Summary of the known E3 ubiquitin ligases targeting BER proteins for ubiquitination.
\r\n\t
\r\n\tSexuality is influenced by the interaction of biological, psychological, social, economic, political, cultural, legal, historical, religious and spiritual factors.” (WHO, 2006a). There is a growing consensus that sexual health cannot be achieved and maintained without respect for, and protection of, certain human rights. The working definition of sexual rights given below is a contribution to the continuing dialogue on human rights related to sexual health. The sexual rights encompass:
\r\n\t
\r\n\t1. sexual relationships and the right to choose one's partner,
\r\n\t2. sexual expression and the right seek pleasure,
\r\n\t3. sexual consequences and the right co-operation from one's partner,
\r\n\t4. sexual harm and the right to protection,
\r\n\t5. sexual health and the right to information
\r\n\t6. human sexuality and well being.
\r\n\t
\r\n\tThe growing number of rapes and rape victims, sexual harassment cases and the violation of the right to have or resist sex from a marriage, and the need to take consent before sex and the trend of ""living together"" in corporate cities, necessitate a candid and concise book on "" Sexual Ethics"" including a broad definition what is meant by sexual ethics.
Every human cell per day is thought to generate greater than 10,000 DNA base lesions and single strand breaks (SSBs) due to the instability of the DNA molecule [1]. These are largely created by cellular reactive oxygen species that are generated by hydrolysis, oxidative metabolism and environmental factors, including ionising radiation (IR). Typical sites of damage include sites of base loss (abasic sites), oxidised DNA bases (e.g. 8-oxoguanine and thymine glycol) and SSBs. If this DNA damage is left unrepaired, it can cause mutagenesis and genome instability which are contributors to the development of human diseases, including premature ageing, neurodegenerative disorders and cancer. The base excision repair (BER) pathway was first identified in the 1970s by Tomas Lindahl (co-recipient of the 2015 Nobel Prize in Chemistry), who discovered the existence of a uracil DNA N-glycosylase that is able to excise uracil residues from DNA [2]. Lindahl then suggested that in order for repair to be completed, an endonuclease, a DNA polymerase and a DNA ligase would be required. This marked the establishment that a specific repair pathway exists in human cells to repair DNA base damage, and now nearly a half a century later, the major enzymes and mechanisms involved in BER are well known.
As Lindahl had shown, the first step of BER is recognition of the specific damaged DNA base by a DNA glycosylase. In fact 11 DNA glycosylases are now known to exist with each removing particular types of DNA base damage [3, 4]. Indeed there are three uracil DNA glycosylase enzymes that recognise uracil lesions (namely uracil DNA glycosylase, UNG; single-strand-selective monofunctional uracil DNA glycosylase, SMUG1; and thymine DNA glycosylase, TDG), one enzyme that recognises alkylated bases (N-methylpurine DNA glycosylase, MPG), two mismatch-specific glycosylases (methyl-CpG binding domain protein 4, MBD4 and MutY homologue, MUTYH) and five glycosylases that recognise oxidised bases (8-oxoguanine DNA glycosylase 1, OGG1; endonuclease III-like protein 1, NTH1; endonuclease VIII-like proteins 1, 2 and 3; NEIL1, NEIL2 and NEIL3). In general, DNA glycosylases utilise a base-flipping mechanism whereby the base is flipped 180° from the sugar phosphate backbone breaking the hydrogen bonds between the bases in the process, and placing the damaged base into the active site of the DNA glycosylase. However, there are two types of glycosylase enzyme as one type will only remove the damaged base (monofunctional enzyme) whereas another type will remove the base but also cleave the DNA backbone (bifunctional enzyme). The monofunctional DNA glycosylases (UNG, SMUG1, TDG, MPG, MUTYH and MBD4) that remove the damaged base will create an abasic site by cleaving the N-glycosidic bond linking the base to the phosphodiester backbone. The abasic site is then recognised by AP endonuclease 1 (APE1) that cleaves 5′- to the lesion, creating a one nucleotide gap containing a 3′-hydroxyl group on one end, and a 5′-deoxyribose phosphate (5′-dRP) group on the other [5, 6]. The 5′-dRP group is subsequently removed by the lyase activity of DNA polymerase β (Pol β) that also simultaneously inserts the correct, undamaged nucleotide [7, 8]. The remaining nick in the DNA backbone is then sealed by DNA ligase IIIα (Lig IIIα) that is in a stable complex with X-ray cross-complementing protein 1 (XRCC1), to restore the original DNA sequence (Figure 1) [9, 10]. In contrast, bifunctional DNA glycosylases create a single nucleotide gap that is flanked by different ends, depending on the glycosylase employed. OGG1 and NTH1 are known to catalyse β-elimination which creates a 5′-phosphate and a 3′-α,β-unsaturated aldehyde, however, these are thought to be low efficiency activities and therefore with the high cellular abundance of APE1, it is thought that APE1 can actually circumvent this product and cleave the abasic site itself [11]. The bifunctional DNA glycosylases NEIL1, NEIL2 and NEIL3 catalyse β,δ-elimination which create a phosphate moiety on both the 5′- and 3′-end of the single nucleotide gap. Since the 3′-phosphate is not the required end for Pol β activity, this requires removal by polynucleotide kinase phosphatase (PNKP) (Figure 1) [12]. Despite the dependence on either APE1 or PNKP, following bifunctional DNA glycosylase activity the end product is the same as monofunctional DNA glycosylase activity in that both Pol β and XRCC1-Lig IIIα are required to complete the repair process. The pathway described above is commonly referred to as the short patch BER pathway, through which the majority of DNA repair events proceed [13]. However under certain conditions, particularly when the DNA ends are resistant to processing (e.g. if the 5′-dRP becomes reduced and thus cannot be cleaved by Pol β), then long-patch BER is employed (Figure 1). Following the addition of the first nucleotide by Pol β [14], there is a polymerase switch to DNA polymerases δ/ε (Pol δ/ε), which are principally involved in DNA replication. These polymerases typically add two to eight more nucleotides into the repair gap thus generating a 5′-flap structure. This structure is a substrate for flap endonuclease-1 (FEN-1), which acts in a proliferating cell nuclear antigen (PCNA)-dependent manner and then finally DNA ligase I (Lig I) completes the repair process by sealing the remaining nick. It is important to note that with the constant, significant amount of DNA base damage and SSBs being induced in cells, that BER is a constitutively active process.
The mechanism of repair of DNA base damage by the BER pathway. The damaged DNA base is recognised and excised by damage-specific DNA glycosylases that catalyse cleavage of the N-glycosidic bond, creating an abasic site. APE1 recognises the abasic site and cleaves the DNA backbone, generating a single strand break containing a 5′-dRP moiety. The 5′-dRP is subsequently removed by the dRP lyase activity of Pol β that furthermore inserts a new undamaged nucleotide into the repair gap (central branch). If BER is initiated by the NEIL DNA glycosylases (NEIL1, NEIL2 and NEIL3), these enzymes generate a single nucleotide gap containing 3′- and 5′-phosphate ends through β,δ-elimination activity. The 3′-phosphate is subsequently removed by PNKP prior to the activity of Pol β that fills in the repair gap (left branch). Finally, the Lig IIIa-XRCC1 complex completes short patch BER by sealing the remaining nick in the phosphodiester backbone. If the 5′-dRP moiety is resistant to Pol β dRP lyase activity, a polymerase switch to Pol δ/ε occurs, which then stimulate the addition of two to eight more nucleotides into the single nucleotide gap. This generates a 5′-flap structure which is recognised and excised by FEN-1, in a PCNA-dependent manner (right branch). To complete long patch BER DNA ligase I, also in association with PCNA, seals the remaining nick in the DNA backbone.
Since BER is the major cellular mechanism for the repair of DNA base damage and SSBs, and thus for the maintenance of genome stability, it is important that this process is maintained and controlled. The most efficient way of achieving this, particularly in responding to fluctuations in the cellular DNA damage environment, is via controlling cellular protein activity, localisation and overall protein levels. Indeed there is a growing list of the various protein post-translational modifications (PTMs) of BER proteins that have been reported to achieve this [15]. However a role for ubiquitination in controlling BER protein levels, and thus cellular BER activity, has been highlighted particularly in the last decade. Polyubiquitination of BER proteins catalysed by specific E3 ubiquitin ligases has been shown to largely control cellular protein levels via degradation by the 26S proteasome, but additionally monoubiquitination has been observed in some instances that can act by compartmentalising BER proteins or controlling BER protein activity. There are also instances of crosstalk between ubiquitination and other PTMs in controlling cellular BER. Below we aim to summarise all of the available evidence highlighting the enzymes and mechanisms involved in the control of BER proteins through ubiquitination.
Of the four members of the uracil DNA glycosylases, only UNG, SMUG1 and TDG have been shown to be ubiquitinated by specific E3 ubiquitin ligases. Binding of the human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr to UNG and SMUG1 was shown to induce their ubiquitination-dependent proteasomal degradation following expression in 293T cells. This was thought to be promoted through the E3 ubiquitin ligase scaffold proteins, Cullin 1 (Cul1) and Cullin 4 (Cul4), as Vpr interacts with these ligases along with UNG and SMUG1 following overexpression and immunoprecipitation from 293T cells [16]. Vpr was subsequently shown to bind to damage-specific DNA-binding protein 1 (DDB1), which is another component of Cul4A E3 ubiquitin ligases, that mediates the degradation of UNG in 293T cells [17]. This is thought to be a specific mechanism that allows the HIV virus to regulate the levels of abasic sites in viral reverse transcripts and thus promotes viral replication. Therefore whether UNG and SMUG1 are targeted for ubiquitination during normal cellular processing and for BER is not yet known. The third member of the uracil DNA glycosylase family, TDG, is largely known for being regulated by the small ubiquitin-like modifier (SUMO). TDG was shown to be modified by SUMO-1 and SUMO-2/3 on lysine 330 following immunoprecipitation from HeLa cells, and this reduces the abasic site affinity of TDG [18]. TDG SUMOylation induces a conformational change in the protein which overcomes product inhibition and is thus a mechanism for increasing enzymatic turnover [19, 20]. More recently, and similar to UNG and SMUG1, TDG has been shown to be a target for ubiquitination-dependent degradation by a Cul4-DDB1 associated E3 ubiquitin ligase complex [21, 22]. Specifically, TDG degradation was catalysed by Cul4A-DDB1 in association with the RING finger protein ROC1/RBX1 and Cdt2 (collectively called CRL4Cdt2), in a PCNA-dependent manner. This was discovered both in a Xenopus extract system during DNA repair but also in HeLa cells during S phase of the cell cycle where TDG interacts with PCNA, and is thought to provide a mechanism for the regulated control of TDG protein levels. The fourth uracil DNA glycosylase member, MBD4 which actually removes mismatches opposite guanine, has not been reported to be ubiquitinated. However MBD4 has been shown to interact with both the E3 ubiquitin ligase, ubiquitin-like with PHD and RING finger domains 1 (UHRF1) and with the deubiquitinating enzyme, ubiquitin specific protease 7 (USP7) following overexpression of the protein in HEK293T cells [23]. Given these interactions, MBD4 could potentially be a target for regulation by ubiquitination.
The HhH DNA glycosylases are named after the DNA-binding motif which is present in all three members of the family and are OGG1, NTH1 and MUTYH. OGG1 is the major DNA glycosylase targeting 8-oxoguanine DNA base damage and only one report has suggested that it is a target for ubiquitination. Specifically OGG1 was found to be degraded following mild hyperthermia by the E3 ubiquitin ligase C-terminus of Hsc70-interacting protein (CHIP) [24]. CHIP is well known to be involved in protein quality control, by targeting damaged or misfolded proteins for ubiquitination-dependent degradation via interaction with the molecular chaperones Hsc70 and Hsp90 [25], and as will become clear later in this chapter, can target multiple BER proteins for degradation via the proteasome. Degradation of OGG1 by CHIP through heat inactivation in HeLa cells was shown to cause a reduction in the efficiency of repair of oxidised DNA base damage and cell growth inhibition following treatment with a photosensitiser. NTH1 is the second member of the HhH DNA glycosylases that excises oxidised pyrimidines from DNA, including 5-hydroxycytosine and thymine glycol, although there are no current reports that it is directly targeted for ubiquitination. However there is evidence that MUTYH, the third member of the family that specifically removes adenine residues incorrectly incorporated opposite 8-oxoguanine residues during DNA transcription or replication, is ubiquitinated both in vitro and in vivo. Ubiquitination between residues 475 and 500 within the MUTYH protein was shown to be catalysed by the Mcl1 ubiquitin ligase E3/ARF binding protein 1 (Mule/ARF-BP1) that subsequently stimulates proteasomal degradation [26]. This was evidenced in vitro using recombinant proteins, and also in vivo ubiquitination of MUTYH decreased in HEK293T cells following Mule siRNA and led to increased protein stability. A ubiquitination-deficient mutant of MUTYH lacking five critical lysine residues (477, 478, 495, 506 and 507) that were mutated to arginines, was found to be more stable in HEK293T cells than the wild type protein and preferentially bound to chromatin [26]. Mule overexpression in A2780 cells led to an increased mutation frequency following potassium bromate treatment that was predicted to be a consequence of the lack of MUTYH through Mule-dependent degradation. Mule has also been demonstrated to regulate the protein levels of Pol β and Pol λ (see below), and therefore appears to be a critical regulator of BER at both the base excision and gap filling stages. How the activity of Mule is co-ordinated towards these specific proteins and stages is not currently clear.
NEIL1 and NEIL2 both have a broad range substrate specificity that largely covers those of the HhH enzymes OGG1 and NTH1. However, these DNA glycosylases appear more active on single stranded DNA and bubble structures and so may be more important during replication and transcription where these structures are formed [27, 28]. There is also evidence that NEIL1 is active at complex DNA damage sites, where two or more DNA base lesions are formed in close proximity [29, 30], and on telomeric DNA [31]. NEIL3 substrate activity has also proven to be elusive but can similarly act on telomeric DNA [31, 32] and more recent data has described a role for NEIL3 in unhooking of DNA interstrand crosslinks [33]. The only evidence of ubiquitination-dependent regulation of the NEIL DNA glycosylases is through very recent data involving NEIL1. Using an in vitro ubiquitination system in combination with fractionated HeLa cell extracts, NEIL1 was demonstrated to be targeted by two E3 ubiquitin ligases, namely Mule and tripartite motif 26 (TRIM26) [34]. Both enzymes appear to promote ubiquitination of NEIL1 on the same C-terminal lysine residues (319, 333, 356, 357, 361, 374 and 376) within the protein, and an siRNA knockdown of either Mule or TRIM26 in U2OS cells caused an increase in cellular NEIL1 protein levels demonstrating that they both target the protein for ubiquitination-dependent degradation. Interestingly in response to IR-induced DNA damage, there was an accumulation of NEIL1 protein which occurred in a Mule-dependent, but not a TRIM26-dependent, manner. This demonstrated a requirement for both Mule and TRIM26 in controlling the cellular steady state levels of NEIL1, in addition to those required in response to DNA damage.
MPG is a DNA glycosylase that excises alkylated DNA base damage, including 3-methyladenine and 7-methylguanine. There is no current evidence that this enzyme is regulated directly by ubiquitination, although MPG has been reported to interact with the E3 ubiquitin ligases UHRF1 and UHRF2 following overexpression in HEK293 cells, and interacts with UHRF1 in a number of cancer cell lines, including MCF7, HeLa and H1299 [35].
PARP-1 functions in binding to SSBs created during BER, where it mediates poly(ADP-ribosyl)ation of itself and other proteins involved in the repair process and thus promotes the assembly of repair protein complexes, chromatin remodelling and its own eventual dissociation from the DNA. Inhibitors targeting PARP-1 activity have recently been approved for the treatment of BRCA-deficient cancers, through which they cause synthetic lethality. This therapeutic exploitation provides an added incentive to enhance our understanding of the regulation of cellular PARP-1, particularly through ubiquitination.
The first report to show that PARP-1 is ubiquitinated was in mouse embryonic fibroblasts following treatment with the proteasome inhibitor ALLN [36]. PARP-1 ubiquitination was further examined in vitro and shown to involve specifically lysine 48-linked chains, suggesting that this would likely target the enzyme for proteasomal degradation. PARP-1 modification by SUMOylation, specifically SUMO-2 at lysine 203 and 486 induced by the PIASy SUMO E3 ligase, has been demonstrated following overexpression of the enzymes in HeLa cells in response to heat shock stress, which also rendered PARP-1 as a target for ubiquitination by the poly-SUMO-specific E3 ubiquitin ligase ring finger protein 4 (RNF4) [37]. PARP-1 ubiquitination resulted in degradation of the protein, and provides evidence of crosstalk between two PTMs thought to be involved in regulating PARP-1 transcriptional activation, rather than playing a role during BER. Another incidence of crosstalk has been revealed between PARP-1 ubiquitination and poly(ADP-ribosyl)ation. The E3 ubiquitin ligase ring finger protein 146 (RNF146), also known as Iduna, ubiquitinates PARP-1 in vitro and in MCF7 cells overexpressing Iduna leading to its proteasomal degradation providing that PARP-1 itself is poly(ADP-ribosyl)ated [38]. This phenomenon was more pronounced following N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-induced alkylated base damage, suggesting a DNA damage inducible response. Furthermore, an shRNA-induced knockdown of Iduna caused an accumulation of abasic sites following MNNG treatment, and an accumulation of SSBs following IR in MCF7 cells. This is difficult to comprehend given the abundance of cellular APE1 and its ability to cleave any abasic sites following MNNG treatment, and that PARP-1 should still be able to dissociate from IR-induced SSBs following poly(ADP-ribosyl)ation and allow for subsequent repair protein recruitment. However since Iduna has also been shown to polyubiquitinate other BER proteins, including XRCC1 and Lig III, the effects of Iduna on the celllular DNA damage response are not clear cut.
A third E3 ubiquitin ligase has been identified for PARP-1, namely the checkpoint with forkhead-associated and RING finger domain protein (CHFR), which was shown to polyubiquitinate PARP-1 in vitro and following overexpression of CHFR in HEK293T and HCT116 cells in vivo [39]. CHFR regulates the mitotic checkpoint and following mitotic stress PARP-1 was shown to undergo poly(ADP-ribosyl)ation, and similarly to the case for Iduna, this facilitated polyubiquitination-dependent degradation of the protein. CHFR-knockout mouse embryonic fibroblasts displayed elevated PARP-1 levels and did not undergo cell cycle arrest in response to mitotic stress. An additional report similarly described poly(ADP-ribosyl)ated PARP-1 as a CHFR target [40]. CHFR was recruited to laser-induced DNA damage sites in a poly(ADP-ribosyl)ation-dependent manner in U2OS cells as revealed by PARP inhibition and PARP-1 siRNA. Interestingly, lysine 48-linked ubiquitin chains were conjugated to poly(ADP-ribosyl)ated, but not unmodified, PARP-1 by CHFR in vitro in the presence of the E2 conjugating enzyme UbcH5C, but lysine-63 linked chains were added in the presence of Ubc13/Uev1a. Both lysine 48 and 63-linked chains were then found attached to PARP-1 following irradiation of CHRF-overexpressing HCT116 cells. Potentially more important than its eventual degradation, CHFR-mediated ubiquitination prompted the displacement of PARP-1 from chromatin, and CHFR-knockout mouse embryonic fibroblasts were demonstrated to display delayed SSB repair kinetics and increased sensitivity to IR.
As multiple E3 ubiquitin ligases have been implicated as effectors of PARP-1 ubiquitination, more research is required to determine which of these are crucially involved in the regulation of steady state PARP-1 levels and which function specifically during BER. It is apparent that PARP-1 regulation is multifaceted, with the added complexity of crosstalk between ubiquitination and other PTMs such as SUMOylation and poly(ADP-ribosyl)ation, therefore it may be some time before the intricacies of this regulation are elucidated.
APE1 is the major enzyme targeting abasic sites for incision in human cells, and both an over-abundance and lack of this protein can cause genome instability, so the protein levels must be tightly regulated. APE1 was first shown to be monoubiquitinated within the N-terminus of the protein in HCT116 cells by overexpression of the E3 ubiquitin ligase mouse double minute homologue 2 (MDM2), the major enzyme regulating the p53 tumour suppressor protein [41]. Depletion of MDM2 consequently increased APE1 protein levels, thought to be as a result of reduced ubiquitination-dependent degradation. The same authors then reported that phosphorylation of APE1 at threonine 233 by cyclin-dependent kinase 5 (Cdk5)-enhanced MDM2-dependent ubiquitination of APE1 [42]. Indeed, a phosphomimetic mutant (T233E) of APE1 exhibited augmented ubiquitination following expression in HCT116, SW480 and A549 cells. However MDM2 knockout mouse embryonic fibroblasts expressing the phosphomimetic mutant of APE1 still displayed significant APE1 ubiquitination, demonstrating the existence of other E3 ubiquitin ligases for the protein. In fact utilising an in vitro ubiquitination assay incorporating APE1 as a substrate and fractionated proteins from HeLa whole cell lysates has revealed that the major E3 ubiquitin ligase targeting APE1 for ubiquitination was ubiquitin protein ligase E3 component N-recognin 3 (UBR3) [43]. In vitro ubiquitination of APE1 by UBR3 was localised within the N-terminus on multiple lysine residues (6, 7, 24, 25, 27, 31, 32 and 35). UBR3 knockout mouse embryonic fibroblasts displayed significantly higher APE1 protein levels, suggesting that ubiquitination targeted APE1 for proteasomal degradation, and consequently led to an increase in endogenously formed DNA double strand breaks and genomic instability. A third E3 ubiquitin ligase has recently been identified for APE1, namely the Parkinson’s disease-associated protein, Parkin [44]. Overexpression of Parkin was found to ubiquitinate APE1 in A549 cells, and in an engineered mouse embryonic fibroblast cell line containing low APE1 protein overexpression of both Parkin and APE1 caused a decrease in protein stability. However, inducible expression of Parkin in 293-PaPi cells did not alter endogenous APE1 protein levels and a combination of Parkin and hydrogen peroxide treatment only caused an ~30% reduction in the protein, suggesting that Parkin may only have a minor role in APE1 regulation.
PNKP acts to remove the 3′-phosphate group remaining from the actions of NEIL1–3 during BER, but also displays kinase activity for 5′-DNA ends and thus plays a role in the repair of SSBs and double strand breaks. A crosstalk between phosphorylation and ubiquitination has been revealed to be important in the regulation of PNKP protein levels. Phosphorylation catalysed by the ataxia telangiectasia mutated (ATM) protein kinase on serines 114 and 126 of PNKP was shown to stabilise the protein in response to oxidative stress in HCT116 cells, which was mediated through inhibition of ubiquitination, and which was required for efficient SSB repair [45]. An in vitro ubiquitination assay, using PNKP as a substrate in combination with fractionated proteins from HeLa whole cell lysates, revealed that Cul4A-DDB1 in association with the WD-40 repeat protein serine-threonine kinase receptor-associated protein (STRAP) was the major E3 ubiquitin ligase complex that was targeting PNKP for ubiquitination, specifically on lysines 414, 417 and 484. A phosphomimetic mutant (serine 114 and 126 to glutamic acid) was more stable than the wild type protein following expression in HCT116 cells, and the protein itself was resistant to in vitro ubiquitination by Cul4A-DDB1-STRAP. Mouse embryonic fibroblasts from STRAP knockout cells also had significantly elevated PNKP protein levels due to reduced ubiquitination-dependent degradation, and displayed increased resistance to oxidative stress. In addition, an interaction between PNKP and the deubiquitination enzyme ataxin-3 has been demonstrated in vivo, and which promotes the 3′-phosphatase activity of PNKP in vitro [46]. However whether this enzyme contributes to regulating PNKP protein levels, particularly in opposition to Cul4A-DDB1-STRAP-mediated ubiquitination, has yet to be investigated.
FEN-1 acts to remove the flap structures created by Pol δ/ε during long-patch BER.Ubiquitinated FEN-1 has been observed at the end of a sequence of PTMs initiated in late S phase of the cell cycle [47]. It was observed in HeLa cells that phosphorylation of FEN-1 at serine 187, promotes SUMOylation at lysine 168 with SUMO-3, which in turn stimulates polyubiquitination at lysine 354 by the E3 ligase pre-mRNA processing factor 19 (PRP19) to stimulate proteasomal degradation. This was largely discovered through overexpression of individual components within the pathway in HeLa cells, rather than examining endogenous proteins. Furthermore, PRP19 was only characterised in ubiquitinating FEN-1 in vitro using partially purified HeLa cell extracts and a complete suppression of ubiquitination was not observed following immunodepletion of PRP19, suggesting the existence of alternative E3 ubiquitin ligases for FEN-1. Nevertheless, this sequence of events beginning in late S phase is thought to regulate FEN-1 protein levels at the end of DNA replication, rather than being required for long-patch BER. Therefore further work is required to determine whether this, or an alternate mechanism for FEN-1 ubiquitination, plays a role in the regulation of this protein during BER.
Pol β is the principal polymerase employed within the BER pathway, and primarily acts to insert the correct nucleotide into the repair gap, but also acts as a dRP lyase activity. The stability of Pol β was found to be significantly reduced in XRCC1 deficient EM-C11 cells and in HeLa cells following XRCC1 siRNA treatment, suggesting that Pol β and XRCC1-Lig IIIα form a stable complex that protects Pol β from degradation [48]. The major E3 ubiquitin ligase for Pol β was then revealed through the utilisation of in vitro ubiquitination assays in combination with fractionated HeLa cell extracts to be CHIP. Ubiquitination was localised to the 8 kDa N-terminal domain, which contains the dRP lyase activity, and CHIP depletion by siRNA in HeLa cells led to increased protein levels of Pol β whereas overexpression of CHIP reduced cellular Pol β. Interestingly, this investigation highlighted that CHIP also appeared to be involved in the ubiquitination-dependent degradation of XRCC1 and Lig IIIα, in addition to Pol β. This study was followed by the identification of a second E3 ubiquitin ligase that specifically catalysed monoubiquitination of Pol β [49]. Monoubiquitination was shown to occur in the same 8 kDa N-terminal region as that targeted by CHIP, but was catalysed by Mule. The precise ubiquitinated residues were identified as lysine 41, 61 and 81, and a lysine to arginine mutant Pol β protein was more stable than the wild type protein following expression in HeLa cells. Monoubiquitinated Pol β was observed exclusively within the cytoplasm in HeLa cells and was therefore deemed a specific target for ubiquitination-dependent degradation mediated by CHIP. Indeed, an siRNA knockdown of Mule decreased the levels of monoubiquitinated Pol β, increased total cellular Pol β levels and caused an increase in the rate of repair of SSBs and alkali-labile sites induced by hydrogen peroxide. Conversely a knockdown of ARF, which inhibits the activity of Mule, caused an increase in monoubiquitinated Pol β and a decrease in the rate of repair of hydrogen peroxide-induced SSBs and alkali-labile sites. A later study agreed that Pol β stability was dependent on XRCC1 and was regulated by ubiquitination-dependent degradation, but reported that this ubiquitination occurred on lysines 206 and 244 and was not reliant on Mule or CHIP [50]. However, the experimental system employed was very artificial, utilising an unusual cell line containing deletions of, amongst others, the ARF protein and modified to stably overexpress Pol β rather than examining endogenous protein levels. The identification of the deubiquitination enzyme that is able to reverse Mule- and CHIP-dependent ubiquitination of Pol β, and in fact the only such enzyme characterised in regulating BER, has been identified as ubiquitin specific protease 47 (USP47). USP47 was purified and identified from fractionated HeLa cell extracts in combination with an in vitro deubiquitination assay using ubiquitinated Pol β as a substrate, and was demonstrated to be capable of removing both CHIP-dependent polyubiquitin chains and Mule-dependent monoubiquitin moieties from Pol β [51]. An siRNA knockdown of USP47 in HeLa cells resulted in an increase in Mule-dependent monoubiquitinated Pol β, a reduction in cytoplasmic and therefore overall Pol β protein levels, and ultimately led to reduced efficiency of repair of SSBs and alkali-labile sites created through oxidative and alkylated DNA base damage. This study led to a complete picture of how Pol β protein levels are regulated in the cellular response to DNA damage, which involves an interplay between Mule, CHIP, ARF and USP47 activities that control a specific cytoplasmic pool of Pol β that acts as a source of protein that can be utilised in the nucleus in the event of any increase in DNA damage. The above studies together establish that Pol β protein levels are tightly regulated by the promotion or reversal of ubiquitination-dependent proteasomal degradation.
Although Pol β is the chief polymerase in the BER pathway, Pol λ is thought to have a back-up role, specifically in the bypass of 8-oxoguanine lesions and thus avoiding the tendency for the misincorporation of the wrong adenine base opposite the lesion. Initial evidence that Pol λ is regulated by ubiquitination was demonstrated by the observation that a Cdk2/cyclin A phosphorylation defective mutant of Pol λ at threonine 553, was less stable than the wild type protein following expression in either 293T or U2OS cells, and that this was mediated via increased ubiquitination [52]. Phosphorylation of Pol λ was observed most notably in late S and G2 phases of the cell cycle and was thought to stabilise the protein via inhibition of ubiquitination and to allow Pol λ to repair any DNA damage incurred at this stage. The major E3 ubiquitin ligase responsible for Pol λ ubiquitination was subsequently identified using the protein as a substrate in in vitro ubiquitination assays containing fractionated HeLa whole cell lysates and shown to be Mule [53]. Mule was found to ubiquitinate Pol λ on lysines 27 and 273 in vitro, and an siRNA-mediated depletion of Mule in HEK293T cells significantly increased Pol λ protein levels. Cdk2/cyclin A-dependent phosphorylation of Pol λ was found to inhibit Mule-dependent ubiquitination, and promote binding of the protein to chromatin via interaction with MutYH. The E3 ubiquitin ligase CHIP has also been shown to ubiquitinate Pol λ in vitro, although there is no evidence that CHIP plays a role in the regulation of cellular Pol λ in vivo [54]. Since Pol λ and Pol β are both regulated by Mule, this suggests that Mule plays a vital role in controlling the polymerase stage of BER, in addition to the base excision stage described above, and thus is a central player in coordinating the cellular DNA damage response.
Pol δ and ε participate in long-patch BER by adding multiple complimentary nucleotides into the repair gap vacated by Pol β, thus creating a 5′-flap structure which is a substrate for FEN-1. Pol δ is synthesised in human cells as a heterotetramer of subunits p125, p68, p50 and p12. Using an in vitro ubiquitination assay with fractionated HeLa cell lysates, the p12 subunit has been shown to be a target for ubiquitination by the E3 ubiquitin ligase RNF8 [55]. An siRNA knockdown of RNF8 in A549 cells led to an increased stability of p12, particularly following UVC irradiation but also following MNNG treatment. However the precise contribution of this mechanism to BER efficiency is currently unknown. Additionally there is no evidence suggesting that Pol ε is regulated by ubiquitination.
Lig IIIα functions in a stable complex with the scaffold protein XRCC1 to seal the nick in the DNA backbone to complete the BER process. Lig IIIα itself been shown to undergo ubiquitination in two separate reports. In the first, CHIP was demonstrated as an E3 ubiquitin ligase for Lig IIIα in vitro, but also an siRNA knockdown of CHIP in HeLa cells caused an accumulation of Lig IIIα protein in vivo as a consequence of a lack of ubiquitination-dependent degradation [48]. A second E3 ubiquitin ligase for Lig IIIα in vitro has been identified as Iduna/RNF146, which ubiquitinates the protein but only when modified by poly(ADP-ribosyl)ation [38]. However in this study, Iduna was shown to interact with and ubiquitinate a number of DNA repair proteins, including both Lig IIIα and XRCC1 but also PARP1 (as discussed previously) which was dependent on protein poly(ADP-ribosyl)ation. Therefore the particular significance of Iduna-mediated ubiquitination of Lig IIIα and XRCC1 specifically on BER regulation remains unclear. XRCC1 has been shown to be phosphorylated in vitro and in vivo by casein kinase 2 (CK2) and this prevents the ubiquitination-dependent degradation of the protein. This was demonstrated by reduced stability of XRCC1 following CK2 siRNA in HeLa cells and that a CK2 phosphorylation deficient mutant of XRCC1 expressed in EM9 cells was less stable than the wild type protein as a direct consequence of increased ubiquitination [56]. A separate study also demonstrated ubiquitination of XRCC1, although conversely a phosphorylation deficient mutant of XRCC1 expressed in U2OS cells appeared not to be stabilised following proteasomal inhibition [57]. Similar to Lig IIIα, XRCC1 has been found to be ubiquitinated in vitro by the E3 ubiquitin ligase CHIP, and an siRNA-mediated depletion of CHIP in HeLa cells resulted in an increase in XRCC1 protein levels owing to a reduction in ubiquitin-dependent protein degradation [48]. Overexpression of CHIP in HeLa cells was also found to cause a reduced stability of XRCC1 protein. These findings were supported by a separate study that demonstrated that CHIP-dependent ubiquitination of XRCC1 occurs, but only when the protein is not bound to Pol β or heat shock protein 90 (HSP90) [50]. Regarding the site of ubiquitination within XRCC1, this has been identified within the BRCA1 C-terminus (BRCT II) motif after it was demonstrated that truncated XRCC1 lacking this domain was considerably more stable than the full length protein when expressed in either HeLa or EM-C11 cells [48]. This ubiquitination site within the BRCT II motif of XRCC1 was also verified in an independent study [57].
Lig I is employed during long-patch BER, but is also involved in DNA replication. The only reported evidence of Lig I ubiquitination is through the Cul4A-DDB1 E3 ubiquitin ligase complex [58]. Overexpression and immunoprecipitation of Lig I from 293T cells revealed that lysine 376, and possibly lysine 79 and 192, were potential ubiquitination sites and that a lysine to arginine mutant of Lig I at four sites (79, 192, 226 and 376) was more stable than the wild type protein to degradation through serum starvation. Lig I was then demonstrated to interact with and to be ubiquitinated in vitro by a Cul4A-DDB1 complex with the associated factor DCAF7. An siRNA knockdown of DCAF7 in GM00847 cells was shown to supress the degradation of Lig I following serum starvation. This study would suggest that Lig I protein levels are controlled during DNA replication, however the impact of this mechanism for the efficiency of long-patch BER, is still unknown.
An increasing amount of evidence is strengthening the fact that BER is carefully regulated and controlled by ubiquitination. This largely appears to be a mechanism for controlling cellular BER protein levels via the 26S proteasome and therefore plays an important role in supressing DNA damage accumulation and coordinating an efficient cellular DNA damage response. In this Chapter we have presented evidence that the majority of BER proteins have been shown in vitro and in vivo to be targeted for ubiquitination by specific E3 ubiquitin ligases. However there are other proteins (e.g. the DNA glycosylases MBD4, MTH1, NEIL2 and NEIL3) which have not yet been demonstrated to be ubiquitinated directly (Table 1). It is interesting to note that some of the identified E3 ubiquitin ligases appear to target more than one BER protein for ubiquitination. For example, Mule can ubiquitinate both the DNA glycosylases NEIL1 and MUYTH, and the DNA polymerases Pol β and Pol λ for ubiquitination-dependent degradation which would suggest that this E3 ubiquitin ligase, and others targeting multiple BER proteins, can control BER at several different points in the repair pathway. The Cullins, Cul1 and Cul4, also appear to regulate several BER members although this is unsurprising given that they represent the largest family of E3 ubiquitin ligases with several hundred members. In fact the most important element of these complexes is the adaptor proteins that provide specificity of ubiquitination to their target protein. Indeed Cdt2, DCAF7 and STRAP have already been identified as adaptors of the Cul4A-DDB1 complexes that target TDG, Lig I and PNKP, respectively for ubiquitination. Nevertheless, we currently do not have a clear understanding of how these ubiquitination events are controlled and co-ordinated to ensure an efficient BER response to DNA damage. In particular there is insufficient knowledge on how the identified E3 ubiquitin ligase enzymes are activated and directed to their specific enzyme targets. This could be achieved by either compartmentalisation of the enzymes or targets within the cell, or by activation of ubiquitination enzymatic activity by PTMs. Secondly, with ubiquitination being a reversible process, the identities of deubiquitination enzymes that work in concert with E3 ubiquitin ligases in the regulated control of BER proteins have not yet been fully elucidated. In fact the only evidence for this is by USP47, which has been demonstrated to be actively involved in the deubiquitination of Pol β. Thirdly, in addition to ubiquitination, it is clear that BER proteins are also regulated by other PTMs, including acetylation, methylation, phosphorylation and SUMOylation. There is some evidence of crosstalk between these modifications and ubiquitination in regulating BER protein levels and activities, particularly for PARP-1, FEN-1 and PNKP, although this is not yet fully understood. However these regulatory “switches” are undoubtedly an efficient way of controlling the cellular BER response to DNA damage. Ultimately further research is necessary in order to fully identify and understand the specific E3 ubiquitin ligase and deubiquitination enzymes for individual BER proteins, and the precise mechanisms that are co-ordinated in association with other PTMs, which act to ensure an efficient repair process.
E3 ubiquitin ligase | BER protein | Reference |
---|---|---|
CHIP | Lig III | [48] |
OGG1 | [24] | |
Pol β | [48] | |
Pol λ | [54] | |
XRCC1 | [48] | |
Cul1 | SMUG1 | [16] |
UNG | [16] | |
Cul4 | Lig I | [58] |
PNKP | [45] | |
SMUG1 | [16] | |
TDG | [21, 22] | |
UNG | [16] | |
Iduna/RNF146 | Lig III | [38] |
PARP-1 | [38] | |
XRCC1 | [38] | |
MDM2 | APE1 | [41] |
Mule | MUTYH | [26] |
NEIL1 | [34] | |
Pol β | [49] | |
Pol λ | [53] | |
RNF8 | Pol δ | [55] |
TRIM26 | NEIL1 | [34] |
UBR3 | APE1 | [43] |
Unknown | MBD4 | |
NEIL2 | ||
NEIL3 | ||
NTH1 | ||
Pol ε |
Summary of the known E3 ubiquitin ligases targeting BER proteins for ubiquitination.
In addition to discovering the molecular details for regulating cellular BER, research into the associations of these and the development of human diseases, including premature ageing, neurodegenerative diseases and cancer is essential. It is understood that BER protein levels are frequently misregulated in these diseases although whether defective ubiquitination is contributory to this effect is largely unknown and understudied. This information may also uncover novel therapeutic strategies for the treatment of specific diseases. Indeed the BER pathway is known to be an attractive therapeutic target, which is exemplified by the success of PARP inhibitors in the treatment of BRCA-deficient breast cancers which block BER and cause synthetic lethality due to the inability of these cells to process DNA double strand breaks. It is therefore entirely possible that the discovery of E3 ubiquitin ligases or deubiquitination enzymes targeting BER proteins may provide novel cellular targets for drugs or small molecule inhibitors which can be used in combination with radiotherapy and/or chemotherapy for treatment of diseases, such as cancer.
Dr. Jason Parsons is currently supported by funding from North West Cancer Research (CR972, CR1016, CR1074 and CR1145) and by the Medical Research Council via a New Investigator Research Grant (MR/M000354/1).
Parasites since antiquity [1] are a serious threat for millions of humans and animals worldwide which bring about chronic debilitating, periodically disabling disease and are responsible for the overwhelming financial loss [2, 3, 4, 5, 6]. Mosquitoes (Diptera: Culicidae) [7, 8] are among them as they can act as vectors for serious parasites and pathogens, including malaria, filariasis, and important arboviruses, such as dengue, yellow fever, chikungunya, West Nile virus, and Zika viruses [9, 10]. Mosquito control and personal protection from mosquito bites are the most meaningful measures for controlling several life-threatening diseases transmitted exclusively by bites from bloodsucking mosquitoes. Repellents evolved, dates back to antiquity; the Pharaoh Sneferu, reigned from around 2613–2589 BCE and the founder of the fourth dynasty of Egypt, and Cleopatra VII, the last pharaoh of ancient Egypt, used bed nets as protection against mosquitoes; the ancient Egyptians used essential oils (EOs) for repelling insects, medicinal benefits, beauty care, and spiritual enhancement and in literally all aspects of their daily life [1]. Insect-repellent plants have been applied traditionally for thousands of years through different civilizations [11]. Such plants were used in various forms such as hanged bruised plants in houses, crude fumigants where plants were burnt to drive away mosquitoes, and oil formulations applied to the skin or clothes [12]. Smoke is undoubtedly the most extensively exploited means of repelling mosquitoes, typically by burning plants in rural tropics and by utilizing spiral-shaped incenses like Katori Senk—an archetypal icon of the humid Japanese summers [13].
Mosquitoes have been considered as a major obstacle to the tourism industry and socioeconomic development of developing countries particularly in the tropical and endemic regions [14]. Mosquito problems are ancient as old as the pyramids, and the presence of malaria in Egypt from circa 800 BCE onward has been confirmed using DNA-based methods, and antigens produced by Plasmodium falciparum leading to tertian fever in mummies from all periods were detected, and all mummies were suffering from malaria at the time of their death [1]. Herodotus noted down that the builders of the Egyptian pyramids (circa 2700–1700 BCE) were given large amounts of garlic almost certainly to protect them against malaria [1]. Despite recent considerable efforts to control vector-borne diseases, malaria alone produces 250 million cases per year and 800,000 deaths including 85% of children under 5 years [15]. Global warming has moved the mosquitoes on the way to some temperate and higher altitudes, affecting people who are vulnerable to such diseases [16]. Recently, malaria is a great problem in Africa, but it was well controlled in Egypt [1]. Ahead of the development and commercial success of synthetic insecticides in the mid-1930–1950s, botanical insecticides were the leading weapons for insect control. Synthetic insecticides are distinguished by their efficacy, speed of action, ease of use, and low cost. Therefore, they drove many natural control methods as botanicals, predators, and parasitoids to shadows [8, 17, 18]. Insecticidal treatment of house walls, in particular, could provide a very helpful reduction of mosquito incidence, but such measures need financial and organizational demand, but poor rural areas in endemic regions do not have sufficient resources for such costly protective measures. Because of health and environmental concerns [8, 17], there is an urgent need to identify new nonhazardous vector management strategies that replace harmful chemical insecticides and repellents. There are no vaccines or other specific treatments for arboviruses transmitted by mosquitoes; therefore, avoidance of mosquito bites remains the first line of defense [9, 18]. Hence, the use of the mosquito repellents (MRs) on exposed skin area is highly recommended.
Insect repellents usually work by providing a vapor barrier deterring mosquitoes from meeting the skin surface. Insect repellents had been used for thousands of years against biting arthropods. Several species of primates were observed anointing their pelage via rubbing millipedes and plants as Citrus spp., Piper marginatum, and Clematis dioica. Wedge-capped capuchins (Cebus olivaceus) were observed rubbing the millipede Orthoporus dorsovittatus onto their coat during the period of maximum mosquito activity [19]. Such millipede contains benzoquinones and insect-repellent chemicals, and it was hypothesized that the anointing behavior was intended to deter biting insects. Laboratory studies revealed a significant repellent effect of benzoquinones against Aedes (Stegomyia) aegypti (the yellow fever mosquito) and Amblyomma americanum (the lone star tick). Such anointing behavior to deter blood-feeding arthropods is also common among birds, and it could be genetically expressed as an “extended phenotype” as it has an obvious adaptive advantage. Evidence for this lies in the fact that benzoquinones applied to filter paper elicited anointing activity among captive-born capuchins [12]. The World Health Organization (WHO) also recommends repellents for protection against malaria as the resistance of Plasmodium falciparum to anti-malarial drugs such as chloroquine is increased. Most of the commercial MRs are prepared using non-biodegradable, synthetic chemicals like N,N-diethyl-3-methylbenzamide (DEET), dimethylphthalate (DMP), and allethrin which may lead to the environment and, hence, the unacceptable health risks in the case of their higher exposure. With an increasing concern for public safety, a renewed interest in the use of natural products of plant origin is desired because natural products are effective, environmentally friendly, biodegradable, inexpensive, and readily available [7, 8, 13, 17, 20]. Repellent application is a reliable mean of personal protection against annoyance and pathogenic infections not only for local people but also for travelers in disease risk areas, particularly in tropical countries; therefore, this chapter focused on assets and liabilities, safety, and future perspective of synthetic and natural MRs that could potentially prevent mosquito-host interactions, thereby playing an important role in reducing mosquito-borne diseases when used correctly and consistently.
The history of synthetic repellents had been reviewed [12]; before World War II, MRs were primarily plant-based with the oil of citronella being the most widely used compound and the standard against which others were evaluated. At that time, the emergence of synthetic chemical repellents starts. There were only three principal repellents: dimethylphthalate discovered in 1929, Indalone® (butyl-3,3-dihydro-2,2-dimethyl-4-oxo-2H-pyran-6-carboxylate) patented in 1937, and Rutgers 612 (ethyl hexanediol), which became available in 1939. Later on and for military use, 6-2-2 of M-250 (a mixture of six parts DMP and two parts each Indalone® and Rutgers 612) was used [13]. The event of World War II was the primary switch on in the development of new repellent technologies because the Pacific and North African theaters posed significant disease threats to allied military personnel. Over 6000 chemicals had been tested from 1942 to 1947 in a variety of research institutions led to the identification of multiple successful repellent chemistries. Such great aim established several independent research projects that inevitably identified one of the most effective and widely used insect repellents to date, DEET. From then on, several compounds have been synthesized relying on previous research, which identified amide and imide compounds as highly successful contact repellents. Among these are picaridin, a piperidine carboxylate ester, and IR3535, which are currently considered DEET competitors in some repellency bioassays [21]. The chemical structures of some synthetic repellents are shown in Figure 1.
Chemical structures of some synthetic repellents.
DEET (N,N-diethyl-3-methylbenzamide) is the standard and most effective broad-spectrum insect-repellent component with a long-lasting effect on mosquitoes, ticks, as well as biting flies, chiggers, and fleas. DEET was discovered as a mosquito repellent by the US Department of Agriculture and patented by the US Army in 1946. It was allowed for public use in 1957, and since then it has been a standard repellent for several insects and arthropods [14]. DEET is the most studied insect repellent and mainly used as a positive control to compare the efficacy of many repellent substances. DEET has a dose-dependent response: the higher the concentration, the longer the protection. DEET, 20–25%, is the conventional concentration used in commercial products. The shorter protection time depended on the mixture as well [14]. In fact, DEET plays a limited role on disease control in endemic regions because of its high cost, unpleasant odor, and inconvenience of the continuous application on the exposed skin at high concentrations [22, 23].
Permethrin is a pyrethroid insecticide derived from the plant Chrysanthemum cinerariifolium. It was registered in the US in 1979 as both repellent and insecticide. Recently, it is the most common insecticide available for use on fabrics such as clothing, bed nets, etc. for its exclusive role as a contact insecticide via neural toxicity and equally as an insect repellent [7, 8, 13, 17]. The protection offered against a broad range of bloodsucking arthropods with negligible safety concerns ranked permethrin-treated clothing an important arthropod protection technique especially when used in combination with other protection strategies as applying topical repellents [13].
Picaridin (1-piperidinecarboxylic acid 2-(2-hydroxyethyl)-1-methylpropylester) is a colorless, nearly odorless piperidine analog that was developed by Bayer in the 1980s through molecular modeling [12]. It is also known as KBR 3023, icaridin, hydroxyethyl isobutyl piperidine carboxylate, and sec-butyl-2-(2-hydroxyethyl)-piperidine-1-carboxylate. Its trade names include Bayrepel and Saltidin, among others. Picaridin was first marketed in Europe in the 1990s and later in the US in 2005 [24, 25]. The efficacy of picaridin is as good as DEET, and notably, 20% picaridin spray was found to protect against three main mosquito vectors, Aedes, Anopheles, and Culex for about 5 h with better efficacy than that of DEET. Therefore, repeated application is required every after 4–6 h [13]. In Australia, a formulation containing 19.2% picaridin provided similar protection as 20% DEET against Verrallina lineata [26]. The same formulation provided >95% protection against Culex annulirostris for 5 h but only 1-hour protection against Anopheles spp. [26]. Picaridin at concentrations of 2–13% v/v in 90% ethanol showed better protection against anophelines in Africa than comparable formulations containing DEET [27]. Field studies against mosquitoes in two locations in Australia indicated that a 9.3% formulation only provided 2-hour protection against V. lineata [26, 28]. It had been concluded that studies showed little significant difference between DEET and picaridin when applied at the same dosage, with a superior persistence for picaridin [29]. To maintain effectiveness than with the higher concentrations (>20%) of picaridin used in the field.
N,N-diethyl-2-phenyl-acetamide (DEPA) is a repellent developed around the same time as DEET and repels a wide range of insects, but DEPA did not get its reputation. The repellency of DEPA has demonstrated almost similar to DEET against mosquito vectors as Ae. aegypti, Ae. albopictus, An. stephensi, and C. quinquefasciatus [13]. It has regained interest recently and could prove to be an important competitor to DEET especially in developing countries due to its low cost, $25.40 per kg compared to $48.40 per kg for DEET [30].
Learning from nature offered a molecule with an impressive performance in comparison to a natural and pure synthetic repellent solution called insect repellent 3535 (IR3535). Scientists got inspirations from nature for the development of the topical IR 3535 with the intention to create a molecule with optimized protection times and low toxicity. The naturally occurring amino acid β-alanine was used as a basic module, and the selected end groups were chosen to avoid toxicity and increase efficacy. IR 3535 was developed by Merck in 1970 and thus named as Merck IR3535; it has been available in Europe, but it was not available in the USA until 1999 [12]. IR3535 is used for humans and animals, as it is effective against mosquitoes, ticks, flies, fleas, and lice. Its chemical formula is C11H21NO3, and its other names are ethyl-N-acetyl-N-butyl-β-alaninate, ethyl butylacetylaminopropionate (EBAAP), β-alanine, and N-acetyl-N-butyl-ethyl ester. The protection of IR 3535 may be comparable to DEET, but it requires frequent reapplication in every 6–8 h. IR3535 is found in products including Skin So Soft Bug Guard Plus Expedition (Avon, New York, NY) [31]. Although 20% IR 3535 provides complete protection against Aedes and Culex mosquitoes (up to 7–10 h), it offers lesser protection against Anopheles (about 3.8 h), which affects its application in malaria-endemic areas [13].Several field studies were identified and indicated that IR 3535 is as effective as similarly, DEET in repelling mosquitoes of the Aedes and Culex genera but may be less effective than DEET in repelling anopheline mosquitoes; an uncontrolled field study of a controlled release formulation of IR 3535 reported that these formulations may provide complete protection against mosquito biting for 7.1–10.3 h [32].
Ethyl anthranilate (EA) is a new member in the scope of entomology which drew a significant attention in repellent research in the recent years and is being considered as an improved alternative to DEET [13, 33]. It is a nontoxic, the US FDA approved volatile food additive. EA is novel and repellent against Ae. aegypti, An. stephensi, and Cx. quinquefasciatus as its ED50 values of EA were 0.96, 5.4, and 3.6% w/v, respectively, and CPTs of EA, 10% w/v, throughout the arm-in-cage method were 60, 60, and 30 min, respectively. Moreover, its spatial repellency was found to be extremely effective in repelling all the three tested species of mosquitoes. EA provided comparable results to standard repellent DEPA. As a result, the repellent activity of EA is promising for developing effective, safe, and eco-friendly alternative to the existing harmful repellents for personal protection against different mosquito species [34].
The comparative efficacy of synthetic repellents had been summarized [14] as follows: Aedes species demonstrated an aggressive biting behavior and Ae. Aegypti, above all, proved to be tolerant to many repellent products. Ae. albopictus was easier to be repelled than Ae. aegypti. DEET is the most studied insect repellent; at higher concentrations, it presented superior efficacy against Aedes species, providing up to 10 h of protection. Although IR3535 and picaridin showed good repellency against this mosquito genus, their efficacy was on average inferior to that provided by DEET. Fewer studies have been conducted on the mosquito species Anopheles and Culex. The repellency profile against Anopheles species was similar for the four principal repellents of interest: DEET provided on average 5–11 h, IR 3535 4–10 h, picaridin 6–8 h, and Citriodora 1–12 h of protection, depending on study conditions and repellent concentration. Culex mosquitoes are easier to repel, and each repellent provided good protection against this species. DEET showed 5–14 h of protection and IR 3535 2–15 h, depending on product concentration, while the test proving the efficacy of picaridin and commercial products containing PMD was discontinued after 8 h of protection. To go over the main points, DEET remains probably the most efficient insect repellent against mosquitoes, effective against sensitive species as Culex as well as more repellent-tolerant species such as Aedes and Anopheles. Even though fewer studies have been conducted on these non-DEET compounds, picaridin and to some extent IR 3535 represent valid alternatives. Consequently, the choice of repellents could be adjusted somehow according to the profile of biting vectors at the travelers’ destination.
Nature is an old unlimited source of inspiration for people [1, 11, 18, 35] as well as for scientific and technological innovations. Recently, global attention has been paid toward exploring the medicinal benefits of plant extracts [4, 11, 36, 37]. Repellents of natural origin are derived from members of the families as Asteraceae, Cupressaceae, Labiatae, Lamiaceae, Lauraceae, Meliaceae, Myrtaceae, Piperaceae, Poaceae, Rutaceae, Umbelliferae, and Zingiberaceae. They have been evaluated for repellency against various mosquito vectors, but few compounds have been found commercially. Increased curiosity in plant-based arthropod repellents was generated after the United States Environmental Protection Agency (US EPA) added a rule to the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) in 1986 exempting compounds considered to be minimum hazardous pesticides [30]. Increased interest has also been driven by the rapid registration process of plant-based repellents by US EPA, which are often registered in less than a year, while the conventional pesticides are registered in an average of 3 years [30]. The public considers botanicals as safer and suitable alternative repellents; most of them are produced and distributed locally and appear on the market for only a short time. Even though many studies have shown that almost all registered commercial products based on botanical active ingredients offer limited protection and require frequent reapplication than even a low concentration of DEET-based repellents, the growing demand for natural alternative repellents in the community illustrates further need to evaluate new botanical repellents critically for personal protection against mosquitoes and mosquito-borne illnesses [7, 8, 13, 17]. The repellent activity of EOs includes some metabolites, such as the monoterpenes α-pinene, cineole, eugenol, limonene, terpinolene, citronellol, citronellal, camphor, and thymol that are repellents against mosquitoes; the sesquiterpene, β-caryophyllene, is repellent against A. aegypti, and phytol, a linear diterpene alcohol, is repellent against Anopheles gambia. Most of the arthropod-repellent compounds are oxygenated, having the hydroxyl group linked to a primary, secondary, or aromatic carbon. In some metabolites having a hydroxyl group linked to a tertiary carbon, as linalool, α-terpineol, and limonene, the repellent activity is suppressed against A. gambiae, suggesting the likelihood that the type of carbon where the hydroxyl substitution is there modulates repellency. Most insect repellents are volatile terpenoids such as terpinen-4-ol. Other terpenoids can act as attractants. More information is widely discussed [7, 38], and chemical structures of some natural repellent compounds are shown in Figure 2.
Chemical structures of some natural repellent compounds found in botanical species.
Compound p-menthane-3,8-diol (PMD is derived from lemon-scented eucalyptus (Eucalyptus citriodora, Myrtaceae) leaves, and its importance as a repelling agent is increasing due to its good efficacy profile as well as its natural basis. PMD is a potent and commercially available repellent discovered in the 1960s via mass screening of plants for repellent activity, for instance, lemon eucalyptus and Corymbia citriodora (Myrtaceae) formerly known as Eucalyptus maculata citriodora. Lemon eucalyptus EO contains 85% citronellal and is already used in cosmetic industries due to its fresh smell. It was discovered when the waste distillate remaining after hydro-distillation of the EO was far more effective at repelling mosquitoes than the EO itself, and it provides very high protection from a broad range of insect vectors for several hours as well [7, 39]. The EO from C. citriodora also contains active constituents like citronella, citronellol, geraniol, isopulegol, and δ-pinene which play important roles in repelling both mosquitoes and ticks. Such compounds provide short-term repellency against mosquitoes, but PMD has a longer protection time than other plant-derived compounds because it is a monoterpene with low volatility than volatile monoterpenes found in most EOs and does not tend to evaporate rapidly after skin application [7, 8, 14].
There have been attempts to commercialize and market the insecticides/repellent products containing eucalyptus oil as such or based upon them. Crude eucalyptus oil was primarily registered as an insecticide and miticide in the USA in 1948, and 29 of such compounds have been registered in the USA until the year 2007 for use as natural insecticide/insect repellent/germicide. Only four products of them have been active, whereas 25 have been canceled. These include Citriodiol, Repel essential insect repellent lotion (two variants), Repel essential insect repellent pump spray, and Repel insect repellent 30 by the United Industrial Corp., USA. Some eucalyptus-based products include the following: Quwenling is successfully marketed as an insect repellent in China and provides protection against anopheles mosquitoes parallel to DEET and has exchanged the widely used synthetic repellent dimethylphthalate; Quwenling contains a mixture of PMD, citronellol, and isopulegone. Mosiguard Natural contains 50% eucalyptus oil, Buzz Away is a commercially available product in China based on citronellal, and MyggA1 Natural is based on PMD from lemon eucalyptus and is shown to repel ticks. More details are widely discussed [40].
The name “Citronella” is derived from the French word “citronelle” around 1858. It was extracted to be used in perfumery and used by the Indian Army to repel mosquitoes at the beginning of the twentieth century and was then registered for commercial use in the USA in 1948. Today, citronella (5–10%) is one of the most widely used natural repellents on the market; such concentrations are lower than most other commercial repellents, whereas higher concentrations can cause skin sensitivity. Among plant-derived substances, products containing Citriodiol showed the most effective repellent profile against mosquitoes. EOs and extracts belonging to plants in the Citronella genus (Poaceae) are commonly used as ingredients of plant-based mosquito repellents, mostly Cymbopogon nardus that is sold in Europe and North America in commercial preparations [39]. Citronella contains citronellal, citronellol, geraniol, citral, α-pinene, and limonene giving an effect similar to that of DEET, but the oils rapidly evaporate causing loss of efficacy and leaving the user unprotected. Among plant-derived substances, products containing Citriodiol showed the most effective repellent profile against mosquitoes. For travelers heading to disease-endemic areas, citronella-based repellents should not be recommended, but if efficacious alternatives are prohibitively expensive or not available, the use of citronella to prevent mosquito bites may provide important protection from disease vectors. Even though citronella-based repellents only give protection from host-seeking mosquitoes for a short time (2 h), formulations could prolong such time (please see the formulation section).
The aromatic plants of the Meliaceae family which include neem, Azadirachta indica, Carapa procera, Melia azedarach, Khaya senegalensis, and Trichilia emetica contain substances of the limonoid group and insecticidal and repellent effects on insects [18]. Neem provided a protection of 98.2% for 8 h against An. darlingi. Regardless of being not approved by US EPA for use as a topical insect repellent, neem is widely advertised as a natural alternative to DEET, and it has been tested for repellency against a wide range of arthropods of medical and veterinary importance. MiteStop®, based on a neem seed extract, had a considerable repellent effect on bloodsucking mosquitoes, tabanids, ceratopogonids, simuliids, as well as licking flies [41]. Several field studies from India have shown the very high efficacy of neem-based preparations, contrasting with findings of intermediate repellency by other researchers. However, these contrasting results may be due to differing methodologies and the solvents used to carry the repellents.
Methyl jasmonate (MJ) is derived from the nonvolatile jasmonic acid and has the ultimate vapor pressure for a repellent (0.001 mmHg at 25°C) which is quite higher than DEET. It repels only Cx. quinquefasciatus but does not repel Ae. aegypti, An. gambiae, Phlebotomus flies, and Glossina morsitans, which restricts the application of MJ to C. quinquefasciatus mosquitoes only. On the other hand, MJ has been found to cause aversion in a number of ticks such as nymphal I. ricinis and Hyalomma marginatum rufipes Koch, etc. [30].
EOs are used against insects [20, 42, 43, 44, 45, 46, 47, 48, 49, 50] throughout the globe. EOs are distilled from members of the Lamiaceae (mint family), Poaceae (aromatic grasses), and Pinaceae (pine and cedar family). EOs could be used for farm animal protection against nuisance flies and lice [47]. Almost all of the botanical repellents are also used for food flavoring or in the perfume industry, indicating that they are safer than DEET. The most effective oils include thyme, geraniol, peppermint, cedar, patchouli, and clove that have been found to repel malaria, filarial, and yellow fever vectors for a period of 60–180 mins. Most of these EOs are highly volatile, and this contributes to their poor longevity as mosquito repellents. As a result, repellents containing only EOs in the absence of an active ingredient such as DEET should not be recommended as repellents for use in disease-endemic areas, whereas those containing high levels of EOs could cause skin irritation, especially in the presence of sunlight [39]. Although EOs effectively repel mosquitoes as irritants, repellents, antifeedants, or maskants, unfortunately, relatively few have been commercialized, despite being widely used in candles and as topical insect repellents. Botanical, herbal, or natural-based repellents include one or several plant EOs. These oils are considered safe by the EPA at low concentrations but provide a limited duration of protection against mosquitoes (<3 h). Citronella (discussed previously) is the principal and sometimes only active ingredient in many plant-based insect repellents [7]. Eucalyptus oil is used as an antifeedant mainly against biting insects as eucalyptus-based products used on humans as insect repellent can give protection from biting insects up to 8 h depending upon the concentration of the essential oil. Such repellent activity could be extended up to 8 days when eucalyptus EOs are applied on the clothes. Eucalyptus oil (30%) can prevent mosquito bite for 2 h; however, the oil must have at least 70% cineole content [40]. On the other hand, E. citriodora EO alone showed an insufficient protection against the three main mosquito species [14].
Insect repellents containing DEET are broadly used among populations. DEET should be used with caution as it may damage spandex, rayon, acetate, and pigmented leather and it could dissolve plastic and vinyl (e.g., eyeglass frames). Moreover, DEET damages synthetic fabrics and painted and varnished surfaces, precluding its use in bed nets and in many urban settings [51]. Being the gold standard of repellents, the safety profile of DEET is largely studied. There is an estimated 15 million people in the UK, 78 million people in the USA, and 200 million people globally that use DEET each year safely when it is applied to the skin at the correct dose indicated at the commercial preparation (in the case of it not being swallowed or rubbed into the mucous membranes). DEET has been used since 1946 with a tiny number of reported adverse effects, many of which had a history of excessive or inappropriate use of repellent. Its toxicology has been more closely scrutinized than any other repellent, and it has been deemed safe for human use, including its use on children, pregnant women, and lactating women [39]. Even though insect repellents containing DEET are safe, some side effects have been described, mainly after inappropriate use such as dermatitis, allergic reactions, neurologic and cardiovascular side effects, as well as encephalopathy in children. In addition, there are a small number of reports of systemic toxicity in adults following dermal application. The safety profile in the second and third trimester of pregnancy has been well known through inspection of very low placental cord concentrations after maternal application of DEET, but animal models do not indicate any teratogenic effects. DEET also blocks mammalian sodium and potassium ion channels contributing to the numbness of lip following the application of DEET [13]. Approval for use in young children is a controversial issue between countries, with some recommending lower concentrations, whereas others suggesting that higher strengths can be used. However, the causation between the few reported cases of encephalopathy in children and the topical use of DEET cannot be supported by a good evidence base [14, 39].
When permethrin is impregnated appropriately in cloths and nets, toxicity fearfulness is minimal [52]. Although synthetic pyrethroids are utilized worldwide as active ingredients in MRs [15] due to their relatively low toxicity to mammals [53], inappropriate application at high doses initiates neurotoxic effects such as tremors, loss of coordination, hyperactivity, paralysis, and an increase in body temperature. Other side effects include skin and eye irritation, reproductive effects, mutagenicity, alterations in the immune system, etc. [13]. Recent studies also showed that some pyrethroids are listed as endocrine disruptors and possible carcinogens [53] and pyrethroids might cause behavioral and developmental neurotoxicity, with special concern revolving around infants and children, due to their potential exposure during a sensitive neurodevelopmental stage [54]. More evidence in the recent years indicates that pyrethroid insecticides can reduce sperm count and motility, cause deformity of the sperm head, increase the count of abnormal sperm, damage sperm DNA, induce its aneuploidy rate, affect sex hormone levels, and produce reproductive toxicity [55]. Moreover, an elevated concentration of transfluthrin in the gaseous phase during the indoor application of an electric vaporizer was detected, but they found inhalation risk of airborne transfluthrin was low. The exposure levels and potential risk of pyrethroids during the applications of other types of commonly used MRs remain unknown [53]. On the other hand, long-term exposure to pyrethroid-based MRs in indoor environments causes chronic neurotoxicity, for example, dysfunction of blood-brain barrier permeability, oxidative damage to the brain, [56] and cholinergic dysfunction which cause learning and memory deficiencies [57]. Even though ventilation through natural air exchange and conditioner dissipate of airborne pollutants, residues persisting in the air and/or on indoor surfaces could potentially cause continuous exposure to the residents.
US EPA-OPP’s Biochemical Classification Committee classified IR 3535 as a biochemical in 1997, because it is functionally identical to naturally occurring beta-alanine in that both repel insects, the basic molecular structure is identical, the end groups are not likely to contribute to toxicity, and it acts to control the target pest via a nontoxic mode of action [58]. No reported toxicity has been made so far against IR 3535, and it induces less irritation to mucous membranes and exhibits safer oral and dermal toxicity than DEET which makes it an attractive alternative to DEET in disease-inflicted endemic regions [13]. The ester structure of the propionate grants essential advantages because of a short metabolic degradation and quick excretion as a simple water-soluble acid [58]. Picaridin has the advantage of being odorless and non-sticky or greasy. Moreover, unlike DEET, picaridin does not damage plastics and synthetics. In some studies, picaridin induces no adverse toxic reactions in animal studies but exhibits low toxicity and less dermatologic and olfactory irritant in other studies. Consequently, picaridin’s comparable efficacy to DEET and its suitability of application and favorable toxicity profile ranked it as an attractive option and unquestionably an acceptable alternative for protection against mosquitoes and other hematophagous arthropods to control the menace of vector-borne diseases in endemic areas [13]. DEPA does not show cytotoxicity or mutagenicity [59], thereby increasing its suitability in direct skin application. It also exhibits moderate oral toxicity (mouse oral LD50 900 mg/kg) and low to moderate dermal toxicity (rabbit and female mouse LD50 of 3500 and 2200 mg/kg, respectively) [60]. Acute and subacute inhalation toxicity studies of DEPA have also been reported [61] which indicate its applicability as aerosol formulations. Indalone was an early synthetic repellent effective against both mosquitoes and ticks. It was even more effective than DEET; however, its chronic exposure induced kidney and liver damage in rodents which restricted its application [13]. EA is approved by the US FDA, WHO and European Food Safety Authority (EFSA) [62, 63]. Furthermore, EA has been listed in the “generally recognized as safe” [64] list by the Flavour and Extract Manufacturers Association (FEMA) [65]. EA does not damage synthetic fabrics, plastics, and painted and varnished surfaces which further widen the utility of EA in bed nets, cloths, and different surfaces in the endemic settings [14, 66].
Because many conventional pesticide products fall into disfavor with the public, botanical-based pesticides should become an increasingly popular choice as repellents. There is a perception that natural products are safer for skin application and for the environment, just because they are natural and used for a long time compared to synthetic non-biodegradable products [14]. In contrast to DEET, some natural repellents are safer than others, and plant-based repellents do not have this strictly tested safety evidence, and many botanical repellents have compounds that need to be used with caution [39]. PMD has no or very little toxicity to the environment and poses no risks to humans and animals. PMD has been developed and registered for use against public health pests and is available as a spray and lotion. Not much is known about the toxicity of eucalyptus oils; however, they have been categorized as GRAS by the US EPA. Further, the oral and acute LD50 of eucalyptus oil and cineole to rat is 4440 mg/kg body weight (BW) and 2480 mg/kg BW, respectively, making it much less toxic than pyrethrins (LD50 values 350–500 mg/kg BW; US EPA, 1993) and even technical grade pyrethrum (LD50 value 1500 mg/kg BW) [40]. PMD is an important component of commercial repellents in the US and registered by US EPA and Canadian Pest Management Regulatory Agency in 2000 and 2002, respectively [13]. In contrary, lemon eucalyptus EO does not have US EPA registration for use as an insect repellent. PMD is the only plant-based repellent that has been advocated for use in disease-endemic areas by the Centers for Disease Control (CDC), due to its proven clinical efficacy to prevent malaria, and is considered to pose no risk to human health [39]. In 2005, the US Centers for Disease Control and Prevention made use of its influence by endorsing products containing “oil of lemon eucalyptus” (PMD), along with picaridin and DEET as the most effective repellents of mosquito vectors carrying the West Nile virus [67]. PMD provides excellent safety profile with minimal toxicity. In studies using laboratory animals, PMD demonstrated no adverse effects apart from eye irritation. It is safe for both children and adults as the toxicity of PMD is very low. However, the label indicates it should not be used on children under the age of 3 [7].
The safety of neem is extensively reviewed; azadirachtin is nontoxic to mammals and did not show chronic toxicity. Even at high concentrations, neem products were neither mutagenic nor carcinogenic, and they did not produce any skin irritations or organic alterations in mice and rats. On the other hand, reversible reproduction disturbances could occur due to the daily feeding of aqueous leaf extract for 6 and 9 weeks led to infertility of rats at 66.7 and 100%, respectively. Using unprocessed and aqueous neem-based products should be encouraged if applied with care. The pure compound azadirachtin, the unprocessed materials, the aqueous extracts, and the seed oil are safe to use even as insecticides to protect stored food for human consumption, whereas nonaqueous extracts turn out to be relatively toxic [8]. From the ecological and environmental standpoint, azadirachtin is safe and nontoxic to fish, natural enemies, pollinators, birds, and other wildlife. Azadirachtin is classified by the US EPA as class IV (practically nontoxic) [7, 8, 17] as azadirachtin breaks down within 50–100 h in water and is degraded by sunlight as the half-life of azadirachtin is only 1 day, leaving no residues. Safety and advantages of EOs are widely discussed [7, 8, 17, 39]. There is a popular belief that EOs are benign and harmless to the user. Honestly, increasing the concentration of plant EOs as repellents could increase efficacy, but high concentrations may also cause contact dermatitis. Some of the purified terpenoid ingredients of EOs are moderately toxic to mammals. Because of their volatility, EOs have limited persistence under field conditions. With few exceptions, the oils themselves or products based on them are mostly nontoxic to mammals, birds, and fish. Many of the commercial products that include EOs (EOs) are on the “generally recognized as safe” [64] list fully approved by the US FDA and EPA for food and beverage consumption. Moreover, EOs are usually devoid of long-term genotoxic risks, and some of them show a very clear antimutagenic capacity which could be linked to an anticarcinogenic activity. The prooxidant activity of EOs or some of their constituents, like that of some polyphenols, is capable of reducing local tumor volume or tumor cell proliferation by apoptotic and/or necrotic effects. Due to the capacity of EOs to interfere with mitochondrial functions, they may add prooxidant effects and thus become genuine antitumor agents. The cytotoxic capacity of the essential oils, based on a prooxidant activity, can make them outstanding antiseptic and antimicrobial agents for personal uses, that is, for purifying air, personal hygiene, or even internal use via oral consumption and for insecticidal use for the preservation of crops or food stocks. Some EOs acquired through diet are actually beneficial to human health [68, 69]. Eugenol is an eye and skin irritant and has been shown to be mutagenic and tumorigenic. Citronellol and 2-phenylethanol are skin irritants, and 2-phenylethanol is an eye irritant, mutagen, and tumorigenic; they also affect the reproductive and central nervous systems [30]. Hence, it is advised that EOs with toxic profile should be used for treating clothing rather than direct application to individual’s skin [13]. Although EOs are exempt from registration through the US EPA, they can be irritating to the skin, and their repellent effect is variable, dependent on formulation and concentration. The previously mentioned safety and advantages designate that EOs could find their way from the traditional into the modern medical, insecticidal, and repellent domain.
Several diseases transmitted by mosquitoes cause high losses of human and animal lives every year. DEET is considered as a “gold standard” to which other candidate repellents are compared; therefore, DEET is the most ever-present active ingredient used in commercially available repellents, with noteworthy protection against mosquitoes and other biting insects. Unfortunately, the widespread use and effectiveness of commercial formulations containing DEET and other synthetic substances could lead to resistance [70, 71]. Some health and environmental concerns lead to the search for natural alternative repellents. The use of repellent plants has been used since antiquity [1], and it is the only effective protection available for the poor people against vectors and their associated diseases [71]. Ethnobotanical experience is passed on orally from one generation to another, but it needs to be preserved in a written form and utilized as a rich source of botanicals in repellent bioassays. Then again, the growing demand for natural repellents points up the further necessity to evaluate new plant-based products critically for personal protection against mosquitoes and mosquito-borne diseases [7, 8, 17, 18]. Regarding environmental and health concerns, plant-based repellents are better than synthetic molecules. Even though many promising plant repellents are available, their use is still limited; therefore, advance understanding of the chemical ecology of pests and the mode of repellency would be helpful for identifying competitor semiochemicals that could be incorporated into attractant or repellent formulations. There are numerous commercially available formulations enhancing the longevity of repellent, by controlling the rate of delivery and the rate of evaporation. Such formulations are very useful to people living in the endemic areas in the form of sprays, creams, lotions, aerosols, oils, evaporators, patch, canister, protective clothing, insecticide-treated clothing, and insecticide-treated bed nets [7, 8, 17]. The potential uses and benefits of microencapsulation and nanotechnology are enormous including enhancement involving nanocapsules for pest management and nanosensors for pest detection [7, 8]. Nanoparticles are effectively used to control larvae [72, 73, 74, 75, 76] and to repel adults of mosquitoes [77, 78].
Polymer-based formulations allow entrapping active ingredients and provide release control. Encapsulation into polymeric micro/nanocapsules, cyclodextrins, polymeric micelles, or hydrogels constitutes an approach to modify physicochemical properties of encapsulated molecules. Such techniques, applied in topical formulations, fabric modification for personal protection, or food packaging, have been proven to be more effective in increasing repellency time and also in reducing drug dermal absorption, improving safety profiles of these products. In this work, the main synthetic and natural insect repellents are described as well as their polymeric carrier systems and their potential applications [79]. Encapsulated EO nanoemulsion is prepared to create stable droplets to increase the retention of the oil and slow down release. The release rate correlates well to the protection time so that a decrease in release rate can prolong mosquito protection time. Microencapsulation is another way to slowly release the active ingredients of repellents. In laboratory conditions, the microencapsulated formulations of the EOs showed no significant difference with regard to the duration of repellent effect compared to the microencapsulated DEET used at the highest concentration (20%). It exhibited >98% repellent effect for the duration of 4 h, whereas, in the field conditions, these formulations demonstrated the comparable repellent effect (100% for a duration of 3 h) to Citriodiol®-based repellent (Mosiguard®). In both test conditions, the microencapsulated formulations of the EOs presented longer duration of 100% repellent effect (between 1 and 2 h) than non-encapsulated formulations [80]. Microencapsulation reduces membrane permeation of CO while maintaining a constant supply of the citronella oil [81]. Moreover, using gelatin Arabic gum microcapsules also prolonged the effect of natural repellents. In addition, the functionalization of titanium dioxide nanoparticles on the surface of polymeric microcapsules was investigated as a mean to control the release of encapsulated citronella through solar radiation. The results showed that functionalizing the microcapsules with nanoparticles on their surface and then exposing them to ultraviolet radiation effectively increased the output of citronella into the air for repelling the mosquitoes without human intervention, as the sunlight works as a release activator [82].
It is recommended to use US EPA-registered insect repellents including one of the active ingredients: DEET, Picaridin, IR3535, Oil of lemon eucalyptus (OLE), Para-menthane-diol (PMD), and 2-undecanone. Synthetic MRs are applied for years but induced some safety and environmental concerns; as a result, the advancement in the development of repellents from the botanical origin is encouraged. But some obstacles are hindering botanical repellents which as the source availability, standardization, commercialization, and analyses in order to certify the efficacy and safety [7]. Commercially available repellents are provided in Table 1. For saving time and efforts, a high-throughput chemical informatics screen via a structure-activity approach, molecular-based chemical prospecting [83], as well as computer-aided molecular modeling [84] would accelerate the exploration of new environmentally safe and cost-effective novel repellents which activated the same chemosensory pathways as DEET at a fairly shorter time and lower costs [13]. The selection of various repellents could be tailored along with the profile of safety concerns and biting vectors at the travelers’ and military destinations by reducing annoyance and the incidence of illness. The use of these technologies to enhance the performance of natural repellents may revolutionize the repellent market and make EOs a more viable option for use in long-lasting repellents. Green technologies and cash cropping of repellent plants afford a vital source of income for small-scale farmers and producers in developing countries and raise the national economy. Moreover, in some developing countries where tourism is a chief source of national income, the use of repellents would increase the pleasure and comfort of tourists. Finally, much faster work needs to be done to discover new and safe repellents for personal protection from mosquitoes.
Repellent composition | Dose | Study variety | Mosquito spp. | Mean CPT | Protection | Reference | |||
---|---|---|---|---|---|---|---|---|---|
% | Time interval | ||||||||
Bio Skincare® | Natural oil of jojoba, rapeseed, coconut, and vit. E | 1.2 g/arm | Arm-in-cage | An. arabiensis | 100 52 | 3–4 h 6 h | [85] | ||
BioUD® spray | 7.75% 2-undecanone | 1 ml/600 cm2 | Arm-in-cage | Ae. aegypti | 96.1 86.7 81.7 79.5 70.1 68.2 | 1 h 2 h 3 h 4 h 5 h 6 h | [86] | ||
Ae. albopictus | 94.5 98.3 93.1 79.4 87.4 76.3 | 1 h 2 h 3 h 4 h 5 h 6 h | |||||||
7.75% 2-undecanone | 1 ml/600 cm2 | Field trial in North Carolina (USA) | Ae. atlanticus/tormentor (23.3%) Psorophora ferox (54.7%) | 98.4 94.2 92.2 79 | 3 h 4 h 5 h 6 h | ||||
Field trial in Canada | Ae. vexans (32%) Ae. euedes (29.3%) Ae. stimulans (15.3%) | 95.5 95.6 | 4 h 6 h | ||||||
Bite Blocker® lotion | Glycerin, lecithin, vanillin, oils of coconut, geranium, and soybean (2%) | 1 ml/650 cm2 | Arm-in-cage | Ae. albopictus Cx. nigripalus | 5.5 h 8.3 h | [87] | |||
Bite Blocker Xtreme® | 3% soybean oil 6% geranium oil 8% castor oil | Field trial in Canada | Ae. vexans (32%) Ae. euedes (29.3%) Ae. stimulans (15.3%) | 93.9 53.7 | 4 h 6 h | [86] | |||
Buzz Off Insect Repellent® | Natural plant extract | 1 g/forearm | Arm-in-cage | Ae. aegypti Ae. vigilax Cx. Annulirostris Cx. quinquefasciatus | 0 min 0 min 160 min 50 min | [88] | |||
Baygon® | Oils of canola, eucalyptus, peppermint, rosemary, and sweet birch | 1 ml/650 cm2 | Arm-in-cage | Ae. albopictus Cx. nigripalus | 0.2 h 4.7 h | [87] | |||
Citronella candles | 3% citronella | Field trial in Canada | Aedes spp. | 42.3 | [89] | ||||
Citronella incense | 5% citronella | Field trial in Canada | Aedes spp. | 24.2 | [89] | ||||
GonE!® | Aloe vera, camphor, menthol, oils of eucalyptus, lavender, rosemary, sage, and soybean | 1 ml/650 cm2 | Ae. albopictus Cx. nigripalus | 0.0 h 2.8 h | [87] | ||||
Green Ban for People® | Citronella 10%, peppermint oil 2% | Arm-in-cage | Ae. aegypti | 14 min | [90] | ||||
Herbal Armor® | Citronella 12%, peppermint oil 2.5%, cedar oil 2%, lemongrass oil 1%, geranium oil 0.055 | Arm-in-cage | Ae. aegypti | 18.9 min | [90] | ||||
Kor Yor 15 DEET lotion® | DEET 24%, dimethylphthalate 24% | 0.1 ml/30 cm2 | Arm-in-cage | Ae. aegypti | 3 h | [91] | |||
DEET 24%, dimethylphthalate 24% | 0.1 ml/30 cm2 | Arm-in-cage | Ae. aegypti | 3 h | [92] | ||||
MeiMei® cream | Citronella and geranium oils | Indoor test | Ae. aegypti | 97 97 85 44 27 | 30 min 50 min 70 min 90 min 120 min | [93] | |||
Citronella and geranium oils | Field trial in South Korea | Aedes (7.8%) Armigeres (5.9%) Anopheles (42.2%) Culex (44.1%) | 90 57 56 34 | 30 min 90 min 150 min 210 min | [94] | ||||
Mistine censor® | IR 3535 12%, rosemary, lavender, and eucalyptus | 0.1 ml/30 cm2 | Arm-in-cage | Ae. aegypti | 1 h | [91] | |||
IR 3535 12%, rosemary, lavender, and eucalyptus | 0.1 ml/30 cm2 | Arm-in-cage | Ae. aegypti | 1 h | [92] | ||||
Mospel® | Clove oil 10% Makaen oil 10% | 1 g/600 cm2 | Arm-in-cage | An. stephensi | 4–5 h | [95] | |||
1 g/lower leg | Walk-in exposure room test | 7–8 h | |||||||
MosquitoSafe® | Geraniol 25%, mineral oil 74%, aloe vera 1% | 1 ml/650 cm2 | Arm-in-cage | Ae. albopictus | 2.8 h | [87] | |||
Neem Aura® | Aloe vera, extract of barberry, chamomile, goldenseal, myrrh, neem, and thyme; oil of anise, cedarwood, citronella, coconut, lavender, lemongrass, neem, orange, rhodium wood | 1 ml/650 cm2 | Arm-in-cage | Ae. albopictus Cx. nigripalus | 0.2 h 4.2 h | [87] | |||
Odomos® cream | Advanced Odomos (12% N,N-diethylbenzamide) | 8 mg/cm2 | Arm-in-cage (Duration of the test: 4 h) | Cx. nigripalus | 3.8 h | [96] | |||
10 mg/cm2 | >4 h | 100 | |||||||
10 mg/cm2 | Ae. aegypti | 4 h | 96.5 | ||||||
12 mg/cm2 | >4 h | 100 | |||||||
Advanced odomos | 10 mg/cm2 | Field trial in India Duration of the test: 11 h | An. culicifacies An. stephensi An. annularis An. subpictus | 11 h | 100 | ||||
10 mg/cm2 | Cx. quinquefasciatus | 9 h | 98.8 | ||||||
10 mg/cm2 | Ae. aegypti | 6.2 h | 92.5 | ||||||
Raid Dual Action and Raid Shield | transfluthrin-based spatial repellent products | Laboratory (wind tunnel) and | Aedes aegypti | 95 and 74 | [97] | ||||
semi-field (outdoor enclosure) in Florida | 88 and 66 | ||||||||
Repel Care® | Turmeric oil 5% E. citriodora 4.5% | 2 ml/750 cm2 | Field trial in Thailand (duration of the test: 9 h) | Ae. aegypti (1.2%) Others (<1%) Cx. vishnui (77.1%) Cx. quinquefasciatus (13.8%) Cx. gelidus (3.4%) Cx. tritaeniorhynchus (1.6%) | 100 | ||||
Duration of the test: 8 h | Ae. albopictus (99.9%) Ar. subalbatus (0.01%) | 100 96.9 92.4 91.8 | |||||||
Turmeric oil 5% E. citriodora 4.5% | 0.1 ml/30 cm2 | Arm-in-cage | Ae. aegypti | 1 h | [92] | ||||
Sketolene® lotion | DEET, E. citriodora oil 15% | 0.1 ml/30 cm2 | Arm-in-cage | Ae. aegypti | 3 h | [92] | |||
Soffell® (citronella oil) | DEET 13%, citronella oil | 0.1 ml/30 cm2 | Arm-in-cage | Ae. aegypti | 4 h | [92] | |||
Soffell® (floral fragrance) | DEET 13%, geranium | 4 h | |||||||
Soffell® (fresh fragrance) | DEET 13%, orange | 4 h | |||||||
Soffell® lotion | DEET, E. citriodora oil 15% | 0.1 ml/30 cm2 | Field trial in Thailand (duration of the test: 120 min) | Ae. gardnerii Ae. lineatopennis An. barbirostris Cx. Tritaeniorhynchus Cx. gelidus | 100 | (120 min) | [91] | ||
Sumione® | Metofluthrin-treated emanators | 900-cm2 paper fan emanators impregnated with 160 mg metofluthrin | Field trials in PA, USA | Aedes canadensis | 85–100 | [98] | |||
4000-cm2 paper strip emanators impregnated with 200 mg metofluthrin | Laboratory-reared Aedes aegypti | 89–91 | |||||||
Metofluthrin-impregnated paper strip emanator | In Florida | Ochlerotatus spp. | 91–95 | ||||||
Metofluthrin-impregnated paper strip emanator | In Washington State | Aedes vexans | 95–97 | ||||||
SunSwat® | Oils of bay, cedarwood, citronella, goldenseal, juniper, lavender, lemon peel, patchouli, pennyroyal, tansy, tea tree, and vetiver | 1 ml/650 cm2 | Arm-in-cage | Ae. albopictus Cx. nigripalus | 0.2 h 4.2 h | [87] | |||
Tipskin® | Bergamot oil, citronella oil, camphor oil, and vanillin | 0.1 ml/30 cm2 | Arm-in-cage | Ae. aegypti | 0 h | [91] | |||
Bergamot oil, citronella oil, camphor oil, and vanillin | 0.1 ml/30 cm2 | Arm-in-cage | Ae. aegypti | 0.5 h | [92] | ||||
OFF! Clip-On® | Metofluthrin | Field study in USA | Ae. albopictus and Ae. taeniorhynchus | 3 h | 70 and 79 | [99] | |||
Anopheles quadrimaculatus, Culex erraticus, and Psorophora columbiae | Up to 84 | [100] | |||||||
Mosquito Cognito® | Linalool | Anopheles quadrimaculatus, Culex erraticus, and Psorophora columbiae | Up to 84 | [100] | |||||
No-Pest Strip® | Dichlorvos | [100] | |||||||
Thermacell® | d-cis/trans allethrin | [100] |
Commercial mosquito-repellent products.
Authors are listed below with their open access chapters linked via author name:
",metaTitle:"IntechOpen authors on the Global Highly Cited Researchers 2018 list",metaDescription:null,metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"New for 2018 (alphabetically by surname).
\\n\\n\\n\\n\\n\\n\\n\\n\\n\\nJocelyn Chanussot (chapter to be published soon...)
\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\nYuekun Lai
\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\n\\nPrevious years (alphabetically by surname)
\\n\\nAbdul Latif Ahmad 2016-18
\\n\\nKhalil Amine 2017, 2018
\\n\\nEwan Birney 2015-18
\\n\\nFrede Blaabjerg 2015-18
\\n\\nGang Chen 2016-18
\\n\\nJunhong Chen 2017, 2018
\\n\\nZhigang Chen 2016, 2018
\\n\\nMyung-Haing Cho 2016, 2018
\\n\\nMark Connors 2015-18
\\n\\nCyrus Cooper 2017, 2018
\\n\\nLiming Dai 2015-18
\\n\\nWeihua Deng 2017, 2018
\\n\\nVincenzo Fogliano 2017, 2018
\\n\\nRon de Graaf 2014-18
\\n\\nHarald Haas 2017, 2018
\\n\\nFrancisco Herrera 2017, 2018
\\n\\nJaakko Kangasjärvi 2015-18
\\n\\nHamid Reza Karimi 2016-18
\\n\\nJunji Kido 2014-18
\\n\\nJose Luiszamorano 2015-18
\\n\\nYiqi Luo 2016-18
\\n\\nJoachim Maier 2014-18
\\n\\nAndrea Natale 2017, 2018
\\n\\nAlberto Mantovani 2014-18
\\n\\nMarjan Mernik 2017, 2018
\\n\\nSandra Orchard 2014, 2016-18
\\n\\nMohamed Oukka 2016-18
\\n\\nBiswajeet Pradhan 2016-18
\\n\\nDirk Raes 2017, 2018
\\n\\nUlrike Ravens-Sieberer 2016-18
\\n\\nYexiang Tong 2017, 2018
\\n\\nJim Van Os 2015-18
\\n\\nLong Wang 2017, 2018
\\n\\nFei Wei 2016-18
\\n\\nIoannis Xenarios 2017, 2018
\\n\\nQi Xie 2016-18
\\n\\nXin-She Yang 2017, 2018
\\n\\nYulong Yin 2015, 2017, 2018
\\n"}]'},components:[{type:"htmlEditorComponent",content:'New for 2018 (alphabetically by surname).
\n\n\n\n\n\n\n\n\n\nJocelyn Chanussot (chapter to be published soon...)
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nYuekun Lai
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nPrevious years (alphabetically by surname)
\n\nAbdul Latif Ahmad 2016-18
\n\nKhalil Amine 2017, 2018
\n\nEwan Birney 2015-18
\n\nFrede Blaabjerg 2015-18
\n\nGang Chen 2016-18
\n\nJunhong Chen 2017, 2018
\n\nZhigang Chen 2016, 2018
\n\nMyung-Haing Cho 2016, 2018
\n\nMark Connors 2015-18
\n\nCyrus Cooper 2017, 2018
\n\nLiming Dai 2015-18
\n\nWeihua Deng 2017, 2018
\n\nVincenzo Fogliano 2017, 2018
\n\nRon de Graaf 2014-18
\n\nHarald Haas 2017, 2018
\n\nFrancisco Herrera 2017, 2018
\n\nJaakko Kangasjärvi 2015-18
\n\nHamid Reza Karimi 2016-18
\n\nJunji Kido 2014-18
\n\nJose Luiszamorano 2015-18
\n\nYiqi Luo 2016-18
\n\nJoachim Maier 2014-18
\n\nAndrea Natale 2017, 2018
\n\nAlberto Mantovani 2014-18
\n\nMarjan Mernik 2017, 2018
\n\nSandra Orchard 2014, 2016-18
\n\nMohamed Oukka 2016-18
\n\nBiswajeet Pradhan 2016-18
\n\nDirk Raes 2017, 2018
\n\nUlrike Ravens-Sieberer 2016-18
\n\nYexiang Tong 2017, 2018
\n\nJim Van Os 2015-18
\n\nLong Wang 2017, 2018
\n\nFei Wei 2016-18
\n\nIoannis Xenarios 2017, 2018
\n\nQi Xie 2016-18
\n\nXin-She Yang 2017, 2018
\n\nYulong Yin 2015, 2017, 2018
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\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:null},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5319},{group:"region",caption:"Middle and South America",value:2,count:4828},{group:"region",caption:"Africa",value:3,count:1471},{group:"region",caption:"Asia",value:4,count:9370},{group:"region",caption:"Australia and Oceania",value:5,count:837},{group:"region",caption:"Europe",value:6,count:14788}],offset:12,limit:12,total:108345},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{topicId:"16"},books:[{type:"book",id:"6926",title:"Biological Anthropology",subtitle:null,isOpenForSubmission:!0,hash:"db6aa70aa47f94b3afa5b4951eba6d97",slug:null,bookSignature:"Dr. Alessio Vovlas",coverURL:"https://cdn.intechopen.com/books/images_new/6926.jpg",editedByType:null,editors:[{id:"313084",title:"Dr.",name:"Alessio",surname:"Vovlas",slug:"alessio-vovlas",fullName:"Alessio Vovlas"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6931",title:"Personality Disorders",subtitle:null,isOpenForSubmission:!0,hash:"cc530c17b87275c5e284fcac8047d40e",slug:null,bookSignature:"Dr. Catherine Athanasiadou-Lewis",coverURL:"https://cdn.intechopen.com/books/images_new/6931.jpg",editedByType:null,editors:[{id:"287692",title:"Dr.",name:"Catherine",surname:"Athanasiadou-Lewis",slug:"catherine-athanasiadou-lewis",fullName:"Catherine Athanasiadou-Lewis"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6947",title:"Contemporary Topics in Graduate Medical Education - Volume 2",subtitle:null,isOpenForSubmission:!0,hash:"4374f31d47ec1ddb7b1be0f15f1116eb",slug:null,bookSignature:"Dr. Stanislaw P. Stawicki, Michael S. S Firstenberg, Dr. James P. Orlando and Dr. Thomas John Papadimos",coverURL:"https://cdn.intechopen.com/books/images_new/6947.jpg",editedByType:null,editors:[{id:"181694",title:"Dr.",name:"Stanislaw P.",surname:"Stawicki",slug:"stanislaw-p.-stawicki",fullName:"Stanislaw P. Stawicki"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7102",title:"Pneumonia",subtitle:null,isOpenForSubmission:!0,hash:"99c408d20813ec62ec65467c3597d63f",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7102.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7134",title:"Syphilis",subtitle:null,isOpenForSubmission:!0,hash:"fff77c1e77772f2f9affe655a80cdf52",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7134.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7309",title:"Temporal Bone",subtitle:null,isOpenForSubmission:!0,hash:"e0582cee55e94a3b49cc659548e881d8",slug:null,bookSignature:"Prof. Ghada Amin Ahmed Khalifa, Dr. Suzan Ahmed Mohamed Salem and Dr. Islam Mohamed Saad",coverURL:"https://cdn.intechopen.com/books/images_new/7309.jpg",editedByType:null,editors:[{id:"212735",title:"Prof.",name:"Ghada Amin Ahmed",surname:"Khalifa",slug:"ghada-amin-ahmed-khalifa",fullName:"Ghada Amin Ahmed Khalifa"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7665",title:"Digestive system - Surgical Treatment of Benign and Malignant Diseases",subtitle:null,isOpenForSubmission:!0,hash:"2dcc510dce568cb27018a47917639e72",slug:null,bookSignature:"Dr. Pasquale Cianci and Dr. Enrico Restini",coverURL:"https://cdn.intechopen.com/books/images_new/7665.jpg",editedByType:null,editors:[{id:"196218",title:"Dr.",name:"Pasquale",surname:"Cianci",slug:"pasquale-cianci",fullName:"Pasquale Cianci"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7797",title:"Caregiving and Home Care",subtitle:null,isOpenForSubmission:!0,hash:"61a5bab01bf8228ef9fb7e3c16072e78",slug:null,bookSignature:"Prof. Michael John Stones",coverURL:"https://cdn.intechopen.com/books/images_new/7797.jpg",editedByType:null,editors:[{id:"289526",title:"Prof.",name:"Michael John",surname:"Stones",slug:"michael-john-stones",fullName:"Michael John Stones"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7841",title:"New Insights Into Metabolic Syndrome",subtitle:null,isOpenForSubmission:!0,hash:"ef5accfac9772b9e2c9eff884f085510",slug:null,bookSignature:"Dr. Akikazu Takada",coverURL:"https://cdn.intechopen.com/books/images_new/7841.jpg",editedByType:null,editors:[{id:"248459",title:"Dr.",name:"Akikazu",surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7886",title:"Photodynamic Therapy",subtitle:null,isOpenForSubmission:!0,hash:"eae80b20d0afc385dbc2b8e798a4bf66",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7886.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7888",title:"Hepatitis A",subtitle:null,isOpenForSubmission:!0,hash:"e027bb08025546d9beb242d55e87c84c",slug:null,bookSignature:"Dr. Costin Teodor Teodor Streba, Dr. Cristin Constantin Vere and Dr. Ion Rogoveanu",coverURL:"https://cdn.intechopen.com/books/images_new/7888.jpg",editedByType:null,editors:[{id:"55546",title:"Dr.",name:"Costin Teodor",surname:"Streba",slug:"costin-teodor-streba",fullName:"Costin Teodor Streba"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7916",title:"Syncope",subtitle:null,isOpenForSubmission:!0,hash:"ec1cc652454dd39df331418b4b7108c7",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7916.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:34},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:33},{group:"topic",caption:"Business, Management and Economics",value:7,count:10},{group:"topic",caption:"Chemistry",value:8,count:30},{group:"topic",caption:"Computer and Information Science",value:9,count:25},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:15},{group:"topic",caption:"Engineering",value:11,count:71},{group:"topic",caption:"Environmental Sciences",value:12,count:13},{group:"topic",caption:"Immunology and Microbiology",value:13,count:3},{group:"topic",caption:"Materials Science",value:14,count:38},{group:"topic",caption:"Mathematics",value:15,count:14},{group:"topic",caption:"Medicine",value:16,count:136},{group:"topic",caption:"Nanotechnology and Nanomaterials",value:17,count:6},{group:"topic",caption:"Neuroscience",value:18,count:6},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:9},{group:"topic",caption:"Physics",value:20,count:20},{group:"topic",caption:"Psychology",value:21,count:2},{group:"topic",caption:"Robotics",value:22,count:6},{group:"topic",caption:"Social Sciences",value:23,count:13},{group:"topic",caption:"Technology",value:24,count:10},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:3},{group:"topic",caption:"Genesiology",value:300,count:1},{group:"topic",caption:"Machine Learning and Data Mining",value:521,count:1},{group:"topic",caption:"Intelligent System",value:535,count:1}],offset:12,limit:12,total:266},popularBooks:{featuredBooks:[{type:"book",id:"7878",title:"Advances in Extracorporeal Membrane Oxygenation",subtitle:"Volume 3",isOpenForSubmission:!1,hash:"f95bf990273d08098a00f9a1c2403cbe",slug:"advances-in-extracorporeal-membrane-oxygenation-volume-3",bookSignature:"Michael S. Firstenberg",coverURL:"https://cdn.intechopen.com/books/images_new/7878.jpg",editors:[{id:"64343",title:null,name:"Michael S.",middleName:"S",surname:"Firstenberg",slug:"michael-s.-firstenberg",fullName:"Michael S. Firstenberg"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8299",title:"Timber Buildings and Sustainability",subtitle:null,isOpenForSubmission:!1,hash:"bccf2891cec38ed041724131aa34c25a",slug:"timber-buildings-and-sustainability",bookSignature:"Giovanna Concu",coverURL:"https://cdn.intechopen.com/books/images_new/8299.jpg",editors:[{id:"108709",title:"Dr.",name:"Giovanna",middleName:null,surname:"Concu",slug:"giovanna-concu",fullName:"Giovanna Concu"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7614",title:"Fourier Transforms",subtitle:"Century of Digitalization and Increasing Expectations",isOpenForSubmission:!1,hash:"ff3501657ae983a3b42fef1f7058ac91",slug:"fourier-transforms-century-of-digitalization-and-increasing-expectations",bookSignature:"Goran S. Nikoli? and Dragana Z. Markovi?-Nikoli?",coverURL:"https://cdn.intechopen.com/books/images_new/7614.jpg",editors:[{id:"23261",title:"Prof.",name:"Goran",middleName:"S.",surname:"Nikolic",slug:"goran-nikolic",fullName:"Goran Nikolic"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7062",title:"Rhinosinusitis",subtitle:null,isOpenForSubmission:!1,hash:"14ed95e155b1e57a61827ca30b579d09",slug:"rhinosinusitis",bookSignature:"Balwant Singh Gendeh and Mirjana Turkalj",coverURL:"https://cdn.intechopen.com/books/images_new/7062.jpg",editors:[{id:"67669",title:"Prof.",name:"Balwant Singh",middleName:null,surname:"Gendeh",slug:"balwant-singh-gendeh",fullName:"Balwant Singh Gendeh"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7087",title:"Tendons",subtitle:null,isOpenForSubmission:!1,hash:"786abac0445c102d1399a1e727a2db7f",slug:"tendons",bookSignature:"Hasan Sözen",coverURL:"https://cdn.intechopen.com/books/images_new/7087.jpg",editors:[{id:"161402",title:"Dr.",name:"Hasan",middleName:null,surname:"Sözen",slug:"hasan-sozen",fullName:"Hasan Sözen"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7955",title:"Advances in Hematologic Malignancies",subtitle:null,isOpenForSubmission:!1,hash:"59ca1b09447fab4717a93e099f646d28",slug:"advances-in-hematologic-malignancies",bookSignature:"Gamal Abdul Hamid",coverURL:"https://cdn.intechopen.com/books/images_new/7955.jpg",editors:[{id:"36487",title:"Prof.",name:"Gamal",middleName:null,surname:"Abdul Hamid",slug:"gamal-abdul-hamid",fullName:"Gamal Abdul Hamid"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7701",title:"Assistive and Rehabilitation Engineering",subtitle:null,isOpenForSubmission:!1,hash:"4191b744b8af3b17d9a80026dcb0617f",slug:"assistive-and-rehabilitation-engineering",bookSignature:"Yves Rybarczyk",coverURL:"https://cdn.intechopen.com/books/images_new/7701.jpg",editors:[{id:"72920",title:"Prof.",name:"Yves",middleName:"Philippe",surname:"Rybarczyk",slug:"yves-rybarczyk",fullName:"Yves Rybarczyk"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7837",title:"Geriatric Medicine and Gerontology",subtitle:null,isOpenForSubmission:!1,hash:"e277d005b23536bcd9f8550046101979",slug:"geriatric-medicine-and-gerontology",bookSignature:"Edward T. Zawada Jr.",coverURL:"https://cdn.intechopen.com/books/images_new/7837.jpg",editors:[{id:"16344",title:"Dr.",name:"Edward T.",middleName:null,surname:"Zawada Jr.",slug:"edward-t.-zawada-jr.",fullName:"Edward T. Zawada Jr."}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7123",title:"Current Topics in Neglected Tropical Diseases",subtitle:null,isOpenForSubmission:!1,hash:"61c627da05b2ace83056d11357bdf361",slug:"current-topics-in-neglected-tropical-diseases",bookSignature:"Alfonso J. Rodriguez-Morales",coverURL:"https://cdn.intechopen.com/books/images_new/7123.jpg",editors:[{id:"131400",title:"Dr.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7610",title:"Renewable and Sustainable Composites",subtitle:null,isOpenForSubmission:!1,hash:"c2de26c3d329c54f093dc3f05417500a",slug:"renewable-and-sustainable-composites",bookSignature:"António B. Pereira and Fábio A. O. Fernandes",coverURL:"https://cdn.intechopen.com/books/images_new/7610.jpg",editors:[{id:"211131",title:"Prof.",name:"António",middleName:"Bastos",surname:"Pereira",slug:"antonio-pereira",fullName:"António Pereira"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8416",title:"Non-Equilibrium Particle Dynamics",subtitle:null,isOpenForSubmission:!1,hash:"2c3add7639dcd1cb442cb4313ea64e3a",slug:"non-equilibrium-particle-dynamics",bookSignature:"Albert S. Kim",coverURL:"https://cdn.intechopen.com/books/images_new/8416.jpg",editors:[{id:"21045",title:"Prof.",name:"Albert S.",middleName:null,surname:"Kim",slug:"albert-s.-kim",fullName:"Albert S. Kim"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8008",title:"Antioxidants",subtitle:null,isOpenForSubmission:!1,hash:"76361b4061e830906267933c1c670027",slug:"antioxidants",bookSignature:"Emad Shalaby",coverURL:"https://cdn.intechopen.com/books/images_new/8008.jpg",editors:[{id:"63600",title:"Prof.",name:"Emad",middleName:null,surname:"Shalaby",slug:"emad-shalaby",fullName:"Emad Shalaby"}],productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:4398},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"7878",title:"Advances in Extracorporeal Membrane Oxygenation",subtitle:"Volume 3",isOpenForSubmission:!1,hash:"f95bf990273d08098a00f9a1c2403cbe",slug:"advances-in-extracorporeal-membrane-oxygenation-volume-3",bookSignature:"Michael S. Firstenberg",coverURL:"https://cdn.intechopen.com/books/images_new/7878.jpg",editors:[{id:"64343",title:null,name:"Michael S.",middleName:"S",surname:"Firstenberg",slug:"michael-s.-firstenberg",fullName:"Michael S. Firstenberg"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8299",title:"Timber Buildings and Sustainability",subtitle:null,isOpenForSubmission:!1,hash:"bccf2891cec38ed041724131aa34c25a",slug:"timber-buildings-and-sustainability",bookSignature:"Giovanna Concu",coverURL:"https://cdn.intechopen.com/books/images_new/8299.jpg",editors:[{id:"108709",title:"Dr.",name:"Giovanna",middleName:null,surname:"Concu",slug:"giovanna-concu",fullName:"Giovanna Concu"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7614",title:"Fourier Transforms",subtitle:"Century of Digitalization and Increasing Expectations",isOpenForSubmission:!1,hash:"ff3501657ae983a3b42fef1f7058ac91",slug:"fourier-transforms-century-of-digitalization-and-increasing-expectations",bookSignature:"Goran S. Nikoli? and Dragana Z. Markovi?-Nikoli?",coverURL:"https://cdn.intechopen.com/books/images_new/7614.jpg",editors:[{id:"23261",title:"Prof.",name:"Goran",middleName:"S.",surname:"Nikolic",slug:"goran-nikolic",fullName:"Goran Nikolic"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7062",title:"Rhinosinusitis",subtitle:null,isOpenForSubmission:!1,hash:"14ed95e155b1e57a61827ca30b579d09",slug:"rhinosinusitis",bookSignature:"Balwant Singh Gendeh and Mirjana Turkalj",coverURL:"https://cdn.intechopen.com/books/images_new/7062.jpg",editors:[{id:"67669",title:"Prof.",name:"Balwant Singh",middleName:null,surname:"Gendeh",slug:"balwant-singh-gendeh",fullName:"Balwant Singh Gendeh"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7087",title:"Tendons",subtitle:null,isOpenForSubmission:!1,hash:"786abac0445c102d1399a1e727a2db7f",slug:"tendons",bookSignature:"Hasan Sözen",coverURL:"https://cdn.intechopen.com/books/images_new/7087.jpg",editors:[{id:"161402",title:"Dr.",name:"Hasan",middleName:null,surname:"Sözen",slug:"hasan-sozen",fullName:"Hasan Sözen"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7955",title:"Advances in Hematologic Malignancies",subtitle:null,isOpenForSubmission:!1,hash:"59ca1b09447fab4717a93e099f646d28",slug:"advances-in-hematologic-malignancies",bookSignature:"Gamal Abdul Hamid",coverURL:"https://cdn.intechopen.com/books/images_new/7955.jpg",editors:[{id:"36487",title:"Prof.",name:"Gamal",middleName:null,surname:"Abdul Hamid",slug:"gamal-abdul-hamid",fullName:"Gamal Abdul Hamid"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7701",title:"Assistive and Rehabilitation Engineering",subtitle:null,isOpenForSubmission:!1,hash:"4191b744b8af3b17d9a80026dcb0617f",slug:"assistive-and-rehabilitation-engineering",bookSignature:"Yves Rybarczyk",coverURL:"https://cdn.intechopen.com/books/images_new/7701.jpg",editors:[{id:"72920",title:"Prof.",name:"Yves",middleName:"Philippe",surname:"Rybarczyk",slug:"yves-rybarczyk",fullName:"Yves Rybarczyk"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7837",title:"Geriatric Medicine and Gerontology",subtitle:null,isOpenForSubmission:!1,hash:"e277d005b23536bcd9f8550046101979",slug:"geriatric-medicine-and-gerontology",bookSignature:"Edward T. Zawada Jr.",coverURL:"https://cdn.intechopen.com/books/images_new/7837.jpg",editors:[{id:"16344",title:"Dr.",name:"Edward T.",middleName:null,surname:"Zawada Jr.",slug:"edward-t.-zawada-jr.",fullName:"Edward T. Zawada Jr."}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7123",title:"Current Topics in Neglected Tropical Diseases",subtitle:null,isOpenForSubmission:!1,hash:"61c627da05b2ace83056d11357bdf361",slug:"current-topics-in-neglected-tropical-diseases",bookSignature:"Alfonso J. Rodriguez-Morales",coverURL:"https://cdn.intechopen.com/books/images_new/7123.jpg",editors:[{id:"131400",title:"Dr.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7610",title:"Renewable and Sustainable Composites",subtitle:null,isOpenForSubmission:!1,hash:"c2de26c3d329c54f093dc3f05417500a",slug:"renewable-and-sustainable-composites",bookSignature:"António B. Pereira and Fábio A. O. Fernandes",coverURL:"https://cdn.intechopen.com/books/images_new/7610.jpg",editors:[{id:"211131",title:"Prof.",name:"António",middleName:"Bastos",surname:"Pereira",slug:"antonio-pereira",fullName:"António Pereira"}],productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"7698",title:"Educational Psychology",subtitle:"Between Certitudes and Uncertainties",isOpenForSubmission:!1,hash:"740943e2d029253e777150e98ebe2f0d",slug:"educational-psychology-between-certitudes-and-uncertainties",bookSignature:"Victori?a Trif",coverURL:"https://cdn.intechopen.com/books/images_new/7698.jpg",editedByType:"Edited by",editors:[{id:"201656",title:"Ph.D.",name:"Victorița",middleName:null,surname:"Trif",slug:"victorita-trif",fullName:"Victorița Trif"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8747",title:"Asphalt and Asphalt Mixtures",subtitle:null,isOpenForSubmission:!1,hash:"6083f7c9881029f1e033a1e512af7e20",slug:"asphalt-and-asphalt-mixtures",bookSignature:"Haitao Zhang",coverURL:"https://cdn.intechopen.com/books/images_new/8747.jpg",editedByType:"Edited by",editors:[{id:"260604",title:"Prof.",name:"Haitao",middleName:null,surname:"Zhang",slug:"haitao-zhang",fullName:"Haitao Zhang"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8516",title:"Metacognition in Learning",subtitle:null,isOpenForSubmission:!1,hash:"5fa6eaad7b509b8b7ec5124d79e5f605",slug:"metacognition-in-learning",bookSignature:"Nosisi Feza",coverURL:"https://cdn.intechopen.com/books/images_new/8516.jpg",editedByType:"Edited by",editors:[{id:"261665",title:"Prof.",name:"Nosisi",middleName:"N.",surname:"Feza",slug:"nosisi-feza",fullName:"Nosisi Feza"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7000",title:"Legume Crops",subtitle:"Characterization and Breeding for Improved Food Security",isOpenForSubmission:!1,hash:"4d0f73bf883bbb984cc2feef1259a9a7",slug:"legume-crops-characterization-and-breeding-for-improved-food-security",bookSignature:"Mohamed Ahmed El-Esawi",coverURL:"https://cdn.intechopen.com/books/images_new/7000.jpg",editedByType:"Edited by",editors:[{id:"191770",title:"Dr.",name:"Mohamed A.",middleName:null,surname:"El-Esawi",slug:"mohamed-a.-el-esawi",fullName:"Mohamed A. El-Esawi"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8292",title:"Oral Health by Using Probiotic Products",subtitle:null,isOpenForSubmission:!1,hash:"327e750e83634800ace02fe62607c21e",slug:"oral-health-by-using-probiotic-products",bookSignature:"Razzagh Mahmoudi",coverURL:"https://cdn.intechopen.com/books/images_new/8292.jpg",editedByType:"Edited by",editors:[{id:"245925",title:"Dr.",name:"Razzagh",middleName:null,surname:"Mahmoudi",slug:"razzagh-mahmoudi",fullName:"Razzagh Mahmoudi"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8323",title:"Traditional and Complementary Medicine",subtitle:null,isOpenForSubmission:!1,hash:"60eadb1783d9bba245687adf284d4871",slug:"traditional-and-complementary-medicine",bookSignature:"Cengiz Mordeniz",coverURL:"https://cdn.intechopen.com/books/images_new/8323.jpg",editedByType:"Edited by",editors:[{id:"214664",title:"Associate Prof.",name:"Cengiz",middleName:null,surname:"Mordeniz",slug:"cengiz-mordeniz",fullName:"Cengiz Mordeniz"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8347",title:"Computer Architecture in Industrial, Biomechanical and Biomedical Engineering",subtitle:null,isOpenForSubmission:!1,hash:"3d7024a8d7d8afed093c9c79ec31f15a",slug:"computer-architecture-in-industrial-biomechanical-and-biomedical-engineering",bookSignature:"Lulu Wang and Liandong Yu",coverURL:"https://cdn.intechopen.com/books/images_new/8347.jpg",editedByType:"Edited by",editors:[{id:"257388",title:"Dr.",name:"Lulu",middleName:null,surname:"Wang",slug:"lulu-wang",fullName:"Lulu Wang"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7583",title:"Advanced Computational Fluid Dynamics for Emerging Engineering Processes",subtitle:"Eulerian vs. Lagrangian",isOpenForSubmission:!1,hash:"896509fa2e7e659811bffd0f9779ca9d",slug:"advanced-computational-fluid-dynamics-for-emerging-engineering-processes-eulerian-vs-lagrangian",bookSignature:"Albert S. Kim",coverURL:"https://cdn.intechopen.com/books/images_new/7583.jpg",editedByType:"Edited by",editors:[{id:"21045",title:"Prof.",name:"Albert S.",middleName:null,surname:"Kim",slug:"albert-s.-kim",fullName:"Albert S. Kim"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7839",title:"Malaria",subtitle:null,isOpenForSubmission:!1,hash:"91cde4582ead884cb0f355a19b67cd56",slug:"malaria",bookSignature:"Fyson H. Kasenga",coverURL:"https://cdn.intechopen.com/books/images_new/7839.jpg",editedByType:"Edited by",editors:[{id:"86725",title:"Dr.",name:"Fyson",middleName:"Hanania",surname:"Kasenga",slug:"fyson-kasenga",fullName:"Fyson Kasenga"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7093",title:"Pneumothorax",subtitle:null,isOpenForSubmission:!1,hash:"0b1fdb8bb0448f48c2f234753898f3f8",slug:"pneumothorax",bookSignature:"Khalid Amer",coverURL:"https://cdn.intechopen.com/books/images_new/7093.jpg",editedByType:"Edited by",editors:[{id:"63412",title:"Dr.",name:"Khalid",middleName:null,surname:"Amer",slug:"khalid-amer",fullName:"Khalid Amer"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"1268",title:"Industrial Robot",slug:"automation-industrial-robot",parent:{title:"Automation",slug:"automation"},numberOfBooks:1,numberOfAuthorsAndEditors:30,numberOfWosCitations:6,numberOfCrossrefCitations:2,numberOfDimensionsCitations:14,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"automation-industrial-robot",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"152",title:"Robot Arms",subtitle:null,isOpenForSubmission:!1,hash:"ad134b214c187871a4740c54c479eccb",slug:"robot-arms",bookSignature:"Satoru Goto",coverURL:"https://cdn.intechopen.com/books/images_new/152.jpg",editedByType:"Edited by",editors:[{id:"6232",title:"Prof.",name:"Satoru",middleName:null,surname:"Goto",slug:"satoru-goto",fullName:"Satoru Goto"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:1,mostCitedChapters:[{id:"15864",doi:"10.5772/16383",title:"From Robot Arm to Intentional Agent: the Articulated Head",slug:"from-robot-arm-to-intentional-agent-the-articulated-head",totalDownloads:2867,totalCrossrefCites:1,totalDimensionsCites:4,book:{slug:"robot-arms",title:"Robot Arms",fullTitle:"Robot Arms"},signatures:"Christian Kroos, Damith C. Herath and Stelarc",authors:[{id:"24913",title:"Dr.",name:"Christian",middleName:null,surname:"Kroos",slug:"christian-kroos",fullName:"Christian Kroos"},{id:"34698",title:"Dr.",name:"Damith C.",middleName:null,surname:"Herath",slug:"damith-c.-herath",fullName:"Damith C. Herath"},{id:"34699",title:"Mr.",name:null,middleName:null,surname:"Stelarc",slug:"stelarc",fullName:"Stelarc"}]},{id:"15859",doi:"10.5772/16799",title:"Robotic Grasping of Unknown Objects",slug:"robotic-grasping-of-unknown-objects1",totalDownloads:2988,totalCrossrefCites:1,totalDimensionsCites:3,book:{slug:"robot-arms",title:"Robot Arms",fullTitle:"Robot Arms"},signatures:"Mario Richtsfeld and Markus Vincze",authors:[{id:"1121",title:"Dr.",name:"Mario",middleName:null,surname:"Richtsfeld",slug:"mario-richtsfeld",fullName:"Mario Richtsfeld"},{id:"26352",title:"Dr.",name:"Markus",middleName:null,surname:"Vincze",slug:"markus-vincze",fullName:"Markus Vincze"}]},{id:"15855",doi:"10.5772/17732",title:"Kinematics of AdeptThree Robot Arm",slug:"kinematics-of-adeptthree-robot-arm",totalDownloads:13096,totalCrossrefCites:0,totalDimensionsCites:2,book:{slug:"robot-arms",title:"Robot Arms",fullTitle:"Robot Arms"},signatures:"Adelhard Beni Rehiara",authors:[{id:"29287",title:"Dr.",name:"Adelhard",middleName:"Beni",surname:"Rehiara",slug:"adelhard-rehiara",fullName:"Adelhard Rehiara"}]}],mostDownloadedChaptersLast30Days:[{id:"15855",title:"Kinematics of AdeptThree Robot Arm",slug:"kinematics-of-adeptthree-robot-arm",totalDownloads:13096,totalCrossrefCites:0,totalDimensionsCites:2,book:{slug:"robot-arms",title:"Robot Arms",fullTitle:"Robot Arms"},signatures:"Adelhard Beni Rehiara",authors:[{id:"29287",title:"Dr.",name:"Adelhard",middleName:"Beni",surname:"Rehiara",slug:"adelhard-rehiara",fullName:"Adelhard Rehiara"}]},{id:"15857",title:"Knowledge-Based Control for Robot Arm",slug:"knowledge-based-control-for-robot-arm",totalDownloads:3780,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"robot-arms",title:"Robot Arms",fullTitle:"Robot Arms"},signatures:"Aboubekeur Hamdi-Cherif",authors:[{id:"9479",title:"Prof.",name:"Aboubekeur",middleName:null,surname:"Hamdi-Cherif",slug:"aboubekeur-hamdi-cherif",fullName:"Aboubekeur Hamdi-Cherif"}]},{id:"15856",title:"Solution to a System of Second Order Robot Arm by Parallel Runge-Kutta Arithmetic Mean Algorithm",slug:"solution-to-a-system-of-second-order-robot-arm-by-parallel-runge-kutta-arithmetic-mean-algorithm",totalDownloads:3608,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"robot-arms",title:"Robot Arms",fullTitle:"Robot Arms"},signatures:"S. Senthilkumar and Abd Rahni Mt Piah",authors:[{id:"33444",title:"Dr.",name:"S.",middleName:null,surname:"Senthilkumar",slug:"s.-senthilkumar",fullName:"S. Senthilkumar"},{id:"101075",title:"Prof.",name:"Abd.Rahni",middleName:null,surname:"Mt.Piah",slug:"abd.rahni-mt.piah",fullName:"Abd.Rahni Mt.Piah"}]},{id:"15861",title:"3D Terrain Sensing System Using Laser Range Finder with Arm-Type Movable Unit",slug:"3d-terrain-sensing-system-using-laser-range-finder-with-arm-type-movable-unit",totalDownloads:2937,totalCrossrefCites:0,totalDimensionsCites:2,book:{slug:"robot-arms",title:"Robot Arms",fullTitle:"Robot Arms"},signatures:"Toyomi Fujita and Yuya Kondo",authors:[{id:"24469",title:"Dr.",name:"Toyomi",middleName:null,surname:"Fujita",slug:"toyomi-fujita",fullName:"Toyomi Fujita"},{id:"36556",title:"Mr",name:"Yuya",middleName:null,surname:"Kondo",slug:"yuya-kondo",fullName:"Yuya Kondo"},{id:"128029",title:"Prof.",name:"Yuya",middleName:null,surname:"Kondo",slug:"yuya-kondo",fullName:"Yuya Kondo"}]},{id:"15852",title:"Modeling Identification of the Nonlinear Robot Arm System Using MISO NARX Fuzzy Model and Genetic Algorithm",slug:"modeling-identification-of-the-nonlinear-robot-arm-system-using-miso-narx-fuzzy-model-and-genetic-al",totalDownloads:4865,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"robot-arms",title:"Robot Arms",fullTitle:"Robot Arms"},signatures:"Ho Pham Huy Anh, Kyoung Kwan Ahn\nand Nguyen Thanh Nam",authors:[{id:"22699",title:"Dr.",name:"Ho Pham Huy",middleName:null,surname:"Anh",slug:"ho-pham-huy-anh",fullName:"Ho Pham Huy Anh"},{id:"25030",title:"Dr.",name:"Ho Pham Huy",middleName:null,surname:"Anh",slug:"ho-pham-huy-anh",fullName:"Ho Pham Huy Anh"},{id:"39132",title:"Dr.",name:"Nguyen Thanh",middleName:null,surname:"Nam",slug:"nguyen-thanh-nam",fullName:"Nguyen Thanh Nam"}]},{id:"15865",title:"Robot Arm-Child Interactions: A Novel Application Using Bio-Inspired Motion Control",slug:"robot-arm-child-interactions-a-novel-application-using-bio-inspired-motion-control",totalDownloads:3304,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"robot-arms",title:"Robot Arms",fullTitle:"Robot Arms"},signatures:"Tanya N. Beran and Alejandro Ramirez-Serrano",authors:[{id:"26083",title:"Dr.",name:"Tanya",middleName:null,surname:"Beran",slug:"tanya-beran",fullName:"Tanya Beran"},{id:"37822",title:"Dr.",name:"Alejandro",middleName:null,surname:"Ramirez-Serrano",slug:"alejandro-ramirez-serrano",fullName:"Alejandro Ramirez-Serrano"}]},{id:"14974",title:"Distributed Nonlinear Filtering Under Packet Drops and Variable Delays for Robotic Visual Servoing",slug:"distributed-nonlinear-filtering-under-packet-drops-and-variable-delays-for-robotic-visual-servoing",totalDownloads:2519,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"robot-arms",title:"Robot Arms",fullTitle:"Robot Arms"},signatures:"Gerasimos G. Rigatos",authors:[{id:"5488",title:"Dr.",name:"Gerasimos G.",middleName:null,surname:"Rigatos",slug:"gerasimos-g.-rigatos",fullName:"Gerasimos G. Rigatos"}]},{id:"15862",title:"Design of a Bio-Inspired 3D Orientation Coordinate System and Application in Robotised Tele-Sonography",slug:"design-of-a-bio-inspired-3d-orientation-coordinate-system-and-application-in-robotised-tele-sonograp",totalDownloads:2547,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"robot-arms",title:"Robot Arms",fullTitle:"Robot Arms"},signatures:"Courreges Fabien",authors:[{id:"24499",title:"Dr.",name:"Fabien",middleName:null,surname:"Courreges",slug:"fabien-courreges",fullName:"Fabien Courreges"}]},{id:"15859",title:"Robotic Grasping of Unknown Objects",slug:"robotic-grasping-of-unknown-objects1",totalDownloads:2988,totalCrossrefCites:1,totalDimensionsCites:3,book:{slug:"robot-arms",title:"Robot Arms",fullTitle:"Robot Arms"},signatures:"Mario Richtsfeld and Markus Vincze",authors:[{id:"1121",title:"Dr.",name:"Mario",middleName:null,surname:"Richtsfeld",slug:"mario-richtsfeld",fullName:"Mario Richtsfeld"},{id:"26352",title:"Dr.",name:"Markus",middleName:null,surname:"Vincze",slug:"markus-vincze",fullName:"Markus Vincze"}]},{id:"15858",title:"Cartesian Controllers for Tracking of Robot Manipulators under Parametric Uncertainties",slug:"cartesian-controllers-for-tracking-of-robot-manipulators-under-parametric-uncertainties",totalDownloads:2994,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"robot-arms",title:"Robot Arms",fullTitle:"Robot Arms"},signatures:"R. Garcia-Rodriguez and P. Zegers",authors:[{id:"24519",title:"Dr.",name:"Rodolfo",middleName:null,surname:"Garcia-Rodriguez",slug:"rodolfo-garcia-rodriguez",fullName:"Rodolfo Garcia-Rodriguez"},{id:"35461",title:"Dr.",name:"Pablo",middleName:null,surname:"Zegers",slug:"pablo-zegers",fullName:"Pablo Zegers"}]}],onlineFirstChaptersFilter:{topicSlug:"automation-industrial-robot",limit:3,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10080",title:"Vortex Dynamics",subtitle:null,isOpenForSubmission:!0,hash:"ea97962e99b3e0ebc9b46b48ba5bea14",slug:null,bookSignature:"Dr. Zambri Harun",coverURL:"https://cdn.intechopen.com/books/images_new/10080.jpg",editedByType:null,editors:[{id:"243152",title:"Dr.",name:"Zambri",middleName:null,surname:"Harun",slug:"zambri-harun",fullName:"Zambri Harun"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8903",title:"Carbon Based Material for Environmental Protection and Remediation",subtitle:null,isOpenForSubmission:!0,hash:"19da699b370f320eca63ef2ba02f745d",slug:null,bookSignature:"Dr. Mattia Bartoli and Dr. Marco Frediani",coverURL:"https://cdn.intechopen.com/books/images_new/8903.jpg",editedByType:null,editors:[{id:"188999",title:"Dr.",name:"Mattia",middleName:null,surname:"Bartoli",slug:"mattia-bartoli",fullName:"Mattia Bartoli"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8771",title:"Raman Scattering",subtitle:null,isOpenForSubmission:!0,hash:"1354b3097eaa5b27d9d4bd29d3150b27",slug:null,bookSignature:"Dr. Samir Kumar and Dr. Prabhat Kumar",coverURL:"https://cdn.intechopen.com/books/images_new/8771.jpg",editedByType:null,editors:[{id:"296661",title:"Dr.",name:"Samir",middleName:null,surname:"Kumar",slug:"samir-kumar",fullName:"Samir Kumar"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10073",title:"Recent Advances in Nanophotonics-Fundamentals and Applications",subtitle:null,isOpenForSubmission:!0,hash:"aceca7dfc807140870a89d42c5537d7c",slug:null,bookSignature:"Dr. Mojtaba Kahrizi and Ms. Parsoua Abedini Sohi",coverURL:"https://cdn.intechopen.com/books/images_new/10073.jpg",editedByType:null,editors:[{id:"113045",title:"Dr.",name:"Mojtaba",middleName:null,surname:"Kahrizi",slug:"mojtaba-kahrizi",fullName:"Mojtaba Kahrizi"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10132",title:"Applied Computational Near-surface Geophysics - From Integral and Derivative Formulas to MATLAB Codes",subtitle:null,isOpenForSubmission:!0,hash:"38cdbbb671df620b36ee96af1d9a3a90",slug:null,bookSignature:"Dr. Afshin Aghayan",coverURL:"https://cdn.intechopen.com/books/images_new/10132.jpg",editedByType:null,editors:[{id:"311030",title:"Dr.",name:"Afshin",middleName:null,surname:"Aghayan",slug:"afshin-aghayan",fullName:"Afshin Aghayan"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10110",title:"Advances and Technologies in Building Construction and Structural Analysis",subtitle:null,isOpenForSubmission:!0,hash:"df2ad14bc5588577e8bf0b7ebcdafd9d",slug:null,bookSignature:"Dr. Ali Kaboli and Dr. Sara Shirowzhan",coverURL:"https://cdn.intechopen.com/books/images_new/10110.jpg",editedByType:null,editors:[{id:"309192",title:"Dr.",name:"Ali",middleName:null,surname:"Kaboli",slug:"ali-kaboli",fullName:"Ali Kaboli"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10175",title:"Ethics in Emerging Technologies",subtitle:null,isOpenForSubmission:!0,hash:"9c92da249676e35e2f7476182aa94e84",slug:null,bookSignature:"Prof. Ali Hessami",coverURL:"https://cdn.intechopen.com/books/images_new/10175.jpg",editedByType:null,editors:[{id:"108303",title:"Prof.",name:"Ali",middleName:null,surname:"Hessami",slug:"ali-hessami",fullName:"Ali Hessami"}],productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9284",title:"Computational Aeroacoustics",subtitle:null,isOpenForSubmission:!0,hash:"7019c5e5985faef7dc384c87dca5c8ef",slug:null,bookSignature:"Prof. Ramesh K. Agarwal",coverURL:"https://cdn.intechopen.com/books/images_new/9284.jpg",editedByType:null,editors:[{id:"38519",title:"Prof.",name:"Ramesh K.",middleName:null,surname:"Agarwal",slug:"ramesh-k.-agarwal",fullName:"Ramesh K. Agarwal"}],productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:16},humansInSpaceProgram:{},teamHumansInSpaceProgram:{},route:{name:"chapter.detail",path:"/books/ubiquitination-governing-dna-repair-implications-in-health-and-disease/regulation-of-the-base-excision-repair-pathway-by-ubiquitination",hash:"",query:{},params:{book:"ubiquitination-governing-dna-repair-implications-in-health-and-disease",chapter:"regulation-of-the-base-excision-repair-pathway-by-ubiquitination"},fullPath:"/books/ubiquitination-governing-dna-repair-implications-in-health-and-disease/regulation-of-the-base-excision-repair-pathway-by-ubiquitination",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()