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Schneider, L. Häussler and S.V. Roth",authors:[{id:"120781",title:"Dr.",name:"Konrad",middleName:null,surname:"Schneider",fullName:"Konrad Schneider",slug:"konrad-schneider"}]},{id:"37253",title:"Structure of Polypropylene Fibres Coloured with Organic Pigments",slug:"structure-of-polypropylene-fibres-coloured-with-organic-pigments",totalDownloads:3033,totalCrossrefCites:0,signatures:"Jan Broda",authors:[{id:"104226",title:"Prof.",name:"Jan",middleName:null,surname:"Broda",fullName:"Jan Broda",slug:"jan-broda"}]}]},relatedBooks:[{type:"book",id:"3043",title:"New Polymers for Special Applications",subtitle:null,isOpenForSubmission:!1,hash:"dd782fff3bea8992c224dfd3280d6cd1",slug:"new-polymers-for-special-applications",bookSignature:"Ailton De Souza Gomes",coverURL:"https://cdn.intechopen.com/books/images_new/3043.jpg",editedByType:"Edited by",editors:[{id:"135416",title:"Dr.",name:"Ailton",surname:"De Souza Gomes",slug:"ailton-de-souza-gomes",fullName:"Ailton De Souza Gomes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"38960",title:"Conducting Polymers Application",slug:"conducting-polymers-application",signatures:"Kareema Majeed Ziadan",authors:[{id:"142196",title:"Prof.",name:"Kareema",middleName:"Majeed",surname:"Zaidan",fullName:"Kareema Zaidan",slug:"kareema-zaidan"}]},{id:"38963",title:"Hydrogel Films on Optical Fiber Core: Properties, Challenges, and Prospects for Future Applications",slug:"hydrogel-films-on-optical-fiber-core-properties-challenges-and-prospects-for-future-applications",signatures:"Sergey V. Kazakov",authors:[{id:"143029",title:"Prof.",name:"Sergey",middleName:null,surname:"Kazakov",fullName:"Sergey Kazakov",slug:"sergey-kazakov"}]},{id:"38964",title:"Microwave Absorption and EMI Shielding Behavior of Nanocomposites Based on Intrinsically Conducting Polymers, Graphene and Carbon Nanotubes",slug:"microwave-absorption-and-emi-shielding-behavior-of-nanocomposites-based-on-intrinsically-conducting-",signatures:"Parveen Saini and Manju Arora",authors:[{id:"149897",title:"Dr.",name:"Parveen",middleName:null,surname:"Saini",fullName:"Parveen Saini",slug:"parveen-saini"},{id:"156193",title:"Dr.",name:"Manju",middleName:null,surname:"Arora",fullName:"Manju Arora",slug:"manju-arora"}]},{id:"38962",title:"Polymerization of Thin Film Polymers",slug:"polymerization-of-thin-film-polymers",signatures:"Markus Woehrmann and Michael Toepper",authors:[{id:"140469",title:"M.Sc.",name:"Markus",middleName:null,surname:"Woehrmann",fullName:"Markus Woehrmann",slug:"markus-woehrmann"},{id:"142641",title:"Dr.",name:"Michael",middleName:null,surname:"Toepper",fullName:"Michael Toepper",slug:"michael-toepper"}]},{id:"38958",title:"New Polymer Networks for PDLC Films Application",slug:"new-polymer-networks-for-pdlc-films-application",signatures:"Ana Isabel Mouquinho, Krasimira Petrova, Maria Teresa Barros and João Sotomayor",authors:[{id:"35978",title:"Prof.",name:"Maria Teresa",middleName:null,surname:"Barros",fullName:"Maria Teresa Barros",slug:"maria-teresa-barros"},{id:"54274",title:"Dr.",name:"Krasimira",middleName:null,surname:"Petrova",fullName:"Krasimira Petrova",slug:"krasimira-petrova"},{id:"122246",title:"Prof.",name:"Joao",middleName:null,surname:"Sotomayor",fullName:"Joao Sotomayor",slug:"joao-sotomayor"},{id:"142973",title:"MSc.",name:"Ana Isabel",middleName:null,surname:"Mouquinho",fullName:"Ana Isabel Mouquinho",slug:"ana-isabel-mouquinho"}]},{id:"38954",title:"Photopolymers for Use as Holographic Media",slug:"photopolymers-for-use-as-holographic-media",signatures:"Michael R. Gleeson, Jinxin Guo and John T. Sheridan",authors:[{id:"139817",title:"Dr.",name:"Michael R.",middleName:null,surname:"Gleeson",fullName:"Michael R. Gleeson",slug:"michael-r.-gleeson"}]},{id:"38956",title:"From Ruthenium Complexes to Novel Functional Nanocomposites: Development and Perspectives",slug:"from-ruthenium-complexes-to-novel-functional-nanocomposites-development-and-perspectives",signatures:"Karen Segala and Angela S. Pereira",authors:[{id:"142258",title:"PhD.",name:"Karen",middleName:null,surname:"Segala",fullName:"Karen Segala",slug:"karen-segala"},{id:"143174",title:"Dr.",name:"Angela",middleName:null,surname:"Pereira",fullName:"Angela Pereira",slug:"angela-pereira"}]},{id:"38961",title:"Bulk Preparation of Radiation Crosslinking Poly (Urethane-Imide)",slug:"bulk-preparation-of-radiation-crosslinking-poly-urethane-imide-",signatures:"Chengfei Zhou",authors:[{id:"141573",title:"Prof.",name:"Zhou",middleName:null,surname:"Chengfei",fullName:"Zhou Chengfei",slug:"zhou-chengfei"}]},{id:"38965",title:"Oxidative Polymerization of Aniline: Molecular Synthesis of Polyaniline and the Formation of Supramolecular Structures",slug:"oxidative-polymerization-of-aniline-molecular-synthesis-of-polyaniline-and-the-formation-of-supramol",signatures:"I.Yu. Sapurina and M.A. Shishov",authors:[{id:"149374",title:"Dr.",name:"Irina",middleName:"Yurievna",surname:"Sapurina",fullName:"Irina Sapurina",slug:"irina-sapurina"}]},{id:"38957",title:"Nitrogen-Rich Polymers as Candidates for Energetic Applications",slug:"nitrogen-rich-polymers-as-candidates-for-energetic-applications",signatures:"Eric Pasquinet",authors:[{id:"146467",title:"Dr.",name:"Eric",middleName:null,surname:"Pasquinet",fullName:"Eric Pasquinet",slug:"eric-pasquinet"}]},{id:"38955",title:"Electroreductive Synthesis of Polysilanes with Ordered Sequences",slug:"electroreductive-synthesis-of-polysilanes-with-ordered-sequences",signatures:"Manabu Ishifune",authors:[{id:"141447",title:"Dr.",name:"Manabu",middleName:null,surname:"Ishifune",fullName:"Manabu Ishifune",slug:"manabu-ishifune"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"56811",title:"Use, Applications and Mechanisms of Intracellular Actions of Camelid VHHs",doi:"10.5772/intechopen.70495",slug:"use-applications-and-mechanisms-of-intracellular-actions-of-camelid-vhhs",body:'In 1993, Hamers-Casterman discovered the presence of heavy-chain-only antibodies in the sera of Camelidae and assessed that these antibodies are still capable of recognizing an extensive repertoire of antigens despite the absence of the light chain. Single-domain antibodies from camels are called nanobodies. They stated that this discovery could be of inestimable value to the development and engineering of soluble VH domains or new immunological molecules for diagnostic, therapeutic, and biochemical purposes [1]. This discovery gave rise to a whole new research field in which single-domain antibodies are used for a wide range of applications. Some of these will be reviewed in the current chapter.
The structural properties of conventional IgG antibodies are well known. These consist of two heavy-chain polypeptides and two light-chain polypeptides, each of which is folded into four and two domains, respectively. A variable domain is situated at the N-terminus of both chains (VH and VL) and, as the name suggests, its sequence diverges between IgG antibodies. Paired VH-VL domains make up the variable fragment (Fab) and are responsible for the recognition and binding of the target antigen. The sequence of the other domains is well conserved between IgGs, which led to the designation of these domains as constant domains. Heavy-chain-only antibodies differ from conventional IgG antibodies by the lack of a light-chain polypeptide and the first constant domain of the heavy-chain polypeptide (CH1). Consequently, the antigen-binding fragment of heavy-chain antibodies from camels consists of one single domain, termed the VHH domain. This unit forms the functional and structural equivalent of the Fab in conventional IgG antibodies [2]. The smallest antibody fragment that can be produced from conventional IgG antibodies is a short-chain variable fragment (ScFv, ±27 kDa), which consists of a VH and VL domain linked via a polypeptide. In the continuous search for smaller antibody formats, HCAbs were a thrilling novelty, because their discovery allowed researchers to produce an even smaller antibody fragment of only ±15 kDa. This antibody format derived from camels consists of an isolated VHH domain also known as a single-domain antibody or a nanobody (Nb) (Figure 1). In addition, human single-domain antibodies VH and VL have been engineered from human conventional antibodies [3, 4, 5], and sharks develop heavy-chain-only antibodies (HCAbs) too [6].
Schematic representation of a conventional IgG antibody and a camelid heavy-chain-only antibody (HCAb). For both antibody formats, the smallest producible antibody fragment is depicted: a short-chain variable fragment (ScFv, ±27 kDa) and a nanobody (Nb, ±15 kDa), respectively.
The structural features of nanobodies are quite similar to those of the variable domain of conventional IgGs. The core structure of the immunoglobulin domain is formed by four framework regions (FR), whereas antigen binding occurs through three complementarity-determining regions (CDRs). The latter are located in loops in between β-strands that form the variable immunoglobulin domain. Importantly, FR2 of the VHH domain often contains amino acid substitutions of residues that are involved in hydrophobic interactions between the VH and the VL domains of conventional IgGs (V37 → F/Y, G44 → E/Q, L45 → R, and W47 → G/F/L; Kabat numbering). These substitutions lie at the heart of the single-domain nature of nanobodies because they reduce the hydrophobicity of the former VL interface and improve the nonstickiness of the domain. There are other examples of amino acid substitutions that frequently take place, but these appear to be of less importance [7, 8]. Since nanobodies only consist of one domain, one might wonder whether nanobodies have a diverse antibody repertoire. After all, they lack the VH-VL combinatorial diversity in the antigen-binding site. Nanobodies have counterbalanced the absence of the three hypervariable loops of the VL domain by an extension of the hypervariable loops in the VHH domain. These loops show substantial variation in both conformation and length compared with the corresponding loops of the VH domain. This implies that a larger structural repertoire and thus a sufficient diversification in antigen-binding sites can be obtained [9]. More specifically, the introduction of additional Cys residues in the CDRs creates extra disulfide bridges within the VHH domain, and these are in part responsible for the diversification of the structural repertoire. The disulfide bridges crosslink the antigen-binding loops, resulting not only in the stabilization of the domain but also in the induction of constraints in CDR1 or CDR3. These constraints probably lead to novel loop conformations and thus in an increase in paratope repertoire. Furthermore, VHHs are more prone to insertion and deletion events near or within the paratope compared to VHs. This is translated into an increase of the surface area of the hypervariable regions and contributes to the structural variation [10].
Several monoclonal antibodies (mAbs) have already been approved for clinical use [11], but some limitations are still present despite their success. This includes their large size, relative instability, which imposes restrictions on the administration route and their relative expense of manufacturing. The potential of nanobodies as a therapeutic agent was rapidly recognized as they overcome some of the aforementioned limitations of mAbs. The small size of nanobodies in combination with their extended CDR loops allows them to bind into clefts and cavities, whereas mAbs preferably recognize flat and concave surfaces. Many biological interactions take place in clefts, and nanobodies can target these otherwise inaccessible surfaces and thus function as neutralizing agents or antagonists of protein-protein interactions. More specifically, this property is advantageous when it comes to therapeutically targeting infectious diseases since the essential epitopes of pathogens are often hidden. When cancer has to be targeted, the small size permits a better tissue penetration and thus a significant improvement of the effective antibody concentrations that can be reached in solid tumors. Unfortunately, this advantageous property comes with a price. The small size of nanobodies results in their rapid clearance from the human body and thus in a limited in vivo half-life (a few hours). Therefore, nanobodies are often linked to a serum albumin-binding monomer to prolong serum half-life. The monomeric nature of nanobodies simplifies antibody engineering. For instance, nanobodies can be assembled into multimers, thereby increasing their potency due to avidity effects. The development of therapy resistance can also be curbed by creating bispecific nanobodies. The creation of a targeted drug delivery vehicle is also possible, since nanobodies can easily be linked with drugs [12, 13, 14, 15, 16, 17]. Additionally, the outstanding stability of nanobodies under extreme conditions opens the possibility to more patient-friendly routes of administration. In general, mAbs are administered via injections, but due to the extraordinary stability of nanobodies, they can be administered orally, topically, and even via inhalation [15, 18, 19]. The cost of nanobody production lies several times below those of mAb production. The fact that nanobodies are efficiently produced in microbial systems keeps the expenses low. Considering the fact that immunotherapy involves administration of relatively high doses of antibody during prolonged periods, this is a factor that should not be underestimated [7, 8, 20]. Currently, there are no nanobody-based products approved as therapeutic agent, but several products are in the pipeline or in advanced clinical trials. Their value in treating envenoming [21], infections [22], amyloidosis [23, 24], cancer, and other pathologies [25, 26] has already been proven. The research concerning the use of nanobodies as a therapeutic agent is mainly performed on extracellular targets. Nonetheless, nanobodies can also aid in identifying intracellular targets since they directly target a resident, endogenous protein, similar to how a conventional drug acts. RNAi-based approaches rather eradicate, or at least downregulate, expression which is quite different from the mode of action of an average drug. Hence, caution is warranted when making predictions regarding the therapeutic value of a given protein target using this approach. Moreover, nanobodies retain their functionality in the reducing intracellular environment. The major stumbling block toward a successful clinical implementation however is their inability to traverse the cell membrane. For that reason, most experiments are limited to cell cultures and transgenic animals. In the following paragraph, the use of nanobodies to target intracellular proteins with possible therapeutic implications will be described.
About 500 million people worldwide are chronically infected with hepatitis B virus or hepatitis C virus (HBV or HCV). Infection induces an acute and chronic inflammatory liver disease, which puts the patient at risk of developing liver cirrhosis and possibly hepatocellular carcinoma. Currently, there is no vaccine available against HCV, and there is also no cure for most people who are already infected with HBV [27]. Initially, therapy existed of a strict and intensive treatment with ribavirin and PEGylated interferon. This regimen was however associated with severe side effects [28], emphasizing the importance of further research into the pathogenesis of the viruses and how they evade our immune systems. Extensive research led to the discovery of direct-acting antivirals (DAAs), which are small compounds targeted against viral enzymes. The second-generation DAAs are highly potent in treatment, show less side effects, and have a less intensive treatment regimen [29]. However, during infection a large number of viral variants are continuously produced, resulting in the presence of quasi species within the patient. This heterogeneity implies that not all therapeutic agents will be equally effective and that drug resistance may develop. Therefore, the search for other therapeutics remains useful. Sarrazin et al. mention that compounds targeting a more conserved region of viral proteins have a better chance of efficacy. Importantly, compounds targeting the active site of the viral polymerase show a high barrier to the development of resistance, due to the fact that mutations at this site often result in loss of polymerase function [30]. As stated previously, nanobodies can bind epitopes localized in clefts, like the active site of an enzyme, and thus are perfect candidates for antiviral drug development.
The potency of nanobodies for counteracting HCV infection has been evaluated. Several nonstructural HCV proteins have been targeted via nanobodies: NS5B, NS3, NS4A, and NS4B [28, 31, 32, 33]. NS5B functions as an RNA-dependent RNA polymerase. NS3 has a dual function and displays serine protease activity in its N-terminal region and helicase activity in its C-terminal region. The helicase is involved in the replication of the viral genome and is also thought to increase the translational efficiency of the polyprotein by melting highly stable secondary structures in the HCV RNA [34]. The N-terminal serine protease domain is, together with NS4A, involved in downstream processing of the HCV polyprotein with the formation of mature proteins [32]. NS4B plays a major role in HCV replication by inducing an ER membrane web on which HCV replication takes place [31]. Nanobodies against the different nonstructural proteins were obtained via screening of a VH/VHH library constructed from peripheral blood mononuclear cells of an 8-month-old naïve male dromedary. Recombinant nanobodies reduced NS5B activity by two-thirds (ELISA) [28], and NS3 helicase activity was inhibited up to 88–100% in the presence of the nanobodies, depending on the assay used [33]. Cell-based assays were performed on Huh7 cells (human hepatoma cell line) transfected with RNA (genomic replicon of heterologous HCV). The nanobodies also led to a significant reduction of HCV RNA levels in Huh7 cells transfected with the JFH1 genotype 2a strain, both inside the cells as in the culture medium, when compared to control conditions. Overall, the nanobodies were capable of eliciting responses of a magnitude similar as seen for conventional therapeutic strategies (ribavirin + PEGylated interferon or telaprevir) [28, 31, 32, 33]. Furthermore, treatment of cells with the nanobodies against NS3/NS4A and NS4B induced the expression of genes involved in the innate immune response (IRF3, IL28-B, and IFN-β). This is interesting because the innate immune response signaling is interrupted by the virus [31, 32]. In general, these studies lack a detailed insight into the molecular mechanisms behind the observed effects. The authors used computerized modeling to make an assumption about which epitopes are recognized by the nanobodies. Crystallization studies would allow a more detailed view and could help to resolve remaining questions. Even more, the crystal structures could lay the foundation for small molecule development and thus be invaluable. The nanobodies certainly have potential, but there are some remaining questions that need to be resolved before continuing with animal experiments.
As mentioned earlier, currently the biggest obstacle for using nanobodies as a therapeutic against intracellular targets is their inability to traverse cellular membranes. In the aforementioned articles, it was reported that coupling the nanobody with a cell-penetrating peptide (penetratin) seemingly promoted cellular uptake of the nanobody with efficiencies of roughly 80% [28]. However, some caution is warranted here, since the mechanisms behind the internalization of CPPs are still a matter of debate. Even more, in the highly cited article of Richard et al., it has been shown that experiments used to detect the occurrence of CPP internalization are sensitive to artifacts. It appeared that even mild fixation protocols used for fluorescence imaging can induce an artifactual redistribution of these peptides in the nucleus. Furthermore, the highly cationic nature of, for example, penetratin peptides lead to their strong binding to the overall negatively charged plasma membrane [35]. It is thus of crucial importance to remove membrane-bound peptide before analyzing cellular uptake of the construct. Initially, it was thought that CPPs allowed the delivery of biomolecules without relying on endocytosis. Adaptations of the used protocols, however, gave rise to data supporting an active process of cellular internalization involving endocytosis. Applications with CPPs and the controversial issues regarding their internalization mechanisms are elaborately reviewed and will not be discussed in detail [36, 37]. Internalization via endocytosis is however associated with a major drawback, since the delivered biomolecule needs to escape from the endosomal vesicles before it traffics back to the plasma membrane for recycling or it fuses with lysosomes. This might strongly limit the bioavailability of the compound, thus curbing its efficacy. Finally, the nonspecificity of CPP-conjugated constructs imposes a risk of drug-induced toxic effects on normal tissues [37]. In conclusion, a meticulous evaluation of intracellular uptake of the bioactive molecule and of possible toxic effects on normal tissues is warranted, before taking any further steps in its development as a therapeutic agent.
The genome of hepatitis B virus (HBV) is translated into HBV surface proteins, polymerase protein, X protein, or core and pre-core proteins [38]. Targeting the hepatitis B surface antigen (HBsAg) and the hepatitis B core antigen (HBcAg) with antiviral drugs to, respectively, reduce viral secretion and replication is a feasible strategy. HBsAg is the major component of the viral envelope. HBcAg, on the other hand, is the structural unit of the nucleocapsid that encloses the viral genome within a viral particle [38, 39].
To obtain nanobodies against the aforementioned proteins, a llama was immunized with recombinant HBcAg and HbsAg. The peripheral blood cells and cervical lymph node cells were used to construct a VHH library. Both immune and naïve libraries are good sources for retrieving antigen-specific binders. However, in general, superior binding affinities are observed for nanobodies originating from immune libraries, since they were subjected to in vivo affinity maturation. On the other hand, naïve libraries offer an elegant solution for those cases where immunization is difficult due to the lack of an antigen, low immunogenicity, or toxic antigens [39]. The nanobodies against HBsAg were cloned in frame with an ER-targeting signal and an ER retention signal. Co-transfection of these nanobodies and a HBV-expressing plasmid in HepG2 cells induced the intracellular accumulation of HBsAg and caused a reduction of HbsAg particle secretion of approximately 80–90%. The in vivo potential of the HBsAg nanobodies was examined in a SCID mouse. The mouse model for HBV infection was created using a hydrodynamics-based transfection method. Remarkably, measured HBsAg levels in the plasma decline in the presence of the nanobody, and this reduction goes hand in hand with an increase in intracellular HBsAg levels. This observation implies that less virions are secreted. The researchers assume that the observed effects are either due to the disruption of the interaction between the nucleocapsid and the S-type of viral membrane proteins or due to the prevention of the interaction between individual proteins in the ER [40].
The current anti-HIV treatment strategy, known as highly active antiretroviral therapy (HAART), has changed the field and has turned HIV into a chronic manageable disease. However, patients are lifelong bound to this regimen, its associated side effects, and drug-drug interactions. Sometimes, treatment fails due to multidrug resistance which warrants research for alternative drugs [41]. Nanobodies could serve as a useful purpose in the treatment of HIV infection and have been successfully raised against Rev and Nef. Rev is involved in the nuclear export of late viral mRNA to the cytoplasm. Rev multimers form a higher affinity complex with RRE (Rev-response element), and this affinity is a determining factor for the efficiency of RNA export [42, 43]. The idea of targeting Nef with antivirals came from the observation that a limited amount of patients, infected with Nef-deleted HIV, presented a lack of disease progression. The Nef protein exerts multiple functions: CD4 downregulation, major histocompatibility complex downregulation (MHC1), activation of p21-activated protein kinase (pak2), and enhancement of virion infectivity. These functions can be targeted each independently from one another since the activities are genetically separable. Interfering with Nefs’ capacity to downregulate CD4 appears to be the most effective strategy [44].
Vercruysse et al. produced nanobodies against the N-terminal multimerization domain of Rev, because its ability to form multimers is essential for its function. One nanobody is capable of efficiently inhibiting Rev multimerization in cell-based assays. The nanobody induces a cytoplasmic delocalization of Rev. that is similar to that observed for Rev mutants incapable of multimerization. In addition, the nanobody is able to suppress the Rev-dependent expression of late viral mRNAs and consequently also de novo virus production [42]. Further experiments were performed to elucidate whether the nanobody displays a broad-spectrum anti-HIV activity. This was examined by infecting several cell lines, expressing the nanobody in a stable manner, with different HIV-1 subtypes. Virus replication was monitored 5 days post infection by measuring cytopathogenic effects and the presence of virus-associated p24 levels in the supernatant. The nanobody strongly reduced p24 levels for infected cells compared to a control nanobody. More specifically, p24 levels were reduced by >10 folds for subtype A, > 100 folds for subtypes C and G, and >10,000 folds for subtypes B, D, and H [45]. The cells proved to be resistant to viral replication and survived infection. These results are relevant, considering the fact that subtypes A, B, and C are the most prevalent genetic forms on a global scale [46].
Bouchet et al. picked Nef, a HIV-1 nonstructural protein, as target for antiviral therapy. Using cell-based assays and in vivo assays, it was established that the Nef-specific nanobody efficiently counteracted Nef-induced CD4 downregulation and p21-activated protein kinase (pak2) activation. The functional effects of the nanobody are thought to result from its interference with the interaction between Nef and other cellular partners [47]. Nef-induced CD4 downregulation in infected cells is important to prevent interaction between the envelope protein (Env) of the budding virion and CD4 of the host cell, since this interaction might impede the formation of fully infectious particles [44]. The nanobody is capable of reducing the rate of Nef-induced CD4 internalization back to levels measured in uninfected cells. The biological relevance of this observation was tested in a mouse model (CD4+/HIV Nef Tg mouse) that presents a downregulation of cell surface CD4, an altered thymic CD4 T-cell development, and a profound peripheral CD4 T-cell depletion. The nanobody rescued the Nef-mediated thymic CD4+ T-cell maturation defect and reversed the downregulation of cell surface CD4 in vivo. T-cell receptor signaling normally leads to profound actin cytoskeleton rearrangements. The Nef-pak2 complex, however, halts these rearrangements by deregulating cofilin, an actin-severing factor. Actin polymerization in infected T cells is thus strongly disturbed. The nanobody disrupts the Nef-Pak2 complex and counteracts as such the inhibition of actin remodeling in a dose-dependent manner. Finally, it was also observed that the inhibition of specific Nef functions by the nanobody resulted in the reduction of virus infectivity of new progeny virions by 80% (molar ratio of 1:1) [47].
Current HAART targets four different steps in the HIV-1 replication circle: the conversion of viral genomic RNA into dsDNA, the maturation of budding viral particles, the entry of the virus into new target cells, and the insertion of viral DNA into a host cell chromosome. Although current strategy is effective, it remains important to explore novel treatment strategies. The development of compounds that inhibit less explored drug targets would be of benefit, and structural biology can aid in defining new drug targets [48]. Nanobodies targeted against both Rev. and Nef appear to have pronounced effects on pathogeny of HIV-1. Crystallization studies to elucidate the exact binding epitopes for both nanobodies are thus of paramount importance since they could aid in new small compound design.
There exists a multitude of antimicrobial drugs, but compounds capable of neutralizing the produced toxins are often lacking. The question whether or not antibodies hold great potential as toxin-neutralizing agents has been investigated by several researchers. Examples of studies where monoclonal antibodies are used as antitoxins are listed in the review of Chow et al. [49]. Several researchers have exploited nanobodies as a means to neutralize toxins. Intrabodies have been employed to counteract following toxins: ricin, Salmonella SpvB protein, and botulinum neurotoxin.
Ricin is a naturally occurring toxin derived from the castor bean plant and a well-known type 2 ribosome-inactivating protein. It achieves an inhibition of eukaryotic ribosomes by the depurination of a specific adenine in the 28S ribosome resulting in cell death. Exposure might be lethal, and unfortunately current treatments are mainly of a symptomatic and supportive nature [50]. Herrera et al. constructed a bispecific nanobody, named JJX12, consisting of a VHH targeted against the enzymatic subunit of ricin coupled with a VHH targeted against the galactose-binding subunit [51]. JJX12 fully protects mice against a ricin challenge (molar ratio of 4:1). The protective effects observed for the bispecific construct are superior to those observed for an equimolar mixture of the nanobodies and are the result of both extracellular and intracellular effects. JJX12 promotes aggregation of ricin in solution and makes cell-bound ricin-JJX12 complexes more resistant to dissociation as shown by ricin competition assays with lactose [51]. In the presence of these complexes, further ricin binding to the cell surface is reduced by shielding cell surface receptors for the galactose-binding subunit of ricin [52]. The presence of aggregates changes the internalization and intracellular trafficking of ricin. Internalization of the aggregates occurs via a macropinocytosis-like mechanism rather than via receptor-mediated clathrin-dependent and clathrin-independent endocytosis, which is normally observed for ricin. Furthermore, biochemical and live cell imaging techniques showed a 54% reduction of the retrograde transport of ricin to the trans-Golgi network and the accumulation of ricin in late endosomes in the presence of JJX12, which probably targets ricin for degradation [51].
Salmonella bacteria are Gram-negative enterobacteria associated with human enteric fever. The systemic virulence of the bacterium is largely dependent on the SpvB gene, encoding an actin ADP-ribosylating toxin that is secreted into the host cell cytosol. The toxin interferes with actin polymerization resulting in apoptotic cell death. Nanobodies targeted against the SpvB protein are capable of blocking its enzymatic and cytopathic effects. By means of in vitro radioactivity and fluorescence assays, it was demonstrated that the nanobody completely rescues actin polymerization from the inhibitory effects of the SpvB toxin at a molar ratio of 1:1. Cell-based assays, performed on RAW macrophages and Vero cells, confirmed these observations, since cells exposed to the toxin presented no signs of cell rounding or actin cytoskeleton disintegration in the presence of the nanobody [53].
Botulinum neurotoxins (BoNTs) produced by the Gram-positive bacterium Clostridium botulinum can cause flaccid paralysis in humans, which can last for several months. The toxins deliver their light chain, possessing a protease function, to the motor neurons. The protease cleaves SNARE proteins and as such prevents the release of acetylcholine from presynaptic nerve terminals at the neuromuscular junction causing a neuromuscular blockade [54, 55]. Two different strategies were used to suppress botulinum neurotoxin intoxication. Tremblay et al. investigated the potential of using nanobodies as a protease inhibitor per se [55], whereas Kuo et al. implemented the nanobody as a part of a targeted F-box agent to induce accelerated degradation of the protease [54]. A nanobody with nanomolar affinity (Kd ̴ 1 nM) for the light chain of BoNT serotype A (A-Lc) was used for both strategies. Serotype A is associated with the longest persistence and is thus most relevant for therapeutic intervention. The nanobody allows a near stoichiometric inhibition of BoNT-A function as shown by an in vitro FRET-based SNAP25 cleavage assay [55]. The production of cells expressing the nanobody in a stable manner could offer an elegant solution to problems associated with transient transfection techniques and was consequently implemented in the studies performed with the targeted F-box reagent.
Kuo et al. made a fusion protein between a nanobody and a truncated F-Box protein (TrCP) that is capable of associating with Skp1 and Cullin1, with the formation of the SCF complex. This complex, called targeted F-box (TFB), functions as an E3 ubiquitin ligase, thus targeting BoNT proteases for proteasomal degradation. Two constructs were made in which a nanobody targeted against either A-Lc or B-Lc was incorporated. The TFB fusion proteins reduce A-Lc and B-Lc levels with 65 and 50%, respectively (capture ELISA experiments), and decrease the half-life of the A-Lc protease (from ̴3.7 to ̴1.5 days). Application of MG132, a proteasome inhibitor, results in the accumulation of poly-ubiquitinylated BoNT protease and eliminates the effect of the TFB fusion proteins on its steady-state levels. This indicates that the observed effects are due to the increased degradation of the BoNT protease. Furthermore, in the presence of the TFB fusion proteins, cells are less sensitive to BoNT-A intoxication and also recover 2.5 times faster [54].
Proteins exert crucial roles in a variety of cellular processes. Each of these proteins has to adopt its native tridimensional structure to acquire the functional biological state and thus to act faultlessly. However, sometimes proteins fail to either fold correctly or to maintain the native state due to the presence of mutations or increased protein levels. When these proteins escape the inherent quality control systems, serious diseases can develop. These disorders can be characterized by the deposition of misfolded peptides or proteins in the nervous system or other tissues and organs resulting in pathological and insoluble aggregates.
Preventive and curative treatments are often lacking. These therapeutic approaches are feasible when using nanobodies as a tool: increasing the stability of the correctly folded proteins, neutralization of toxic protein/peptide species, and inhibiting or reversing the aggregation of misfolded proteins into oligomers or fibrils [56]. Several research groups have already exploited the use of nanobodies for targeting protein misfolding diseases [57, 58, 59]; however, most of the time, they aim at extracellular targets. We will focus on the intracellular application of nanobodies.
Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disease characterized by an extended N-terminal poly-alanine stretch of polyadenylate-binding protein nuclear 1 (PABPN1). The poly-alanine stretch is extended from 10 to 12–17 alanines. The mutant protein forms aggregates in skeletal muscles, and this phenomenon is, at least in part, responsible for the disease, although the exact pathological mechanisms are still poorly understood. PABPN1 is a multifunctional protein and is involved in pre-mRNA polyadenylation, transcription regulation, and mRNA nucleocytoplasmic transport [56].
Verheesen et al. screened a nonimmune VHH library for PABPN1-selective binders. Panning yielded six nanobodies with affinities ranging between 5 and 57 nM. Initial experiments were performed with nanobody 3F5 (Kd = 5 nM), which binds PABPN1 at its N-terminal coiled-coiled domain. Co-transfection of mutant PABPN1 and nuclear targeted 3F5 (3F5-NLS) in HeLa and COS cells showed a dose-dependent reduction in the formation of aggregates (37% → 10% in HeLa cells, P < 0.01). The expression of the nanobody neither induces cytotoxic effects (MTT assay) nor has any effects on mutant PABPN1 expression levels [60]. A more in-depth analysis on how the formation of intranuclear inclusions is prevented revealed that the nanobody reduces the formation of oligomers of mutant PABPN1 but not of insoluble aggregates [61]. The in vivo efficiency of the six nanobodies was tested in a Drosophila model of OPMD in which the expression of mutant PABN1 and the nuclear targeted nanobodies is induced with the muscle-specific driver Mhc-Gal4. Nanobody 3F5-NLS showed the best in vivo efficacy and alleviated several symptoms of OPMD in the Drosophila model, including prevention of degenerative effects on flight muscles and the restoration of muscle fiber ultrastructure (Z and M bands). Transcriptome analysis performed to evaluate thorax gene expression patterns demonstrated that 3F5-NLS induced a partial or complete rescue of 58% of the genes deregulated by the presence of mutant PABPN1. These effects are the strongest in the early stages (day 2 after induction) but persist during the life span [62].
Gelsolin amyloidosis is an autosomal dominant disease for which currently only symptomatic treatment strategies exist. A point mutation in the GSN gene (G654 A/T) is responsible for the incorrect folding of the secondary domain of mutant gelsolin (D187 N/Y) that adopts a protease-sensitive conformational state. A pathological proteolytic cascade involving furin and MT1-MMP like proteases leads to the secretion of amyloidogenic 8 and 5 kDa peptides in the extracellular matrix and thus to the formation of extracellular deposits [63]. Van Overbeke et al. used gelsolin nanobodies to shield mutant plasma gelsolin (PG) from aberrant furin cleavage [24]. Furin is a membrane-associated pro-protein convertase that is ubiquitously expressed. It cleaves mutant PG as it passes through the trans-Golgi network (TGN) and generates a C-terminal 68 kDa fragment (C68) that is secreted into the extracellular matrix [63]. This initial step in the amyloidogenic cascade is targeted using a Nb that binds mutant PG near the furin cleavage site with low nanomolar affinity (10 nM, in the presence of Ca2+). In vitro experiments demonstrated a dose-dependent decrease of mutant PG cleavage. The C68 signal intensity is reduced by 76% (P < 0.001) when a twofold molar excess of Nb is added. In cell-based assays, the nanobody drastically reduced secretion of C68 in the cell medium. The in vivo efficiency of the nanobody was further analyzed in a gelsolin amyloidosis/nanobody double-positive mouse model expressing human mutant PG. The Nb not only positively affects transgenic mutant gelsolin proteostasis in skeletal muscle tissue but also attenuates the decrease in contraction speed of the extensor digitorum longus in an 8-min fatigue protocol [24]. Using adeno-associated virus as a vehicle, a bispecific nanobody was introduced in these mice that protects against both furin and MT1-MMP, yielding similar effects on muscle contraction speed [64, 65]. Inhibiting the enzymatic activity of furin could be an alternative strategy, and noncompetitive furin-inhibiting nanobodies have been identified although they have not been tested for treatment of gelsolin amyloidosis [66]. However, despite the involvement of furin in several pathological processes, some considerations have to be made regarding its use as a therapeutic target. Although a complete/partial cleavage redundancy of furin toward several substrates was observed in the liver of an interferon-inducible Mx-Cre/loxP, furin knockout mouse model and obvious adverse effect were absent; a complete knockout of furin in a mouse model resulted in embryonic lethality at day 11 [67, 68]. This observation probably precludes their use in chronic treatments because it is rather unlikely that the long-term inhibition of furin does not go hand in hand with severe adverse effects. Therefore, shielding mutant PG from aberrant cleavage seems to be the better strategy. Moreover, this approach is already successfully implemented in the treatment of early-stage familial amyloid polyneuropathy caused by amyloidogenic variants of transthyretin, thus highlighting its feasibility [69].
Over the years, nanobodies have earned their mark as a research tool. A variety of extracellular and intracellular applications using nanobodies exist, and the latter will be discussed here. Intrabodies are often used to unravel protein functions and to gain insight into their dynamics. The versatility of nanobodies and the ease by which they can be engineered allow researchers to use different lines of approach (Figure 2). Chromobodies, consisting of a nanobody fused with a fluorescent protein, allow researchers to recognize and trace endogenous proteins in living cells [70]. Since they are already well known, they will not be discussed in detail here.
Schematic overview of nanobody-based applications in research. Upper panel. Left: Nanobodies can be equipped with a delocalization signal sequence, which allows the enrichment of a protein of interest (POI) at a specific subcellular localization, such as mitochondria. Middle: Nanobodies can exert a direct inhibitory effect which induces a protein knockout. Right: Nanobodies can be used to target a POI for proteasomal degradation. For this purpose, the nanobody is fused with a cullin-RING E3 ubiquitin ligase. Lower panel. Left: A chromobody, consisting of a fusion between a nanobody and a fluorescent protein (FP), allows the visualization and tracing of endogenous proteins in a background of contaminating proteins. Right: This nanobody-based application allows one to determine whether or not two proteins of interest interact. Both proteins are labeled with a different fluorophore. One protein, labeled with GFP, is recruited to a specific location via a GFP Nb coupled with a targeting signal. If the second protein, in this example labeled with RFP, is an interaction partner, both fluorescent signals will co-localize. When a compound interferes with a specific protein-protein interaction, the co-localization is absent.
Nanobodies are an attractive tool for the determination of endogenous protein function. They not only complement well-known RNAi and CRISPR/Cas9 techniques but also allow a more detailed insight by pinpointing specific functions with “surgical precision” by targeting individual protein domains (rather than eliminating the entire protein altogether) and protein conformations, which cannot be achieved by expression modulation. In other words, nanobodies can be of inestimable value to deepen our knowledge of several biological pathways. Researchers have employed several strategies for assessing the functionality of proteins or protein domains, and the different options will be discussed here.
As stated earlier, nanobody cDNAs are available, and these are easily engineered. This implies that the addition of a delocalization tag is fairly straightforward. A variety of targeting sequences are available and can be used to induce the enrichment of both nanobody and its target at specific (ectopic) subcellular compartments. This strategy allows researchers to assess the interaction between the nanobody and its target in the strongly reducing intracellular environment and thus to confirm the in vivo functionality of nanobodies. Moreover, in this way, one can also disturb protein function by restricting free diffusion of the protein and limiting its availability at places where it is needed [71]. Considering that the paratope of the nanobody is located at its N-terminal end, it is safer to fuse the tag at the C-terminal end of the nanobody. Otherwise, a substantial risk at disturbing antigen binding exists [2], although there are examples where a long tag is added to the nanobody N-terminus without disturbing its functionality [72]. Beghein et al. elegantly demonstrated how effectively nanobodies can delocalize their target protein to a variety of subcellular organelles. A survivin Nb (Kd ~ 1 nM) was capable of guiding endogenous survivin in or out the nucleus (nuclear localization sequence tag and nuclear export sequence tag), capturing survivin on the outer membrane of mitochondria (mitochondrial outer membrane tag) and even at the intermembrane area (mitofilin tag) which probably required (partial) unfolding of the nanobody and possibly chaperone-assisted entry into mitochondria. This had not yet been investigated. Also, transport of survivin in the peroxisomes (PST-1 tag) was demonstrated [72]. Since interaction between the nanobody and survivin apparently did not perturb survivin functionality, the tagged nanobody is a perfect research tool for further elucidating survivin biology. This strategy also provided evidence that only actin-free gelsolin is able to migrate to the nucleus (in contrast to the actin-gelsolin complex) to potentially act as a nuclear cofactor for the androgen receptor [73], that fascin plays a role in the formation of filopodia/cell spreading and is also involved in MMP9 secretion, and that the SH3 domain of cortactin directly regulates MMP secretion [74].
Some nanobodies exert a direct inhibitory effect, resulting in a functional knockout of the protein. These nanobodies can help researchers to define the biochemical activities of proteins. For example, mechanistic insights in podosome formation were revealed by two inhibitory nanobodies targeted against L-plastin (LPL). LPL Nb5 is capable of blocking the actin-bundling activity of L-plastin, and LPL-Nb9 locks LPL in an inactive conformation. Experiments involving these nanobodies revealed the participation of L-plastin (LPL) in podosome formation and stability [75]. Furthermore, L-plastin is a component of cancer cell invadopodia and contributes to matrix degradation and cancer cell invasion. These effects are mediated by the actin-bundling activity of L-plastin and its bundling independent role in MMP9 secretion and activity, as revealed by the differential effects observed in the presence of LPL Nb5 and LPL Nb9 [76]. One can also interfere with signaling pathways by specific inhibition of the transcriptional activity of proteins, like beta-catenin and p53 [77, 78]. These nanobodies can be used to elucidate the impact of cofactors and post-translational modifications on the targeted protein and allow us to broaden our understanding of the respective signaling pathways. Insight into pathological mechanisms, which might result in the identification of druggable targets, can also be obtained. For example, nanobodies were used to investigate the role of two enzymatic domains of TcdB, a toxin produced by Clostridium difficile. Using specific inhibition of the effector glycosyltransferase activity or the cysteine protease, it was, among other things, established that the TcdB-cytopathic effects are mainly mediated by the glycosyltransferase activity [79].
Finally, nanobodies are known to stabilize certain protein conformations and are often used as an aid in crystallization experiments [2]. This property also comes in handy when one wants to study the mechanisms by which cellular receptors translate extracellular cues into intracellular responses. Depending on which conformation the receptor adopts after ligand binding, certain downstream signaling events can be either activated or inhibited. Staus et al. have identified nanobodies that preferentially recognize and stabilize the β2 adrenergic receptor in its active or inactive conformation resulting in a variety of functional effects [80]. These experiments indicate that nanobodies, by acting as an allosteric modulator of receptors, can help us to understand receptor biology.
An alternative way to determine the function of a protein of interest (POI) in an in vivo setting is to selectively induce their degradation and study the resulting knockout phenotype. To achieve this goal, three different groups have exploited a combination of nanobodies and the endogenous ubiquitin proteasome pathway, a system that is responsible for selective protein degradation in eukaryotes [81, 82, 83]. Caussinus et al. were the first to use the ubiquitin pathway for targeted degradation by making adaptations of an E3 ubiquitin ligase, more specifically the cullin-RING 1 (CLR1) E3 ligase complex. For this purpose, a fusion between the F-box domain of Slmb and a GFP Nb (VHH GFP4) was made. Slmb is part of an F-box protein, responsible for substrate recognition that is expressed in Drosophila melanogaster. When this construct, called DeGradFP, was expressed in mammalian cells or D. melanogaster embryos, certain GFP-tagged proteins were depleted. DeGradFP was also capable of phenocopying specific loss of function mutations. In spite of these successful results, treatment with DeGradFP was not always followed by the degradation of the targeted protein (e.g., GFP) [81]. In addition to that, a broader application of DeGradFP is still to be demonstrated.
Just like DeGradFP, the cullin-RING E3 ubiquitin ligases were used as the framework for synthetic E3 ligase design. In an attempt to enhance the E3 activity, however, the GFP Nb was fused directly to a truncated adaptor protein instead of the substrate recognition protein. The best results were obtained with Ab-SPOP, a synthetic version of the CLR3 E3 ligase complex, displaying a 10-fold stronger signal reduction of a GFP-tagged protein compared to DeGradFP (50-fold vs. 5-fold). Importantly, the construct degrades only nuclear proteins, and possibly in the future, similar constructs may become available that degrade cytoplasmic proteins. The in vivo effectiveness of Ab-SPOP was confirmed in zebra fish embryos. Ab-SPOP-induced depletion of Hmg2a-citrine, a protein responsible for the modulation of nucleosome and chromatin structure, resulted in various early developmental defects [83]. Fulcher et al. tailored the von Hippel-Lindau (VHL) protein as an affinity-directed protein missile, called AdPROM. Under normoxic conditions, this substrate recognition protein recruits the hypoxia-inducible factor (HIF1α) to the CLR2 E3 ligase. AdPROM is composed of a fusion between the VHL protein and a GFP Nb. It was of crucial importance that the GFP Nb was positioned at the C-terminus of the VHL protein in order to obtain a proper orientation of the target proteins to the CLR2 E3 ligase complex. Since the paratope of a nanobody is localized at the N-terminal end, one should definitely check for potential detrimental effects of this fusion on the binding capacity of the nanobody itself. However, the affinity-directed protein missile was competent in inducing the specific degradation of GFP-tagged VPS34 and PAWS1 proteins in human cell lines, which was further substantiated by the observation of functional effects. Interestingly, during these experiments the researchers observed the co-degradation of UVRAG which is a regulatory component of the VPS34 kinase complex. This suggests that AdPROM has the potential of destroying protein complexes although only individual proteins are targeted [82]. Targeted degradation of proteins of interest by the use of nanobodies holds great potential and might be the perfect complement to CRISPR/Cas systems or RNAi in the elucidation of protein function. The tunability of this system is a huge benefit. Future experiments should point out whether the GFP Nb can be replaced by highly selective nanobodies targeted against specific proteins. In this way, one could investigate the functions of the protein of interest in a more direct manner, without the requirement of protein tags.
Nanobodies can be utilized for the detection of protein-protein interactions in cell-based assays. There is a large supply of in vitro methods which can be used for the detection of protein-protein interactions. These methods are widely used and highly efficient for high-throughput screenings but are limited by the fact that they don’t operate in intact mammalian cells. Screening for interaction between proteins in their native environment guarantees their proper folding and the presence of necessary cofactors or regulatory proteins. Both nanobody-based methods rely on the interaction between a GFP Nb and a GFP-tagged protein. Herce et al. covalently linked a GFP Nb with a protein that accumulates at a specific subcellular location. In mammalian cells, this protein could be, for example, laminin B1 or centrin, which results in the delocalization of the GFP Nb to the nuclear lamina or the cytoplasmic centrioles, respectively. Subsequently, a GFP-tagged protein will be recruited to a specific location. If the second protein of interest, labeled with another fluorophore, interacts with the first protein of interest, the fluorophores will co-localize at a discrete spot. This interaction can be visualized by a single-fluorescence snapshot. Interestingly, this technique also allows screening for inhibitors of protein-protein interactions [84]. Another recently developed technique uses biocompatible engineered upconversion nanoparticles (UCNPs) conjugated with GFP Nbs. Visualization of the interaction between two proteins of interest is based on the lanthanide resonance energy transfer (LRET). As a proof of concept, they probed for the indirect interaction between the mitochondrial proteins TOM20 and TOM7. The latter was expressed as a fusion protein with EGFP and the former as a fusion protein with dsRed and a Halo tag. This Halo tag was subsequently labeled with tetramethylrhodamine (TMR), while the EGFP was recognized by the GFP Nb-labeled UCNPs. Co-localization of both proteins results in the detection of LRET-sensitized TMR emission. Remarkably, TOM7 and TOM20 are spatially separated by TOM40. The capacity of this technique for reporting indirect long-distance interactions might be of interest to unravel cellular protein complexes [85].
Nanobodies are highly versatile tools with interesting biochemical properties, which result in their application in various fields ranging from basic research and diagnostics to therapy. In this chapter, we aim to shed light on their multifunctionality and in this way encourage other researchers to include this technology in their future projects. Since their discovery in 1993, the numbers of publications wherein nanobodies are employed are gradually increasing which indicate that their merit has been proved. Here, we have shown that nanobodies have a high therapeutic potential and form an ideal stepping stone to drug development. Despite isolated cases, nanobodies are not capable of traversing the cellular membrane, preventing their direct use as a therapeutic. The effects observed with nanobody treatment are established through multiple mechanisms. Nanobodies can act as an inhibitor of enzymatic activity, interfere with specific protein-protein interactions, and shield a protein of interest from aberrant cleavage, or they can be used as a tool to target proteins for proteasomal degradation. We believe that effects triggered by nanobodies in vitro or in vivo are a faithful representation of what to expect with conventional pharmacological drugs, since both compounds directly target the resident endogenous protein. However, since current experiments are often limited to cell-based assays, animal experiments are warranted to confirm their effectiveness. Furthermore, nanobodies have a lot to offer as a research tool. They can help researchers to elucidate protein functions and thereby gain insight in biological pathways. Several strategies are possible, ranging from subcellular delocalization to the induction of protein knockouts. Last but not least, nanobodies may represent an adequate answer to problems encountered with (conventional) antibody reproducibility [86, 87]. Indeed, particularly polyclonal antibodies run out of stock at some point in the future, making experimental verification impossible. Because nanobody cDNAs are readily obtained and researchers all over the world can use exactly the same nanobody in their experiments, problems of reproducibility can be reduced. In the future, we hope to stimulate a closer consultation within the nanobody field and by doing so taking the research to the next level.
This work was supported by grants from the Research Foundation Flanders (Fonds Wetenschappelijk Onderzoek (FWO) Vlaanderen) and Ghent University (BOF13/GOA/010). AS and LB are supported by the Agency for Innovation by Science and Technology in Flanders (IWT-Vlaanderen). We apologize to those researchers whose work could not be cited.
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\\n\\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\\n\\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\\n\\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n5. TERMINATION
\\n\\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\\n\\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\\n\\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\\n\\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n\\nLast updated: 2020-11-27
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
\n\n\n\n
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). 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