Comparison of maximum S/B ratios obtained by S440 mutants.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"2131",leadTitle:null,fullTitle:"eLearning - Theories, Design, Software and Applications",title:"eLearning",subtitle:"Theories, Design, Software and Applications",reviewType:"peer-reviewed",abstract:"The term was coined when electronics, with the personal computer, was very popular and internet was still at its dawn. 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\r\n\r\n\tThe book would look into providing an overview of the recently published research as well and set directions to future scientific research, by highlighting the gaps and voids. It is hoped that both scientific and non-scientific audiences will benefit from the contents of this publication.
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A prolific author, editor, scientist, and administrator who works tirelessly promoting healthy food habits, food, and nutrient security.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"194281",title:"Dr.",name:"Viduranga Yashasvi",middleName:null,surname:"Waisundara",slug:"viduranga-yashasvi-waisundara",fullName:"Viduranga Yashasvi Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science and Technology from the Department of Chemistry, the National University of Singapore in 2010. From July 2009 to March 2013, she was a lecturer at Temasek Polytechnic, Singapore, after which she relocated to her motherland of Sri Lanka. There she spearheaded the Functional Food Product Development Project at the National Institute of Fundamental Studies from April 2013 to October 2016. Dr. Waisundara was a senior lecturer on a temporary basis at the Department of Food Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is currently the Deputy Principal of the Australian College of Business and Technology–Kandy Campus, in Kandy, Sri Lanka. 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There are three types of heat treatment; (1) low temperature long time (LTLT) pasteurization, (2) high temperature short time (HTST) pasteurization, and (3) ultra-high temperature (UHT) treatment. In all types of heat treatment, the Maillard reaction occurs in milk.
The Maillard reaction (nonenzymatic glycation) is a chemical reaction between amino group and carbonyl group; it is the extremely complex reaction that usually takes place during food processing or storage. In the case of milk, lactose reacts with the free amino acid side chains of milk proteins (mainly ε-amino group of lysine residue) to proceed to early, intermediate, and advanced stages of Maillard reaction and forms enormous kinds of Maillard reaction products. The reactions of lactose and milk proteins have been frequently investigated and the formations of various Maillard reaction products in milk during heat treatment have been demonstrated [1]. In the general Maillard reaction, firstly an Amadori product is generated, and it progresses to the 3-deoxyosone or 1-deoxyosone route depending on the reaction pH. In the case of the Maillard reaction of disaccharides such as lactose, there is a third reaction route. It is the 4-deoxyosone route. A main carbohydrate in milk is lactose. Thus, the Maillard reaction in milk progresses via the above described three routes. Finally, the Maillard reaction results in the formation of melanoidins (browning compounds).
The Maillard reaction shows various effects on milk proteins such as bioavailability, solubility, forming property, emulsifying property, and heating stability [1-4]. In addition, the formation of flavor compounds and browning compounds is caused as the consequences of the Maillard reaction between lactose and milk proteins [1, 5].
As for the effect of the Maillard reaction on the bioavailability of milk proteins, various studies were performed. Generally, in the Maillard reaction in milk, lactose mainly reacts with ε-amino group of lysine residue of milk proteins. Thus, the lysine loss by the Maillard reaction increases with a severity of heat treatment. The modified lysine cannot be available as a nutrient any more. For example, steam injection process (direct heating) generated 3.6% (120°C for 400 sec) and 6.8% (130°C for 290 sec) of the blocked lysine in whole milk. The indirect heating at 115°C for 10 to 40 min increased the modified lysine from 11.0 to 13.0% [6]. In addition, it was revealed that the lysine residues in skim milk powder were more susceptible to heating than those in skim milk [7].
Le et al. [3] recently suggested that the Maillard reaction was responsible for the solubility loss in milk protein concentrate powder. It was also reported that the glycated β-lactoglobulin was more stable at acidic pH and more stable against heating. The glycation of β-lactoglobulin, moreover, could improve its forming and emulsifying properties [4]. These results suggested the usefulness of the Maillard reaction for enabling milk proteins to have different properties.
The Maillard reaction has a lot of effects on the function of milk proteins and sensory property of milk and dairy products as described above. Particularly, in the manufacturing of milk, the excess progress of Maillard reaction and the formation of melanoidins are undesired, because a commercial value of milk is drastically decreased by them. Therefore, the detection of the Maillard reaction products is important for the quality control of milk. So far, several heat-induced markers have been proposed to control and check the heat treatment given to milk and dairy products. For example, furosine, hydroxymethylfurfural (HMF), and lactulose concentrations have been recognized to be the most promising indicators, since these concentrations increase with the heat treatment [1]. In Japan, protein reducing substance value (PRS) obtained by a ferricyanide assay is also widely-used conventional indicator [8]. It is based on the detection of reducing substances such as sulfhydryl group which are generated by heating in the fraction of acid-precipitated milk protein. These method, however, are generally time-consuming and complicated.
We proposed an assay method for determining the ability of milk to reduce 3’-[1-[(phenylamino)-carbonyl]-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzensulfonic acid hydrate (XTT: Figure 1) as a method of evaluating the extent of the Maillard reaction [8-11]. The tetrazolium salt XTT is reduced to water-soluble formazan which is suitable for the spectrophotometric measurement. Taking account into an economical view and a rapidity of assay, we tried to develop a microplate assay. The assay conditions were as follows: XTT concentration, 0.5 mM; reaction pH, 7.0; menadione concentration, saturation level (ca. 0.55 mM); reaction temperature, room temperature; volume of XTT solution, 60 μL; volume of sample solution, 40 μL; detection wavelength, 492 nm; reference wavelength, 600 nm; reaction time, 20 min. The procedure of the XTT assay was as follows: the XTT solution was added into each well in a microplate. Afterward, the sample solution was added to the well. After mixing on a microplate shaker at 500 rpm for 15 sec, a difference in the absorbance between 492 and 600 nm was read on a microplate reader as the absorbance at 0 min. After 20 min, the absorbance difference was read again. An increase in the absorbance for 20 min was recorded as the ability of the sample to reduce XTT (XTT reducibility).
Structure of tetrazolium salt XTT.
Using the XTT assay described above, the XTT reducibility of milk was examined (Figure 2). In this test, an LTLT milk (Milk A: 65°C for 30 min) and two kinds of UHT milk (Milk B: 130°C for 2 sec, Milk C: 140°C for 3 sec) were used. When the milk was mixed with XTT solution, intense orange color which was derived from the XTT formazan was recognized. As shown in Figure 2, Milk C showed the highest XTT reducibility and the order of XTT reducibility was Milk C, B, and A. At the same time, the HMF content in Milk B and C was also determined as the conventional indicator of the Maillard reaction, because it was reported that the HMF content clearly increased with the severity of the heating treatment of milk [12, 13]. As a result, the content of HMF in Milk C (12.6 μM) was higher than that of Milk B (8.95 μM). From these results, it was revealed that the XTT assay could estimate the degree of thermal stress delivered to the milk as well as the HMF value.
In addition, the changes in the XTT reducibility during storage of UHT milks (Milk B and C) were investigated. For purpose of comparison, the PRS of Milk B and C were also examined by the ferricyanide assay [8]. The UHT milks were stored at 4°C and 37°C for about 4 weeks (Figure 3, 4). The XTT reducibility of Milk B and C gradually decreased depending on the storage period and the rate of decrease in the XTT reducibility was clearly larger at higher storage temperature (Figure 3). This result strongly suggested that, when the XTT assay is applied to the milk heated under a given condition, the result can serve to estimate not only the heating condition but also the storage period after heat treatment if the storage temperature is known or if storage period is known.
On the other hand, the PRS of Milk B and C were almost constant at all storage conditions (Figure 4). This result showed that the ferricyanide-reducing substances might be stable unlike the XTT-reducing substance. In addition, we found that the HMF value of Milk C did not significantly change during its storage for 60 days at 5°C [11]. It was in accordance with the result of Fink and Kessler about HMF [13]. They also reported that the lactulose concentration of UHT milk was constant throughout the storage period for 70 days at room temperature [13]. It could be concluded, therefore, that the XTT assay is applicable for the estimation of storage conditions which was impossible by the conventional method.
Comparison of XTT reducibility of LTLT milk (Milk A) and UHT milks (Milk B and C).
Changes in XTT reducibility during storage.
Changes in PRS during storage.
In order to clarify the XTT-reducing substance that is formed during the Maillard reaction in milk, we firstly used a model system consisting of lactose and butylamine, and then performed the spectrophotometric analysis of the heated model solution. The model solution of lactose-butylamine heated at 80-100°C for 0-30 min showed a characteristic UV absorption maximum at 320 nm. During the heating at 80-100°C for 30 min, the changes in the absorbance at 320 nm (Figure 5) and the XTT reducibility (Figure 6) were investigated. As a result, both indices increased gradually in accordance with the rise in temperature and heating time. This result indicated that the compound with the absorption maximum at 320 nm was formed by heating. Moreover, the behavior of increase in absorbance at 320 nm was similar to that of the XTT reducibility. Since the similar trend was recognized in the time course of both indices, the XTT reducibility was plotted against the absorbance at 320 nm. In consequence, a significant relationship between them was recognized with a correlation coefficient of 0.967 (n = 19, p < 0.001). From these results it was found that the compound with the absorption maximum at 320 nm might be responsible for the reduction of XTT.
The 13C- and 1H-NMR analyses of the compound with the absorption maximum at 320 nm which was extracted from lactose-butylamine model solution heated at 100°C for 15 min were performed. The signals of the 13C- and 1H-NMR could be assigned the compound as the aminoreductone, 1-(butylamino)-1,2-dehydro-1,4-dideoxy 3-hexulose (Figure 7). This compound was reported as the Maillard reaction product formed in the 4-deoxyosone route. It was also reported as the characteristic compound in the Maillard reaction of disaccharides [14]. In addition, we demonstrate a linear relationship between the XTT reducibility and the amount of aminoreductone which was determined more specifically by HPLC [10]. These results strongly indicated that the aminoreductone formed during Maillard reaction of lactose was mainly responsible for the reduction of XTT.
Effect of heating temperature and time on the absorbance at 320 nm.
Effect of heating temperature and time on the XTT reducibility.
Structure of aminoreductone generated by the Maillard reaction of lactose and butylamine.(R = butyl group)
From these results, we presumed that the aminoreductone is formed by the Maillard reaction between lactose and ε-amino groups of milk proteins, and then it is responsible for the reduction of XTT. However, at that time, there was no report to prove the presence of aminoreductone in milk. Thus, we tried to demonstrate it using model system consisting of lactose and milk proteins and UHT milk.
As a model system of milk, the solution consisting of lactose (4.6%) and casein (2.6%), α-lactalbumin (0.12%), or β-lactoglobulin (0.32%) was used and heated at 130°C for 15 min. After heating, the characteristic absorption maximum or shoulder at 320 nm was recognized. In addition, the changes of the absorbance at 320 nm (Figure 8) and the XTT reducibility (Figure 9) were investigated. In all model systems, the increases in the absorbance at 320 nm and the XTT reducibility depended on the heating time. Because similar tendencies were observed between two indices in all model systems, correlations were examined. Consequently, there were significant linearities as follows: casein (r = 0.993, n = 6, p < 0.001), α-lactalbumin (r = 0.996, n = 6, p < 0.001), and β-lactoglobulin (r = 0.975, n = 6, p < 0.001). From these results, it was suggested that aminoreductone is generated in the Maillard reaction between lactose and milk proteins and it is responsible for the reduction of XTT.
As described above, a possibility of the formation of aminoreductone on the milk proteins during the Maillard reaction with lactose was clearly shown. However, direct demonstration of the presence of aminoreductone in milk had not been accomplished because of a difficulty in isolation of an intact aminoreductone from milk proteins. For instance, aminoreductone is labile and hence not suitable for enzyme hydrolysis and multiple extraction steps. To achieve the practical application of the XTT assay in food industries including dairy products, it was essential to demonstrate the presence of aminoreductone in milk. Because of this background, we attempted to isolate aminoreductone from milk proteins using 2,4-dinitrophenylhydrazine (DNP), a common labeling reagent for the carbonyl group, and Cu2+ [16]. A mechanism of derivatization of aminoreductone in milk is shown in Figure 10. In this derivatization step, Cu2+ plays as an oxidizing agent against aminoreductone, and the oxidized aminoreductone (OAR) has two or three carbonyl groups. Finally, it was assumed that two or three carbonyl groups in OAR are derivatized by DNP (OAR-DNP).
Effect of heating time on the absorbance at 320 nm.
Effect of heating time on the XTT reducibility.
Derivatization mechanism of aminoreductone in milk using DNP and Cu2+.
The derivatization using DNP and Cu2+ was applied to aminoreductone in UHT milk (140°C, 3 sec). In this study, the UHT milk was reheated at 130°C for 15 min in order to increase the content of aminoreductone, because the original content of aminoreductone in the commercially available UHT milk was not so high. As a result, the reheating of UHT milk could increase the content of DNP derivative by 40 times. The DNP derivative which was thought to be corresponding to OAR-DNP in the reheated UHT milk was purified by preparative normal-phase HPLC and preparative reversed-phase HPLC. Finally, the purified compound (4.2 mg) was obtained from 980 mL of UHT milk and analyzed by 13C- and 1H-NMR. The NMR signals of the DNP derivative from UHT milk could be assigned to the structure of OAR-DNP shown in Figure 10. In addition, the NMR signals of DNP derivative from UHT milk were nearly the same as those of the OAR-DNP from lactose-butylamine model system. These results demonstrated that aminoreductone was formed by the Maillard reaction on the milk proteins and present in milk.
Therefore, considering the above, the principle of the present XTT assay can be concluded as follows (Figure 11): (1) Lactose and ε-amino groups of lysine residue in milk proteins react non-enzymatically to form the Amadori product by the heating process. (2) Aminoreductone structure is formed on the milk proteins after elimination of galactose moiety from lactose through 4-deoxyosone pathway. (3) Aminoreductone is oxidized by XTT, whereas XTT is simultaneously reduced to the corresponding water-soluble formazan.
It would be thought that the above mentioned steps (1) and (2) progresses depending on the time and temperature of heating process in milk production, so the XTT assay can differentiate the extent of heat treatment of milk. Based on the study using model system of lactose and butylamine, the relationship between aminoreductone concentration and XTT reducibility was examined. As a result, there was a good linearity was recognized (r = 0.98) and a regression equation was y = 0.606 x + 0.046, in which x and y represented the concentration of aminoreductone (mM) and the XTT reducibility [17]. Based on this equation, the concentration of aminoreductone in UHT milk could be estimated as 0.44 mM.
Principle of XTT assay.
As described above, during the course of elucidation of the XTT-reducing substance, Cu2+ was used as the oxidizing agent (Figure 10), because we empirically knew that it was easily decomposed by the addition of Cu2+ [18]. In fact, the aminoreductone extracted from the heated model solution of lactose and butylamine was rapidly oxidized by the addition of Cu2+, and simultaneously the XTT reducibility was also lost. On the other hand, in our previous work, it was revealed that the commercially available UHT milk contains Cu2+ at the concentration of 30 μg/L [18]. Thus, it was easily presumed that the aminoreductone formed by the heating process was gradually oxidized by endogenous Cu2+ in milk during storage period. This was the reason why that the XTT reducibility decreased depending on the storage period (Figure 3). The detailed investigation about the relationship between the aminoreductone concentration, Cu2+ concentration, and storage stability of milk is now in progress.
The functionalities of aminoreductone have attracted interest and, so far, some studies were performed. Trang et al. [17] reported a protective effect of aminoreductone against riboflavin (vitamin B2) photolysis. It is well known that the milk is important source of riboflavin and its content is 1.5 mg/L. It is stable to heat and oxidation, but is rapidly photo-degraded. In experimental condition at 7000 lux light intensity, the riboflavin (1.5 mg/L) was almost completely degraded for 150 min. On the other hand, the addition of aminoreductone (0.22 mM: half concentration in UHT milk) could extend the half-life period of riboflavin. The protective effect of aminoreductone against riboflavin photolysis was higher than that of ascorbic acid which was famous antioxidant. In addition, the antioxidative activity of aminoreductone was reported [19]. From these results, it was suggested that the aminoreductone formed by the Maillard reaction would contribute to keep the nutritional value and sensory quality of milk.
Furthermore, aminoreductone showed antimicrobial activity against Helicobacter pylori (H. pylori). In vitro it effectively inhibited the growth of 24 kinds of H. pylori strains including antibiotic-resistant strains and had a bactericidal activity [20, 21]. The Killing ability was observed even in acidic condition. In addition, aminoreductone also had the antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) [21, 22]. These results indicated that foods containing aminoreductone, such as milk and dairy products, have a potential health benefits in medical practice.
In this chapter, the demonstration of the presence of aminoreductone formed by the Maillard reaction in milk and the specific assay method for aminoreductone were focused and introduced. Since the novel functionality of aminoreductone have come out one after another, the information of aminoreductone obtained by the XTT assay would gain importance in the quality control in milk and dairy products.
When the human genome project was completed in 2003, most researchers expected dramatic developments in various fields such as biology, etiology, and drug discovery. However, progression did not remarkably accelerate. One of the causes is that protein-protein interactions (PPIs) are still not well understood. In the cell, many proteins interact with each other and cooperate to fulfill their roles in biological phenomena. It is reported that there are 150,000–300,000 PPIs in the human interactome [1, 2]. Therefore, PPI assays are very important for biology, diagnosis, and drug discovery.
The conventional PPI assays, which are available both in vitro and in cellulo, are Förster/fluorescence resonance energy transfer (FRET)-based assays, bioluminescent resonance energy transfer (BRET) assays, and protein-fragment complementation assays (PCAs).
For FRET-based assays, two fluorescent proteins or two fluorescent dyes are fused to proteins that interact with each other. When the interaction occurs, the two fluorescent proteins (dyes) are in close proximity, and then the energy transfer is induced, resulting in changes of the fluorescent intensities. In BRET assays, a bioluminescent enzyme and fluorescent protein (dye) are fused to proteins that interact with each other, and the energy is transferred from the bioluminescent enzyme to the fluorescent protein (dye). FRET- and BRET-based assays are the most common and sophisticated methods.
For PCA, the enzyme or fluorescence is divided into two fragments. The split fragments are fused to interacting proteins. Upon interaction, the split fragments come close, and then the full length of the structure is reconstituted, resulting in the recovery of the enzyme activity or fluorescence. PCA in cells and lysates is a user-friendly method that gives a high signal/background (S/B) ratio [3]. Moreover, we reported in vitro PCA using purified firefly luciferase (Fluc) fragments for the first time [4, 5]. The development of PCA is described in Section 2.
Recently, we developed a novel PPI assay, named firefly luminescent intermediate-based protein-protein interaction assay, FlimPIA [6, 7, 8, 9, 10]. FlimPIA utilizes the unique reaction of Fluc, which is divided into two half steps. We describe the principle of FlimPIA in Section 3.1 and the several improvements of FlimPIA in Sections 3.2–3.6. Then, the advantages and disadvantages of FlimPIA compared to another PPI assays such as the in vitro PCA are described in the final section.
Conventional PCA is used in vivo and in cultured cells (in cellulo). Although Porter et al. performed a Fluc-based PCA in vitro, the assay requires cell lysate, and the components in the lysate might affect the PPIs. We succeeded in developing a Fluc-based PCA in vitro using purified probes in a defined solution [4, 5].
For the Fluc-based PCA in vitro, a well-known interacting pair, FKBP12 (a 12 kD domain of FK506-binding protein) and FRB (FKBP-rapamycin-associated protein), was utilized. The association between these proteins depends on the presence of an antibiotic, rapamycin [11, 12]. Two pairs of split Photinus pyralis Fluc—the pair of the N-terminal domain (amino acids [aa] 1–437) and the C-terminal domain (aa 394–547) and the pair of the N-terminal domain (aa 1–398) and the same C-terminal domain (aa 394–547)—were selected in several split sites of Fluc [13], which worked well for in cellulo PCA. The gene encoding FKBP12 or FRB was fused to the 5’ end of each domain, and the genes were inserted into the pET32 vector, which originally encodes thioredoxin (Trx), yielding four fusion protein genes, FKBP-N, FKBP-C, FRB-N, and FRB-C. These proteins were expressed in the soluble fraction of E. coli BL21(DE3) pLysS and purified by immobilized metal affinity chromatography (Figure 1A).
Detection via Fluc-based PCA using purified probes. (A–C) Detection of FKBP-FRB association. (A) Purified probes. Lane 1, FKBP-N; Lane 2, FRB-N; Lane 3, FRB-N; Lane 4, FRB-C. (B) PCA using the purified probes at 50 nM each, with/without equimolar rapamycin (n = 3). (C) Control experiments (n = 3). (D, E) Detection of p53-Mdm2 association. (D) PCA using the purified probes at 50 nM each (n = 3). (E) Inhibition of p53-Mdm2 interaction by Nutlin-3 (n = 3). ©American Chemical Society.
The two interacting pairs, FKBP-N and FRB-C, FKBP-C and FRB-N, were mixed, and rapamycin was added to the pair (Figure 1B). The luminescence intensities of the mixture of the interacting pairs and rapamycin were remarkably increased immediately after adding the two substrates, luciferin and ATP. On the other hand, the luminescence intensities of the mixture of the interacting pair (FKBP12 and FRB) without rapamycin and noninteracting pair were very low (Figure 1C). The signal and stability of the pair of the N-terminal domain (aa 1–437) and the C-terminal domain (aa 384–547) were higher than those of the other pair of N-terminal domain (aa 1–398) and the same C-terminal domain. When the first pair was used, the luminescence signal displayed rapamycin dose dependence, and the limit of detection was determined as 250 pM. These results clearly showed that the PPI could be detected with a high S/B ratio and high sensitivity using the purified probes.
Because the rapamycin-dependent FKBP-FRB association is very strong, another interacting pair, p53 and Mdm2, was investigated (Figure 1D and E) [14, 15]. p53 suppresses cell growth as a tumor suppressor. The oncoprotein Mdm2 binds to p53 and downregulates the function of p53 in certain cancer cells. In the assay of p53-Mdm2 interaction using p53-C and Mdm2-N, the signal intensity and S/B ratio rose with higher concentrations of the probes of the interacting pair. To investigate the reversibility of the PCA, an inhibitor of the p53-Mdm2 interaction, Nutlin-3, was added to the mixture of p53-C and Mdm2-N. The luminescence intensity decreased depending on the concentration of Nutlin-3.
The in vitro PCA opens the way to study PPIs of cytotoxic proteins, which is impossible to perform in cells. Furthermore, the possibility that the cellular components affect PPIs can be excluded.
In this section, we describe a novel PPI assay, FlimPIA, which we recently developed and continue to improve.
In contrast to PCA, in which the structure of Fluc is divided into two domains as the probes, FlimPIA divides the reaction catalyzed by Fluc into two half-reactions. Fluc catalyzes the conversion of firefly
The conformational change of Fluc. Fluc is composed of a large N-terminal domain and a smaller C-terminal domain, which rotates ∼140° according to the reactions to proceed from the adenylation reaction to the oxidative luminescent reactions: Key Lys residues (K529 and K443) are shown in light and dark blue, respectively. Another key residue H245 is shown in cyan. ©American Chemical Society.
Two mutant Photinus pyralis Flucs were designed for FlimPIA; one is H245D/K443A/L530R, which can produce LH2-AMP but cannot catalyze LH2-AMP to form OxL, and the other is K529Q, which very slowly produces LH2-AMP but maintains the catalytic steps in the oxidative luminescence half-reaction. Each mutant is fused to proteins that interact with each other. The interaction brings the mutants close together, and then LH2-AMP, which H245D/K443A/L530R produces, is utilized by K529Q, resulting in OxL production (Figure 3). The mutant H245D/K443A/L530R acts as the “Donor” providing LH2-AMP, and the mutant K529Q works as the “Acceptor” of LH2-AMP [7].
The working principle of FlimPIA. ©American Chemical Society.
When FKBP12 and FRB are fused to the Donor and Acceptor, respectively, the luminescence intensity increased depending on the concentration of rapamycin (Figure 4A, B). The EC50 values of the cognate pairs were 10.2 ± 0.6 and 16.0 ± 2.1 nM, respectively, which correspond well with the reported KD value of the association between FKBP12/rapamycin and FRB. FK506 (tacrolimus) is commonly used as an immunosuppressant to prevent the rejection of organ transplants and inhibits the rapamycin-dependent association between FKBP12 and FRB [14]. The luminescence intensity decreased upon FK506 addition (Figure 4C). The S/B ratio increased depending on the concentration of PPI when the concentration of probes and rapamycin was up to 500 nM (Figure 4D). In addition, the association between FKBP12 and FRB could be detected in 40% fetal bovine serum diluted in phosphate buffered saline, suggesting the applicability of the assay to clinical samples.
Detection via FlimPIA in vitro. (A-D) Detection of FKBP-FRB association. (A) Luminescence time course at several rapamycin concentrations. A mixture of FKBP/Donor and FRB/Acceptor (50 nM each) was used. (n = 3). (B) Specific detection of FKBP12-FRB interaction. The four possible combinations of four Fluc mutants, namely, FKBP/Donor, FRB/Donor, FKBP/Acceptor and FRB/Acceptor (50 nM each) were tested for their rapamycin dose-dependency. The relative luminescence integrated for 1.5−1.6 s after substrate addition is shown (n = 3). (C) Competition of PPI (protein−protein interaction) by FK506. Rapamycin (80 nM) and FK506 at indicated concentration were added to the mixture of FKBP/Donor and FRB/Acceptor (80 nM each). The luminescence integrated for 0.8−0.9 s after substrate addition is shown (n = 3). (D) Time course of S/B (signal/background) ratio obtained with the mixture of FKBP/Donor and FRB/Acceptor with and without equimolar rapamycin. The ratio of the two light intensities at the indicated time point is shown. Sample with 40% fetal bovine serum and 750 nM proteins is also shown (n = 3). (E–F) Detection of p53-Mdm2 association. (E) Luminescence time course of the cognate (Mdm2/Donor and p53/Acceptor) and control pairs (25 nM each) (n = 3). (F) Competition of PPI by a specific inhibitor. Nutlin-3 (bottom) at indicated concentration was added to the mixture of p53/Donor and Mdm2/Acceptor (25 nM each) (n = 3). The luminescence integrated for 0.8−0.9 s after substrate addition is shown. The ribbon model of Mdm2 (purple)-p53 peptide (light green) complex is also shown. ©American Chemical Society.
Next, p53 and Mdm2 were used as interacting proteins. The luminescence intensity of the mixture of the interacting pair (p53-Donor and Mdm2-Acceptor) was higher than the intensities of noninteracting pairs (p53-Donor and p53-Acceptor, Mdm2-Donor and Mdm2-Acceptor) (Figure 4E). The inhibition of the p53-Mdm2 interaction by Nutlin-3 was observed (Figure 4F). The result clearly shows that FlimPIA is a versatile system and can analyze transient interactions.
The original FlimPIA had exhibited high background signal, which was mainly caused by the remaining adenylation activity of the Acceptor. As mentioned above, the C-terminal domain rotates according to the reactions proceeding from the adenylation to the oxidative luminescence reactions (Figure 2). Therefore, we tried to entrap the Acceptor conformation into the oxidation conformation [10].
According to the report by Branchini et al. that the structure of Fluc could be fixed into the oxidative luminescence conformation by chemical trapping, we first took the same approach to entrap Acceptor mutant [21]. Specifically, all cysteine residues in the Acceptor were substituted with serine or alanine residues. Then, the residues at positions 108 and 447 were substituted with cysteine residues and cross-linked by 1,2-bis-(maleimide)ethane (BMOE) (Figure 5A).
FlimPIA using the trapped Acceptor by bis-maleimide crosslinker (A–C) The trapping by bis-maleimide crosslinker (1). (D–E) The trapping by bis-maleimide crosslinker (2). (A) Scheme of the trapped Acceptors by BMOE. Residues shown in yellow were used for the N−C linkage. (B, D) Suppression of overall luminescent activity by chemical trapping of the Acceptor. The enzyme (10 nM) was reacted with 75 µM LH2 and 10 mM ATP. The luminescent intensities with and without chemical modification by BMOE were compared (n = 3). (C, E) The mixture of FKBP/Donor and trapped FRB/Acceptor (50 nM each) was added with/without 50 nM rapamycin (n = 3). ©American Chemical Society.
The luminescence of the cross-linked Acceptor was almost diminished compared to the non-cross-linked Acceptor (Figure 5B). The Acceptor and Donor were fused to FRB and FKBP12, respectively. In a FlimPIA using the cross-linked Acceptor, the background signal was eliminated, and the signal induced by the interaction was significantly higher than the background signal (Figure 5C). Taken together, the results clearly showed that the Acceptor can be trapped into the oxidation conformation and the sensitive FlimPIA was successfully developed, giving a high S/B ratio.
As the substitution of the all cysteine residues considerably reduced the luminescence intensity, next, we tried to use the original Acceptor retaining the cysteine residues and put the cysteine residues at positions 108 and 447, which were then cross-linked by BMOE. As a result, one-fifth of the luminescence intensity of the cross-linked Acceptor was retained, probably due to miss- and/or incomplete cross-linking (Figure 5D). Although there was some background signal, an apparent improvement in luminescent intensity was observed. When the same concentration (50 nM each) of the probes and rapamycin were used, the maximum S/B ratio was improved from 2.6 to 5.3, compared with the original system (Figure 5E).
During another attempt to select paired cysteine residues for possible cross-linking of N-C domains, the introduction of S198C/S440C mutations on the background of original Acceptor was attempted. However, the obtained clone was later found to be contaminated with the S440C mutant retaining only one mutation. The resultant S440C mutant showed higher ability as the Acceptor, whereas the S198C/S440C mutant did not act as the Acceptor. To understand the effect of this mutation, we performed saturation mutagenesis of the S440 residue. The substitution of leucine, phenylalanine, and tryptophan, which have bulky and/or large side chains, gave a higher maximal S/B ratio in FlimPIA (Table 1) [9]. Additionally, not all the mutants with bulky or long side chains showed higher S/B ratios. Although the precise reason is not known, it might be because mutations often affect protein stability and/or aggregation.
S440X | S/B ratio | S440X | S/B ratio |
---|---|---|---|
L | 7.93 ± 0.60 | Q | 2.11 ± 0.01 |
F | 5.69 ± 0.12 | R | 2.08 ± 0.41 |
W | 4.94 ± 0.06 | S | 1.87 ± 0.24 |
M | 3.65 ± 0.35 | N | 1.86 ± 0.08 |
K | 3.45 ± 0.20 | V | 1.85 ± 0.25 |
A | 2.86 ± 0.22 | D | 1.80 ± 0.13 |
Y | 2.81 ± 0.37 | G | 1.67 ± 0.26 |
H | 2.57 ± 0.19 | I | 1.55 ± 0.21 |
C | 2.32 ± 0.13 | T | 1.52 ± 0.22 |
E | 2.31 ± 0.10 | P | 1.09 ± 0.11 |
Comparison of maximum S/B ratios obtained by S440 mutants.
We expected that the bulky and/or large side chains at this position could form steric hindrance with hinge region and the C-terminal domain from the structural modeling based on the adenylation conformation structure of Luciola cruciata Fluc with bound substrate analog (Figure 6A). On the other hand, there seemed no severe inhibition in the model of the oxidative luminescence conformation.
Possible steric hindrance of adenylation conformation with the S440 L mutation. (A) Structure of Fluc (left) and a model of Fluc S440L (right), each at adenylation conformation. The Leu440 residue (shown in white) is enlarged in the inset. Drawn with PyMOL software. (B) Adenylation activity measured by the N-terminal domain method. Error bars mean ±SD (n = 3).
Then we examined the adenylation and oxidative luminescence activities of the S440L Acceptor. The amounts of LH2-AMP produced by the new and conventional Acceptors were examined according to the method using the N-terminal domain of Fluc as a selective detector of LH2-AMP [18]. The LH2-AMP produced by the new Acceptor was less than one-fifth of the LH2-AMP produced by the conventional Acceptor (Figure 6B). On the other hand, the kinetics against LH2-AMP are shown in Table 2. Because the concentration of the LH2-AMP that the Acceptor uses in FlimPIA is low, the Vmax/Km is the most important kinetics parameter. The value of the new Acceptor decreased to 33.6% of the value of the conventional Acceptor; therefore, the luminescence intensity in FlimPIA might decrease to some extent. Taken together, the balance of the adenylation and oxidative activities of the new Acceptor gave the highest S/B ratio in the Acceptors, which we have developed.
Vmax (× 106 RLU*/sec) | Km (μM) | Vmax/Km (× 106 RLU/s μM−1) | |
---|---|---|---|
K529Q | 1.40 ± 0.16 | 0.513 ± 0.018 | 2.11 ± 0.01 |
K529Q/S440L | 0.296 ± 0.031 | 0.321 ± 0.013 | 2.08 ± 0.41 |
Oxidative luminescence activity of K529Q and S440L/K529Q (1 nM each).
Relative light units
When the C-terminal domain of Fluc rotated to proceed from the adenylation step to the oxidative luminescence steps, the flexible hinge region between N- and C-terminal domains is considered highly important (Figure 2). Furthermore, the hinge region sits close to the active site in the adenylation conformation. To obtain suitable mutants for the Acceptor, semi-random mutations at the residues 436–439 in the hinge region were introduced [6]. The amino acid residues that enzymes in acyl-adenylate-forming enzyme superfamily contain at the corresponding positions were chosen in the semi-random library. The mutant R437K/L438I was selected from the library, because the mutants showed lower adenylation activity (~15% of the wild-type Fluc) and slightly higher oxidative luminescence activity (116% of the wild-type Fluc).
A single mutation, R437K, or a double mutation, R437K/L438I, was introduced into the conventional Acceptor (K529Q). The overall luminescence activity and the oxidative luminescence activity of the two new Acceptors were compared to that of the conventional Acceptor (Figure 7A, B). The overall activities of both new Acceptors decreased almost tenfold compared with that of the conventional Acceptor, whereas the oxidative luminescence activities were almost maintained. These results showed that R437K is a key residue for Acceptor activity.
FlimPIA in vitro using the new Acceptor mutated in the hinge region. (A) Overall luminescent activity of the conventional Acceptor and the two new Acceptors. Reactions with LH2 and ATP (n = 3). (B) Luminescent activity of the Acceptors with LH2-AMP as a substrate (n = 3). (C) 3D models of the Acceptors at adenylation conformation. The wild-type Fluc (left), the conventional Acceptor (middle), and the mutant M1 (right) are shown. In the conventional Acceptor, the shortest distance between the active site against LH2 (529Q) and R437 was ~3.8 Å, which was shorter in the mutant (~1.6 Å). (D) FlimPIA with 50 nM each of FKBP/Donor and FRB/the new Acceptor with/ without 50 nM rapamycin (n = 3).
The kinetics properties of the conventional and the new Acceptors fused to FRB are shown in Table 3. The lower overall activities and the similar oxidative luminescence activities are probably due to the remarkably lower Vmax values for LH2 and ATP and similar Vmax and Km values for LH2-AMP. Moreover, in the structural model of the adenylation conformation, the mutated residue K437 sits close to the active site residues such as K529, suggesting some inhibition of the adenylation activity (Figure 7C).
Km for LH2 | Vmax (× 104 RLU/s) for LH2 | Km for ATP | Vmax (104 RLU/s) for ATP | Km for LH2-AMP | Vmax (×106 RLU/s) for LH2-AMP | |
---|---|---|---|---|---|---|
K529Q | 95.0 ± 12.1 | 3.49 ± 0.20 | 424 ± 55 | 2.50 ± 0.11 | 0.412 ± 0.055 | 1.04 ± 0.04 |
K529Q/R437L | 115 ± 4.0 | 5.52 ± 0.08 | 307 ± 25 | 3.94 ± 0.11 | 0.605 ± 0.063 | 0.737 ± 0.027 |
K529A/R437K/L438I | 62.7 ± 4.1 | 35.1 ± 0.7 | 306 ± 25 | 39.8 ± 1.1 | 0.710 ± 0.093 | 1.28 ± 0.06 |
Kinetics properties of Acceptors fused to FRB.
When the FKBP12-FRB interaction was detected by FlimPIA, the maximum S/B ratio reached approximately 4, whereas it was approximately 2.5 in the conventional assay (Figure 7D). Taken together, we succeeded in finding a suitable mutant for the Acceptor in the semi-random library of the hinge region. Furthermore, these results suggest that the hinge region is important for controlling the two half-reactions of Fluc and supports the hypothesis that the C-terminal domain rotates to accomplish the half-reactions.
The overall activities of the improved Acceptor (R4437K/K529Q) mentioned in Section 3.4 showed a tenfold decrease, and the oxidative luminescence activities were almost maintained. However, the S/B ratio increased only 1.6-fold. To investigate this discrepancy, the Acceptor was reacted with (1) LH2 + ATP, (2) LH2-AMP, and (3) LH2 + ATP + LH2-AMP (Figure 8A). The luminescence intensity in the case of (3) should be equal to the sum of the intensities of (1) and (2). However, the intensity in (3) was remarkably lower than the sum. Therefore, we thought that some competition may exist in the oxidative luminescence steps. It was reported that dehydroluciferyl-AMP (L-AMP), which is converted from LH2-AMP, competes with LH2-AMP in the oxidative luminescence steps, and coenzyme A (CoA) converts L-AMP to dehydroluciferyl-coenzyme A, which is a less potent competitor of LH2-AMP. First, we added CoA to the mixture of FlimPIA (Figure 8B). In the presence of CoA, the maximum S/B ratio reached 8, representing a twofold improvement, when 50 nM of each probe was used.
Optimization of assay condition in vitro. (A) An experimental simulation of FlimPIA using the conventional Acceptor. (B) The responses with and without 50 nM rapamycin in the presence of 1 mM CoA and 20 mM ATP. (C) The responses in the presence of 1 mM CoA and 1 mM ATP. (D) The results of tube-based luminometer with rapid mixing of the probes and substrates.
Next, we optimized the concentration of ATP, as it was designed so that the Km value of the Acceptor for ATP was lower than that of the wild type to suppress the adenylation activity, but the Km value of the Donor for ATP was maintained to provide LH2-AMP. The optimal concentration of ATP was 1 mM, and the maximal S/B ratio reached approximately 40, representing a fivefold improvement, when 50 nM of each probe was used (Figure 8C).
Finally, we had optimized the reaction conditions. As the increase of luminescence occurred as soon as substrates were added, a luminometer equipped with a stirrer was used to mix and react the substrates quickly (Figure 8D). The luminescence intensity increased quasi-linearly from 0.2 to 0.6 s after the reaction start and then reached a plateau. The maximal S/B ratio reached more than 60 when 100 nM of each probe was used.
Taken together, these improvements achieved a remarkably higher S/B ratio and sensitivity [6].
In this section, we describe the advantages and disadvantages of FlimPIA compared to the conventional PPI assay, FRET, and PCA, which are available in cellulo and in vitro.
To determine if FlimPIA is applicable in cellulo or in vivo, the FKBP-Donor and FRB-Acceptor were transiently expressed in cultured cells (Figure 9) [7]. The response was clearly observed in cells when rapamycin was added, and the luminescence intensity increased depending on the concentration of rapamycin.
FKBP12-FRB association detected by FlimPIA in cultured cells. ©American Chemical Society.
However, the maximal S/B ratio was less than 2.5, and the detectable range of the concentration of rapamycin was rather narrow. Although the S/B ratio of FRET is often as low as that of FlimPIA in cells, PCA gives a high S/B ratio both in vitro and in cellulo.
The same Fluc derived from P. pyralis was applied to both Fluc-based PCA in vitro and FlimPIA. Then, the thermostability of probes was compared [10]. The probes of Fluc-based PCA (FKBP-C and FRB-N) and the probes of FlimPIA (FKBP-Donor and FRB-Acceptor) were preincubated with or without rapamycin at 37°C (Figure 10A). After 30 minutes, half of the luminescence signal was retained in FlimPIA, and on the other hand, the luminescence signal was almost completely diminished in PCA. The rate of the luminescence decay in FlimPIA was approximately one-fourth of the rate of the decay in PCA (Figure 10B).
Comparison of thermostability in vitro. (A) Probes (50 nM each) were preincubated at 37°C with or without equimolar rapamycin. The luminescent intensity was measured for 4 s after adding substrates (LH2 and ATP). Left: FlimPIA, Right: Fluc-based PCA. Red: incubation for 0 min with rapamycin, Orange: 15 min with rapamycin, pink: 30 min with rapamycin, green: 0 min without rapamycin, light blue: 15 min without rapamycin, dark blue: 30 min without rapamycin. (n = 3) (B) Inactivation time course. Relative luminescent intensities at 4 s after reaction start were normalized at the value obtained with 0 min pre-incubation (n = 3). ©American Chemical Society.
The S/B ratio of FRET is rather low, but on the other hand, PCA shows a high S/B ratio and high sensitivity. The conventional FlimPIA described in Section 3.1 showed that the maximal S/B ratio was 2.5, which is generally lower than the S/B ratio of PCA [7]. However, the S/B ratio dramatically increased by the improvements described in Section 3.2-3.5 and was equal to or higher than the S/B ratio of PCA [6, 9, 10].
The detectable limits of the concentration of rapamycin in Fluc-based PCA, the conventional FlimPIA, and the improved FlimPIA were compared, when 50 nM of each probe (FKBP-C and FRB-N, or FKBP-Donor and FRB-Acceptor) and rapamycin were used. The limits were 250 pM in Fluc-based PCA and 10 pM in FlimPIA using the K529Q/S440L mutant as the Acceptor [4, 9, 10]. The sensitivity of the improved FlimPIA was higher than the sensitivity of Fluc-based PCA.
A fundamental limitation of FRET is that the detectable distance between the two probes is less than several nanometers, because the fluorescent signal is inversely proportional to the sixth power of the distance. A part of fibronectin type III, the seventh and eighth domains (Fn7-8), has a rigid structure with a 7 nm N-C terminal distance [10]. Ohashi et al. reported that a FRET signal using YPet and CyPet could not be observed by inserting Fn7-8 between the two fluorescent proteins [22]. The limit of the detectable distance between the two probes determines the detectable dimensions of the interacting protein.
Therefore, we compared the limit of the detectable distance between the probes in our assay. To examine this, Fn7-8 was inserted between FKBP12 and one of the probes (C-terminal domain for PCA, cerulean for FRET, and Donor for FlimPIA) (Figure 11). The large probes were mixed with FRB-N, FRB-YPet, and FRB-Acceptors, respectively. As expected, the FRET signal was very weak when rapamycin was added to the mixture of FKBP12-Fn7-8-Cerulean and FRB-YPet, whereas the signal derived from the mixture of FKBP12-Cerulean and FRB-YPet was clearly observed (not shown). In the case of PCA using FKBP12-Fn7-8-C and FRB-N, the luminescence intensity was not significantly increased by the addition of rapamycin when the concentrations of the probes were moderate (100 nM each), while some response was observed with higher concentrations (750 nM) of each probe (not shown). However, the response of FlimPIA was clearly observed, even when 100 nM each of FKBP-Fn7-8-Donor and FRB-Acceptor was used.
Detectable distance between the probes in vitro. (A) Scheme of the assays. A long (7 nm) Fn7-8 domain is inserted between a binding domain (FKBP12) and a probe. Signals with and without equimolar rapamycin were compared. (B) FRET using 40 nM each of FKBP-Fn7-8-Cerulean and the FRB-YPet as a probe pair. (C) Fluc-PCA using 100 nM each of FKBP-Fn7-8-C and FRB-N (n = 3). (D) FlimPIA using 100 nM each of FKBP-Fn7-8-Donor and FRB-Acceptor (left) (n = 3). ©American Chemical Society.
We reported the development of Fluc-based PCA using purified probes for the first time. However, the stabilities of the probes were low due to the split forms. The problem might be overcome by using another enzyme with a highly stable structure.
Furthermore, we developed a unique PPI assay, called FlimPIA, wherein the catalytic reaction of Fluc is divided into two half-reactions. FlimPIA has several advantages, especially in vitro. Our next challenge is to improve the response in cellulo.
This project was supported partly by SENTAN and SICORP, Japan Science and Technology agency, Japan; by JSPS KAKENHI Grant Numbers JP15H04191, JP17K06920, and JP24040072 from the Japan Society for the Promotion of Science, Japan; by Kikkoman Co.; by Dynamic Alliance for Open Innovation Bridging Human, Environment and Materials from MEXT, Japan; and by the ‘Leave a Nest’ Microtech-Nichion award.
The authors declare that there are no conflicts of interest.
As this section deals with legal issues pertaining to the rights of individual Authors and IntechOpen, for the avoidance of doubt, each category of publication is dealt with separately. Consequently, much of the information, for example definition of terms used, is repeated to ensure that there can be no misunderstanding of the policies that apply to each category.
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\\n\\nIntechOpen - Registered publisher with office at 5 Princes Gate Court, London, SW7 2QJ - UNITED KINGDOM
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\\n\\nTERMS
\\n\\nAll Works published on the IntechOpen platform and in print are licensed under a Creative Commons Attribution 3.0 Unported License, a license which allows for the broadest possible reuse of published material.
\\n\\nCopyright on the individual Works belongs to the specific Author, subject to an agreement with IntechOpen. The Creative Common license is granted to all others to:
\\n\\nAnd for any purpose, provided the following conditions are met:
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The CC BY 3.0 license permits Works to be freely shared in any medium or format, as well as the reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as the source Work is cited and its Authors are acknowledged in the following manner:
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\\n\\nRepublishing – More about Attribution Policy can be found here.
\\n\\nThe same principles apply to Works published under the CC BY-NC-SA 3.0 license, with the caveats that (1) the content may not be used for commercial purposes, and (2) derivative works building on this content must be distributed under the same license. The restrictions contained in these license terms may, however, be waived by the copyright holder(s). Users wishing to circumvent any of the license terms are required to obtain explicit permission to do so from the copyright holder(s).
\\n\\nDISCLAIMER: Neither the CC BY 3.0 license, nor any other license IntechOpen currently uses or has used before, applies to figures and tables reproduced from other works, as they may be subject to different terms of reuse. In such cases, if the copyright holder is not noted in the source of a figure or table, it is the responsibility of the User to investigate and determine the exact copyright status of any information utilised. Users requiring assistance in that regard are welcome to send an inquiry to permissions@intechopen.com.
\\n\\nAll rights to Books and all other compilations published on the IntechOpen platform and in print are reserved by IntechOpen.
\\n\\nThe copyright to Books and other compilations is subject to separate copyright from those that exist in the included Works.
\\n\\nAll Long Form Monographs/Compacts are licensed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license granted to all others.
\\n\\nCopyright to the individual Works (Chapters) belongs to their specific Authors, subject to an agreement with IntechOpen and the Creative Common license granted to all others to:
\\n\\nUnder the following terms:
\\n\\nThere must be an Attribution, giving appropriate credit, provision of a link to the license, and indication if any changes were made.
\\n\\nNonCommercial - The use of the material for commercial purposes is prohibited. Commercial rights are reserved to IntechOpen or its licensees.
\\n\\nNo additional restrictions that apply legal terms or technological measures that restrict others from doing anything the license permits are allowed.
\\n\\nThe CC BY-NC 4.0 license permits Works to be freely shared in any medium or format, as well as reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as it is not used for commercial purposes. The source Work must be cited and its Authors acknowledged in the following manner:
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\\n\\nAll Book cover design elements, as well as Video image graphics are subject to copyright by IntechOpen.
\\n\\nEvery reproduction of a front cover image must be accompanied by an appropriate Copyright Notice displayed adjacent to the image. The exact Copyright Notice depends on who the Author of a particular cover image is. Users wishing to reproduce cover images should contact permissions@intechopen.com.
\\n\\nAll Video Lectures under IntechOpen's production are subject to copyright and are property of IntechOpen, unless defined otherwise, and are licensed under the Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. This grants all others the right to:
\\n\\nShare — copy and redistribute the material in any medium or format
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\\n\\nAll software used on the IntechOpen platform, any used during the publishing process, and the copyright in the code constituting such software, is the property of IntechOpen or its software suppliers. As such, it may not be downloaded or copied without permission.
\\n\\nUnless otherwise indicated, all IntechOpen websites are the property of IntechOpen.
\\n\\nAll content included on IntechOpen Websites not forming part of contributed materials (such as text, images, logos, graphics, design elements, videos, sounds, pictures, trademarks, etc.), are subject to copyright and are property of, or licensed to, IntechOpen. Any other use, including the reproduction, modification, distribution, transmission, republication, display, or performance of the content on this site is strictly prohibited.
\\n\\nPolicy last updated: 2016-06-08
\\n"}]'},components:[{type:"htmlEditorComponent",content:'Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
\n\nIntechOpen only publishes manuscripts for which it has publishing rights. This is governed by a publication agreement between the Author and IntechOpen. This agreement is accepted by the Author when the manuscript is submitted and deals with both the rights of the publisher and Author, as well as any obligations concerning a particular manuscript. However, in accepting this agreement, Authors continue to retain significant rights to use and share their publications.
\n\nHOW COPYRIGHT WORKS WITH OPEN ACCESS LICENSES?
\n\nAgreement samples are listed here for the convenience of prospective Authors:
\n\n\n\nDEFINITIONS
\n\nThe following definitions apply in this Copyright Policy:
\n\nAuthor - in order to be identified as an Author, three criteria must be met: (i) Substantial contribution to the conception or design of the Work, or the acquisition, analysis, or interpretation of data for the Work; (ii) Participation in drafting or revising the Work; (iii) Approval of the final version of the Work to be published.
\n\nWork - a Chapter, including Conference Papers, and any and all text, graphics, images and/or other materials forming part of or accompanying the Chapter/Conference Paper.
\n\nMonograph/Compacts - a full manuscript usually written by a single Author, including any and all text, graphics, images and/or other materials.
\n\nCompilation - a collection of Works distributed in a Book that IntechOpen has selected, and for which the coordination of the preparation, arrangement and publication has been the responsibility of IntechOpen. Any Work included is accepted in its entirety in unmodified form and is published with one or more other contributions, each constituting a separate and independent Work, but which together are assembled into a collective whole.
\n\nIntechOpen - Registered publisher with office at 5 Princes Gate Court, London, SW7 2QJ - UNITED KINGDOM
\n\nIntechOpen platform - IntechOpen website www.intechopen.com whose main purpose is to host Monographs in the format of Book Chapters, Long Form Monographs, Compacts, Conference Proceedings and Videos.
\n\nVideo Lecture – an audiovisual recording of a lecture or a speech given by a Lecturer, recorded, edited, owned and published by IntechOpen.
\n\nTERMS
\n\nAll Works published on the IntechOpen platform and in print are licensed under a Creative Commons Attribution 3.0 Unported License, a license which allows for the broadest possible reuse of published material.
\n\nCopyright on the individual Works belongs to the specific Author, subject to an agreement with IntechOpen. The Creative Common license is granted to all others to:
\n\nAnd for any purpose, provided the following conditions are met:
\n\nAll Works are published under the CC BY 3.0 license. However, please note that book Chapters may fall under a different CC license, depending on their publication date as indicated in the table below:
\n\n\n\n
LICENSE | \n\t\t\tUSED FROM - | \n\t\t\tUP TO - | \n\t\t
\n\t\t\t Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported (CC BY-NC-SA 3.0) \n\t\t\t | \n\t\t\t\n\t\t\t 1 July 2005 (2005-07-01) \n\t\t\t | \n\t\t\t\n\t\t\t 3 October 2011 (2011-10-03) \n\t\t\t | \n\t\t
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The CC BY 3.0 license permits Works to be freely shared in any medium or format, as well as the reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as the source Work is cited and its Authors are acknowledged in the following manner:
\n\nContent reuse:
\n\n© {year} {authors' full names}. Originally published in {short citation} under {license version} license. Available from: {DOI}
\n\nContent adaptation & reuse:
\n\n© {year} {authors' full names}. Adapted from {short citation}; originally published under {license version} license. Available from: {DOI}
\n\nReposting & sharing:
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\n\nRepublishing – More about Attribution Policy can be found here.
\n\nThe same principles apply to Works published under the CC BY-NC-SA 3.0 license, with the caveats that (1) the content may not be used for commercial purposes, and (2) derivative works building on this content must be distributed under the same license. The restrictions contained in these license terms may, however, be waived by the copyright holder(s). Users wishing to circumvent any of the license terms are required to obtain explicit permission to do so from the copyright holder(s).
\n\nDISCLAIMER: Neither the CC BY 3.0 license, nor any other license IntechOpen currently uses or has used before, applies to figures and tables reproduced from other works, as they may be subject to different terms of reuse. In such cases, if the copyright holder is not noted in the source of a figure or table, it is the responsibility of the User to investigate and determine the exact copyright status of any information utilised. Users requiring assistance in that regard are welcome to send an inquiry to permissions@intechopen.com.
\n\nAll rights to Books and all other compilations published on the IntechOpen platform and in print are reserved by IntechOpen.
\n\nThe copyright to Books and other compilations is subject to separate copyright from those that exist in the included Works.
\n\nAll Long Form Monographs/Compacts are licensed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license granted to all others.
\n\nCopyright to the individual Works (Chapters) belongs to their specific Authors, subject to an agreement with IntechOpen and the Creative Common license granted to all others to:
\n\nUnder the following terms:
\n\nThere must be an Attribution, giving appropriate credit, provision of a link to the license, and indication if any changes were made.
\n\nNonCommercial - The use of the material for commercial purposes is prohibited. Commercial rights are reserved to IntechOpen or its licensees.
\n\nNo additional restrictions that apply legal terms or technological measures that restrict others from doing anything the license permits are allowed.
\n\nThe CC BY-NC 4.0 license permits Works to be freely shared in any medium or format, as well as reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as it is not used for commercial purposes. The source Work must be cited and its Authors acknowledged in the following manner:
\n\nContent reuse:
\n\n© {year} {authors' full names}. Originally published in {short citation} under {license version} license. Available from: {DOI}
\n\nContent adaptation & reuse:
\n\n© {year} {authors' full names}. Adapted from {short citation}; originally published under {license version} license. Available from: {DOI}
\n\nReposting & sharing:
\n\nOriginally published in {full citation}. Available from: {DOI}
\n\nAll Book cover design elements, as well as Video image graphics are subject to copyright by IntechOpen.
\n\nEvery reproduction of a front cover image must be accompanied by an appropriate Copyright Notice displayed adjacent to the image. The exact Copyright Notice depends on who the Author of a particular cover image is. Users wishing to reproduce cover images should contact permissions@intechopen.com.
\n\nAll Video Lectures under IntechOpen's production are subject to copyright and are property of IntechOpen, unless defined otherwise, and are licensed under the Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. This grants all others the right to:
\n\nShare — copy and redistribute the material in any medium or format
\n\nUnder the following terms:
\n\nUsers wishing to repost and share the Video Lectures are welcome to do so as long as they acknowledge the source in the following manner:
\n\n© {year} IntechOpen. Published under CC BY-NC-ND 4.0 license. Available from: {DOI}
\n\nUsers wishing to reuse, modify, or adapt the Video Lectures in a way not permitted by the license are welcome to contact us at permissions@intechopen.com to discuss waiving particular license terms.
\n\nAll software used on the IntechOpen platform, any used during the publishing process, and the copyright in the code constituting such software, is the property of IntechOpen or its software suppliers. As such, it may not be downloaded or copied without permission.
\n\nUnless otherwise indicated, all IntechOpen websites are the property of IntechOpen.
\n\nAll content included on IntechOpen Websites not forming part of contributed materials (such as text, images, logos, graphics, design elements, videos, sounds, pictures, trademarks, etc.), are subject to copyright and are property of, or licensed to, IntechOpen. Any other use, including the reproduction, modification, distribution, transmission, republication, display, or performance of the content on this site is strictly prohibited.
\n\nPolicy last updated: 2016-06-08
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