Characteristics of different glycoside hydrolase family containing enzymes with a demonstrated xylanase activity.
\r\n\tVarious disciplines characterize the constituent components comprising mechatronics, which include physical systems modeling, sensors and actuators, signals and systems, computers and logic systems, and software and data acquisition.
\r\n\tMany new MEMS and Nanotechnology applications will emerge, expanding beyond that which is currently identified or known. Here are a few applications of current interest: new phenomena are addressed nowadays in science and technology.
\r\n\tIn this book, we will deal with physical systems modeling., discuss the physical phenomena involved, the adequate methodology to deal with them, and report a selection of papers recently published for possible applications for MEMS and Nanotechnology.
\r\n\r\n\tIn summary, Nano- and micro-electromechanical systems (NEMS/MEMS) are useful for applications ranging from: The design of MEMS accelerometers, gyroscopes, electrostatic actuators, and microresonators; Interfacial engineering for NEMS/MEMS; Biosensors, magnetic biochips, in vitro diagnostics, cell sorting, magnetic nanoparticles, spin electronic materials and sensors, magnetic inductive heads, and magnetic integrated inductors and transformer’s; Flexible substrates for electronics, sensors, and energy conversion platforms; Nanofabrication and nanopatterning technologies, including self-assembly for device fabrication.
\r\n\t
Increasing energy costs and environmental concerns have pushed the global demand for sustainable renewable fuels. The impacts of plant biomass gain particular interest due to their availability as the most abundant raw material worldwide and certainly play an important role because of its significant role as a renewable source of energy [1]. Plant biomass refers to lignocellulosic biomass and its growing demand for the more effective utilization appears to evolve as one of the most important area with great industrial interest. Lignocellulose is composed of the structural polymers of cellulose, hemicellulose, pectin, and lignin. Cellulose is the most abundant polysaccharide in nature followed by hemicelluloses. Xylan is a major structural component of hemicullose and makes up 20–40% of total plant biomass [1].
Various hydrolyzing enzymes are required to degrade lignocellulosic biomass. Carbohydrate-active enzymes, the second largest group of industrial enzymes are sourced from animals, plants, and microorganisms. The hydrolytic enzymes make up nearly 75% of the total extent of industrial enzymes worldwide [2]. Efficient degradation of plant biomass remains a major challenge that requires the availability of enzymes for the hydrolysis of lignocellulosic biomass. Biomass can be efficiently degraded by combining multiple enzymes that hydrolyze complex polysaccharides into fermentable sugars under ideal industrial conditions. These enzymes must be active during a wide range of conditions, such as high temperature and pH [3]. Xylanases are a crucial group of depolymerizing enzymes used for the hydrolysis of the xylan that is a major component of hemicellulose. There is a critical need for thermophilic xylanases operating more efficiently at higher temperatures than current commercially available ones. Xylanase producing thermophilic microorganisms are of prime importance and well-suited for industrial applications. Therefore, there is growing interest in exploring thermophilic microorganisms from extreme environment for biotechnological applications toward biomass degradation. Because of their biotechnological characteristics, xylanases are most often produced from microorganisms for commercial applications. Recently, there has been much industrial interest in xylanases for biofuel production, chemical and pharmaceutical industries, wood pulp bioleaching, papermaking, the manufacture of food and beverages, and animal nutrition. Let us look briefly at the genesis and some promising industrial uses of xylanases.
Lignocellulosic biomass is a potential raw material and its growing demand for the more effective utilization appears to evolve as one of the most important technologies with great industrial interest. Hemicellulose is a complex of polymeric carbohydrates including xylan, xyloglucan (heteropolymer of d-xylose and d-glucose), glucomannan (heteropolymer of d-glucose and d-mannose), galacto-glucomannan (heteropolymer of d-galactose, d-glucose and d-mannose) and arabinogalactan (hetero-polymer of d-galactose and arabinose) [4]. Xylan is a major structural polysaccharide found in the cell walls of plants, in which they may constitute more than 30% of the dry weight [5].
The structure of xylan holds a backbone of β-1,4-linked xylopyranosyl residues with an equatorial configuration and a diversity of substituted groups such as arabinose, acetyl, glucuronic acids, ferulic acid, and p-coumaric acid [6]. However, the structure of xylan is variable, ranging from linear 1,4-β-linked polyxylose sugars other than d-xylose, but the main chain of xylan is analogous to that of cellulose, composed of d-xylose instead of d-glucose. Moreover, xylan interacts with lignin and polysaccharides through covalent and non-covalent linkages, respectively. Different types of covalent linkages are responsible to interconnect xylan and lignin in the secondary cell wall [7]. These covalent interactions include glycosidic linkages between xylopyranosyl and p-coumaric acid and ester linkages between arabinofuranosyl residues and p-coumaric acid or ferulic acid. Feruloyl residues in arabinoxylans are known to be bridging units between xylan and lignin. The distribution pattern of the substituents on xylan affects a series of functional properties, including their solubility, interactions with other polymeric cell wall substances, degradability by enzymes, and solution behavior [8]. In addition, a relationship between the chemical structure of xylan results in a certain degree of complexity of xylan-containing materials, that may have several different xylan polymers of related structures but differ by more or less important features [8].
Xylanases are a crucial group of depolymerizing enzymes used for the hydrolysis of the xylan that is a major component of hemicellulose. Enzymatic depolymerization of hemicellulose to monomer sugars needs the synergistic action of multiple enzymes. These enzymes include endo-xylanase (endo-1,4-β-xylanase), β-xylosidase (xylan-1,4-β-xylosidase), α-glucuronidase (α-glucosiduronase), α-arabinofuranosidase (α-l-arabinofuranosidase) and acetylxylan esterase. Among them endo-xylanases and β-xylosidases are the two key enzymes responsible for the hydrolysis of xylan. Endo-xylanases randomly cleaves the xylan backbone into xylo-oligosaccharides, while β-xylosidases further hydrolyze the xylo-oligosaccharides from non-reducing end into xylose monomers. The removal of side groups is catalyzed by α-d-glucuronidases, α-l-arabinofuranosidases, ferulic acid esterases, acetylxylan esterases and p-coumaric acid esterases [9, 10].
Initially xylanases were classified into two groups, those with low molecular weight (less than 30 kDa) and basic isoelectric points (pI), secondly those with high molecular weight (greater than 30 kDa) and acidic pI. However, this classification system was unable to classify most of the recently discovered xylanases [11]. Afterward, another classification system was introduced that were based on the comparisons of primary structure of the catalytic domains and these enzymes were grouped into families based on related sequences. This classification system now considered the standard means for the classification of enzymes including xylanases. In addition, this classification system gave an extra edge that classifies the glycosidases in general [11]. The most extensive group of enzymes is “Glycoside hydrolases” that refers to catalyze the glycosidic bond cleavage between carbohydrates or between carbohydrate and non-carbohydrate moiety. In glycoside hydrolases (GH) families, some family protein folds are more conserved than their amino acid sequences, and these families are further grouped into clans. Presently, 14 different clans have been proposed (GH-A to GH-N), with most clans encompassing two or more than two families [11].
According to the information provided in the Carbohydrate-Active Enzymes Database (CAZy), xylanases have been classified into 13 families, however only the GH10 (formerly F) and GH11 families (formerly G) with exclusive activities for endo-β-xylanase in them. The difference between these two families based on sequence, different catalytic properties, substrate specificity, three-dimensional structure and mechanism of action [11, 12]. Besides the GH family 10 and 11, xylanases activity are also found in families of GH5, GH7, GH8, GH16, GH26, GH43, GH52 and GH62 [11, 13]. For the reason that some bifunctional enzymes are containing two catalytic domains, for example xylanases having domain of family GH10 or GH11 and it contains a domain of glycosidase as well. Among the other families, GH8 xylanases act solely on xylan whereas GH5, GH7, and GH43 xylanases also show activities as endo-glucanases, licheninases or arabino-furanosidases. Therefore, the enzymes with xylanase activity are solely not only confined to families GH10 and GH11 but also expanded to include other families like GH5, GH7, GH8, GH16, GH43, GH52, GH62 [11].
Xylanases belongs to GH families 10 and 11, which hydrolyze glycosidic bonds by acid base-assisted catalysis through a double displacement mechanism leading to retention of anomeric configuration at the cleavage site [14]. The xylanases from GH family 10 belongs to clan GH-A and the crystal structures display an (α/β)8 barrel fold or “salad bowl” shape with extended loops creating a catalytic cleft that contains at least four to seven xylose-binding subsites [15]. The catalytic site contains two glutamate residues, one acting as a nucleophile and the other as an acid/base catalyst. Catalytic amino acids and enzymatic mechanism are conserved, presenting a domain for catalysis of 250–450 amino acids. From the biochemical point of view, most of them have high molecular weight though there are reports of low molecular weight enzymes [16]. The values of their pI are generally alkaline (8.0–9.5), however, some also have acid values and all of them sustain the same three-dimensional structure. Most of the substrate binding subsites are highly conserved in xylanases, but the affinity differences between these subsites significantly affect their mode of action, as well as substrate and product preferences [17]. As heat stability has great concern in commercial usages of xylanases. For this purpose, a number of studies analyzed the crystal structures of thermostable xylanases. Intra- and intermolecular interactions in structural topography such as disulfide bond and hydrogen bond, compact the overall fold and stabilized N and C terminal end, fusion with CBM (carbohydrate-binding motif) and lower B-factor have been proposed to bestow the enzyme for increased heat stability [18].
The xylanases from the GH11 family belongs to clan GHC. It displays exclusive substrate specificity toward xylose containing substrates and a preference for insoluble polymeric substrates. The structure of GH11 is highly homologous and contains a single major α-helix and two extended pleated β-sheets which form a jelly-roll fold [19]. The structural features include a compact globular structure and a thumb-like structure as an 11-residue long loop that connects β-strands β8 and β7, and a long cleft that spans the entire molecule and contains the active site [20]. The catalytic machinery is composed of two glutamate residues, acting as a nucleophile and an acid/base catalyst, located in the middle of the long cleft [19]. Moreover, catalytic amino acids and enzymatic mechanism of GH11 are conserved and presenting domains for catalysis of 180–200 amino acids that fold into β-sheet conformation curved on itself.
GH 5 is the largest glycoside hydrolase family with varying activities including endo-1,4-β-xylanase. It hydrolyzes the β-1,4 xylan chain at a specific site directed by the position of an α-1,2-linked glucuronate moiety. The structural analysis XynA (of the family 5 xylanase) showed that, the catalytic domain displayed a common (β/α)8 barrel fold [21]; whereas, the β-barrels aligned well with those of another family 5 enzyme. The α-helices and loops were different, showing variances in the positioning, length and orientation. The xylanases belongs to family GH8 are classified in clan CH-M also contains endo-1,4-β-xylanase along with other glycoside hydrolase enzymes. It has also the aptitude to hydrolyze the β-1,4 xylan chain and exhibits the (α/α)6 barrel structure formed by six inner and six outer α helices [22]. Similarly, the GH26 are the member of the clan CH-A and exhibits the (β/α)8 structure. This family contains different glycoside hydrolase enzymes including β-1,3-xylanase, capable of hydrolyzing β-1,3-xylan. Activity, mechanisms and the structure of other member of glycoside hydrolase enzymes are listed in Table 1.
GH family | Fold | Clan | Mechanism | Nucleophile/proton donor | Xylanase Activity | PDB No.* |
---|---|---|---|---|---|---|
GH5 | (β/α)8 | CH-B | Retaining | Glu/Glu | Endo-β-1,4-xylanase (EC 3.2.1.8), Arabinoxylan-specific endo-β-1,4-xylanase (EC 3.2.1.-) | 2Y8K 5G56 4U3A |
GH7 | β-jelly roll | CH-B | Retaining | Glu/Glu | Endo-β-1,4-glucanase (EC 3.2.1.4), Endo-β-1,3–1,4-glucanase (EC 3.2.1.73) | 1EG1 3OVW |
GH8 | (α/α)8 | CH-M | Inverting | Asp/Glu | Endo-1,4-β-xylanase (EC 3.2.1.8) | 1H13 1XW2 |
GH10 | (β/α)8 | CH-A | Retaining | Glu/Glu | Endo-1,4-β-xylanase (EC 3.2.1.8), Endo-1,3-β-xylanase (EC 3.2.1.32) | 4QCE 1NQ6 1 W32 |
GH11 | β-jelly roll | CH-A | Retaining | Glu/Glu | Endo-1,4-β-xylanase (EC 3.2.1.8), Endo-1,3-β-xylanase (EC 3.2.1.32) | 3WP3 1YNA 1XNK |
GH30 | (β /α) 8 | GH-A | Retaining | Glu/Glu | Endo-β-1,4-xylanase (EC 3.2.1.8), Endo-β-1,4-xylanase (EC 3.2.1.136), β-xylosidase (EC 3.2.1.37) | 4FMV 4FMV |
GH43 | 5-fold β-propeller | GH-F | Inverting | Asp/Glu | Xylanase (EC 3.2.1.8), β-xylosidase (EC 3.2.1.37) | 5GLN 2EXJ |
Characteristics of different glycoside hydrolase family containing enzymes with a demonstrated xylanase activity.
PDB, Protein data base number.
Demystifying definitional issue for common understanding, the xylanases are enzymes commonly found in microorganisms, marine algae, protozoans, snails, crustaceans, insects, seeds, plants, and other natural sources [23]. Recently, there has been much industrial interest in xylanases for wood pulp bioleaching, papermaking, the manufacture of food and beverages, animal nutrition, and bioethanol production. Because of their biotechnological characteristics, xylanases are most often produced from microorganisms for commercial applications.
Nature is replete with myriad microorganisms producing enzymatic complexes that degrade cellulose and hemicellulose releasing sugars, used for attainment of products with high economical value [24]. Microbial xylanases are of prime importance in industrial application. Most of commercial enzymes are accrued from mesophilic microorganisms. The thermostable enzymes from thermophilic micro-organisms can better meet the need of high temperatures in the industrial processes for preparing end products. Of course there is a growing interest for multiple studies in exploring the importance of enzymes producing thermophilic microorganisms in relationship with biotechnological application. The microorganisms being extremophilic in nature can survive and thrive in extreme environments on account of which thermo-stability is provided to industrial processes. Biological sources including bacteria, fungi and yeasts have been reported as xylanase producing organisms in a natural process.
Xylanase producing thermophilic bacteria are found in variegated environments and the recent one was isolated in Tunisian hot springs. Various thermophilic
In comparison with the bacteria, the filamentous fungi have been in use as most potent industrial enzyme producers for the last five decades. Filamentous fungi are exuberant producers of xylanolytic enzymes in medium being used for the purpose. The genomes of lignocellulolytic fungi like for example
Other thermophilic fungus like genus
In the field of biotechnology, the thermophilic micro-organisms from archeal domain have been reported/isolated with ability to express enzymes that can tolerate high temperatures (80–115°C), extreme pH, and high salt concentration [38]. These thermophilic enzymes with attribute of hydrolyzing lignocellulosic biomass were characterized, cloned and expressed in various hosts.
Sources | Gene | Substrate | Xylanase activity | References |
---|---|---|---|---|
Xyn11B | Beechwood Xylan | 382.0 U/mg | [36] | |
XynA | Beechwood Xylan | 250.69 U/mg | [41] | |
— | Birchwood Xylan | 5098.28 U/mg | [42] | |
XynA | Beechwood Xylan | 5768 U/mg | [43] | |
XynBS27 | Oat spelt Xylan | 3272.0 U/mg | [44] | |
XAn11 | Birchwood Xylan | 909.4 U/mg | [45] | |
XAn11 | Birchwood Xylan | 415.1 U/mg | [45] | |
XynSL4 | Birchwood Xylan | 244.7 U/mg | [28] | |
Xyn6 | Oat spelt xylan | 172 mg/L | [46] | |
Xyn2 | Birchwood Xylan | 1600 U/mg | [47] | |
MYCTH_56237 | RBB-Xylan* | 1533.7 U/mg | [48] | |
MYCTH_49824 | RBB-Xylan* | 1412.5 U/mg | [48] | |
MYCTH_39555 | Birchwood Xylan | 105.42 U/mg | [49] |
Sources of microbial xylanases with demonstrated activity.
RBB-Xylan, Remazol brilliant blue-Xylan.
To acquire a pure form of a particular enzyme from a given source is challenging. Also it is inconvenient to have cultivation of bacteria or fungi for large scale protein production that often leads to many interfering enzymes. It might need multiple purification steps to get the intended enzymes purified from a pool of proteins which in turn will increase the cost. Therefore, recombinant DNA technology is recommendable for application with success prospects for desired object [50]. Recombinant DNA technology allows large scale expression of enzymes in both homologous and heterologous protein expression. The genes of enzymes with industrial importance were reportedly cloned and expressed in expression hosts in order to enhance specific enzymes production plus improvement in substrate utilization, and other commercially useful properties. Likewise, genes encoding thermophilic xylanases from different sources have been cloned with the objectives of overproduction of the xylanases and changing its properties to suit commercial applications [9].
Although previously it has been reported that the expression of the xylanase genes usually cannot be functionally expressed in
Filamentous fungus is the promising organism for protein expression and its production by fermentation has a long history in industrial area. Even developed other expression systems for recombinant protein expression, fungal expression system also considered an appropriate candidate for the expression [9]. Natural capability of fungal expression system to secrete large amounts of proteins into the medium gave an advantage to this expression system. Furthermore, it has feasibility for functional expression of other xylanases from remote sources by using of native xylanase expressing machinery [7, 9]. Most of the xylanase genes have been expressed in fungi under homologous expression system and frequently used fungus as expression hosts are
Yeasts considered as excellent and attractive host for the expression of heterologous proteins and offer many advantages over the other established expression systems especially in protein maturation [59]. The methylotrophic yeast
In most of the cases xylanases need to undergo some genetic modifications in order to enhance expression level, enzymes activity and that might have some influence on substrate specificity and stability to high temperature and pH. The gene encoding cellulolytic and xylanolytic enzymes are usually regulated by a repressor/inducer system in fungi. Xylanolytic transcriptional regulators have been reported in thermophilic fungi. The strong promoter MtPpdc (pyruvate decarboxylase) recently used for the overexpression of xylanases from
In order to fulfill the demands of industrial requirements, gene mining and protein engineering are applied to develop thermostable xylanases. Although some of thermophilic xylanases were produced from thermophiles but their lower expression levels and specific activities making them unable to be applied efficiently. The higher specific activity with enhanced thermostability of xylanases is therefore needed through genetic engineering. Recently the thermostability of mesophilic xylanase (AuXyn10A from
The enzymatic degradation reaction of insoluble polysaccharides had great importance. However, glycoside hydrolase enzymes often inaccessible to the active site of the appropriate enzymes, such polysaccharides relatively inefficiently. In order to overcome these problems, many of the glycoside hydrolases that utilize insoluble substrates are modular, comprising catalytic modules appended to one or more non-catalytic carbohydrate-binding modules (CBMs) [72]. Two xylanase genes belongs to family GH11 (xynC81 and xynC83) from a thermophilic strain
Moreover, some xylanases bears CBMs specific for cellulose, which probably assist indirectly localization of xylanase to the xylan substrate, since it is in close association with cellulose. The number of characterized fungal xylanases harboring CBM1 module is relatively reduced. It includes xylanases from
The metal ion and chemical reagents had been proved to be one of the critical factors which affected the enzyme activity of xylanases. The effect of metal ions and chemical reagents on the xylanase activities has been determined on various metal ions (Na+, K+, Ca2+, Li+, Co2+, Cr3+, Ni2+, Cu2+, Mg2+, Fe3+, Zn2+, Pb2+, and Ag+) and chemical reagents (SDS, β-mercaptoethanol, ethanol, Triton X-100, and EDTA) at the standard condition. Ca2+, Pb2+, K+, Mn2+, EDTA, β-ME, Cu2+ and Triton X-100 were reported to enhance enzyme activity by 6.4–29.9% [81], while Fe3+, Cd2+, Hg2+, and Ba2+ completely suppressed the xylanase activity. Besides this, the enzyme had certain ability to resist the Fe2+, Mg2+, Ag2+, SDS, ethanol and SDS. Xylanase activity was not inhibited by chelating reagents such as EDTA and EGTA. Moreover, it is predicted that Ca2+ and Mg2+ ions enhance the enzyme activity by stabilizing the enzyme–substrate complex. In contrast, EDTA is a chelating agent and it removes ions from the enzymes, thus inhibits the enzyme activity [7]. More detailed studies are needed in order to understand the mechanistic effect of metal ions on enzyme activity. Similarly, a xylanase activity isolated from
As thermophilic enzymes are preferred over the mesophilic enzymes complements because of high temperatures, which had a great influence on many factors such as decreases contamination risk and viscosity of substrate [82]. In a study carried out with the effect of xylanase activity from
Evaluation of the pH stability is a vital part of any enzyme characterization before it can be exploited commercially. Similarly effect of pH had great influence on the xylanase activity. The effect of pH on extracellular xylanase from
Species | Strain | pH | Temperature | References |
---|---|---|---|---|
TH7C1(T) | 11.0 | 70°C | [26] | |
JAM-AC0309 | 8.0 | 65°C | [86] | |
SL4 | 7.0 | 70°C | [28] | |
WBI | 7.0 | 65°C | [87] | |
F32 | 6.6 | 75°C | [88] | |
Cpt20 | 10.0 | 80 °C | [89] | |
Tpbgl | 3.5 | 95°C | [90] | |
MT4 | 7.0 | 90°C | [91] | |
AN1 | 6.0 | 75°C | [92] | |
Pol6 | 3.0 | 65°C | [93] | |
S582 | 6.5 | 70°C | [94] | |
J18 | 7.0 | 75°C | [95] | |
MEY-1 | 4.5 | 85°C | [96] | |
S168 | 6.5 | 80 °C | [97] | |
B3–11(2) | 5.0 | 50 °C | [98] |
List of xylanase producing microbial species/strains with demonstrated pH and temperature.
Because of their biotechnological characteristics, xylanases are most often produced from microorganisms for commercial applications. The environmental hostility and lethality to most of living organisms due to extreme hot environments is obvious but such factors are counter-productive in the presence of specialized microorganisms. These microorganisms from harsh environments can tolerate high or low temperatures, extremes pH and high concentrations of salts. Based on the unique stability of their enzymes at high temperature, extremes of pH they are expected to be a powerful tool in industrial biotransformation processes that run at harsh conditions. Enzymes derived from extremophiles have great importance to the local enzymes because they can perform industrial processes even under harsh conditions, under which conventional proteins are completely denatured. The extremophile research, the high demands of the biotech industries for tailor-made novel biocatalysts, and the rapid development of new techniques such as genomics, proteomics, metabolomics, directed evolution and gene shuffling will stimulate the development of new industrial processes on the basis of biocatalysts from extremophiles.
Enzymatic hydrolysis of xylan has become attractive due to its biotechnological applications in the food, animal feed, waste treatment, ethanol production, textile, and pulp and paper industries [11]. Xylanases gained its importance for the saccharification process in degradation of lignocellulosic biomass, because xylanases assist the hydrolysis of xylan and ultimately leads to the hydrolysis of hemicellulose and cellulose, to obtain industrially important products [99]. In addition, biofuel production from lignocellulosic biomass has great concern in industrial sectors worldwide. However, biofuel production is still a bottleneck, because the initial conversion of biomass into sugars requires multiple enzymes (including xylanases) with high activity and excellent enzyme properties. Therefore, recent development in biotechnological applications xylanases toward the biomass conversion is on way [100]. Moreover, highly stable enzymes, active under high temperature and wide range of pH, displayed several advantages over the enzymes from mesophilic or neutrophilic origin. For example, highly active xylanases under extreme conditions reduce the contamination risk due to fast reaction rate. In second generation ethanol industries, mild pretreatment of biomass requires to reduce the total costs and sustain the high contents of hemicellulose. However, high dosage of other enzymes is still needed for the complete conversion of hemicellulose. Therefore, the biotechnological application of xylanases especially thermophilic xylanases and its interaction with other enzymes such as cellulases, xylosidases, arabinofuranosidase seems to be an effective in saccharification process.
The use of xylanases, as accessory enzymes, has shown to improve the hydrolysis of xylan and cellulose, and it has contributed to the reduction of enzyme dosage, but it seems to be a substrate dependent reaction [101]. Recently, less severe pretreatments of lignocellulosic biomass are gaining popularity, thus, hemicellulase characterization and studies regarding synergism of cellulases and xylanases, can contribute to reducing pretreatment severities and enhancing glucose and xylose release [102]. Xylanases are very important in bioconversion of xylan into value added products, such as xylitol. Xylitol is used in soft drinks, candies, ice cream, chewing gum and various pharmaceutical products. Xylitol have key role in sweeten food products and used as a natural sweetener in toothpaste. Xylanases have great importance in the bio-bleaching of wood pulp and in the bioprocessing of textiles.
Xylanases are very useful in manufacturing of animal feed. Xylanases reduce the viscosity and enhance the absorption rate by degrading the starch polysaccharides in rich fiber and barley based feeds. Pre-treatment of agricultural silage and grain feed employed with xylanases increases the nutritional value and improves the feed digestion in ruminants. Similarly, feed supplementation combined with xylanases for broiler diets, not only increases growth performance like weight gain but also helpful in the yield production of poultry products.
Conclusively, the xylanases have potential applications in a wide range of industrial processes, covering all sectors of industrial enzymes markets. Arguably, these are attractive for research studies and deeper investigation with aims to explore dividends and utility of these useful products in industrial context in relation to industrial enzymes producing organisms.
Microbial xylanases are gaining importance in industrial applications. The thermophilic microorganisms are of interest in the field of biotechnology because of their ability to express enzymes that tolerate high temperature and pH. The thermophilic bacteria, and an archaeal species, there are also filamentous fungi that grow in diverse environments and produce xylanase. New recombinant DNA technology can be used to express xylanases in both homologous and heterologous host organisms. Compared to
This study was supported by National Natural Science Foundation of China (31570067).
The authors declare no conflict of interest.
Answers regarding the value of a medical system can vary depending on various considerations and degrees of interest. Even when considering the universal values of human life and health, their implications are presumed to depend both on the sense of individual values and a country’s history, culture, national character, and surrounding socioeconomics [1, 2]. Meanwhile, if we discuss human dignity’s ethical and moral aspects, the fundamental values of health and life typically exhibit a consensus within the minimum necessary basic range. In other words, the value of the medical system can be considered a mechanism for stable supply (cultivation of a sense of security) that guarantees basic human rights. Given the socio-economic background, the significance of discussing the medical insurance systems of countries from this perspective has recently been increasing. Under these circumstances, the World Health Organization (WHO) has promoted universal health coverage (UHC).
UHC refers to universal access to all people for necessary healthcare services—irrespective of time, place, and their financial condition. UHC, a goal that the healthcare system must strive to achieve, includes basic health services: promotion, prevention, treatment, rehabilitation, and palliative care. This goal takes the civic perspective. Given this background, the understanding and contribution of all members of society (citizens) is essential to the realization of UHC. Its promotion requires a balance between the benefits and burdens at the citizen level. The aforementioned value trends were involved in discussing this balance. In other words, the choices and decisions of individuals and groups are influenced by values. However, issues related to equity and efficiency exist in allocating resources for public goods. The significance of applying value theory and market principles, although limited, has been discussed for a long time [3].
Therefore, the political dimension is also important when considering UHC progress. To promote UHC, some issues regarding evaluating the medical insurance system must be resolved. The increasing importance of socio-economic measures in medical insurance systems has attracted considerable attention. In general, the following three issues have been addressed: (1) The perspective through which the medical insurance system’s outcomes (goals and significance) must be discussed and evaluated. (2) The measurement and analysis of the impact of socio-economic factors on health insurance system outcomes. (3) Determining the operation of the medical insurance system (e.g., benefits and burdens, allocation of resources) based on the aforementioned issues. Each issue has a broad and complex context; thus, consistent effort is required.
The development of public medical resources, especially the financial investment system (national burden and insured burden), is indispensable for the sustainable operation of the medical system. Therefore, an analysis of the characteristics of each country’s political systems is required. As rational policy decision-making is imperative for discussing the financial burden, analytical tools such as those presented in this chapter are necessary. For example, in future studies, a cost-effectiveness analysis (CEA) could be conducted. Additionally, adopting a longitudinal research design (panel data analysis) would make it possible to account for the effects of fluctuations in external factors—such as the real economy—with high accuracy. For example, a report suggests that it is important to optimize resource allocation from the perspective of public interest rather than simply increasing the medical expenses per capita to develop the medical insurance system [4].
Based on the above, harmonizing the public and private sectors is a theme in healthcare insurance systems. This coincides with harmonizing the benefits and burdens of healthcare policy between individuals and society. This requires a macroeconomic analysis of the relationship between health sector outcomes and socio-economic factors. Therefore, this approach also involves financial aspect and discusses the relationship between the real economy and public interest activities. Regarding healthcare services, there is a lot of discussion about payment formulas and price levels in the relationship between stakeholders (economic payers, providers, and service recipients) [5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16]. In other words, there are themes related to the proper allocation of social security funds and the improvement of inefficiencies in the public market. Therefore, a microanalysis is essential in the discussion of healthcare insurance systems. From this perspective, utility theory and welfare economics are applied to elucidate the mechanisms of price formation and treatment selection behavior.
In particular, these themes are becoming more important in the quasi-public medical market, such as Japan’s universal health insurance system, medical resources consisting of social premiums, general taxes (including subsidies), and patient out-of-pocket expenses. For example, rising drug prices and procedure fees have a structure that rebounds from social and individual burdens. Therefore, the significance of comprehensively discussing phenomena and issues that straddle both macro- and micro-aspects has been emphasized (Figure 1). For example, high expectations for cost-effectiveness evidence can be applied to macro- and micro-issues to ensure the sustainability of the system and the appropriateness of resource allocation. From the above, three closely-related perspectives will be discussed: an examination of UHC considering socio-economic factors, examination of the significance of citizens’ value in resource allocation, and examination of price formation considering patients’ economic burden.
Three closely related perspectives are examined: An examination of UHC considering socio-economic factors, the significance of citizens’ value in resource allocation, and price formation considering the economic burden of patients. Note: UHC, universal health coverage.
This chapter explains the concept of the approach required to address the aforementioned issues and introduces examples of related research reports as a guidepost for discussions in the areas concerned. In the first section, the socio-economic factors that affect UHC are examined, and examples of quantitatively evaluating these relationships and their analysis results are provided. Subsequently, the concepts of medical value and methodology, which are indispensable to the ideal development of the medical insurance system, are summarized. Research cases related to the significance of lifesaving and drug discovery are introduced, considering the possibility of allocating public resources. In the final section, the concept of price (fee, charge) formation, which also considers medical value, is organized based on the characteristics of economics and medicine. For example, a report that analyzes the mechanism of price levels, focusing on Japanese private practice (out-of-pocket), is introduced.
Sustainable Development Goal (SDG) 3 comprises 13 targets related to “health and welfare for all.” The other 16 goals were either related—or indirectly contributed—to health. The SDGs aim to “leave no one behind” and are international objectives applicable to developing and advanced countries. UHC is a concept that includes 1) protection from financial risks for all, 2) access to quality primary health services, and 3) access to essential medicines and effective, high-quality, and inexpensive vaccines. Target 3.8 SDG 3, which involves achieving UHC and health improvement worldwide, is considered the most crucial task of the WHO [17].
The measurement approaches and definitions of the UHC index evolved between 2015 and 2019, and the index is now used in every global monitoring report [18]. UHC progress between regions and countries can be compared. Additionally, the UHC service coverage index (SCI) has been calculated as a single number (i.e., score) since the late 2010s, thereby improving comparability between nations. Although the performance of different countries can now be compared, global monitoring alone is insufficient to guide policymaking [19]. Therefore, each country should be encouraged to develop a country-specific global framework. The relationship between the environmental factors surrounding medical care and progress toward UHC should be analyzed to achieve this.
Healthcare systems generally help improve clinical outcomes by increasing public financial investment [20, 21]. Meanwhile, declining birth rates, aging populations, and the maturation of medical systems generally tend to reduce the baseline performance of medical systems. Some reports mention that unemployment and poverty, which are distant causes of catastrophic health costs, are factors that reduce service coverage index levels [22]. Therefore, there is room for countermeasures, including population policies and economic measures. For example, future economic growth strategies could include the promotion of healthcare and life sciences industries. Improvements in health care programs include disease prevention and medical insurance policies.
Problems regarding medical financial systems constitute a significant challenge to achieving UHC. According to the WHO, a healthcare financial system that eliminates the financial constraints of access to health services is crucial [23, 24]. Several previous studies have suggested that UHC is more likely to be achieved when patients’ out-of-pocket medical costs are low [25]. As rational policy decision-making is imperative for discussing the financial burden, analytical aspects, such as UHC and socio-economic factor relationships, are necessary. For example, CEA, a performance analysis of medical functions, is the most common approach for assessing the health benefits for each spent or the cost for each additional health unit. CEA is a tool used to enhance the sustainability of medical systems.
This section introduces an example of the relationship between SCI and major socio-economic indicators to establish UHC levels and economic factors [25]. This study used SCI as a proxy for progress toward UHC in 11 Asian countries. A fixed-effects regression model was employed to analyze panel data from 2015 to 2017, and to explain the interrelationship between the SCI and major socio-economic indicators (health expenditure, unemployment, etc.) Performance analysis (to determine the ratio of the achieved SCI level to gross domestic product or health expenditure displacement) was also conducted. This analysis examines the balance between the degree of achievement related to UHC and a country’s economic level.
The gross domestic product (GDP) and SCI had a significant positive correlation (Spearman’s rank correlation coefficient [Rs] = 0.716, p < 0.01). Health expenditure and SCI were significantly and positively correlated (Rs = 0.743, p < 0.01). When both GDP and SCI indicators were transformed using logarithms, the abovementioned trend did not change significantly (Rs = 0.731, p < 0.01; Figure 2). The results of the panel data analysis showed that GDP per capita significantly contributed to SCI (standardized partial regression coefficient, 1.6129; partial regression coefficient, 0.0049; 95% Confidence interval [CI], 0.0025–0.0074; Table 1). The total population, governmental health expenditure, unemployment, and poverty rates were statistically significant, whereas health expenditure was not significant. The unemployment and poverty rates show a negative trend, and the entire model is statistically significant (R2 = 0.991, F-test: p < 0.001). The ROC curve for health expenditure per GDP for SCI showed a cutoff of 3.7% (p < 0.01) for the Youden index and 4.9% (p < 0.01) for the shortest distance (AUC = 0.8125, 95% CI: 0.6350–0.9899, p < 0.05; Figure 3).
Relationship between economic level (GDP) and SCI (logarithmic transformation, 2017). Note: UHC, universal health coverage; SCI, service coverage index [
UHC index of service coverage (SCI) | Partial regression coefficient | Standardized partial regression coefficient | SE | p-value | 95% CI |
---|---|---|---|---|---|
Population (total: million people) | 0.0049 | 0.1921 | 0.0012 | 0.0001 | 0.0025–0.0074 |
GDP per capita (current USD) | 0.0017 | 1.6129 | 0.0002 | < 0.001 | 0.0013–0.0021 |
Health expenditure (% of GDP) | 2.3481 | 0.4116 | 1.5748 | 0.136 | −0.7386–5.4347 |
Government health expenditures (% of general government expenditures) | 1.4511 | 0.6575 | 0.2804 | < 0.001 | 0.9015–2.0006 |
Unemployment rate (%: ratio of unemployed persons) | −1.4764 | −0.2253 | 0.7105 | 0.0377 | −2.8689–0.0838 |
Poverty rate (%: poverty gap) | −1.6736 | −0.2303 | 0.4674 | 0.0003 | −2.5897–0.7575 |
Model: R2 = 0.991, F test: p < 0.001 |
Panel data analysis of the impact of economic level (GDP, health expenditure, unemployment, and poverty) on SCI.
Note: GDP, gross domestic product; UHC, universal health coverage; SCI, service coverage index; SE, standard error; CI, confidence interval [21].
ROC curve of health expenditure (per GDP: %) for SCI (criterion: Score 70) [
From the results of the performance analysis after the logarithmic transformation of each index, South Korea (high-income country: HIC) scored the lowest (GDP: 0.12 SCI score/USD per capita, health expenditure: 0.07 SCI score/USD per capita; Figure 4), followed by Vietnam (lower-middle-income country: LMIC) and India (LMIC). Japan’s (HIC) performance was moderate, while Indonesia (UMIC), Thailand (UMIC), and Cambodia (LMIC) had relatively high performance. The Philippines (LMIC) had the highest performance (GDP: 1.84 SCI score/USD per capita, health expenditure: 1.04 SCI score/USD per capita). Myanmar (LMIC) was marked as the “dominant quadrant.” The more effective but less expensive quadrant exhibited the best performance in the cost-effectiveness analysis. When the relationship between the proportion of the population aged 65 and above was organized without logarithmic conversion, the SCI score increased with age (Rs = 0.779, p < 0.01), and the performance value decreased (Rs = − 0.830, p < 0.01; Figure 5).
Performance status by country (broad cost-effectiveness analysis based on displacement from 2015 to 2017). Note: SCI, service coverage index. *1: Dominant is positioned in a more cost-effective dimension with increasing outcomes (SCI) even if the economy (GDP) declines. *2: Performance was a cost-effectiveness analysis (difference in outcome “SCI” ÷ difference in the economy “GDP”; displacement from 2015 to 2017). Both indices were logarithmically transformed to consider the elasticity [
Trends in SCI and performance (economic level: GDP) with respect to the aging rate (percentage of the population aged 65 years and above). Note: UHC, universal health coverage; SCI, service coverage index. (†) Myanmar has a different quadrant (dimension) because it is “dominant” [
Each of the four SCI components had a different level of achievement (Figure 6). LMICs were most countries with SCI levels of 60 or below (i.e., Bangladesh, India, Indonesia, and Cambodia), where “infectious diseases” and “service capacity and access” were more widely dispersed. This was compared to the group of countries with SCIs of more than 80 (i.e., South Korea, Japan, Thailand, and China), HIC, and UMIC. Multiple regression analysis used SCI’s annual rate of change as the objective variable and SCI components as the explanatory variable. The results indicate that “service capacity and access” significantly contributed to the SCI level (standardized partial regression coefficient, 0.9209; partial regression coefficient, 0.3581; 95% CI, 0.3142–0.4019). Furthermore, when the GDP per capita and “service capacity and access” values of each country were relatively arranged, with Japan as the standard, a positive correlation was observed between the two indicators (i.e., single correlation: Rs = 0.901, p < 0.01) (Figure A1).
Distribution composition of SCI components according to SCI level (≥ 60 and ≥ 80). Note: SCI, service coverage index [
The present study used SCI as a proxy for the progress of UHC. Currently available service coverage metrics focused on infectious diseases and reproductive, neonatal, maternal, and child health [26]. In this study, the indicators for SCI-related data (Figure A2) were “reproductive, maternal, newborn and child health,” “infectious diseases,” “noncommunicable diseases,” and “service capacity and access.” In addition, the country-by-country socio-economic indicators included “total population,” “population aged 65 and above,” “gross domestic product (GDP) per capita,” “health expenditure per GDP/per capita,” “government health expenditures,” “unemployment rate,” and “poverty rate.” All data were converted into a panel from 2015 to 2017; SCI-related and socio-economic data were also compiled [27, 28, 29].
According to the analysis results derived by applying these data, UHC progress tends to increase as the share of the healthcare domain in government spending increases. Future studies on UHC development measures are important to discuss the appropriate form of resource allocation (public finance) according to sustainability-based productivity and efficiency or value evaluation (national consensus). Based on the statistical analysis results, some cases exist wherein SCI achievement levels differ even among countries at the same economic level. Furthermore, SCI improvement is small, even in countries with high economic investment levels. Exploring these factors and considering improvement measures are assumed to promote UHC progress. This study examined the influences of the maturity of the medical system as an additional country-specific factor (rather than the social system, national character, and culture).
The results showed that when aging and health expenditure exceed a certain level, UHC performance decreases as a country’s need to raise its goal increases. Additionally, the weight of “service capacity and access” to SCI was considerable. This secondary index, which embodies the environment of the healthcare system, can be considered a surrogate index that predicts the maturity of social and medical care. The considerable impact of these factors on UHC implies that stable development cannot be expected simply by expanding the expenditure scale due to the mechanisms related to economic conditions. As a result, policymakers must implement countermeasures based on indicators that can estimate the economic status of the UHC approach, such as its cost-effectiveness.
CEA is often applied to medical-economic evaluations, such as high-priced medicines and health programs, but can also be applied to macro issues, such as medical systems [30]. Cost-effectiveness is an instrument widely used in Western health systems. The instrument provides the information needed to reach a consensus among stakeholders in allocating medical resources and setting medical prices. As UHC progress requires country-specific efforts, as discussed in the introduction, estimating the coefficients that define each country’s UHC progress and socio-economic status is also necessary. Hence, a country-specific performance analysis (CEA: country-specific coefficient calculations) was conducted. In the present study, CEA was performed using economic level as a cost index and SCI level as an effective index.
This approach suggests that regardless of the maturity of the system or the size of the economy, the status of UHC activities in each country can be evaluated based on the displacement of economic and SCI levels achieved.
This section summarizes the conditions and mechanisms of the link between value and price discussion in a medical system.
In a private economy, where the market principle works, goods (and services) are demanded and supplied in the market based on people’s decision-making (free choice and action) depending on changes in price levels. If the market works well, supply and demand will be balanced, and various goods will be properly distributed. The relationship between benefits and burdens in this market is easy to explain. Meanwhile, in a public economy, where the government is the main operator, the market principle works in a limited way. Taxes that enforce the burden are a receiver of supply costs for the demand of goods.
Therefore, public needs and expenditures (including reallocation) are generally determined by the government’s judgment. However, price levels in the public economy are often formed by costs (e.g., size of spending budget), which are both inefficient and inconsistent with market utility (i.e., consumer satisfaction). Additionally, the allocation of public resources may deviate from the balance between supply and demand, and inequity among participants within a group may be promoted. Thus, issues related to Use-value, Marginal utility, and Pareto optimization become apparent in the public economy [31, 32].
Subsequently, the concept of verifying the economic appropriateness of the market function and product price (among others) arises by balancing the number of resources consumed and the results obtained (e.g., cost-effectiveness and performance) [2]. As an example of its widespread use, considering large-scale public investments (e.g., the construction of dams and bridges), the desirability of the project’s implementation is evaluated based on its cost-effectiveness. Additionally, in the private economy, where technological innovation is active, and consumers have numerous choices, the concept of cost-effectiveness is used more actively to incorporate activities and stimulate product appeal. Consequently, the basic and broad concept of cost-effectiveness has developed in social policy decision-making and resource management fields. Its know-how has been cultivated in contract society and management activities and used in social consensus-building and decision-making.
Meanwhile, the provision of medical services is characterized by information asymmetry and restrictions on opportunity costs (options) against the background of health and life. Therefore, healthcare markets differ from common markets that exhibit typical demand and supply; this market has three parties (citizens, insurance, and providers) and faces asymmetric information that creates several market problems (i.e., common equilibrium market laws do not apply), including problems in defining prices. Although this is inherently unfair (bias) in the health sector from the perspective of citizens’ financial burden, the system is based on medical needs such that the needs of the patient, regardless of the outcomes, receive the same medical care. Since such a tendency threatens the system’s sustainability, there have been attempts to improve it as much as possible by utilizing cost-effectiveness and utility theory.
By their very nature, public goods are non-competitive; therefore, the role of price tends to be smaller. Medical care has restrictions on individual choice. However, CEA (including cost-utility analysis [CUA]) is widely used to evaluate medical technology in high-income countries, and prices are determined according to this evaluation. Recently, pricing has become more common with evidence-based or value-based approaches. In this method, a consumer’s natural internal decision-making regarding consumption behavior is externally substituted by other stakeholders under certain conditions (typically advocating the maximization of group benefits) for a certain group or system based on the law of equal marginal utility and expected utility theory. These methods will be considered along with the uncertainty of outcomes and limited rationality of human beings.
The medical systems of many countries have historically operated as part of the social security system, as they gather high public interest from the necessity for all people. Further, against the background of stable supply, the pricing of medical services has often been based on costs. As described in the previous section, numerous developed countries face structural issues, such as declining birth rates, aging populations, and rising costs of medical services; thus, verification of price levels has become an urgent concern [25]. Therefore, the need to build a social consensus on the economic burden of the value of medical services has been increasing, and the verification of price levels while considering cost-effectiveness has further expanded [33]. Against this background, discussions on value evaluation and price levels in the medical field are being conducted using various approaches to consider cost-effectiveness.
Utility refers to the degree of subjective satisfaction or demand fulfillment that each consumer obtains when consuming a certain good or service and is considered a fundamental concept in economics [34]. When interpreted broadly, human economic activities and all human behaviors (including the selection of medical services) aim to maximize the utility to be acquired as the background. Thus, this concept can explain the background of stakeholder behavior changes (e.g., decisions and choices) in the field of health care [35]. Furthermore, a method supported by varied theories related to utility was assumed as an approach to value evaluation.
In summary, “value” is regarded as the meaning of the existence (usefulness or significance in a narrow sense) of an object regardless of whether it is “tangible or intangible.” For example, in the public sector, meaning is often organized using exchange value and use-value. A value is diverse and difficult to quantify in general; however, it should be explained to the parties concerned (Figure 7) [36] when discussing it as part of a social system. This perspective is even more important for the effective utilization (fair distribution) of public properties. Aspects related to life and health should first be discussed from the perspective of “use-value” in developing society. Furthermore, medical care is expected to be provided to everyone at a fairly low cost (public aspect).
The conception of value assessment in the quasi-public healthcare system: The balance of the valuation of technical innovations and the guarantee that all patients have access. The public medical marketplace requires a system that considers both use and exchange values [
Therefore, several countries worldwide have more or less developed the medical field as a public system, following the lead of the 1978 Alma Ata Declaration. Specifically, Japan’s universal health insurance system is assumed to have experienced this trend (see Figure 8). However, highly specialized professionals and therapeutic materials require large investments in developing medical resources, and their supply is restricted. Therefore, to operate and develop medical care as a social system—considering the “exchange value” content that accompanies scarcity and building a system that incorporates certain market principles (economic aspect)—are crucial [2]. This perspective is also important in discussing consistency within the real economy.
Significance and key characteristics of value measurement in the public economy (decision-making and resource allocation) [
Thus, in a quasi-public healthcare market such as Japan, it is desirable to provide mature and widespread medical care at low-cost while guaranteeing a high economic level for innovative (or effective) medical care and specialized resources. Moreover, a system that balances the use and exchange of values is necessary. As previously mentioned, assessing value in the medical field involves various restrictions. Value evaluation can be performed in several ways, which are inadequate for consistency with the real economy or developed as a theory of price setting. The approach to value evaluation that contributes to the discussion of economic activities and official prices in the healthcare system is as follows:
Generally, in microeconomics, prices converge based on supply and demand equilibrium with the background of utility theory, and efficiency is thus maximized. Incorporating herein the perspective of equity (well-being), public interest value is discussed based on the balance between patient utility value (preference, willingness to pay) and medical finance (income reallocation, finance balance) (Figure 9). The balance between increasing utility and cost per health program unit while weaving individuals and society is thus considered. As a result, if utility is maximized in a certain budget range, the higher performance increases the utility in a total of the entire population, and the stakeholders’ “value” increases. Compared to the conceptual discussion of value, it is relatively possible to discuss consistency with a real economy or a general value; hence, it is considered suitable for examining the medical price of the public sector.
Concept of value evaluation of health care based on utility theory and cost-effectiveness considering welfare economics.
The value of medical services can be indirectly evaluated in the public sector by applying the marginal utility theory and scales based on preferences while considering different conditions and objectives from those in the private sector [37]. Incidentally, in the medical field, a method for measuring and analyzing patient utility values as a type of health-related quality of life has been developed. The application of this concept to CEA is CUA, which is a type of CEA. Based on the above, the medical value is calculated as “health recovery (patient outcomes such as utility)/resource consumption (direct medical cost) ⇒ medical performance = medical, economic value” [38] (Figure 10). A related concrete methodology is cost-effectiveness analysis, which considers health programs’ medical and economic position.
Concept of economic performance: One of the methods used to discuss the economic value of healthcare. “Value” in social activities is determined by the balance between capital investment and its returns. If a certain amount of money is paid to use a certain service (function), its value is determined by performance, equal to the amount of service (function) divided by the cost. For the consumption of one budget item, the greater the result, the higher is the value. The amount in terms of “restoration of health” is used as an index of “function” in the medical field [
This explains the socio-economic significance of the medical services provided by balancing public costs and earned utility in the medical market. It is believed that the higher the performance, the greater the utility (clinical outcomes for patients) as part of the value of the budget range.
This section introduces reports that discuss the socio-economic significance of the spread of lifesaving medical devices and the research and development (R&D) of expensive pharmaceuticals (at the time of 2010).
First, a case of microeconomic valorization of end-stage renal failure is discussed [39]. With the progression of renal impairment in patients with chronic kidney disease, the dysregulation of electrolyte and water metabolism and retention of uremic toxins can significantly impact health status and even threaten life [40]. Treatment with hemodialysis (HD) should target maintaining the amount and composition of body fluids within the normal range. The study subjects were aged >20 years and had received HD for at least 6 months. HD patients were prospectively observed for 36 months, and patient utility was assessed based on the EQ-5D, from which quality-adjusted life years (QALYs) were estimated. Medical costs were calculated based on the medical service fees. Cost-effectiveness, defined as the incremental cost-utility ratio (ICUR), was analyzed socially. A total of 29 patients (mean age; 59.9 ± 13.1 years) undergoing 437 dialysis sessions were analyzed.
Utility-based EQ-5D score was 0.75 ± 0.21, and the estimated total medical cost for 1 year of maintenance HD (MHD) treatment was 45,200 ± 8800 USD. On average, the ICUR was 68,800 ± 44,700 USD/QALY (Figure 11). When comparing the ICUR based on the causes of kidney failure, the value for diabetic nephropathy was higher than that for glomerulonephritis (81,700 ± 62,800 vs. 68,200 ± 40,700). The ICUR after 36 months of observation increased mainly in patients below 65 years of age (all P < 0.05; <65, P < 0.01; ≥ 65, not significant) (Figure 12). MHD could improve the socio-economic status of older-adult patients with end-stage kidney disease; however, the ICUR for diabetic nephropathy was higher than that for glomerulonephritis (Table 2). However, the ICUR does not deteriorate in older-adult patients. Therefore, measures to prevent malnutrition and establish the optimum time per session and frequency of dialysis (i.e., optimal dialysis volume) are necessary to further improve MHD’s cost-effectiveness.
Utility values (EQ-5D score) during the first 4 weeks of observation and the 36th week. Four-week interval after the classification of primary diseases for end-stage kidney disease (glomerulonephritis, diabetes mellitus, and the whole) [
Change in cost-effectiveness (ICUR) between the first 4 weeks of observation and the 36th four-week interval. *p < 0.05, **p < 0.01 [
Parameter | All Subjects | Glomerulonephritis | Diabetic nephropathy | Others | ||
---|---|---|---|---|---|---|
Utility(QALYs) | ||||||
Mean ± SD | 0.75 ± 0.21 | 0.73 ± 0.17 | 0.68 ± 0.23 | 0.83 ± 0.22 | ||
Median | 0.73 | 0.71 | 0.60 | 1.00 | ||
* | ** | ** | ||||
Mean ± SD | 45,200 ± 8800 | 45,300 ± 8800 | 51,100 ± 10,700 | 41,100 ± 4100 | ||
Median | 43,300 | 44,100 | 43,500 | 41,900 | ||
** | ** | ** | ||||
Mean ± SD | 68,800 ± 44,700 | 68,200 ± 40,700 | 81,700 ± 52,800 | 54,600 ± 27,400 | ||
Median | 58,700 | 60,900 | 81,100 | 44,400 | ||
** | ** | ** | ||||
Dialysis time (hour per intervention) | ||||||
Mean ± SD | 4.35 ± 0.50 | 4.19 ± 0.39 | 4.08 ± 0.43 | |||
95%CI(two-sample population mean) | 0.16(0.01.0.28) | 0.11(-0.01.0.23) 0.27(0.16, 0.37) | ||||
Cr(mg/dL) | ||||||
Mean ± SD | 9.93 ± 2.11 | 9.47 ± 2.39 | 10.97 ± 3.24 | |||
95%CI(two-sample population mean) | 0.45(-0.78, 1.70) | 1.50(-0.09, 3.09) 1.04(-0.29, 2.38) | ||||
BUN(mg/dL) | ||||||
Mean ± SD | 67.09 ± 15.62 | 69.43 ± 16.92 | 72.43 ± 12.38 | |||
95%CI(two-sample population mean) | 2.34(-4.87, 9.56) | 2.99(-4.20, 10.20) 5.34(0.02, 10.65) | ||||
Age(years) | ||||||
Mean ± SD | 63.59 ± 12.30 | 63.78 ± 4.27 | 51.78 ± 14.08 | |||
95%CI(two-sample population mean) | 0.18(-1.88, 2.26) | 12.00(9.19, 14.81) 11.81(8.63, 14.99) |
Cost-effectiveness by utility and cost in patients on maintenance hemodialysis (MHD).
*p<0.05. **p<0.01. The data source for this analysis was the mean value over 4 weeks in 2011. BUN. blood urea nitrogen: CI. Confidence interval: Cr. creatinine: SD. Standard deviation: QALYs. Quality-adjusted life years. These values were analyzed by distinguishing between the primary disease of end-stage kidney disease (ESKD), glomerulonephritis, diabetic nephropathy, and others during the first 4 weeks of observation [39].
The present findings may contribute to the reexamination of the socio-economic value of MHD therapy, which is a lifesaving medical treatment.
Subsequently, a case of socio-economic valuation of a (then) new drug for the refractory nephrotic syndrome was discussed [41]. Nephrotic syndrome is the generic name for the pathological conditions associated with proteinuria (≥3.5 g/day), hypoproteinemia, and generalized edema. The disorder is further classified as a primary nephrotic syndrome (caused by primary glomerular disease) or secondary nephrotic syndrome (caused by systemic disorders). The syndrome rapidly improves with steroid (e.g., prednisolone) and immunosuppressant (e.g., cyclosporine) treatment. Refractory cases (frequent relapse type, steroid dependence, or steroid resistance) may also occur, requiring steroid therapy for prolonged periods, for which side effects become a major issue. Therefore, there is a need for novel medical strategies to suppress relapse while reducing reliance on steroids. The regimen has not been clinically verified regarding the use of rituximab in patients with steroid-dependent nephrotic syndrome and frequently relapsing nephrotic syndrome. Still, there is a lack of evidence in health economics [42].
Therefore, we conducted a prospective clinical study of 30 patients before (with steroids and immunosuppressants) and after introducing rituximab therapy (Figure A3). Relapse rates and total medical expenses were selected as the primary endpoints for treatment effectiveness and treatment costs, respectively. As a secondary endpoint, cost-effectiveness was compared before and after rituximab administration in relation to previous pharmacotherapy. The observation period was 24 months before and after rituximab initiation. The authors demonstrated a statistically significant improvement in the relapse rate, from a mean of 4.30 events before administration to a mean of 0.27 events after administration. Furthermore, a significantly better prognosis emerged in the cumulative avoidance of relapse rate by Kaplan–Meier analysis (p < 0.01) (Figure 13). Finally, the total medical costs decreased from 2923 USD to 1280 USD per month, and pre-post cost-effectiveness was confirmed to be dominant (Figure 14). Thus, treatment with rituximab may be superior to previous pharmacological treatments from a health economics perspective (Table 3). Although this study did not directly observe patient utility, the excellent results in recurrence rates suggest an improvement in HRQOL.
Kaplan–Meier curves of the cumulative avoidance rate of the first relapse [
Mutual relationship between urinary protein levels and total medical cost (before and after rituximab therapy) [
Items | Pre-administration | Post-administration | Difference (after-before) |
Medical cost difference (points/24 months) | 725,403 | 317,707 | -407,696 |
(USD/24 months) | (70,155) | (30,726) | (-39,429) |
Relapse difference (times/24 months) | 4.30 | 0.27 | -4.03 |
Pre-post CEA (points/24 months/times) | 101,082 | ||
(USD/24 months/times) | (9776) | ||
Reference: pre-post CEA with a case in which the analysis was restricted to 17 months (points/17 months/times) | 50,982 | ||
(USD/17 months/times) | (4931) | ||
Items | Pre-administration | Post-administration | Difference (after-before) |
Medical cost difference (points/24 months) | 725,403 | 401,539 | -323,864 |
(USD/24 months) | (70,155) | (38,833) | (-31,321) |
Number of relapses (times/24 months) | 4.30 | 0.27 | -4.03 |
Pre-post CEA (points/24 months/times) | 80,297 | ||
(USD/24 months/times) | (7766) | ||
Reference: pre-post CEA with a case in which the analysis was restricted to 17 months (points/17 months /times) | 29,445 | ||
(USD/17 months/times) | (2848) |
Medical economics analysis (pre-post-CEA) accounting for the medical costs of rituximab.
The analysis has been corrected for the number of months. Pre-post CEA was calculated as [medical cost (post-pre)/medical effectiveness (post-pre)] (suppression amount for medical costs accumulated over 24 months per one-time reduction[avoid] in relapses). Expressed as points per 24 months per time. Analyzing the cost-effectiveness (the ratio of total medical costs and a number of relapses, after correction for the number of months) before and after rituximab therapy revealed that cost-effectiveness improved in medical, economic terms. This was 317,707 points (30,726 USD) per 24 months (0.27 times) after rituximab therapy compared with 725,403 points (70,155 USD) per 24 months (4.30 times) before therapy [41].
As this study indicates the superior cost-effectiveness of rituximab against refractory nephrotic syndrome, health economics is expected to be actively applied to the valuation of technical innovations such as drug discovery.
The discussion of value covers the whole range of activities related to the health and welfare field, such as examinations and diagnoses provided by medical facilities, surgery, and hospitalization, as well as medication, therapeutic materials, and care provided by caregivers. Prices (i.e., official prices in Japan) are attached to several services. Professionals who typically work in clinical or long-term care sites may not be very aware of these prices. However, the financial resources for the operation of medical and long-term care facilities are based on the price of services provided to patients/family members and long-term care recipients, who are the so-called beneficiaries. The medical institution charges to insurer for various services provided to the assured patient, which become the source of salary payments and reinvestment for the parties concerned. Therefore, if the price, value to be generated, and amount of resources consumed are not well balanced, the motivation for the employment of professionals and profitability assumedly decreases, thus making sustainable facility management difficult.
Consequently, the supply of medical and long-term care will decline, which is a significant problem for residents, including patients and their families [43, 44, 45]. Therefore, the price levels at which service recipients and providers are mutually satisfied (or convinced) should be discussed. However, determining the characteristics and effects of the target market is necessary to discuss the appropriateness of the price, considering the theory related to human choice and behavior (outlined in the previous section). In particular, as the field of health and welfare has service characteristics that are different from those in other fields, it is necessary to consider and interpret the mechanism of the market. Against this background, this section explains the basic price and its calculation methods.
The behavior and motivation of market economic agents and the pricing mechanism for goods and services, including resource allocation and income distribution, should be considered for price optimization. Overall, the general economic approach is limited because of various uncertainties related to highly specialized technologies in medical science. Thus, examining price settings in the medical field is generally difficult because of the complex involvement of various factors. A price-setting approach in medical treatment can be divided into two major categories: “market-based” and “input-based” [46]. The “market-based” approach determines the price level by considering the actual market price of medical treatment, while the “input-based” approach is based on the consumption of goods and services. Generally, prices are presumed to have been formed in the public medical market using these approaches in countries with a mature medical system.
Approaches to explain the public price of individual medical technologies (services) have also been discussed. For example, from the standpoint of a medical provider (supply approach), “technical difficulty” and “medical cost” are often selected from the viewpoint of quality evaluation and business management. Furthermore, for the payer (or beneficiary), the methods of “patient outcome,” “economic performance,” and “willingness to pay” are often selected from the perspective of market and value evaluation (Figure 15) [48, 49, 50]. Additionally, cases exist in which certain preconditions are set to use these indicators. For example, in Japan’s universal health insurance system, most prices charged to public insurers by medical institutions are centered on direct medical costs, based on the consumption of medical resources—considering their clinical usefulness and hospital operability. Technical fees (e.g., surgery fees), influenced by doctors’ specialties, are considered technical difficulties. Furthermore, overseas (developed countries) market prices are referred to when determining the public prices for pharmaceutical resources and medical devices.
Theory of the price-setting approach (in general and within the range of this examination) [
As the socio-economic environment surrounding the medical system becomes more severe, even public prices that follow the theory of the public economy are expected to play a role in improving the system’s performance and increasing its sustainability. In other words, verifying the structure of price formation and the appropriateness of its level has become a major concern for medical stakeholders. Based on this, an analysis of factors that affect prices is also expected. However, when developing official price research in the medical field, the following must be noted: There are not enough research reports to study the analytical model required for factor analysis. This condition is especially true in Japan. In addition, the formation of official prices involves various subsidy programs (politics), and thus, the analytical approach becomes too complicated. Therefore, in this chapter, as an initial study on medical prices, we introduce a survey on price differences between Japan and overseas and price factors in the private market.
This study examines the mechanism of market price reference and the influence of the real economy (citizens’ economic burden) on the public price, contributing to the arrangement of public price discussions in the future.
This section presents a method for setting the price level based on the analysis of medical expenses of Japanese medical institutions for foreign visitors (FVs). Furthermore, international comparisons of price levels for Japanese tourists (patients) in foreign countries have been conducted previously [47]. This section elucidates the “market-based” and “input-based” approaches discussed in 4.1, and discusses the “foreign price reference system,” which is part of the setting of public prices in Japan. In recent years, the supply of medical services centered on pharmaceutical products has been based on global R&D, manufacturing, and sales systems. In addition, some patient groups also exhibit cross-border consultation behaviors. In other words, it is inferred that discussions with a view to the globalization of medical care are indispensable for the progress of UHC, even if they are indirect.
The costs were analyzed based on socio-economic ranges in this calculation, considering clinical characteristics and economic activities. The costs related to general medical care and public investment in hospital management and healthcare infrastructure through the insurance system and various taxation systems that support Japan’s medical system are also considered. For example, social insurance burdens (e.g., insurance contributions and subsidies, such as operational grants to medical institutions) and additional expenses for FVs (e.g., interpretation, coordinator, equipment, and risk management costs) were used as calculation items.
Three medical institutions with more than 400 beds were chosen as target facilities, and their locations (urban or rural) were considered. Additional factors (such as the occupancy and profit rate of each facility) were considered in the calculation. Data collection involved medical practice and medical institution management surveys. The medical practice survey used time study (i.e., occupation time of medical staff and institutional equipment) and medical records (i.e., electronic and management ledgers): Some were self-reported alternatives based on their professional experience. The medical institution management survey collected financial statements (profit and loss balance sheets), number of patients and medical treatments, number of staff and equipment, unit purchase price, and the area of each department.
The medical expenses for FVs were broadly divided into “additional expenses of foreign medical treatment” and “increased expenses of regular medical treatment.” The following definitions for additional and increased expenses were applied: additional expenses for new and additional services (e.g., interpretation and transportation) for non-locally insured patients. The increased expenses for medical services were similarly offered to the locally-insured patients. However, for non-locally-insured patients, the unit price and quantity increased (e.g., consultation hours and staff). Profit was included in this calculation as a necessary resource for reinvestment by medical institutions to realize sustainable management while appropriately responding to the medical needs of FVs. However, when determining profit margins, the historical average of each institution was adopted to avoid the distortion of price levels and the expensive economic burden on FVs owing to excessive profits. The profits gained from FVs were essentially the same as those from Japanese patients.
Compared with the medical expenses (point system) of Japanese patients, those for FVs were 1.31 times (1 point 0.12 dollars) higher for pharyngitis, 1.56 times (1 point 0.14 dollars) higher for urticaria with allergies, 2.21 times (1 point 0.20 dollars) higher for hemorrhagic cystitis, 3.66 times (1 point 0.34 dollars) higher for in patients with severe pneumonia, 1.22 times (1 point 0.11 dollars) higher for general appendicitis, and 2.92 times (1 point 0.27 dollars) higher for endoscopic cholangitis treatment (Figure 16). Moreover, the operating expense for trochanteric fractures of the femur was 3.59 times (1 point 0.33 dollars) higher. Figure 17 shows the amount billed when providing medical treatment to Japanese overseas travelers (overseas FVs) in each country. The survey indicated that although the total number of patients was 18 (one in each country, except for the USA, Australia, Italy, and China), the actual medical payment was approximately USD 20.32–158.75/bill (medical expenditures for medical examination and drug cost) in 12 countries. The highest price was in the USA, at USD 158.75/bill (medical fees may be partially unknown), followed by Austria with USD 79.38 (purchasing power parity 86.28)/bill and Belgium with USD 73.93 (purchasing power parity 73.93)/bill. In summary, including additional research, the medical expenses for FV patients were 1.22–3.66 times higher than those for Japanese patients, 1.31–2.21 times higher for outpatients (pharyngitis, urticaria, and cystitis), and 1.22–3.66 times higher for inpatients (e.g., with severe pneumonia, appendicitis, cholangitis, and femoral fractures).
Calculation of price levels for foreign visitors (seven diseases) [
International comparison of medical expenses (pharyngitis and outpatients) [
The concept of factors that form the parturition price operated by the private medical care system (out-of-pocket) and the actual situation of the difference in price level due to regional characteristics [51] is introduced. This approach spans both “market-based” and “input-based” approaches, as discussed in Section 4.1. For the sustainable operation of the medical system, it is important to consider the stability of hospital management and the financial burden on citizens. In other words, it is presumed that discussions that consider the relationship between economic factors and medical treatment behavior are indispensable for the progress of UHC. This study has the advantage of developing purely causal inferences on that subject, considering the bias of other social support (subsidies). It is useful to indirectly re-recognize how the ratio of out-of-pocket expenses to the official price of public medical insurance affects the choice of consultation.
In Japan, parturition (normal childbirth), which differs from injury and illness, is not covered by the medical insurance system. This service is self-financed medical care. However, as financial support for childbirth expenditures, the Health Insurance Act provides a lump-sum childbirth and childcare allowance of JPY 420,000 per child (2021). As this system aims to reduce the financial burden of childbirth, it is also important from the perspective of measures against declining birth rates. However, the average price of childbirth is rising, and the actual cost of childbirth often exceeds JPY 420,000. Therefore, while an increase in the amount of lump-sum childbirth and childcare payments has been requested, the out-of-pocket price structure of childbirth is unclear; that is, actual costs have not been understood. Therefore, the government considers the appropriate amount of lump-sum childbirth and childcare payments to realistically grasp the situation of childbirth expenditures with services and prices.
Against the background of these trends, Japan’s regional levels of parturition prices and the factors that helped inform them were analyzed. First, a hypothesis that market principles would have a greater effect on the level formation was proposed; then, the factors that affect childbirth expenditures were structured. Consequently, price formation was considered to involve delivery costs, outcomes, supply/demand, solvency, and official (public) prices. From the provider’s perspective, “guarantee of provision cost (from a stable management viewpoint),” “overall market level and internal harmony (operation of facility),” “guarantee of quality (characteristics of the medical field),” and “competitiveness of regions (balance between supply and demand)” were selected. From the perspective of pregnant women, the elements of “interest in security (from the outcome perspective),” “interest in added value (from the amenity perspective),” “interest in the brand (from the perspective of other added values),” “restrictions on solvency (from an economic perspective),” and “access conditions (from the various types of burden)” were selected. Generally, childbirth expenditure is affected by various factors, including different factors related to facility type (e.g., general hospital, clinic, and maternity home), delivery method (e.g., natural childbirth, cesarean section, and painless delivery), timing (weekdays/daytime, night/holidays, year-end/new year), region (prefectures, cities/regions), and others (e.g., optional services such as attending a birth with family).
Consequently, the average parturition price by region in Japan was investigated. First, when the actual situation of childbirth expenditure by prefecture was analyzed using national birth-related statistical data (around 2016) [52, 53], the national average was 505,759 ± 41,906 JPY/case. A difference of approximately 1.5 times was confirmed between the highest (Tokyo City: No.1 in Figure 18) and lowest (Tottori Prefecture: No.48 in Figure 18) areas. Subsequently, multivariate analysis (multiple regression analysis) was performed to analyze the factors that differed depending on regional characteristics. Based on the factor structure described above, the objective variable was the parturition price. The explanatory variables were citizen income (solvency), “public medical expense (hospitalization unit price),” “pregnant woman’s age (risk factor),” “birth population (childbirth demand),” and “obstetric facility (supply capacity),” and “specialized equipment (maternal-fetal intensive care unit). The statistical software SPSS (IBM) was used for analysis, and the significance level was set at 5%. The results indicate that prefectural income, age at parturition, number of births, and density of equipment (facilities) affect parturition prices (Table 4). In particular, the citizen income (standard partial regression coefficient: 0.561, p < 0.001) tended to be highly related to parturition prices. The standard partial regression coefficient of birth population was negative (−0.628, p = 0.014), but the simple regression coefficient was positive (0.721, p < 0.01).
Distribution of parturition prices by region (prefecture). Note: The data source was “mean and median of childbirth costs by prefecture” (All-Japan Federation of National Health Insurance Organizations, announced in 2017).
Childbirth expenditures (normal childbirth, yen / case, FY2016) | Standardized partial regression coefficient | F-value | p-value | VIF |
---|---|---|---|---|
Annual income per citizen of the prefecture (yen / year) | 0.561 | 17.588 | 0.000 | 2.68 |
1-day hospitalization unit public price for all beds (overall: yen / day) | 0.281 | 4.106 | 0.054 | 2.88 |
Pregnant woman age (years) | 0.331 | 4.384 | 0.047 | 3.74 |
Total number of births (cases) | −0.628 | 7.011 | 0.014 | 8.42 |
Average number of births per hospital facility (number of deliveries: cases) | 0.312 | 3.272 | 0.083 | 4.46 |
Maternal and fetal intensive care unit per birth population (MFICU: number of beds) | −0.257 | 5.162 | 0.032 | 1.91 |
Decentralized analysis of the model: p < 0.001 | ||||
Socio-economic factors are affecting parturition price levels (multiple regression analysis).
Note: MFICU, maternal-fetal intensive care unit.
This chapter discussed the macroscopic mechanisms of the relationship between UHC progress and socio-economic factors to promote the sustainable development of health insurance systems. Against that background, the clinical economic considerations were presented to discuss the relationship between value and price from a micro perspective (e.g., health technology assessment).
Examining the effects of socio-economic factors of GDP and governmental health expenditures on the development of UHC showed a statistically significant positive correlation between these factors and UHC service coverage index. Furthermore, it was understood that the declining birth rate, aging population, and maturing healthcare system impacted the progress of UHC. Unemployment and poverty, distant causes of catastrophic healthcare costs, reduced the service coverage index level because of the mechanisms related to vital statistics and economic conditions. Thus, policymakers must implement countermeasures based on indicators that can estimate the economic status of the UHC approach, such as its cost-effectiveness. The sufficiency of public healthcare resources was considered important in addressing this issue. Furthermore, it was inferred that sharing healthcare values among stakeholders would be meaningful for this purpose.
Assuming that it contributes to the discussion of the real economy and official prices related to the medical field, the medical value should be evaluated by applying the marginal utility theory and cost-utility analysis. Despite some limitations, the benefits and burdens based on the value of medical care should be discussed when designing a system related to the operation of medical insurance. In this chapter, valuation research cases related to the significance of lifesaving and drug discovery were introduced, considering the possibility of allocating public resources. Furthermore, present chapter presented the price formation mechanism in the clinical field based on medical value. The price level was organized with reference to the case (childbirth) of private medical care in Japan. Factors such as the age at parturition, income level, and facility utilization rate have a price impact.
Promoting harmonization with socio-economic trends and improving explanatory power for those who bear the economic burden are key points for the future development of medical insurance systems. Long-term research using a broader range of socio-economic indicators is needed for a more accurate interpretation and deeper analysis of the obtained findings.
This study was funded by the Government of Japan Health and Labor Sciences Research Grant (grant no. JP19DA1004).
The author declares no conflicts of interest associated with this manuscript.
Trends in the country-specific economic level (GDP) and SCI components (service capacity and access). Note: UHC, universal health coverage; SCI, service coverage index [
The UHC service coverage index (SCI): Summary of tracer indicators and computation [
Overview of the regimen used (images). In this study, rituximab was administered four times every 6 months. For the first 6 months after the first dose of rituximab, the dosage of prednisolone and cyclosporine was reduced each month and stopped [
The authors gratefully acknowledge Ms. Naoko Tsukamoto and Ms. Noriko Yoshida for their contributions to the chart adjustment.
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On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. 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This chapter aims for those who need to teach Kalman filters to others, or for those who do not have a strong background in estimation theory. Following a problem definition of state estimation, filtering algorithms will be presented with supporting examples to help readers easily grasp how the Kalman filters work. Implementations on INS/GNSS navigation, target tracking, and terrain-referenced navigation (TRN) are given. In each example, we discuss how to choose, implement, tune, and modify the algorithms for real world practices. Source codes for implementing the examples are also provided. In conclusion, this chapter will become a prerequisite for other contents in the book.",book:{id:"7466",slug:"introduction-and-implementations-of-the-kalman-filter",title:"Introduction and Implementations of the Kalman Filter",fullTitle:"Introduction and Implementations of the Kalman Filter"},signatures:"Youngjoo Kim and Hyochoong Bang",authors:null},{id:"77284",title:"The Paradigm of Complex Probability and Isaac Newton’s Classical Mechanics: On the Foundation of Statistical Physics",slug:"the-paradigm-of-complex-probability-and-isaac-newton-s-classical-mechanics-on-the-foundation-of-stat",totalDownloads:1581,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The concept of mathematical probability was established in 1933 by Andrey Nikolaevich Kolmogorov by defining a system of five axioms. This system can be enhanced to encompass the imaginary numbers set after the addition of three novel axioms. As a result, any random experiment can be executed in the complex probabilities set C which is the sum of the real probabilities set R and the imaginary probabilities set M. We aim here to incorporate supplementary imaginary dimensions to the random experiment occurring in the “real” laboratory in R and therefore to compute all the probabilities in the sets R, M, and C. Accordingly, the probability in the whole set C = R + M is constantly equivalent to one independently of the distribution of the input random variable in R, and subsequently the output of the stochastic experiment in R can be determined absolutely in C. This is the consequence of the fact that the probability in C is computed after the subtraction of the chaotic factor from the degree of our knowledge of the nondeterministic experiment. We will apply this innovative paradigm to Isaac Newton’s classical mechanics and to prove as well in an original way an important property at the foundation of statistical physics.",book:{id:"11066",slug:"the-monte-carlo-methods-recent-advances-new-perspectives-and-applications",title:"The Monte Carlo Methods",fullTitle:"The Monte Carlo Methods - Recent Advances, New Perspectives and Applications"},signatures:"Abdo Abou Jaoudé",authors:[{id:"248271",title:"Dr.",name:"Abdo",middleName:null,surname:"Abou Jaoudé",slug:"abdo-abou-jaoude",fullName:"Abdo Abou Jaoudé"}]},{id:"46862",title:"Analysis of Balancing of Unbalanced Rotors and Long Shafts using GUI MATLAB",slug:"analysis-of-balancing-of-unbalanced-rotors-and-long-shafts-using-gui-matlab",totalDownloads:8487,totalCrossrefCites:4,totalDimensionsCites:4,abstract:null,book:{id:"3845",slug:"matlab-applications-for-the-practical-engineer",title:"MATLAB",fullTitle:"MATLAB Applications for the Practical Engineer"},signatures:"Viliam Fedák, Pavel Záskalický and Zoltán Gelvanič",authors:[{id:"85462",title:"Associate Prof.",name:"Viliam",middleName:null,surname:"Fedak",slug:"viliam-fedak",fullName:"Viliam Fedak"},{id:"154498",title:"Prof.",name:"Pavel",middleName:null,surname:"Záskalický",slug:"pavel-zaskalicky",fullName:"Pavel Záskalický"},{id:"169849",title:"Dr.",name:"Zoltan",middleName:null,surname:"Gelvanič",slug:"zoltan-gelvanic",fullName:"Zoltan Gelvanič"}]},{id:"65445",title:"Power Flow Analysis",slug:"power-flow-analysis",totalDownloads:5131,totalCrossrefCites:4,totalDimensionsCites:5,abstract:"Power flow, or load flow, is widely used in power system operation and planning. The power flow model of a power system is built using the relevant network, load, and generation data. Outputs of the power flow model include voltages at different buses, line flows in the network, and system losses. These outputs are obtained by solving nodal power balance equations. Since these equations are nonlinear, iterative techniques such as the Newton-Raphson, the Gauss-Seidel, and the fast-decoupled methods are commonly used to solve this problem. The problem is simplified as a linear problem in the DC power flow technique. This chapter will provide an overview of different techniques used to solve the power flow problem.",book:{id:"7678",slug:"computational-models-in-engineering",title:"Computational Models in Engineering",fullTitle:"Computational Models in Engineering"},signatures:"Mohammed Albadi",authors:[{id:"209533",title:"Dr.",name:"Mohammed",middleName:null,surname:"Albadi",slug:"mohammed-albadi",fullName:"Mohammed Albadi"}]},{id:"46614",title:"Modeling of Control Systems",slug:"modeling-of-control-systems",totalDownloads:10519,totalCrossrefCites:0,totalDimensionsCites:1,abstract:null,book:{id:"3845",slug:"matlab-applications-for-the-practical-engineer",title:"MATLAB",fullTitle:"MATLAB Applications for the Practical Engineer"},signatures:"Roger Chiu, Francisco J. Casillas, Didier López-Mancilla, Francisco G.\nPeña-Lecona, Miguel Mora-González and Jesús Muñoz Maciel",authors:[{id:"41151",title:"Dr.",name:"Francisco J.",middleName:null,surname:"Casillas",slug:"francisco-j.-casillas",fullName:"Francisco J. Casillas"},{id:"41153",title:"Dr.",name:"Jesús",middleName:null,surname:"Muñoz-Maciel",slug:"jesus-munoz-maciel",fullName:"Jesús Muñoz-Maciel"},{id:"41154",title:"Dr.",name:"Francisco G.",middleName:null,surname:"Peña-Lecona",slug:"francisco-g.-pena-lecona",fullName:"Francisco G. 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Using firm quarterly data from March 2010 to December 2018, we hypothesized that claims with high positive (negative) slopes are more likely to have large positive (negative) jumps in the future. As such, we expected salient properties of volatile jumps on the written products/contracts. We found that insurance claims for general insurance quoted products cease to be normal. There exist at times some jumps, especially during holidays and weekends. Such jumps are not healthy to the capital structures of firms, as such they need attention. However, it should be noted that gaps or jumps (unless of specific forms) cannot be hedged by employing internal dynamic adjustments. This means that, jump risk is non-diversifiable and such jumps should be given more attention.",book:{id:"10820",title:"Data Clustering",coverURL:"https://cdn.intechopen.com/books/images_new/10820.jpg"},signatures:"Leonard Mushunje, Chiedza Elvina Mashiri, Edina Chandiwana and Maxwell Mashasha"},{id:"81471",title:"Semantic Map: Bringing Together Groups and Discourses",slug:"semantic-map-bringing-together-groups-and-discourses",totalDownloads:20,totalDimensionsCites:0,doi:"10.5772/intechopen.103818",abstract:"This chapter presents a multivariate analysis method which is developed in two steps using a combination of Hierarchical cluster analysis (HCA) and Factorial Correspondence Analysis (AFC). To explain and describe the steps of the method, we use an application example on a survey dataset from young students in Thessaloniki trying to investigate their behavioral profiles in terms of political characteristics and how these may be affected about their attendance to a civic education course offered by the Political Science department in the Aristotle University of Thessaloniki. The method is explained step by step on this example serving as a manual of its application to the researcher. HCA assigns subjects into cluster membership variables and in the next stage, these new variables are jointly analyzed with AFC. Correspondence analysis manages to extract the dimensions of the phenomenon in the study, explaining the inner antithesis between the categories but also giving the opportunity to visualize the information in a two-dimensional space, a semantic map, making interpretation more comprehensive. HCA is then applied again to the AFC’s coordinates of the categories constructing profiles of subjects, assigning them to the categories of the variables.",book:{id:"10820",title:"Data Clustering",coverURL:"https://cdn.intechopen.com/books/images_new/10820.jpg"},signatures:"Theodore Chadjipadelis and Georgia Panagiotidou"},{id:"79491",title:"Fuzzy Perceptron Learning for Non-Linearly Separable Patterns",slug:"fuzzy-perceptron-learning-for-non-linearly-separable-patterns",totalDownloads:17,totalDimensionsCites:0,doi:"10.5772/intechopen.101312",abstract:"Perceptron learning has its wide applications in identifying interesting patterns in the large data repositories. While iterating through their learning process perceptrons update the weights, which are associated with the input data objects or data vectors. Though perceptrons exhibit their robustness in learning about interesting patterns, they perform well in identifying the linearly separable patterns only. In the real world, however, we can find overlapping patterns, where objects may associate with multiple patterns. In such situations, a clear-cut identification of patterns is not possible in a linearly separable manner. On the other hand, fuzzy-based learning has its wide applications in identifying non-linearly separable patterns. The present work attempts to experiment with the algorithms for fuzzy perceptron learning, where perceptron learning and fuzzy-based learning techniques are implemented in an interfusion manner.",book:{id:"10820",title:"Data Clustering",coverURL:"https://cdn.intechopen.com/books/images_new/10820.jpg"},signatures:"Raja Kishor Duggirala"},{id:"80937",title:"Assessing Heterogeneity of Two-Part Model via Bayesian Model-Based Clustering with Its Application to Cocaine Use Data",slug:"assessing-heterogeneity-of-two-part-model-via-bayesian-model-based-clustering-with-its-application-t",totalDownloads:24,totalDimensionsCites:0,doi:"10.5772/intechopen.103089",abstract:"The purpose of this chapter is to provide an introduction to the model-based clustering within the Bayesian framework and apply it to asses the heterogeneity of fractional data via finite mixture two-part regression model. The problems related to the number of clusters and the configuration of observations are addressed via Markov Chains Monte Carlo (MCMC) sampling method. Gibbs sampler is implemented to draw observations from the related full conditionals. As a concrete example, the cocaine use data are analyzed to illustrate the merits of the proposed methodology.",book:{id:"10820",title:"Data Clustering",coverURL:"https://cdn.intechopen.com/books/images_new/10820.jpg"},signatures:"Ye-Mao Xia, Qi-Hang Zhu and Jian-Wei Gou"},{id:"78846",title:"Clustering Algorithms: An Exploratory Review",slug:"clustering-algorithms-an-exploratory-review",totalDownloads:146,totalDimensionsCites:0,doi:"10.5772/intechopen.100376",abstract:"A process of similar data items into groups is called data clustering. Partitioning a Data Set into some groups based on the resemblance within a group by using various algorithms. Partition Based algorithms key idea is to split the data points into partitions and each one replicates one cluster. The performance of partition depends on certain objective functions. Evolutionary algorithms are used for the evolution of social aspects and to provide optimum solutions for huge optimization problems. In this paper, a survey of various partitioning and evolutionary algorithms can be implemented on a benchmark dataset and proposed to apply some validation criteria methods such as Root-Mean-Square Standard Deviation, R-square and SSD, etc., on some algorithms like Leader, ISODATA, SGO and PSO, and so on.",book:{id:"10820",title:"Data Clustering",coverURL:"https://cdn.intechopen.com/books/images_new/10820.jpg"},signatures:"R.S.M. Lakshmi Patibandla and Veeranjaneyulu N"},{id:"78463",title:"Clustering by Similarity of Brazilian Legal Documents Using Natural Language Processing Approaches",slug:"clustering-by-similarity-of-brazilian-legal-documents-using-natural-language-processing-approaches",totalDownloads:157,totalDimensionsCites:1,doi:"10.5772/intechopen.99875",abstract:"The Brazilian legal system postulates the expeditious resolution of judicial proceedings. However, legal courts are working under budgetary constraints and with reduced staff. As a way to face these restrictions, artificial intelligence (AI) has been tackling many complex problems in natural language processing (NLP). This work aims to detect the degree of similarity between judicial documents that can be achieved in the inference group using unsupervised learning, by applying three NLP techniques, namely term frequency-inverse document frequency (TF-IDF), Word2Vec CBoW, and Word2Vec Skip-gram, the last two being specialized with a Brazilian language corpus. We developed a template for grouping lawsuits, which is calculated based on the cosine distance between the elements of the group to its centroid. The Ordinary Appeal was chosen as a reference file since it triggers legal proceedings to follow to the higher court and because of the existence of a relevant contingent of lawsuits awaiting judgment. After the data-processing steps, documents had their content transformed into a vector representation, using the three NLP techniques. We notice that specialized word-embedding models—like Word2Vec—present better performance, making it possible to advance in the current state of the art in the area of NLP applied to the legal sector.",book:{id:"10820",title:"Data Clustering",coverURL:"https://cdn.intechopen.com/books/images_new/10820.jpg"},signatures:"Raphael Souza de Oliveira and Erick Giovani Sperandio Nascimento"}],onlineFirstChaptersTotal:6},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:36,paginationItems:[{id:"82195",title:"Endoplasmic Reticulum: A Hub in Lipid Homeostasis",doi:"10.5772/intechopen.105450",signatures:"Raúl Ventura and María Isabel Hernández-Alvarez",slug:"endoplasmic-reticulum-a-hub-in-lipid-homeostasis",totalDownloads:2,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"82409",title:"Purinergic Signaling in Covid-19 Disease",doi:"10.5772/intechopen.105008",signatures:"Hailian Shen",slug:"purinergic-signaling-in-covid-19-disease",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82374",title:"The Potential of the Purinergic System as a Therapeutic Target of Natural Compounds in Cutaneous Melanoma",doi:"10.5772/intechopen.105457",signatures:"Gilnei Bruno da Silva, Daiane Manica, Marcelo Moreno and Margarete Dulce Bagatini",slug:"the-potential-of-the-purinergic-system-as-a-therapeutic-target-of-natural-compounds-in-cutaneous-mel",totalDownloads:9,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82103",title:"The Role of Endoplasmic Reticulum Stress and Its Regulation in the Progression of Neurological and Infectious Diseases",doi:"10.5772/intechopen.105543",signatures:"Mary Dover, Michael Kishek, Miranda Eddins, Naneeta Desar, Ketema Paul and Milan Fiala",slug:"the-role-of-endoplasmic-reticulum-stress-and-its-regulation-in-the-progression-of-neurological-and-i",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}}]},overviewPagePublishedBooks:{paginationCount:32,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI)",institutionString:"Australian College of Business & Technology",institution:null}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. Her research interests include microalgal biotechnology with an emphasis on microalgae-based products.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",institutionURL:null,country:{name:"Brazil"}}}]},{type:"book",id:"7953",title:"Bioluminescence",subtitle:"Analytical Applications and Basic Biology",coverURL:"https://cdn.intechopen.com/books/images_new/7953.jpg",slug:"bioluminescence-analytical-applications-and-basic-biology",publishedDate:"September 25th 2019",editedByType:"Edited by",bookSignature:"Hirobumi Suzuki",hash:"3a8efa00b71abea11bf01973dc589979",volumeInSeries:4,fullTitle:"Bioluminescence - Analytical Applications and Basic Biology",editors:[{id:"185746",title:"Dr.",name:"Hirobumi",middleName:null,surname:"Suzuki",slug:"hirobumi-suzuki",fullName:"Hirobumi Suzuki",profilePictureURL:"https://mts.intechopen.com/storage/users/185746/images/system/185746.png",biography:"Dr. Hirobumi Suzuki received his Ph.D. in 1997 from Tokyo Metropolitan University, Japan, where he studied firefly phylogeny and the evolution of mating systems. He is especially interested in the genetic differentiation pattern and speciation process that correlate to the flashing pattern and mating behavior of some fireflies in Japan. He then worked for Olympus Corporation, a Japanese manufacturer of optics and imaging products, where he was involved in the development of luminescence technology and produced a bioluminescence microscope that is currently being used for gene expression analysis in chronobiology, neurobiology, and developmental biology. 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Samim Al Azad and Slimane Ed-dafali",hash:"86a6d33cf601587e591064ce92effc02",volumeInSeries:1,fullTitle:"Leadership in a Changing World - A Multidimensional Perspective",editors:[{id:"418514",title:"Dr.",name:"Muhammad",middleName:null,surname:"Mohiuddin",slug:"muhammad-mohiuddin",fullName:"Muhammad Mohiuddin",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038UqSfQAK/Profile_Picture_2022-05-13T10:39:03.jpg",institutionString:"Université Laval",institution:{name:"Université Laval",institutionURL:null,country:{name:"Canada"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Business and Management",value:86,count:1}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:1}],authors:{paginationCount:229,paginationItems:[{id:"318170",title:"Dr.",name:"Aneesa",middleName:null,surname:"Moolla",slug:"aneesa-moolla",fullName:"Aneesa Moolla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/318170/images/system/318170.png",biography:"Dr. Aneesa Moolla has extensive experience in the diverse fields of health care having previously worked in dental private practice, at the Red Cross Flying Doctors association, and in healthcare corporate settings. She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",country:{name:"Spain"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. 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