane of thee host cell via the cellular receptors, and the envelope fuses with the membrane. The viral RNA is released by the nucleocapsid with a yet unknown mechanism and serves as mRNA for translation of all viral proteins and as template during RNA replication. Virion assembly and release of them to the extracellular milieu complete the replication cycle. Reprinted with permission from PNAS 2002, vol. 99 no. 18 11555-11557. Copyright 2002 National Academy of Sciences, U.S.A.
During West Nile virion assembly, C proteins bind to the newly replicated RNA and wrap around it to form an icosahedral shell. This nucleocapsid will be enveloped by cellular membrane derived from the endoplasmic reticulum and will bud into the lumen as immature virions on which E and prM proteins form 60 heterotrimeric spikes. Immature virions are then transported to the mildly acidic compartments of the trans-Golgi network triggering a rearrangement of E proteins on the immature virion; the lower pH induces a structural transition such that E proteins form 90 antiparallel homodimers on the surface of the virion [67] (Figure 4). Under acidic conditions, prM remains associated with the virion and protrudes from the surface of an otherwise smooth virus particle. This pH-dependent conformational change increases the susceptibility of prM for a furin-like serine protease [68].The pr peptide dissociates from the particle upon release of the virion to the extracellular milieu by exocytosis, which starts 10-12 h after cell infection. However, this furin processing of prM is rather inefficient and many virions still contain prM proteins even after their release to the extracellular milieu, which will reorganize back to prM/E heterodimers.
This inefficient and incomplete maturation leads to the secretion of a mixture of mature, immature and partially mature particles from flavivirus-infected cells. A high number of prM-containing particles have been described for WNV. Until recently, fully immature virions were considered to be unable to cause infection as they cannot undergo the structural rearrangements required for membrane fusion [69]. However, newer studies proved that even fully immature virions of flaviviruses can cause infection by antibodies [70, 71]. Regarding partially immature virions, multiple studies have shown that they can also be infectious [17, 72]. It seems that the mature part of these virions is responsible for cell binding and entry after which the further processing of remaining prM may take place inside the cell. Further studies are needed to estimate the “cut-off” regarding the number of prM proteins on viral surface that allow the viral particle to be infectious.
5. Epidemiology
Avian species are considered the primary hosts of West Nile virus, and in an endemic region, virus is maintained in an enzootic cycle between mosquitoes and birds [73]. Birds from more than 300 avian species have been reported dead from West Nile virus [74]. Disease can also be caused in humans and other mammals, particularly horses, considered as alternative hosts of WNV; main route of infection is through the bite of infected mosquitoes. However, the virus can also spread between individuals by blood transfusion and organ transplantation and few reports have also proposed the transmission from mother to newborn via the intrauterine route or via breast-feeding [75-77]. Most human infections remain asymptomatic, West Nile fever (a mild flu like fever) develops in approximately 20 to 30% of infected persons and West Nile neuroinvasive disease in <1% [78], characterized by encephalitis, meningitis, acute flaccid paralysis and even long-term neurological sequeale [79]. Nonetheless, horses and humans develop viremia levels of low magnitude (<105 PFU/ml) and short duration insufficient to infect mosquitoes and thus do not serve as amplifying hosts for WNV in nature [80]. On the contrary, various avian species, both migratory and sedentary, develop viremia levels sufficient to infect most feeding mosquitoes [81]. Hence, WNV is maintained in an enzootic cycle with wild and domestic birds being the main amplifying hosts and ornithophilic mosquitoes, especially of the Culex species, the main vectors. Moreover, local movements of resident birds and long-range travel of migratory birds may both contribute to the spread of WNV [82, 83]. Various studies have provided indirect evidence that WNV is transported by migratory birds, especially via their migration routes from breeding areas of Europe to wintering areas in Africa [84-87].
WNV strains are grouped into at least 7 genetic lineages [88] (Figure 5). Lineage 1 is the most widespread, containing isolates found in Europe, North America, Asia, Africa and Australia. This linage is further divided into at least two different clades: WNV-1a is found mainly in Africa, Europe, North America and Asia and is further divided in six evolution clusters [89].WNV 1-b contains the Australian Kunjin virus. A third clade containing Indian isolates is now classified as Lineage 5 [90]. Lineage 2 strains are mainly distributed in Sub-Saharan Africa and Madagascar, but in the last decade they have been introduced in Europe. Lineage 3 contains a strain circulating in certain Culex and Aedes species mosquitoes in southern Moravia, Czech Republic, namely “Rabensburg virus”, not known to be pathogenic to mammals [91]. Lineage 4 is represented by a strain isolated from Dermacentor marginatus ticks from the Caucasus [92]. A re-classification of Sarawak Kunjin virus as lineage 6 has been proposed as this strain is different to other Kunjin viruses. The African Koutango virus is closely related to WNV and a seventh lineage has been proposed for this strain. An eighth lineage has been proposed for WNV strains detected in Culex pipiens mosquitoes captured in Spain in 2006, which could not be assigned to previously described lineages of WNV [93].
Figure 5.
Phylogenetic tree of a 236-nt NS5 genomic region. Phylogenetic analysis based on a 236-nt NS5 genomic region of 15 West Nile virus strains, representatives of all recognized lineages, focusing on Lineage 2 strains circulating in South Eastern Europe. Analysis was performed using MEGA version 5. GenBank accession numbers and geographic origins of strains used in this analysis are: NY99 (AF202541, USA); Kunjin virus (D00246, Australia); 804994 (DQ256376, India); Nea Santa-Greece-2010 (HQ537483, Greece); magpie-Greece/10 (JQ954395, Greece); goshawk-Hungary/04 (DQ116961, Hungary); Italy/2011/AN-2 (JN858070, Italy); ); SPU116/89 (EF429197, South Africa); B956 (AY532665, Uganda); Reb VLG 07 (FJ425721, Russia); Sarafend (AY688948, Israel); Kunjin virus/strain Sarawak (L49311, Malaysia); Rabensburg 97-103 (AY765264, Czech Republic); LEIV-Krnd88-190 (AY277251, Russia); Koutango DakAaD 5443 (L48980, Senegal). Neighbor-joining tree was constructed from a difference matrix employing the Kimura 2-parameter correction. One thousand bootstrap pseudo-replicates were used to test the branching (shown as percentages, with a cut-off value of 50%).
Lineage 2 was considered to be endemic in Sub-Saharan Africa and Madagascar, however, since 2004 strains have been observed in Hungary from birds of prey [94] and in 2007 in Russia from mosquito pools during a disease outbreak with 67 human cases [95]. In 2010 it caused outbreaks in Romania [96] and Greece [4] and in 2011 it was detected for the first time in Italy [97, 98]. The Greek and Italian strains showed the highest homology to Hungarian and South African strains, differing from the Russian lineage 2 strains detected in 2007. However, in Italy no major human disease outbreak occurred; only one human case was reported with mild clinical expression [97]. Genetic analysis of the Italian strains revealed the presence of histidine at 249 aa position of NS3, just like the Hungarian strains, in contrast to the Greek strains that contained proline at that position, the presence of which has been already implicated with high pathogenicity of lineage 1 strains [99].
6. Pathogenesis
Most of our knowledge regarding WNV dissemination and pathogenesis derives from the study in rodent models. After an infected mosquito bite, WNV infects keratinocytes and Langerhans cells [100,101] which migrate to lymph nodes resulting in a primary viremia [102]. Then the virus spreads to peripheral visceral organs like kidney and spleen where a new replication stage occurs, in epithelium cells and macrophages respectively [103]. Depending on the level of viremia, the peak of which comes at day 3 p.i. in mice, the virus may cross the blood-brain barrier (BBB) and enter the central nervous system (CNS), causing meningo-encephalitis. Various ways have been proposed for WNV entry to CNS; TNF-a mediated change in endothelial cell permeability have been proposed to facilitate CNS entry [104], as well as infection of olfactory neurons and spread to the olfactory bulb [105]. Other ways involve direct axonal retrograde transport from infected peripheral neurons [106] or transport of the virus by infected immune cells trafficking to the CNS [107]. WNV infects neurons in various parts of the CNS causing loss of architecture, degeneration and cell death. In a later stage mononuclear cells infiltrate the infected regions although it is not really clear if they help stop infection or contribute to pathogenesis destroying infected cells and releasing cytokines [108]. Infection and injury of brain stem, hippocampal and spinal cord is observed in both humans and rodents that succumb to the disease. Persistence of WNV in mice was found to be tissue dependent. Infectious virus could persist as long as 4 months p.i., especially in mice that did not exhibit disease during acute infection and especially in the skin and spinal cord [109]. This persistence may also occur in humans after mild febrile illness or subclinical infections; 3% of WNV-positive blood donors were found to have detectable WNV RNA in blood between 40 and 104 days after their index donation [110].
In wild birds, less is known regarding pathogenesis of WNV. The virus has been detected by histology and RT-PCR in various tissues e.g. brain, liver, lungs, heart, spleen and kidneys of various avian species e.g. crows, blue jays, goshawks, magpies [111, 112, 94, 6]. Various avian species were found to be viremic for 6 days post inoculation and viremic titers high enough to transmit the virus to mosquitoes via their bites [113]. In wild birds, infectious WNV was detected for as long as 6 weeks in tissues [114,115]. However it is important to clarify that immune response, virulence and viral persistence is to a great degree species dependent, with great variations among various avian species in different geographical areas, as well as strain dependent, implicating various genetic determinants of virulence.
7. Immune response
Immune response of animals and humans to WNV infection is divided to innate and adaptive.
Innate response includes interferons, complement and innate cellular immunity
Interferons type I (IFN-α and IFN-β), type II (IFN-γ), and type III (IFN- λ) IFNs play an essential protective role limiting infection of many viruses. IFN-α/β is produced by most of the cells following viral infection and induces an antiviral state to the cell, “activating” the relevant genes. It also creates a linkage between innate and adaptive immune responses by various mechanisms e.g. activation of B and T cells or dendritic-cell maturation [116, 117, 118]. IFN-γ is produced by γδ Τ cells, CD8+ T cells, and natural killer cells and limits early viral dissemination to the CNS through several mechanisms [119, 120]. WNV has evolved various countermeasures, at least 6 different mechanisms, against interferons function [121]. Hence, IFN administration cannot be considered of significant therapeutic importance for WNV disease control [122].
Several nucleic acid sensors e.g. TLR3, cytoplasmic dsRNA, RIG-I and MDA5 bind to viral RNA and activate transcription factors like IRF3 and IRF7 as well as IFN-stimulated genes [123-126].
Complement is a system of proteins in serum and molecules on cell surface that recognize pathogens and induce pathogen clearance. Three pathways exist for complement activation the classical, the lectin and alternative pathways, which are initiated by binding of C1q, mannan-binding lectins or hydrolysis of C3 respectively. All three pathways have been found to be important for controlling WNV lethal infections [127- 129].
There is data suggesting that macrophages and dendritic cells may directly inhibit WNV. Macrophages can control infection through cytokine and chemokine secretion, enhanced antigen presentation and direct viral clearance [130]. γδ T cells also limit WNV infection in an early stage [131].
Adaptive response includes humoral and cellular response
Humoral immunity plays a vital role in protection from WNV infection. Experimental studies demonstrated complete lethality of B-cell-deficient and IgM-/- mice infected with WNV, whereas they were protected by transfer of immune sera [132,133]. IgM titers at day 4 p.i. could predict the disease outcome at prospective experiments. IgG can also protect from infection, however, in primary infection their role is less vital: Being produced after days 6-8, the disease outcome has been determined, since both viral shedding to CNS and clearance from tissues have already occurred [132, 134]. The vast majority of neutralizing antibodies are directed against all three domains of E protein. However the most potent neutralizing antibodies are directed on DIII possibly inhibiting viral fusion at post-attachment stage [135, 136]. In humans, antibodies against prM have also been recognized but with limited neutralizing activity [70, 137, 138]. Antibody neutralization is a procedure where multiple antibodies, above an estimated threshold “manage” to neutralize the virion’s activity and render it non-infectious. This threshold was estimated to be 30 antibodies per virion for a highly accessible epitope of DIII of E protein [139-141]. It is important, however, to understand the following aspects: The level of neutralizing antibodies does not always correlate with protection against WNV. WNV have 180 E proteins on their surface. Steric phenomena because of the dense icosahedral arrangements of these proteins do not allow the equivalent display of all the epitopes. There are also many structurally distinct epitopes, not easily accessible to certain neutralizing antibodies. It is characteristic that studies showed a reduction of the neutralizing ability of antibodies correlated to the maturation state of WNV: Maturation reduces the accessibility of some of the epitopes on the virion [17]. Thus, these antibodies cannot efficiently neutralize the virus even if at high levels of concentration. This can lead to completely different result: Antibody dependent enhancement (ADE) of infection is possible in cells bearing activating Fc-γ receptors [141, 142] and thus a mild infection with sufficient levels of antibodies can become even life-threatening due to the inability of the antibodies to neutralize the virions.
Antibodies against NS1, a protein secreted in the serum of patients during acute phase of disease and expressed on the surface of infected cells considered to be a cofactor in virus replication, have been found to be non-neutralizing but protecting through both Fc-γ receptor-dependent and independent mechanisms [143].
T lymphocytes (part of cellular response mechanism) have been demonstrated to be vital for the protection against WNV infection. Recognizing an infected cell through the viral antigen fragments associated with MHC class I molecules on the infected cells’ surface, cytotoxic (CD8+) T cells secrete cytokines and lyse the cells directly (perforin, granzymes A and B) or indirectly via Fas-Fas ligand interactions [144, 145]. Studies showed that for the protection against lineage I, perforin played the most important role and, in contrast, lineage II strain Sarafend was controlled more efficiently by granzymes [146, 147]. CD4+ T cells contribute through multiple mechanisms, and preliminary data suggest that CD4+ T cells restrict pathogenesis in vivo [148]. Except IFN–α/β, T-cell immune response is extremely essential regarding the control of WNV in the CNS, their presence being correlated with virus clearance [146, 149, 150]. WNV infection induces the secretion of the chemokine CXCL10 from neurons, recruiting effector CD8+ T cells via the chemokine receptor CXCR3 [151].Expression of chemokine receptor CCR5 and its ligand CCL5 is up-regulated by WNV and is associated with CNS infiltration of CD4+ and CD8+ T cells, NK1.1+ and macrophages expressing the receptor [152].
All the above data provide solid evidence that a combination of various aspects of both innate and adaptive immune response cooperate to control WNV infection in the periphery and CNS.
8. Genetic determinants of virulence
Various studies especially in the last decade have recognized a variety of genetic determinants of virulence for West Nile virus strains. Specific mutations have been found to attenuate or strengthen virus pathogenicity via various mechanisms. Those that have been found to be the most important will be reported here, focusing on the ones that seem to have major impact on the replication mechanisms of WNV.
Mutations at the Envelope protein at residues 154 to 156, which abolished the N-linked glycosylation motif (N-Y-S/T) was proved to attenuate virus pathogenicity in mouse models [153]; these mutations seem to alter the protein such that it cannot be recognized by oligosaccharyl-transferase, thus glycan loss is caused [154]. This glycosylation motif has been recognized to various flaviviruses and spatially is located in close proximity to the center of the fusion peptide of DII of E protein, and thus is considered to increase the stability of the protein to a fusion-active form even at high temperatures [155, 156]. This proved to be really important for the multiplication of the virus to avian cell and animal models: results showed that E glycosylated WNV variants multiplied more efficiently to avian cell cultures and at high temperatures, causing at the same time high viremic titers and pathogenicity to chicks [157]. Most of the Lineage I virulent strains as well as recent virulent Lineage II strains associated with the Greek outbreak carry the N-glycosylation site, suggesting it a prerequisite for the efficient circulation and amplification of the virus in a mosquito-avian transmission cycle [158, Valiakos et al. unpublished data]. Of course it is possible that E glycosylation affects other aspects of the WNV replication cycle as well such as target cell tropism, virion assembly and release etc.
We have already referred to the NS4B protein proven dual role of involvement to virus replication mechanism (enhances helicase activity) and evasion of host innate immune defense (inhibits IFN α/β response). Studies proved that substitution of cysteine (an amicoacid which is often critical for the proper function of a protein) with serine at position 102 of NS4B, (Cys102Ser) leads to sensitivity to high temperatures as well as attenuation of the neuroinvasive and neurovirulent phenotypes in mice [159]. It was determined previously that the first 125 amino acids of the N-terminal of NS4B protein of flaviviruses are sufficient for the inhibition of IFN-α/β signaling [160]. Hence, this mutation which is located in this region of WNV may attenuate the viral ability to inhibit IFN signaling. Attenuation of the viral pathogenicity, characterized by lower viremia levels and no lethality to mice, was caused by a P38G mutation in the NS4B protein [161]; this was proven to be related to an induce of higher innate and adaptive immune response in mice, with higher type I IFNs and IL-1β levels and stronger memory and effector T cells responses. An adaptive mutation (E249G) in the NS4B gene resulted in reduced in-cell viral RNA synthesis, probably affecting the involvement of NS4B to the virus replication mechanism [162].
xlinkA protein, as already stated, plays important role in RNA replication and viral particles assembly, and is also the major suppressor of IFN-β transcription. It was found that an A30P mutation of a Kunjin subtype WNV strain resulted in a reduced ability of the virus to inhibit IFN response, leading to increased levels of IFNs synthesis [27]. However this mutation implemented in North American Lineage 1 strains did not cause significant changes to phenotype indicating that in many cases the effect of mutations under study can be strain-specific. D73H and M108K were mutations found to be related to poor replication and non mortality to mice [163].
NS3 protein includes the serine protease at the N-terminal and the RNA helicase, an NTPase and an RTPase at the C-terminal. The introduction of a T249P in North American Linage 1 strain was found to be sufficient to generate a phenotype virulent to American crows [99]. A H249P mutation is considered to be the main cause of increased virulence of Lineage 2 strain that caused the major WNV disease outbreak in 2010-2011, in Greece. Only the Greek sequences, detected in mosquito pools, corvids and chickens [5, 164, Valiakos et al. unpublished data] contains proline at this locus, while all other Lineage 2 strains contain histidine. The exact mechanism through which this mutation increases the pathogenicity of WNV is unknown, believed though to be related to increased replication rate caused by an enhancement in RNA helicase function; hence, the virus may surpass bird viremia thresholds required for infection of many mosquito species vectors (> 105 PFU/ml. However, recent studies on European Lineage 1 strains Morocco/2003 and Spain/2007 proved that the first was more pathogenic in a mouse model than the second; Morocco/2003 contains a T and Spain/2007 a P at 249 aa position. Hence, a proline residue in position 249 of the NS3 position is not sufficient to enhance virulence, at least in certain cases [165, 166]. Another study detected a potential role of a S365G mutation to enhance viral replication, by lowering the requirement of ATP for ATPase activity, thus allowing the RNA helicase to sustain the unwinding rate of viral RNA under conditions of ATP deficiency [167].
The function of the hydrophobic 2K peptide that spans the ER membrane between NS4A and NS4B remains largely unknown. It is believed that it acts as signal sequence for the translocation of NS4B into the ER lumen. It is removed from the N-terminus of NS4B by a host ER signalase. 2K-V9M mutant virus generates higher viral titers in Oas1b-expressing cells than the wild type virus. The exact mechanism by which the 2K-V9M substitution enables WNV resistance to antiviral action of Oas1bis unknown [167].
Theoretically, substitutions of hydrophobic to hydrophilic amino acids and vice versa as well as substitutions of glycine, proline and cysteine residues are considered to have a potential effect on the secondary structure of proteins. A study performed on Lineage 2 strains of low and high virulence recognized this kind of substitutions at NS3 (S160A and R298G), NS4A (A79T) and NS5 protein (T614P, M625R, M626R) that were present at high virulent strains [168].
9. Conclusions
West Nile virus is considered a serious public health threat, especially for high risk groups (very young and elderly, imunocompromised). Currently there has not been established any antiviral treatment to WNV infections; only supportive care may be administered. Vaccine development is still at an early stage for humans. Hence, preventive measures rely still on reduction of mosquito populations and minimizing vector-host contact. Various diagnostic techniques have been developed the last decades, both molecular and serological, trying to minimize the difficulties arisen from other cross-reactive closely related flaviviruses. Data presented here prove the complexity of the host-virus interaction: Specific host-pathogen-vector interface, cellular tropism, viral structure diversity regarding maturation, immune system recognition and response, genetic diversity are all factors characterized by great variation rendering WNV control extremely difficult. Continuous studies are being demanded to understand the extent of this complexity to further elucidate biological relationships among host, vector and virus that will lead to improved disease control. As more is learned about the biological characteristics of WNV infection, one continuing objective will be to relate this knowledge to the clinical features of disease. An important viral-host determinant is virus attachment, mediated by cellular receptor and allowing subsequent infection. Host defensive behaviors that could affect virus acquisition and transmission should be also further studied. This may help in the design and implementation of more efficient and cost-effective control strategies since introduction of WN virus is an ongoing risk and reality. The ultimate challenge will be to apply the knowledge gained in understanding viral replication and unraveling the complexity leading to pathogenesis in order to prevent and control West Nile virus and its severe manifestations.
Acknowledgement
The research leading to these results received partial funding from the European Union Seventh Framework Programme (2007-2013) under grant agreement no. 222633 (WildTech).
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Athanasiou, Antonia Touloudi, Vassilis Papatsiros, Vassiliki Spyrou, Liljana Petrovska and Charalambos Billinis",authors:[{id:"90827",title:"Dr.",name:"Vassilis",middleName:null,surname:"Papatsiros",fullName:"Vassilis Papatsiros",slug:"vassilis-papatsiros",email:"vpapatsiros@yahoo.com",position:null,institution:{name:"University Of Thessaly",institutionURL:null,country:{name:"Greece"}}},{id:"152688",title:"Prof.",name:"Charalambos",middleName:null,surname:"Billinis",fullName:"Charalambos Billinis",slug:"charalambos-billinis",email:"billinis@vet.uth.gr",position:null,institution:{name:"University Of Thessaly",institutionURL:null,country:{name:"Greece"}}},{id:"153320",title:"Dr.",name:"Lamprini",middleName:null,surname:"Athanasiou",fullName:"Lamprini Athanasiou",slug:"lamprini-athanasiou",email:"lathan@uth.vet.gr",position:null,institution:null},{id:"153321",title:"Dr.",name:"Vassiliki",middleName:null,surname:"Spyrou",fullName:"Vassiliki Spyrou",slug:"vassiliki-spyrou",email:"spyrou@teilar.gr",position:null,institution:null},{id:"153322",title:"Dr.",name:"George",middleName:null,surname:"Valiakos",fullName:"George Valiakos",slug:"george-valiakos",email:"georgevaliakos@gmail.com",position:null,institution:null},{id:"156970",title:"Dr.",name:"Antonia",middleName:null,surname:"Touloudi",fullName:"Antonia Touloudi",slug:"antonia-touloudi",email:"atoul@vet.uth.gr",position:null,institution:null},{id:"156973",title:"Dr.",name:"Liljana",middleName:null,surname:"Petrovska",fullName:"Liljana Petrovska",slug:"liljana-petrovska",email:"Liljana.Petrovska@ahvla.gsi.gov.uk",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Classification ",level:"1"},{id:"sec_3",title:"3. Structure and genome",level:"1"},{id:"sec_4",title:"4. Replication cycle",level:"1"},{id:"sec_5",title:"5. Epidemiology",level:"1"},{id:"sec_6",title:"6. Pathogenesis",level:"1"},{id:"sec_7",title:"7. Immune response",level:"1"},{id:"sec_8",title:"8. Genetic determinants of virulence",level:"1"},{id:"sec_9",title:"9. Conclusions ",level:"1"},{id:"sec_9_2",title:"Acknowledgement",level:"2"}],chapterReferences:[{id:"B1",body:'SmithburnK. CHughesT. PBurkeA. WPaulJ. H1940A Neurotropic Virus Isolated from the Blood of a Native of Uganda. Am. J. Trop. Med. Hyg. s1-20(4):471-92.\n\t\t\t'},{id:"B2",body:'LanciottiR. SRoehrigJ. TDeubelVSmithJParkerMSteeleKet al1999Origin of the West Nile Virus Responsible for an Outbreak of Encephalitis in the Northeastern United StatesScience. 286544823337\n\t\t\t'},{id:"B3",body:'TsaiT. FPopoviciFCernescuCCampbellG. LNedelcuN. 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Alvarez",slug:"miguel-a.-alvarez"},{id:"102395",title:"Dr.",name:"Beatriz",middleName:null,surname:"Del Río",fullName:"Beatriz Del Río",slug:"beatriz-del-rio"},{id:"102398",title:"Dr.",name:"Maria Cruz",middleName:null,surname:"Martin",fullName:"Maria Cruz Martin",slug:"maria-cruz-martin"},{id:"102399",title:"Dr.",name:"Noelia",middleName:null,surname:"Martinez",fullName:"Noelia Martinez",slug:"noelia-martinez"},{id:"102400",title:"Dr.",name:"Victor",middleName:null,surname:"Ladero",fullName:"Victor Ladero",slug:"victor-ladero"},{id:"102402",title:"Dr.",name:"Maria",middleName:null,surname:"Fernandez",fullName:"Maria Fernandez",slug:"maria-fernandez"},{id:"136005",title:"Dr.",name:"Daniel M.",middleName:null,surname:"Linares",fullName:"Daniel M. Linares",slug:"daniel-m.-linares"}]},{id:"32281",title:"Bacteriophages of Bacillus subtilis (natto) and Their Contamination in Natto Factories",slug:"bacteriophages-of-bacillus-subtilis-natto-and-their-contamination-in-natto-factories",signatures:"Toshirou Nagai",authors:[{id:"96136",title:"Dr.",name:"Toshirou",middleName:null,surname:"Nagai",fullName:"Toshirou Nagai",slug:"toshirou-nagai"}]},{id:"32282",title:"Bacteriophages of Ralstonia solanacearum: Their Diversity and Utilization as Biocontrol Agents in Agriculture",slug:"bacteriophages-of-ralstonia-solanacearum-their-diversity-and-utilization-as-biocontrol-agents-in-agr",signatures:"Takashi Yamada",authors:[{id:"98151",title:"Dr.",name:"Takashi",middleName:null,surname:"Yamada",fullName:"Takashi Yamada",slug:"takashi-yamada"}]},{id:"32283",title:"Application of Therapeutic Phages in Medicine",slug:"therapeutic-bacteriophages",signatures:"Sanjay Chhibber and Seema Kumari",authors:[{id:"99550",title:"Prof.",name:"Sanjay",middleName:null,surname:"Chhibber",fullName:"Sanjay Chhibber",slug:"sanjay-chhibber"},{id:"99568",title:"Dr.",name:"Seema",middleName:null,surname:"Kumari",fullName:"Seema Kumari",slug:"seema-kumari"}]},{id:"32284",title:"Successes and Failures of Bacteriophage Treatment of Enterobacteriaceae Infections in the Gastrointestinal Tract of Domestic Animals",slug:"successes-and-failures-of-bacteriophage-treatment-of-enterobacteriaceae-infections-in-the-gastrointe",signatures:"L.R. 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Kurtböke",authors:[{id:"97789",title:"Dr.",name:"İpek",middleName:null,surname:"Kurtböke",fullName:"İpek Kurtböke",slug:"ipek-kurtboke"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"74229",title:"Calculation of the Electronic Properties and Reactivity of Nanoribbons",doi:"10.5772/intechopen.94541",slug:"calculation-of-the-electronic-properties-and-reactivity-of-nanoribbons",body:'\n
\n
1. Introduction
\n
Carbon nanoribbons (CNRs) are strips of graphene whose edges symmetry, width and cut orientation give them specific electronic properties. These carbon nanostructures have attracted the attention in both experimental and theoretical fields because of their peculiar properties, which have been studied widely in the last decade as a function of topology, width, as well as doping. [1, 2, 3, 4, 5] Depending the chain-type along the periodic direction, carbon nanoribbons are commonly classified either armchair carbon nanoribbons (ACNR) when these grow through dimer chains, or zigzag carbon nanoribbons (ZCNR) if those have zigzag type chains along the periodic direction. Figure 1 shows a pristine ACNR and ZCNR respectively, their distances between their C – C edged lengths are 13.44 and 24.19 Å respectively, although there could be named referring their length and width (MxN), in such case, both CNRs shown in Figure 1 are 12x2 size.
\n
Figure 1.
Optimized structure of bare (a) ACNR and (b) ZCNR of size 12x2.
\n
Through different experimental techniques, it is possible to obtain carbon nanoribbons. [6, 7, 8] However, these techniques have not succeeded in controlling the edges shape of carbon nanoribbons. For example, Cai et al. [9] have proposed a chemical technique which is able to synthesize narrow nanoribbons having symmetric edges, so that, it is possible to obtain experimentally carbon nanoribbons with perfect edges and specific topology. To date, succeeding methods to obtain CNRs come from two different strategies, namely, top-down, which refers to break down large performed carbon-base structures, i. e., CNTs and multiwall CNTs (MWCNTs) and bottom-up, i. e., using several chemical reactions to tailor building-blocks into a complex structure. Table 1 shows a comparative chart representing synthetic strategies to obtain CNRs, employed characterization techniques, advantages and disadvantages.
Surface assisted polymerization followed by dehydrogenation in an ultra-high vacuum environment
\n
Defined edge type and narrow widths, potential techniques for scale-up
\n
Depends on the precursor’s nature, which defines the ribbon’s dimension
\n
\n\n
Table 1.
Comparative chart of synthetic methods to obtain nanoribbons and their advantages or disadvantages.
\n
Because of their finite dimension, at nanoscale, CNRs have peculiar properties associated to their electronic states close the edges, playing an important role on the reactivity. [17, 18, 19, 20, 21, 22] Several theoretical models, e. g., tight binding, all electron techniques, density functional theory (DFT), etc., have been applied to explore the electronic properties, magnetic states or band structure of carbon nanoribbons. [1, 5, 23] Some of them, have focused on the zigzag topology because they intrinsically have dangling bonds at the edges. This behavior provides active sites for chemical reactions. Moreover, ZCNRs have peculiar properties, e.g., theoretical calculations have shown that ZCNRs have localized electrons largely on the edge C atoms close to the Fermi level. [4, 22] This large contribution of electronic states forms two-fold degenerate flat band at Fermi level, such that, the ground state has spin coupling of each edge ferromagnetic whereas between edges antiferromagnetic. Despite zigzag edges of synthesized carbon nanoribbons have been observed, [8] there is not direct experimental evidence about the magnetic states of ZCNRs. It was theoretically suggested that magnetism of ZCNR could be destroyed substituting defects or vacancies directly on carbon edges. [24]
\n
On the other hand, all hydrogen-passivated ACNRs are semiconducting [22]. However, ACNRs are expected to reach the graphene limit of zero band gap for sufficiently large widths. [25]
\n
Concerning these fascinating properties, CNRs may fit for promising technological applications, mainly if the presence of donor or acceptor impurities bring specific reactive properties. [26, 27] So that, this chapter is proposed as a guidance to help the readers to apply conceptual density functional theory to calculate helpful intrinsic properties, e. g., energetic, electronic and reactivity of one-dimension nanomaterial’s, such as, carbon nanoribbons in order to predict or tune their properties; particularly when they are substitutional doped.
\n
\n
\n
2. Structural and energetic properties
\n
To give insights about the structural stability of nanostructures, firstly, it is suggested to evaluate if the proposal unit cell may array forming a stable crystalline state. Usually, a structural analysis is carried out computing the cohesive energy per atoms o per unit cell. The cohesive energy (EC) is the energy required to disassemble a molecular system into its constituent parts. From a physical point of view, a bound (stable) system has a positive value of EC, which represents the energy gained during the formation of the bound state. To calculate the EC of ACNRs, it is necessary to obtain the optimized energy of the unit cell being aware of the well converged energy with respect to the k-points and the cutoff energy for the planewave basis set, evaluating the impact of the exchange-correlation functional used and its ability to accurately describe both the atom and bulk phase.
\n
Although EC is a reference to know the stability of bulk materials, it differs from a nanoparticle. [28, 29, 30] At nanoscale, size effects on the cohesive energy of nanoparticles has been demonstrated, which decreases with decreasing the particle size. [31] However, slight differences of EC are found when nuclei radii of constituent are similar, which do difficult to analyze or find a trend, e. g., the effect of the relative position of dopants along the NRs. For example, Table 2 shows the calculated values of EC of armchair carbon nanoribbons (ACNR) doped with boron atoms in randomly (ACNR-R) and forming one B nanoisland (ACNR-I) arrangements compared with those pristine ACNRS of size 16x2, 20x2, 16x2 and 20x4 respectively. [32] The arrangement of the nanoisland (ACNR-I) explained in this section is shown in part (a) of Figure 1 numbering from 1 to 6 the C atoms are substituted for impurities. Note that, B doping slightly reduces the cohesive energy of ACNRs compared with the pristine ones with similar EC values mainly found in the largest B-ACNRs. However, at lower doping concentrations, i. e. in the case of the largest ACNR (20x4) very close values of EC are obtained which makes difficult to observe a trend.
\n
\n
\n
\n
\n
\n\n
\n
MxN
\n
Pristine
\n
ACNR -R
\n
ACNR-I
\n
\n\n\n
\n
16x2
\n
7.224 (0.003)
\n
6.992 (−0.272)
\n
7.003 (−0.291)
\n
\n
\n
20x2
\n
7.338 (0.002)
\n
7.143 (−0.224)
\n
7.158 (−0.239)
\n
\n
\n
16x4
\n
7.225 (0.003)
\n
7.112 (−0.142)
\n
7.116 (−0.147)
\n
\n
\n
20x4
\n
7.338 (0.002)
\n
7.249 (−0.119)
\n
7.250 (−0.130)
\n
\n\n
Table 2.
Cohesive per atom (Gibbs free) energy in eV of pristine and B-doped ACNRs of randomly (ANCR-R) and forming a B-nanoisland (ACNR-I) [32].
\n
Because of these CNRs has 3 different chemical species, EC does not provide a suitable way to evaluate the relative stability. Table 2 also shows in brackets the calculated values of the Gibbs free formation energy to take into account the chemical composition of ACNRs. The relative thermodynamic stability that is considered to evaluate the relative stability of multicomponent systems. This approach has been used in binary and tertiary phase thermodynamics and nanostructures other than NRs. [25, 33, 34] it can be calculated by using the following expression:
where \n\nE\n\nx\n\n\n is the binding energy per atom of the B-ACNR for the example shown in Table 1, \n\n\nx\ni\n\n\n corresponds to the molar fraction of the conformant components (H, N, B, C) which satisfies \n\n\n∑\n\n\nx\ni\n\n=\n1\n\n, where \n\n\nx\ni\n\n=\n\n\nn\ni\n\n\nn\nT\n\n\n\n, being \n\n\nn\ni\n\n\nthe number of atoms of specie i in the unit cell and \n\n\nn\nT\n\n\nthe total number of atoms conforming the unit cell. The chemical potential (\n\n\nμ\ni\n\n\n) can be approximate as the binding energy per atom of the singlet ground state of the H2, the triplet ground state of the B2 molecule and the cohesive energy per atom of the graphene sheet respectively. Note that positive values of \n\nδ\nG\n\n represent a metastable structure with respect to the conforming constituents, whereas negative values of \n\nδ\nG\n\n refer to stable structures in accordance with their constituents. As we can observe in Table 2, \n\nδ\nG\n\n suggests that the arrangement of B-nanoisland leads to stabilize energetically the pristine carbon nanoribbons more than the randomly cases.
\n
\n
\n
3. Electronic properties of nanoribbons
\n
The electronic properties of nanoribbons can be inferred from the band structure and total and local density of states (DOS and LDOS) respectively. For the case of NRs, these calculations are relatively simple because they are computed sampling the Brillouin zone only in one direction, i. e., the grown direction from 0 to gamma point. We recommend to use a denser grid than the case of the total energy calculations, including a Gaussian smearing (of width 0.01 eV) to improve the convergence of the integrals of the energy levels for the band structure calculations, for DOS calculations, to use the tetrahedron method with Blöchl corrections. [35, 36]
\n
Pristine CNRs with hydrogen passivated armchair edges passivated are direct bandgap semiconducting, which decreases as their width increases. The edges of ACNRs play an important role on their electronic properties and reactivity because of quantum confinement gaps, which can be characterized by \n\n\nΔ\n\nN\na\n\n\n~\n\nw\na\n\n−\n1\n\n\n\n. [19, 23, 37]
\n
In order to evaluate the electronic nature of nanoribbons, firstly, spin-polarized and non-spin polarized solutions of the Kohn-Sham equations must be taken into account to evaluate possible magnetic configurations, as found in zigzag carbon nanoribbons, [38] that implies the magnetic state is the most stable. For armchair ribbons, the non-magnetic state is always the most stable [22] even for ACNRs doped with boron atoms, [32] so that, for simplicity, we consider the armchair topology as a case of study.
\n
The electronic behavior of ACNRs can be tuned for the influence of substitutional dopants. To illustrate this fact, we think about a unit cell containing one pristine CNR with even number of electrons of valence. If we replace only one carbon atom (with 4 valence electrons) for B (3 valence electrons) or N (5 valence electrons) such change gives one unit cell with odd number of valence electrons, in such cases is necessary to search for spin polarized solutions of the Kohn Sham equation, i. e, to evaluate if there are significant differences with respect to the non-spin polarized solution.
\n
\nFigure 2 presents the band structure, total density of states and local density of states of dopants (shown in line red) of the 12x2 ACNR pristine, B-doped and N-doped substituting two dopants on positions 3 and 4 using the numbering shown in Figure 1. Note that, the pristine ACNR is a semiconducting in agreement with the literature [22] and the positive doping caused for the B moves the Fermi level (EF) to lower energies meanwhile the negative doping related with the N moves the EF to higher energies with respect to the pristine one. In both cases, the closest energy bands to EF are partially unoccupied and occupied respectively giving rise to metallic behavior in both cases.
\n
Figure 2.
Band structure and DOS of (a) pristine, (b) B-doped and (c) N-doped ACNRs of size 12x2.
\n
\n
\n
4. Reactivity of nanoribbons
\n
In order to explore the reactivity of 1D nanomaterial’s, such as nanoribbons, it is mandatory to use appropriate reactivity descriptor. However, there is not a well stablish criteria to accomplish this task without prior knowing of an adsorption mechanism or experimental evidence, particularly for doped nanoribbons.
\n
This is why, it is suggested the employment of two reactivity descriptors that are able to cover covalent and non-covalent interactions. The first one is the electrostatic potential, defined as:
Where \n\n\nZ\nA\n\n\n and \n\n\nR\nA\n\n\n are the atomic number of nucleus A and its position respectively, \n\n\n\n\nR\nA\n\n−\nr\n\n\n\n is its distance from the point \n\nr\n\n and \n\nρ\n\n\nr\n′\n\n\n\n is the electron density in each volume element. This descriptor provides the response of electron density when a positive unit charge is approaching, which is commonly plotted in a color scheme. Because of the electrostatic potential \n\nV\n\nr\n\n\n, is a local property, it has one value for each \n\nr\n\n point in the space surrounding a molecule or unit cell, so that, depending the nature of the ions (for instance positive or negative nature), the electrostatic potential will depend on the radial distance \n\nr\n\n from the nucleus. Commonly is followed that the contour of the electrostatic potential is plotted on the isovalue of the molecular electron density, for example, see the Bader’s suggestion. [39] Be aware that, the chosen outer electron density contour depends on the Van der Waals radii of involving ions, which should reflect the molecular properties we want to observe, e. g., lone pairs, strained bonds, conjugated π systems, etc.
\n
To illustrate, Figure 3 shows the electrostatic potential of pristine, B-doped and N-doped carbon nanoribbons of size 12x2 plotted on the electron density surface of value 0.001 au, computed by using the generalized gradient approximation (GGA) in the form proposed by Perdew et al. for exchange-correlation functional. Figure 3 was built in the software VESTA [40] plotting the charge file and then, adding the cube file containing the local potential. The color scheme used in Figure 3 represents in blue, regions where a positive charge may repel each other, unlike in red, it represents regions where a positive charge, ion or chemical group can interact.
\n
Figure 3.
Molecular electrostatic potential of the nanoribbons (a) pristine (b) B-doped and (c) N-doped of size 12x2.
\n
We can observe from Figure 3a that, hydrogens are weak positive meanwhile the delocalized charge is distributed along the carbon atoms, particularly found in the edged carbons, which is in agreement with the DOS of pristine ACNRs. The lacking of π electrons of the boron atoms is particularly observed in Figure 3b, which influences over their neighbor carbon atoms finding localized charge in such region. On the other hand, the N doping influences over the edges with more negative electrostatic potential than the pristine carbon nanoribbon.
\n
The second reactivity descriptor is the Fukui or frontier functions (Ffs), helpful chemical reactivity descriptors for process controlled by electron transfer. Ffs were introduced for the first time by Parr and Yang, [41], which is convinced from the area of research so-called conceptual Density Functional Theory given by Geerlings in a comprehensive way. [42] Fukui functions play an important role linking the Molecular Orbital Theory with the HSAB principle, [43] they are defined as the change of the electronic density with respect to number of electrons (N), considering the nuclei position fixed, i.e. constant external potential v(\n\nr\n\n):
Where \n\n\nρ\n\nv\n,\nN\n+\n1\n\n\n\nr\n\n\n, \n\n\nρ\n\nv\n,\nN\n\n\n\nr\n\n\n, and \n\n\nρ\n\nv\n,\nN\n−\n1\n\n\n\nr\n\n\n, are the electronic densities of the system with N + 1, N, and N–1 electrons, respectively, all with the ground state geometry of the N electron system. Expressions 4–6 concern the Fukui function for: nucleophilic attack, the chemical change where a molecule gains an electron; electrophilic attack, when a molecule loses charge; and for free radical attacks. [44]
\n
Although, the finite difference approximation to the Fukui functions works for a specific set of configurations whilst for others is worthless to implement (i.e., full configuration interaction), [45] in most cases they are considered a reliable descriptor to indicate how the electron (incoming or outcoming) is redistributed in regions of the molecules. [46] Chemical reactivity is based on the assumption that, when molecules A and B interact in order to form a product AB, occurs a molecular densities-perturbation. [47] As the electronic density contains all sort of information, the chemical reactivity has to be reflected within its sensitivity to infinitesimal electron changes at constant external potential \n\nv\n\nr\n\n\n. Calculation of the frontier orbitals (HOMO or LUMO) are unambiguously defined. Within the frozen orbital approximation, [48] Ffs can be written in terms of the Kohn-Sham orbitals as follows:
In molecules, the relaxation term is usually very small for the discrete nature of Kohn Sham orbitals. So that, if Eqs. 7 and 8 neglect the second-order variations in the electron density, Ffs may approximate to the electron densities of its frontier orbitals.
\n
On the other hand, referring to periodic systems, it is difficult to identify one frontier state because of the continuous character of the Blöch states, which makes difficult to compute the Fukui functions in DFT of the solid state. Although there is scarcely literature on this topic, a very useful reference for the numerical calculation of the condensed Ffs in periodic boundary conditions within the DFT applied to oxide bulk and surfaces is found here. [49]
\n
One qualitative way to obtain Ffs for delocalized periodic systems, such as, the carbon nanoribbons is to extract its electron density and evaluate it by using the Eq. (7) and (8) respectively. From the electronic structure of these nanomaterials we can observe that only one occupied electronic band contributes below and above the Fermi level.
\n
\nFigure 3 depicts the Ffs evaluated for electrophilic attacks respectively for B-doped and N-doped armchair carbon nanoribbons of size 12x2 with doping made on positions 3 and 4 using the numbering shown in Figure 1.
\n
We observe from Figure 4 that the B atoms contributes to form regions where an electrophilic attack can occur on the doped nanoribbons, i. e. larges values of \n\n\nf\n−\n\n\n mean regions where the ACNR will lose charge to stabilize it in a chemical change.
\n
Figure 4.
Fukui functions for nucleophilic attack of (a) B-doped and (b) N-doped ACNRs of size 12x2.
\n
The electrostatic potential and the Fukui functions provide information on the local selectivity for donor-acceptor interactions. In here, the electrostatic potential describes the long-range non-covalent interactions. [50] The evaluation of the incoming charge distribution on nanoribbons states that “The Fukui function is strong while regions of a molecule are chemically softer than the regions where the Fukui function is weak. By invoking the hard and soft acid and bases (HSAB) principle [51] in a local sense, it is possible to establish the behavior of the different sites as function of hard or soft reagents (adsorbates)”. [32, 52, 53, 54] Figure 4 shows the Fukui functions for electrophilic attack, calculated by using Eq. (8), we observe the contribution of doping particularly on the neighboring carbon atoms. Indeed, from parts (b) and (c) of Figure 2 is observed the electronic states of dopants contributing near the Fermi level.
\n
\n
\n
5. Conclusions
\n
In this chapter is presented how the energetic, electronic and reactivity of can be calculated for 1D nanomaterial’s, such as, carbon nanoribbons. Although the carbon nanoribbons are used as case of study, this methodology can be applied for other kind of chemical compositions, in our experience we have explore the reactivity and stability of doped boron nitride at nanoscale. It is worthy to mention that, the evaluation of Fukui functions in periodic boundary conditions is limited in the usual computational approaches, so that, we suggest to support and compare such analysis with others e. g., charge analysis, global reactivity descriptors depending the nature of the involving chemical species.
\n
\n
Acknowledgments
\n
PNS thanks to CONACYT for grant number 252239 and Cátedras CONACYT for Research Fellow.
\n
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"DFT, band structure, DOS, MEP",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/74229.pdf",chapterXML:"https://mts.intechopen.com/source/xml/74229.xml",downloadPdfUrl:"/chapter/pdf-download/74229",previewPdfUrl:"/chapter/pdf-preview/74229",totalDownloads:74,totalViews:0,totalCrossrefCites:0,dateSubmitted:"August 10th 2020",dateReviewed:"October 19th 2020",datePrePublished:"December 3rd 2020",datePublished:null,dateFinished:"November 27th 2020",readingETA:"0",abstract:"It has been demonstrated that matter at low dimensionality exhibits novel properties, which could be used in promising applications. An effort to understand their behavior is being through the application of computational methods providing strategies to study structures, which present greater experimental challenges. It is proven that thin and narrow carbon-based nanostructures, such as, nanoribbons show promising tunable electronic properties, particularly when they are substitutionally functionalized. This chapter is proposed as a guidance to help the readers to apply conceptual density functional theory to calculate helpful intrinsic properties, e. g., energetic, electronic and reactivity of one-dimension nanomaterial’s, such as, carbon nanoribbons. As a case of study, it is discussed the effect of boron atoms on the properties of pristine carbon nanoribbons concerning the main aspect and considerations must take into account in their computational calculations.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/74229",risUrl:"/chapter/ris/74229",signatures:"Pedro Navarro-Santos, Rafael Herrera-Bucio, Judit Aviña-Verduzco and Jose Luis Rivera",book:{id:"10469",title:"Nanofibers",subtitle:null,fullTitle:"Nanofibers",slug:null,publishedDate:null,bookSignature:"Dr. Brajesh Kumar",coverURL:"https://cdn.intechopen.com/books/images_new/10469.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"176093",title:"Dr.",name:"Brajesh",middleName:null,surname:"Kumar",slug:"brajesh-kumar",fullName:"Brajesh Kumar"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Structural and energetic properties",level:"1"},{id:"sec_3",title:"3. Electronic properties of nanoribbons",level:"1"},{id:"sec_4",title:"4. Reactivity of nanoribbons",level:"1"},{id:"sec_5",title:"5. Conclusions",level:"1"},{id:"sec_6",title:"Acknowledgments",level:"1"},{id:"sec_9",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'\nNakada K, Fujita M, Dresselhaus G, Dresselhaus MS. Edge state in graphene ribbons: Nanometer size effect and edge shape dependence. Phys Rev B. 1996;54(24):17954-17961\n'},{id:"B2",body:'\nMartins TB, Miwa RH, da Silva AJR, Fazzio A. Electronic and Transport Properties of Boron-Doped Graphene Nanoribbons. Phys Rev Lett. 2007;98(19):196803.\n'},{id:"B3",body:'\nJiang D-e, Sumpter BG, Dai S. Unique chemical reactivity of a graphene nanoribbon’s zigzag edge. J Chem Phys. 2007;126(13):-.\n'},{id:"B4",body:'\nYu SS, Zheng WT, Wen QB, Jiang Q. 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Computing the Fukui Function in Solid-State Chemistry: Application to Alkaline Earth Oxides Bulk and Surfaces. The Journal of Physical Chemistry A. 2020;124(14):2826-33.\n'},{id:"B50",body:'\nPolitzer P, Murray JS, Peralta-Inga Z. Molecular surface electrostatic potentials in relation to noncovalent interactions in biological systems. Int J Quantum Chem. 2001;85(6):676-84.\n'},{id:"B51",body:'\nPearson RG. Hard and Soft Acids and Bases. J Am Chem Soc. 1963;85(22):3533-9.\n'},{id:"B52",body:'\nMorales-Palacios FG, Navarro-Santos P, Beiza-Granados L, Rivera JL, García-Gutiérrez HA, Herrera-Bucio R. Conjugate addition between syringol and a captodative olefin catalyzed by BF3. 2019;32(12):e4011.\n'},{id:"B53",body:'\nRivera JL, Navarro-Santos P, Guerra-Gonzalez R, Lima E. Interaction of Refractory Dibenzothiophenes and Polymerizable Structures. International Journal of Polymer Science. 2014;2014:11.\n'},{id:"B54",body:'\nRivera JL, Navarro-Santos P, Hernandez-Gonzalez L, Guerra-Gonzalez R. Reactivity of Alkyldibenzothiophenes Using Theoretical Descriptors. J Chem. 2014;2014:8\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Pedro Navarro-Santos",address:"pnavarrosa@conacyt.mx",affiliation:'
CONACYT-Universidad Michoacana de San Nicolás de Hidalgo, Edif. B-1, Francisco J. Múgica, s/n, Mexico
Instituto de Investigaciones Quimico-Biologicas, Universidad Michoacana de San Nicolás de Hidalgo, Edif. B-1, Francisco J. Múgica, s/n, Mexico
'},{corresp:null,contributorFullName:"Jose Luis Rivera",address:null,affiliation:'
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The Open Access model is applied to all of our publications and is designed to eliminate subscriptions and pay-per-view fees. This approach ensures free, immediate access to full text versions of your research.
As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 118,000 international scientists and researchers.
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The Open Access Publishing Fee (OAPF) is payable only after your full chapter, monograph or Compacts monograph is accepted for publication.
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OAPF Publishing Options
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1,400 GBP Chapter - Edited Volume
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*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
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Services included are:
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An online manuscript tracking system to facilitate your work
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XML Typesetting and pagination - web (PDF, HTML) and print files preparation
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Discoverability - electronic citation and linking via DOI
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Permanent and unrestricted online access to your work
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If your manuscript:
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Exceeds 20 pages (for chapters in Edited Volumes), an additional fee of 40 GBP per page will be required
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If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
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Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
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Open Access Funding
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To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at oapf@intechopen.com for further details or assistance.
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For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
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Added Value of Publishing with IntechOpen
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Indexing and listing across major repositories, see details ...
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Long-term archiving
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Visibility on the world's strongest OA platform
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Live Performance Metrics to track readership and the impact of your chapter
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Dissemination and Promotion
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Benefits of Publishing with IntechOpen
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Proven world leader in Open Access book publishing with over 10 years experience
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+4,800 OA books published
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Optimized processes, enabling publication between 8 and 12 months
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Personal support during every step of the publication process
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+108,170 citations in Web of Science databases
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Currently strongest OA platform with over 130 million downloads
As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 118,000 international scientists and researchers.
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The Open Access Publishing Fee (OAPF) is payable only after your full chapter, monograph or Compacts monograph is accepted for publication.
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OAPF Publishing Options
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1,400 GBP Chapter - Edited Volume
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4,000 GBP Compacts Monograph - Short Form
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*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
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Services included are:
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An online manuscript tracking system to facilitate your work
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Personal contact and support throughout the publishing process from your dedicated Author Service Manager
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Assurance that your manuscript meets the highest publishing standards
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English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
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XML Typesetting and pagination - web (PDF, HTML) and print files preparation
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Discoverability - electronic citation and linking via DOI
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Permanent and unrestricted online access to your work
What isn't covered by the Open Access Publishing Fee?
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Exceeds 20 pages (for chapters in Edited Volumes), an additional fee of 40 GBP per page will be required
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If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
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Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
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Open Access Funding
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To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at oapf@intechopen.com for further details or assistance.
\n\n
For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
\n\n
Added Value of Publishing with IntechOpen
\n\n
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Indexing and listing across major repositories, see details ...
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Long-term archiving
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Visibility on the world's strongest OA platform
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Live Performance Metrics to track readership and the impact of your chapter
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Dissemination and Promotion
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Benefits of Publishing with IntechOpen
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Proven world leader in Open Access book publishing with over 10 years experience
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+4,800 OA books published
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Most competitive prices in the market
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Fully compliant with OA funding requirements
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Optimized processes, enabling publication between 8 and 12 months
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Personal support during every step of the publication process
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+108,170 citations in Web of Science databases
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Currently strongest OA platform with over 130 million downloads
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