Most commonly used methods for isolation and characterization of EVs.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombosis and/or obstetric complications and persistent presence of antiphospholipid antibodies (aPL) [1]. aPL cause the activation of cells involved in the vasculature (endothelial cells, platelets, monocytes) and the release of extracellular vesicles (EVs). EVs are submicron particles that are constitutively released from nearly all cell types [2] and circulate in plasma of healthy individuals in concentrations of approximately 1010 EVs/ml [3]. In response to stimuli, such as cell activation due to inflammation and/or apoptosis, increased amounts of EVs are released. The frequencies of plasma EVs, which originate from different cellular origins, can be altered in disease states [4]. Over the last decade, the number of scientific publications describing physiological and pathological functions of EVs has increased significantly. The term”extracellular vesicles” is a collective term that encompasses various subtypes of cell-releasing membranous structures called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many others. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for accurate isolation and characterizations of EVs [5]. MISEV2018 proposes the classification of EVs according to their physical properties (size and density), biochemical composition (protein marker positivity), cells of origin or based on the description of the conditions that induce their release. The heterogeneity of EVs research is, apart from nomenclature, also a reflection of poorly standardized methods of isolation and downstream analysis. Complex biological samples containing non-EV contaminants pose a challenge for both the isolation and characterization of EVs. Usually a combination of different methods is used to obtain good data quality. The most common EVs are of platelet or megakaryocyte origin (> 50%) [6], while about 5-15% of EVs are of endothelial origin [7]. An increase in circulating EVs, especially endothelial EVs, is considered a hallmark of vascular dysfunction and cardiovascular disease. Increased EVs are found particularly in patients with hypertension [8], diabetes [9], acute coronary syndromes [10] and cardiovascular disease [11]. EVs, especially medium to large endothelial EVs, have been studied in patients with APS, who had significantly higher levels of circulating endothelial and platelet EVs compared with healthy controls [12]. One study also reported increased levels of small EVs (sEVs), which are less than 200 nm in size, in the plasma of patients with APS [13]. In addition, they reported on an altered protein profile of sEVs, indicating platelet and endothelial activation. These results show that a complex systemic network that exists in the form of cell–cell communication via sEVs is altered in APS patients.
Extracellular vesicles are small particles composed of a phospholipid bilayer that encloses soluble cytosolic or endosomal material and nuclear components and, unlike a cell, are unable to replicate. EVs can be as small as the smallest physically possible unilamellar liposome (about 20-30 nm) or as large as 1 μm or more [14]. EVs serve as regulators of the transfer of biological information (proteins, nucleic acids, lipids and metabolites), which act both locally and remotely [15]. EVs are found in a variety of human biofluids including serum, plasma, urine, saliva, breast milk, amniotic fluid, ascites fluid, cerebrospinal fluid and even bile [16]. Under normal physiological conditions, they are continuously secreted into the extracellular environment, however, the amount of EVs is increased by activated and apoptotic cells and is associated with different pathologies, including thrombosis [7]. EVs are probably the most extensively studied in cancer and were also found to play a significant role in cancer-associated thrombosis [17]. Over the last decade, EVs have been extensively studied in the field of biomedical research to determine their biological role in normal physiology and in disease state as well as to exploit potential clinical applications in the diagnosis and prognosis of disease. EVs are considered a promising source of biomarkers since they carry different biological materials that reflect the status of the cell of origin. Nevertheless, EVs have also been considered as a therapeutic agent, as an alternative to their synthetic counterparts, such as liposomes [18].
The classification and nomenclature of EVs is complicated and could be confusing due to overlapping definitions. The most common classification of EVs currently used in the literature is the classification of different EVs into subtypes, such as endosomal derived exosomes, membrane derived (microparticles, microvesicles or ectosomes) and apoptotic bodies. This classification is based on the assignment of a specific EV to a particular biogenesis pathway, which remains very difficult to assess [19]. Unless biogenesis is investigated directly, EVs are classified according to their a) physical characteristics such as size: “small EVs” (sEVs; size <100 nm or < 200 nm) and “medium/large” (m/lEVs; size >200 nm), and density; low, medium, high, with defined range, b) biochemical composition (surface expression or by the presence of a specific molecule within EVs), or c) description of a specific condition or cell of origin (Figure 1) [19].
Classification of EVs. EVs can be classified according to their size (Small <100 nm or < 200 nm, Medium/large >200 nm), density (Low, Medium, High) with a defined density range, biogenesis pathway (Exosomes; endosomal derived, Microvesicles; membrane derived and Apoptotic bodies; released upon cell apoptosis) or biochemical composition defining EVs origin, surface proteins or cargo. Created with BioRender.com.
The key biological function of EVs is cell to cell communication and the transfer of biological materials that act closely, but also, and more importantly, remotely. Cargo within the EVs is protected from degradation in the bloodstream and can be successfully transferred to specific cells of interest, affecting several biological functions of these cells. EVs can transfer a wide variety of molecules: heat shock proteins (HSP-90, HSP-70), interleukins (IL), such as tumor necrosis factor-alpha (TNFα), acute phase proteins, such as serum amyloid A [20], enzymes, peptides, growth factors [14]. Therefore, EVs have a wide range of biological functions including immune response, antigen presentation, and the transfer of RNA, including micro RNA (miR) and DNA. Given the fact that EVs migrate through the bloodstream they can have pleiotropic effects that are likely to affect every tissue in the body [14]. In immunity, they modulate immune cells, cell–cell interactions, and transfer of cytokines and chemokines. In the heart and vessels, they stimulate coagulation and thrombosis, modulate angiogenesis, calcification and vascular repair. In the adipose tissue, they modulate angiogenesis, inflammation, cell differentiation and secretion of cytokines. In the bone marrow, they are involved in cell–cell cooperation, cell proliferation, differentiation and maturation. In the central nervous system, they are involved in the integration of neurons and various glial cells, modulate angiogenesis, neuronal plasticity and myelination. In the blood, they influence activation and aggregation of platelets, are directly involved in coagulation, as well as cargo transfer of procoagulant or anticoagulant molecules, cytokines and growth factors [14].
Biological fluids containing EVs, which serve as potential minimally invasive liquid biopsies, have shifted its proteomic and genomic profiling research towards identification of biomarkers for disease diagnosis, prognosis and longitudinal monitoring. Studying EVs and their cargo typically requires separation from a biological matrix (such as a complex fluid or tissue) to analyze the unique EV components. However, isolating EVs from different sources presents certain challenges. For example, in serum and plasma the main challenge is to separate EVs from highly abundant non-EV proteins, such as albumin and globulins and non-EV lipid particles, such as lipoproteins and chylomicrons [21]. These co-purified contaminants pose a challenge for the isolation, analysis, and application of EVs. Correct interpretation and detailed reporting of the nature of EV samples and sample handling including storage, isolation, and analytical procedures for the analysis of EVs is required [18]. Many approaches have been used, including differential ultracentrifugation, density gradient ultracentrifugation, size exclusion chromatography, and affinity/immunoaffinity capture methods. All these approaches have their limitations and advantages, which are challenged by both the source and quantity of starting material and the downstream application [21]. Serial centrifugation enables the separation of EVs from cells, cell debris and larger vesicles such as apoptotic bodies. Ultracentrifugation (UC) exploits high centrifugal speed (100.000 x g) for a sufficient time to allow EVs to pellet. It separates particles based on their size, shape, and flotation density and is less efficient for smaller and less dense particles. Repeated centrifugation can reduce the amount of non-EVs particles, but also reduces the yield and may damage the EVs [21]. Density centrifugation or density ultracentrifugation uses a density gradient medium or cushion of denser solution (e.g. sucrose cushion; sUC) [22] to separate particles of a similar density. This technique takes advantage of the fact that particles denser than the solvent sediment in the suspension, while particles less dense float up. This increases the purity of samples and reduces the potential of mechanical damage to the vesicles [23]. Density gradient ultracentrifugation is successful in separating chylomicrons, very low-density, low-density and intermediate density lipoproteins present in plasma. However, particles of similar density, such as high-density lipoproteins, are co-isolated with the EVs [21]. Size exclusion chromatography (SEC) is a chromatographic method that allows vesicles of a particular size to be separated where EVs retain their structure and physiological function [24]. When performing SEC protein contaminants and aggregates of similar size, are often still present. In addition, the sample has to be further concentrated because of the different pooled fractions, decreasing the yield of isolation. Holcar et al. have investigated the purity of the samples by comparing sUC and SEC; the two most commonly used methods for the isolation of EVs. Transmission electron microscopy (TEM) of EVs isolated with SEC showed increased levels of lipoproteins. This was further confirmed by determining a significant increase of ApoA1 (found in high-density lipoproteins) and ApoB100 (found in very low-density, low-density and intermediate-density lipoproteins) [22]. Based on their results, the presence of lipoproteins in SEC isolates could have a significant impact on downstream analysis. Polymer-based precipitation uses volume-excluding polymers to lower the solubility of EVs and similarly sized non-EV particles which are isolated via low speed centrifugation. The main problem using this method is that protein removal kits must be used [21]. The highest purity of isolated EVs is achieved by using different immunopurification methods, such as immunomagnetic isolation. This method separates EVs on the basis of an antigen–antibody interactions where the antibodies linked to the matrix (e.g. magnets) are directed against a specific antigen of interest on EVs [25]. Using this methodology, a specific EV subpopulation is investigated, however, the information about the general vesicle population is lost. In addition, when using the immunopurification method, EVs stay bound to the matrix, which makes them incompatible with certain downstream analyses (Table 1).
Type of EVs | Isolation of EVs | Characterization of EVs |
---|---|---|
Small | Ultracentrifugation +/− density gradient, SEC, polymer-based approaches, immunopurification | AFM, EM, ELISA, NTA, RPS, DLS, WB |
Medium/Large | Centrifugation +/− density gradient | AFM, EM, NTA, IF, ELISA, flow cytometry |
Most commonly used methods for isolation and characterization of EVs.
Abbreviations: AFM: atomic-force microscopy; DLS: dynamic light scattering; ELISA: enzyme-linked immunosorbent assay; EM: electron microscopy; IF: immunofluorescence microscopy; NTA: nanoparticle tracking analysis; RPS; restrictive pulse sensing; SEC: size exclusion chromatography: EM: transmission electron microscopy WB: western blotting.
The analysis of EVs is greatly hampered by their heterogeneity (size, different populations etc.) and by the complex nature of any biological or clinical sample (the presence of non-EVs contaminants). The characteristics of EVs can be determined by biochemical analysis (immunoblotting, immunosorbent EV assays and flow cytometry) or with physical analysis (electron microscopy (EM), atomic force microscopy (AFM), dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), tunable restrictive pulse sensing (tRPS) and flow cytometry) as well as novel, optical based, technologies (fluorescence-based techniques, surface plasmon resonance, interferometric imaging and electrochemical sensing) [18] (Table 1). Due to challenges in EVs analysis, a combination of different methods is very common.
The physical analyses of EVs involve determining a size range, shape and concentration. The size of EVs can be determined directly by high-resolution imaging, or indirectly, by using optical or electrical readouts. Direct high-resolution imaging includes microscopy methods, such as EM or AFM, to obtain an accurate estimate of individual EVs in nanoscale resolution [18]. EM is used to determine the size and morphology of individual EVs. This method employs an electron beam instead of light to obtain high-resolution images in nanoscale. The most commonly used EM techniques are scanning (SEM) and transmission (TEM). Scanning electron microscopy image will explore the topography of the EVs surface. Since electrons pass through the sample in TEM, a 2D image of EVs will be obtained, which will also provide the information on the inner structure [26]. These electron microscopy methods require fixation or drying of the sample which complicates the translation of observed structures to the native morphology of the EVs. To avoid sample dehydration variations of electron microscopy techniques, such as cryogenic TEM, have been evolved [27]. In the AFM, an extremely sharp tip scans the area and its deflection is translated into topology information. It provides additional information about mechanical properties, such as stiffness and elasticity of the vesicles. In most cases, AFM is performed on dry, immobilized surfaces, which in turn may damage the EVs [28]. This can be prevented by analyzing EVs in a solution [29]. Indirect methods estimate the size and concentration based on the interaction of EVs with light (DLS and flow cytometry), their diffusion trajectories (NTA or their effect on the electrical current (tRPS). DLS is based on the analysis of temporal intensity fluctuation of laser light scattered by a dispersion of freely diffusing EVs. Unlike EM and AFM it measures the collective mobility (diffusion coefficient) of scattering EVs that are present in the measured volume. Flow cytometry is often used to analyze the number of cells and their biochemical composition. EVs are much smaller than cells and are usually not detected due to the low sensitivity of the method. However, adapted protocols have been developed to enable the analysis of EVs [30]. In flow cytometry, the flow of cells is hydrodynamically focused in a flow chamber and enables the illumination of a single cell by several different lasers. The forward light scatter on the cell will allow information on the cells’ sizes while the side scatter will gave information on the granularity and composition [31]. Because the EVs are very small and have a low refractive index, flow cytometers can more accurately determine the EVs larger than 500 nm. Smaller EVs are detected in the background signal and collectively due to the swarm effect, which happens when multiple EVs are simultaneously and not separately illuminated by the laser, creating a swarm [32]. The recent advances in the field of flow cytometry enable to detect also populations as small as 100 nm [33]. NTA measures how fast a particle diffuses in a static solution due to the principle of Brownian particle motion. By analyzing its motion trajectories, it determines the size distribution of vesicles. tRPS is a technique that measures changes in electrical current as each particle passes through an adjustable nanopore [18]. The heterogeneity of the samples is a major problem with all indirect methods. Compared to direct methods the number of EVs that can be analyzed is typically higher, which allows a better estimate of the concentration. This is also due to the fact that these vesicles are in their original state. However, these methods are not able to provide information on the presence of contaminants, such as lipoproteins.
The characterization of EVs to determine the surface markers, markers of origin and proteins they carry allows to infer the functional role of these vesicles in health and disease. Methods might be divided to more conventional ones; the immunoblotting assays or the methods that will employ the capture of the vesicle; immunosorbent methods. Immunoblotting methods are based on the lysis of a vesicle and the analysis of its contents either by direct spotting on a membrane (dot blot) or separation of proteins using SDS PAGE combined with western blotting, in which specific proteins of interest are determined with labeled antibodies. Immunoblotting methods are often used to determine the presence of EVs in a sample. These methods can also be used to determine the purity of samples [18]. Immunosorbent assays are based on the detection of EVs using specific antibodies directed against surface proteins of EVs. Derived from the classical enzyme linked immunosorbent protein assay (ELISA), EVs are captured on a solid surface coated with antibodies that are typically present on the EVs. EVs capture results in a strong enrichment. Analysis of EVs surface proteins is afterwards performed with antibodies directed to a protein of interest on the surface of the EVs. These detection antibodies are conjugated to an enzyme enabling the conversion of a fluorescent/colored substrate that can be quantified with a spectrophotometer [18].
The main cell types involved in vascular hemostasis are endothelial cells, platelets and monocytes. All these cells release EVs, which leads to a complex interplay between different vesicles and different cells. EVs are continuously released in low concentrations from the cells into the intercellular environment, but this is greatly increased during cellular activation and apoptosis. EVs transmit various biological information (in the form of proteins, lipids and nucleic acids). Travelling through the bloodstream, EVs serve as local or distant messengers that transmit information to a variety of cells and tissues. Hemostasis is a very strictly regulated process that maintains normal function of vasculature despite the presence of triggers, such as injury and/or infection. One of the consequences of an altered hemostatic balance is the formation of thrombi, a process in which EVs play an important role [15]. EVs coming from activated cells have been shown to have both procoagulant and proinflammatory effects. Procoagulant effects are related to the fact that some EVs contain anionic phospholipids, mainly phosphatidylserine (PS), on their surface, which contributes to the assembly and activation of the prothrombinase complexes, thus promoting thrombin formation [34]. However, not all EVs carry PS on their surface, suggesting the involvement of other mechanisms contributing to the procoagulant state [35], including other important coagulation factors, such as tissue factor (TF), Factor XII [36], and reduced activity of tissue factor pathway inhibitor (TFPI) and thrombomodulin on endothelial cells [37]. In addition, EVs also induce the expression of adhesion molecules; integrins and selectins on the recipient cells causing platelets, monocytes, and endothelial cells to interact more intensively with each another. Finally, EVs also contribute significantly to the proinflammatory state in the vascular microenvironment by delivering or inducing certain cytokines and chemokines and by transferring nucleic acids and lipids [38]. The effects that these EVs have on different cell types disrupt the normal functioning of the vascular system, leading to the development of different pathologies, including deep vein thrombosis or pulmonary embolism [7] and cardiovascular diseases (atherosclerosis [39], hypertension [8], myocardial infarction [40] and stroke [41]).
EVs from activated platelets can have different effects on endothelial cells, monocytes and other platelets (Figure 2A). Namely, increased levels of intracellular adhesion molecule-1 (ICAM-1), a well-known activator of endothelium was observed on endothelial cells upon stimulation with platelet EVs [42, 43], an effect later ascribed to miR-320b transfer [42]. Increased expression of lymphocyte function-associated antigen-1 LFA-1 (CD11a/CD18) and macrophage antigen-1 Mac-1 (CD11b/CD18); both important in mediating monocyte-endothelium interactions, were observed on monocytes upon stimulation with platelet EVs. These effects are induced by the transfer of arachidonic acid from platelet EVs and appear to be dependent on the activation of protein kinase C [44]. Platelet EVs therefore significantly modulate adhesion of monocytes to endothelial cells. It has also been shown that platelet EVs increase the deposition of platelets on damaged arteries and increase platelet aggregation and adhesion to collagen [45]. By influencing cell adhesiveness, EVs also modulate interactions between leukocytes. Platelet EVs use P-selectin to bridge leukocytes, increase leukocyte-leukocyte interactions and enhance leukocyte accumulation on a P-selectin surface [46, 47]. Platelet EVs can therefore contribute to increased adhesion and aggregation of platelets and leukocytes on blood vessel walls during pathology. In addition, platelet EVs influence the production of cytokines (IL-1β, IL-6, IL-8) [43] and the transfer of miRNA (miRs 142-3p and 223), affecting the activation, proliferation and apoptosis of endothelial cells [48, 49]. In addition, platelet activation by the transfer of arachidonic acid from platelet EVs to other platelets, was observed [50]. Importantly, the role of platelet EVs in hemostasis is not entirely clear, as there is evidence that these EVs can also have anticoagulant effects [51, 52]. Further research is needed to determine, which key stimuli are responsible for determining the final effect of platelet EVs.
Activation of platelets, monocytes and endothelial cells by EVs deriving from different cells. Schematic representation of the potential in vitro mechanisms focusing on vascular function, inflammation and thrombosis. (A) Platelet EVs can stimulate endothelial cells and monocytes via direct interaction or cargo delivery (miR and lipids). Furthermore, platelets EVs can also act via a feedback loop causing platelet aggregation and activation. Platelet EVs induce endothelial cell activation, proliferation and apoptosis by the transfer or miR-223 and miR-142-3p while ICAM-1 expression is induced by the delivery of miR-320b. Increased adhesion between endothelial cells and monocytes as well as between leukocytes in mediated by platelet EVs. (B) EVs released form endothelial cells were found to have a procoagulant profile expressing vWF, TF, PAI-1, PS as well as increased adhesive properties expressing VCAM-1, ICAM-1, E-selectin, and α-integrin. Endothelial EVs promote procoagulant profile of monocytes by induction of the TF expression on these cells. Endothelial EVs induce endothelial dysfunction by attenuating the production of nitric oxide from endothelial cells (C) Monocytes release procoagulant EVs that carry TF and PS. Furthermore, monocyte EVs interact with endothelial cells causing increased expression of adhesion molecules (ICAM-1, VCAM-1 and E-selectin), increased inflammation and procoagulant profile by reducing the expression of anticoagulant molecules (TFPI and Trombomodulin). Monocyte EVs transfer miR cargo (miR125a-5p, miR-222, miR-146a, miR-146b, miR-155) and induce inflammation in endothelial cells. CCL2, C-C motif chemokine ligand 2; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; LFA1; lymphocyte function-associated antigen 1; Mac-1, Macrophage antigen-1; mIR; micro RNA; MyD88, myeloid differentiation primary response gene 88; NO, nitric oxide; PAI-1, plasminogen activator inhibitor-1; PS, phosphatidylserine; TF, tissue factor; TLR4, tool like receptor 4; VCAM-1, vascular cell adhesion molecule 1; vWF, von Willebrand factor. Created with BioRender.com.
Endothelial cell activation and damage play an important role in vascular pathologies, with endothelial EVs being proposed as one of the causative agents in vascular pathologies (Figure 2B). Many proinflammatory factors (e.g. TNF-α, lipopolysaccharide, C-reactive protein and reactive oxygen species) and coagulation stimuli (thrombin, plasminogen activator inhibitor-1 (PAI-1)) can increase the levels of endothelial EVs. These vesicles carry adhesion molecules; ICAM-1, vascular cell adhesion protein 1 (VCAM-1), E-selectin, VE-cadherin, α-integrin, growth factors; endoglin, CD146, vascular endothelial growth factor (VEGF) receptor and molecules involved in coagulation, such as von Willebrand factor (vWF), TF, PAI-1 [53, 54, 55]. The expression of anionic phospholipids; such as PS, together with coagulation molecules, contribute to their procoagulant role. In addition, endothelial EVs may interact with other cells such as monocytes and induce the expression of TF on these cells [56]. Endothelial EVs induce endothelial dysfunction by attenuating the production of nitric oxide from endothelial cells [57]. Conversely, endothelial EVs may also have anticoagulant and antiinflammatory potential [38]. Although they exert different effects that are mostly dependent on the environment they originate from, endothelial EVs are generally believed to impair vascular function [58].
Leukocytes play an important role in the maintenance of vascular homeostasis. The activation of monocytes leads to increased release of monocyte EVs, which contribute to the disturbance of the hemostatic balance (Figure 2C). Monocyte EVs adhere to endothelial cells via LFA-1-ICAM-1 adhesion, as shown by the blocking of LFA-1 [37]. Once internalized, EVs were able to induce extracellular signal-regulated protein kinase (ERK1/2) and nuclear factor-κB (NF-κB) signaling pathways that increase the expression of the adhesion molecules VCAM-1, ICAM-1, and E-selectin on endothelial cells [59]. On the other hand, Tang et al. suggested that monocyte EVs induce
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by venous and/or arterial thrombosis and pregnancy complications in the presence of antiphospholipid antibodies (aPL). aPL are a heterogeneous group of autoantibodies, of which anti-cardiolipin (anti-aCL), anti-β2 glycoprotein I (anti-β2GPI) and lupus anticoagulant (LA), are in the laboratory criteria for the diagnosis of APS [63]. In addition to criteria aPL other, non-criteria aPL, such as antibodies against phosphatidylserine/prothrombin complex, were found to play an important role in APS [64, 65]. These antibodies are, in some patients, the only elevated aPL. Although aPL are persistent in APS patients, thrombosis occurs only occasionally, suggesting the involvement of other triggers that, together with aPL, turn the hemostatic balance in favor of thrombosis. In the development of APS, a two hit theory has been proposed in which the continuous presence of aPL as the first hit and inflammation, trauma, or surgery as a second hit together lead to thrombus formation [66, 67]. APS pathogenesis clearly involves both inflammatory and coagulation pathways in endothelial cells, monocytes, neutrophils, and platelets. Frequently identified prothrombotic mechanism is inhibition of the natural anticoagulant pathways [68]. It has been shown that aPL inhibit the activation of protein C [69] and its ability to inactivate factors V and VIII [70]. In addition, aPL inhibit the activity of TFPI [71] and activation of antithrombin [72]. They have also been found to be involved in fibrinolysis by neutralizing the ability of anti-β2GPI to stimulate tissue-type plasminogen activator [73]. Furthermore, aPL impair the ability of Annexin A5 to form a network on procoagulant anionic phospholipids [74]. aPL also directly bind to vascular cells and trigger their activation, which in response, release prothrombotic molecules and thus contribute significantly to the pathogenesis of APS. The activation of endothelial cells leads to a disruption of the normally anticoagulant endothelial surface [68]. This is achieved by upregulating adhesion molecules (E-selectin, ICAM-1, VCAM-1) [75], molecules involved in coagulation (TF) [76] and by the decrease in endothelial cell derived nitric oxide [77]. The biochemical pathways are not fully defined, but research has suggested several receptor-mediated mechanisms including, annexin A2, TLR4/NF-κB, TLR2, TLR7 and low-density lipoprotein receptor-related protein 8 [68]. In addition to endothelial cells, aPL also act on platelets. Increased production of thromboxane B2, increased platelet adhesion to collagen type I and III and increased platelet activation have been described [66]. Among immune cells, monocytes are the most extensively studied in APS. In APS patients, monocytes have been shown to have a proinflammatory and procoagulant phenotype that is mediated by upregulation of NF-κB, MEK-1/ERK, and p38 MAP kinase pathways [78]. The main player of the procoagulant phenotype is increased surface expression, production and activity of TF on monocytes [79]. Stimulation of monocytes with aPL influences the release of IL-1β [80] and TNFα [81], probably by the activation of NLR family pyrin domain containing 3 inflammasome [82]. Monocyte-endothelial interactions are increased by upregulation of adhesion molecules on both cell types, as well as expression of other molecules, such as monocyte chemoattractant protein-1 by the endothelium, which in turn promotes the synthesis of TF by monocytes [83].
The role of EVs as communicators between different types of cells involved in the pathology of APS have been studied
Characterization of endothelial, monocyte and platelet EVs. Schematic representation of commonly expressed surface protein markers of endothelial cells, monocytes and platelets, as well as markers currently associated with small and medium/large EVs. Endothelial EVs usually express CD51 (Integrin alpha V) which is a part of a complex that binds extracellular matrix proteins, CD144 (Vascular endothelial cadherin), an important cell adhesion molecule in the formation of adherent junctions, CD31 (PECAM-1; platelet endothelial cell adhesion molecule) mediates leukocyte- and platelet-endothelial cell adhesion, CD105 (Endoglin) is a type I membrane glycoprotein and a part of transforming growth factor β receptor complex. Monocyte EVs commonly express CD14 (Cluster of differentiation 14) a known monocyte marker and CD45 (PTPRC; protein tyrosine phosphatase receptor type C) that is leukocyte specific cell surface glycoprotein involved in various cellular processes. Platelet EVs usually express different glycoproteins (CD42; glycoprotein IX, CD41; glycoprotein IIb, CD61; glycoprotein IIIa) that are integrin complex proteins involved in platelet aggregation. All EVs carry adhesion molecules, receptors and lipids that are involved in interaction of EVs with different cells. Furthermore, they carry proteins, nucleic acids and lipids that can be transferred to a target cell. Membrane derived vesicles-microvesicles, are usually larger and express procoagulant molecules, such as TF (Tissue factor), annexins and PS (Phosphatidylserine), whereas tetraspanins (CD9, CD63, CD81) and specific luminal proteins (Clathrin, TSG101 and Alix) are specific for smaller vesicles of endosomal origin-exosomes. Created with BioRender.com.
The role of EVs has been studied in many vascular pathologies, including deep vein thrombosis [7] and cardiovascular disease [38], whose common denominator is endothelial dysfunction. In addition, platelet EVs have been proposed as a useful biomarker for long-term follow-up after myocardial infarction [84], whereas increases in the number of endothelial EVs play a role in many inflammatory diseases, such as atherosclerosis [39]. Studies investigating EVs in patients with APS are limited and heterogeneous (Table 2). To date and to our knowledge, there have been 13 studies investigating EVs in thrombotic APS patients. With one exception, all of them have focused on medium/large EVs. Furthermore, the results of these studies are not completely comparable because the methods for isolating and characterizing EVs are not standardized, the sample sizes in some studies are small and the patient population studied is very heterogeneous (e.g. patients with concomitant autoimmune or other disease). Overall, the studies investigated EVs from the three major cell types involved in the pathogenesis of APS: endothelium, platelets, and monocytes. Studies in the field of cardiovascular diseases and EVs have shown that both platelet and endothelial EVs are elevated in patients with hypertension, compared to healthy blood donors [8], therefore it is important to note that certain proportion of EVs detected in plasma of APS patients might be associated with hypertension. Correlations between the levels of EVs and systolic and diastolic blood pressure needs to be evaluated when investigating EVs in APS patients.
Reference | Patients | Controls | Isolation protocol | Method of quantification | Type of EVs | Main findings |
---|---|---|---|---|---|---|
Combes et al., 1999 [53] | 5 APS, 8 APS + SLE | 17 asympt. aPL+ (6 autoimmune, 4 infections, 5 malignancy, 2 undefined) 30 HBDs | 2 x 1,500 × g (15″) 13,000 × g (1″) | AnxV+ or CD51+ < 1.5 μm (latex beads) | endothelial (CD51+) | ↑ endothelial EVs in aPL+ pts. vs. HBDs. ↑ endothelial EVs in thrombotic aPL+ pts. vs. asympt. aPL+ pts. Levels of SLE aPL- pts. were similar to HBDs. |
Joseph et al., 2001 [85] | 20 APS 14 APS + SLE | 16 SLE 20 HBDs | 2 x 1,500 × g (15″) 13,000 × g (1″) | GPIIb-IIIa+ < 0.8 μm | platelet (GPIIb-IIIa+) | No difference in platelet EVs between APS pts., SLE pts. and HBDs. |
Nagahama et al., 2003 [86] | 24 APS 13 SLE + APS | 30 HBDs | 200 x g (10″, RT), 1000 x g (15″, RT) | AnxV+, CD42a+, CD14+ | platelet (CD42a+) monocyte (AnxV+/CD14+) | ↑ monocyte EVs in APS pts. vs. APS + SLE pts. and vs. HBDs. ↑ P-selectin+ platelets and platelet EVs in APS pts. vs. HBDs. |
Dignat-George et al., 2004 [87] | 23 APS 14 APS + SLE | 28 SLE aPL+ no thrombosis 23 SLE aPL- no thrombosis 25 aPL- with thrombosis 25 HBDs | 2 x 1,500 × g (15″) 13,000 × g (2″) | CD51+ < 0.8 μm (latex beads) | endothelial (CD51+) | ↑ endothelial EVs in APS pts. vs. HBDs and vs. non aPL related thrombotic pts. ↑ endothelial EVs in SLE aPL+ pts. vs. HBDs. No difference between SLE aPL- pts. and non aPL related thrombotic pts. vs. HBDs. ↑ endothelial EVs in aPL+ pts. vs. aPL- pts. and vs. HBDs. No difference between primary or secondary APS. |
Jy et al., 2007 [88] | 60 APS | 28 asympt. aPL+ 39 HBDs | 160 × g (10″) 1500 × g (6″) | CD31+ or CD42+ < 1.5 μm | endothelial (CD31+/CD42-) platelet (CD31+/CD42+) | ↑ platelet and endothelial EVs in APS pts. vs. HBDs. ↑ endothelial EVs in asympt. aPL+ pts. vs. HBDs. No difference in levels of endothelial EVs in APS pts. vs. asympt. aPL+ pts. ↑ platelet EVs in APS pts. vs. asympt. aPL+ pts. No difference in levels of platelet EVs in asympt. aPL+ pts. vs. HBDs. |
Flores-Nascimento et al., 2009 [89] | 11 APS | 9 DVT pts. at diagnosis 10 DVT pts. After 1-3 years of warfarin withdrawal 7 FVL pts. 37 HBDs | 3000 x g (20″) 13,000 x g (30″) | AnxV+, CD14+, CD31+, CD45+, CD61+, CD142+, CD235+ | total (AnxV+) platelet (CD61+) erythrocyte (CD235+) monocyte (CD14+) endothelial (CD31+) leukocyte (CD45+) | No difference in total EVs in DVT pts. at diagnosis, FVL pts., APS pts. and HBDs. ↑ total EVs in DVT 1-3 years and HBDs. No difference in platelet, erythrocyte, monocyte, endothelial and leukocyte EVs in all pts. groups vs. HBDs. |
Vikerfors et al., 2012 [90] | 40 APS, 12 secondary APS | 52 HBDs | Isolation not described | phalloidin-, lacadherin+ or CD14+, CD42a+, CD142+, CD144+ < 1 μm (MegaMix beads) | total (lacadherin+) endothelial (CD144+) platelet (CD42a+) monocyte (CD14+) endothelial (CD144+/CD142+) | ↑ total EVs in APS pts. vs. HBDs. ↑ endothelial, endothelial TF+ and monocyte EVs in APS pts. vs. HBDs. No difference in levels of platelet EVs in APS pts. vs. HBDs. |
Willemze et al., 2014 [91] | 11 APS 19 APS + SLE | 72 asympt. aPL+ | 1,500 x g (10″, 4 °C) 2,000 x g (5″, 4°C) 20,000 x g (30″, 4°C) | not studied | TF+ EVs by a functional assay (TF activity) | ↑ EV-TF activity in APS pts. vs. asympt. aPL+. No difference in EV-TF activity in the presence or absence of underlying SLE. No difference between different APS clinical complications. No correlation between EV-TF activity and aPL subtype. |
Chaturvedi et al., 2015 [92] | 47 aPL+ pts. (38 APS, 2 APS + SLE, 6 asympt. aPL+, 1 aPL+ migraine) | 144 HBDs | 2 x 1,500 × g (15″) 13,000 × g (2″) | AnxV+ or CD14+, CD41+, CD105+, CD142+, CD144+ < 1 μm (latex beads) | total (AnxV+) endothelial (CD105+/CD144+) platelet (CD41+) monocyte (CD14+) TF (CD142+) | ↑ total EVs in aPL+ vs. HBDs. endothelial, platelet, and TF+ EVs in aPL+ vs. HBDs. No difference in levels of monocyte EVs in aPL+ vs. HBDs. |
Breen et al., 2015 [93] | 66 aPL+ pts. (37 thrombotic APS, 11 obstetric APS, 18 asympt. aPL+). | 18 HBD | 2x 2,000 x g (15″, 4°C), 12,000 x g (2″, 4°C) | CD41+, CD51+, CD61+ or CD105+ | endothelial (CD51+/ CD105+) platelet (CD41+/CD61+) | ↑ endothelial and platelet EVs in aPL+ pts. vs. HBDs. ↑ endothelial and platelet EVs in thrombotic APS pts. vs. HBDs. No difference in levels of endothelial and platelet EVs in obstetric APS pts. vs. HBDs. No difference in levels of endothelial and platelet EVs in asympt. aPL+ pts. vs. HBDs. |
Niccolai et al., 2015 [94] | 16 APS | 16 asympt. aPL+ 16 HBDs | 1,500 x g (15″) 3,000 x g (3″) | VPD450+ or CD31+, CD41a+, CD45+ < 0,9 μm (Megamix beads) | total (VPD450+ 7AAD-) endothelial (CD31+) platelet (CD41a+) leukocyte (CD45+) | ↑ total, endothelial, platelet, and leukocyte EVs in APS pts. vs. HBDs, APS pts. vs. asympt. aPL+ pts. and asympt. aPL+ pts. vs. HBDs. ↑ total EVs in APS double and triple positivity vs. single positivity. Different EVs populations (endothelial, platelet and monocyte) did not correlate with aPL positivity. ↑ endothelial EVs in asympt. aPL+ pts. triple positivity vs. single positivity. Total, leukocyte and platelet EVs did not correlate with aPL positivity. |
Hell et al., 2018 [95] | 64 APS 18 APS + SLE 12 APS + LLD | 30 HBDs | 2,500 x g (15″, 15 °C) | not studied | TF+ EVs by a functional assay (TF activity) | No difference in EV-TF activity in LA+ pts. with thrombosis vs. HBDs. No difference in EV-TF activity in single, double or triple aPL+ patients. No difference in EV-TF activity in LA+ pts. with AT vs. VT vs. combination of both. No difference in EV-TF activity and the number of events (thromboses). |
Štok et al., 2020 [13] | 14 APS | 5 aPL- with thrombosis 7 HBD | 820 x g (10″, RT) 2,500 x g (10″, RT) 10,000 x g, (45″, RT) 100,000 x g (2 h15”, 4°C) | NTA | < 200 nm. Multiplex flow cytometry for 38 markers (detection via tetraspanins) | ↑ sEVs in APS pts. vs. HBDs. Platelet (CD41b+, CD42a+), lymphocyte (CD8+), leukocyte (CD45+) and endothelial (CD31+) sEVs were detected. ↑ P-selectin on sEVs from APS pts. vs. HBDs. ↑ CD133/1 on sEVs from APS pts. vs. aPL- pts. with thrombosis. |
Isolation, quantification and characterization of EVs in plasma of APS patients.
Abbreviations: Anx V, annexin V; APS, antiphospholipid syndrome; AT, arterial thrombosis; aPL, antiphospholipid antibodies; asympt., asymptomatic; DVT, deep vein thrombosis; EVs, extracellular vesicles; FVL, factor V Leiden; HBDs, healthy blood donors; LLD, lupus like disease; NTA; nanoparticle tracking analysis; pts., patients; sEVs, small extracellular vesicles; SLE, systemic lupus erythematosus; TF, tissue factor; VT, venous thrombosis; ↑, elevated levels.
The endothelium is the major player in APS pathogenesis, so it is not surprising that endothelial EVs have been the most extensively studied (Table 2). Combes et al. published in 1999 the first study investigating endothelial EVs in APS using flow cytometry to detect endothelial marker integrin CD51+ EVs. They showed increased levels of endothelial EVs in LA+ patients compared to HBDs [53]. In addition, they have also showed a significant increase in endothelial EVs in LA+ patients with a history of thrombosis compared to asymptomatic LA+ patients. On the other hand, Jy et al. found no difference in endothelial EVs (CD31+/CD42-) between aPL+ thrombotic patients and asymptomatic aPL+ group, suggesting that the release of EVs might be related to the autoimmune process involving the presence of aPL [88]. Dignat-George et al. in 2004, showed increased levels of CD51+ endothelial EVs in APS patients and in aPL+ SLE patients compared to HBDs [87]. Increased levels of endothelial EVs were observed in aPL+ patients vs. HBDs as well as in aPL+ patients vs. aPL- patients. Increased levels of endothelial EVs in the plasma of APS patients compared to HBDs were later confirmed also in several other studies [90, 93, 94] (Table 2), in which different endothelial surface markers (CD31+, CD51+, CD105+, CD144+) were examined. Levels of endothelial EVs were shown to be increased in APS patients with exception of one study where the increase was not observed [89]. Chaturvedi et al., on the other hand investigated levels of TF+ endothelial EVs, and found them to be elevated in aPL+ patients, compared to HBDs [92]. A higher TF activity was also observed when comparing APS patients with asymptomatic aPL+ patients [91]. Contrarily, Hell et al. could not observe increased TF activity of endothelial EVs in APS patients vs. HBDs.
Platelet-derived EVs are the most numerous type of vesicles found in the circulation of healthy individuals [96], and their levels are further increased in disease [38]. They are known to play key roles in coagulation, thrombosis, vascular senescence and permeability. It has been suggested that platelet EVs induce vascular dysfunction and influence immune modulation, leading to vascular remodeling. Monocytes contribute to APS pathogenesis also by being the main source of tissue factor, which is one of the key initiators of the coagulation cascade. Similar to platelet EVs, it has been suggested that monocyte EVs cooperate in coagulation and vascular inflammation [38]. However, in APS, monocyte EVs (Table 2) have been less extensively studied compared to endothelial EVs. Joseph et al., showed no difference in plasma levels of CD41+ platelet EVs between APS patients and HBDs [85]. This is consistent with the study by Vikenfors et al. (CD42a+) [97] and by Nascimento et al. (CD61+) [89]. On the other hand, increased levels of platelet EVs (CD41+, CD41a+, CD42+, CD42a+) were found in five other studies [86, 88, 92, 93, 94]. Jy et al. have shown an increase in platelet EVs in APS patients vs. asymptomatic aPL+ suggesting thrombosis rather than aPL may play a role in platelet EVs release [88]. An increase in monocyte EVs in APS patients compared to HBDs was observed by Nagahama et al. and Vikenfors et al. which is in contrast to two other studies where the authors could not see an increase [89, 92]. There is no consensus on whether platelet and monocyte EVs are elevated in APS patients and there is too little data to conclude on the effects of these EVs in APS patients.
To date, only a study by Stok et al. has investigated the presence of sEVs in plasma of APS patients (Table 2). Compared to HBDs, significantly increased levels of sEVs were observed in APS patients. In addition, sEVs from different cellular origin: platelet (CD41b+, CD42a+), lymphocyte (CD8+), leukocyte (CD45+) and endothelial (CD31+) were detected. Flow cytometric characterization of sEVs defined a subpopulation of vesicles that were positive for P-selectin (CD62P) and the endothelial progenitor cell marker (CD133/1). sEVs from APS patients were enriched in surface expression of P-selectin, suggesting endothelial and platelet activation in APS. In addition, APS patients showed increased CD133/1 expression compared to aPL- patients with thrombosis, suggesting endothelial damage in APS [13]. The authors of this study suggest that increased levels of sEVs with distinct biological properties circulate in patients with thrombotic APS.
One mechanism by which aPL promote thromboses is through their binding to endothelial cells causing the activation of endothelial cells [98, 99] which in response, release EVs that might modulate the activation of other adjacent cells [87, 100]. These effects were investigated on endothelial cells [87, 100, 101, 102] and placental explants [103] involving both small EVs and medium/large EVs (Table 3). A study by Dignat-George et al., showed a significant 4-fold increase in endothelial EVs with procoagulant activity after stimulation of human umbilical vein endothelial cells (HUVEC) with plasma of APS patients [87]. Only a moderate, non-significant increase was observed after HUVEC stimulation with the plasma from HBDs. In addition, endothelial EVs released after HUVEC stimulation with APS plasma, significantly reduced the normalized clotting time ratio. Wu et al. showed data where stimulation of HUVEC with anti-β2GPI caused the formation of an endothelial cell inflammasome and the release of EVs that were enriched in mature IL-1β, with a distinct mIR profile and caused endothelial activation [101]. However, activation of HUVEC does not appear to involve IL-1β receptor, but most likely follows the TLR/myd88-IRAK4 signaling pathway. Pericleous et al. [102] investigated the effect of purified polyclonal IgG from patients with APS (APS-IgG) and healthy controls (HC-IgG) on HUVEC [102]. HUVEC exposed to APS-IgG, produced significantly more endothelial EVs than those exposed to HC-IgG and a larger proportion of these EVs carried surface E-selectin. Levels of ICAM-1+, endoglin+ and VE-cadherin+ EVs did not differ from the ones stimulated with HC-IgG. VCAM-1+ and TF+ endothelial EVs could not be detected. Later Betapudi et al., also observed a 2-fold increase in levels of endothelial EVs released from HUVEC stimulated with anti-β2GPI [100]. EVs in obstetric APS patients were studied by Tong et al. [103], whereby exposure of first trimester human placental explants to monoclonal anti-β2GPI and IgG fractions from five anti-β2GPI positive APS patients did not affect the number or size of EVs. However, an increase in levels of mitochondrial DNA was observed in these vesicles that activated endothelial cells through a TLR-9-mediated pathway. This is supporting the idea that EV-associated mitochondrial DNA could be pathological in pregnant women with aPL.
Reference | Cell type | Stimulation | Isolation protocol | Method of quantification of EVs | Levels | Other major findings |
---|---|---|---|---|---|---|
Dignat-George et al., 2004 [87] | HUVEC | plasma from APS pts. or HBDs | direct use of cell culture supernatant | AnxV+ (total EVs) < 0.8 μm (latex beads) | ↑ | ↑ endothelial EVs with procoagulant activity. |
Wu et al., 2015 [101] | HUVEC | anti-β2GPI purified from APS pts. plasma and from rabbits immunized with β2GPI | 2,500 × g (15 “) 13,000 × g (2 “) 100,000 × g (90″) | qPCR, immunoblotting, inflammasome staining | NA | Anti-β2GPI caused formation of an endothelial cell inflammasome and the release of EVs that were enriched in mature IL-1β, had a distinct miR profile, and caused endothelial activation. |
Pericleous et al., 2013 [102] | HUVEC | purified IgG from APS pts. and HBDs | 3,000 × g (5″) 12,000 × g (60″) | AnxV+ (total EVs) CD62E+ (E-selectin), CD106+ (VCAM-1), CD54+ (ICAM-1), CD142+ (TF), CD105+ (endoglin), CD144+ (VE-cadherin) < 1 μm (latex beads) | ↑ AnxV+ and E-selectin+ | No difference in levels of ICAM-1+, endoglin+, and VE-cadherin+ EVs after APS IgG stimulation vs. HBD IgG. VCAM-1+ and TF+ EVs could not be detected. |
Betapudi et al., 2013 [100] | HUVEC | anti-β2GPI purified from 3 APS pts., HBDs and rabbits immunized with β2GPI | 1,500 × g, (30″) 13,000 × g (2″) | CD144+ < 1 μm (latex beads) | ↑ | Anti-β2GPI antibodies stimulate endothelial EVs release via nonmuscle myosin motor protein-dependent pathway. |
Tong et al., 2017 [103] | 1st trimester human placenta explants, HMEC-1 | murine monoclonal anti-β2GPI, purified IgG from 5 APS pts. and HBDs | 2,000 × g, (5″) 20,000 × g (60″) 100,000 × g (60″) | NTA | Not increased | ↑ mean and modal size of EV after aPL stimulation. ↑ of mtDNA in EVs after aPL stimulation. EVs from placental explants activated HMEC-1 through TLR-9 receptor signaling. |
Isolation, quantification and characterization of EVs derived from endothelial cells after stimulation with aPL.
Abbreviations: Anx V, annexin V; APS, antiphospholipid syndrome; aPL, antiphospholipid antibodies; β2GPI, β2-glycoprotein I; EVs, extracellular vesicles; HBDs, healthy blood donors; HUVEC, human umbilical vein endothelial cells; HMEC-1, human dermal microvascular endothelial cells; ICAM-1, intercellular adhesion molecule 1; IgG, immunoglobulin G; IL, interleukin; mtDNA, mitochondrial DNA; NA, not applicable; NTA, nanoparticle tracking analysis; pts., patients; TF, tissue factor; TLR, toll-like receptor; VCAM-1, vascular cell adhesion molecule 1; ↑, elevated levels.
Extracellular vesicles are small phospholipid bilayer particles that carry various biologically active molecules, such as proteins, lipids and nucleic acids. Their key biological function is cell–cell communication and the transfer of cargo. EVs normally circulate in the bloodstream of healthy individuals, but their levels are elevated in various pathological conditions, including APS. The classification, isolation and characterization of EVs has been developing in an accelerated manner over the last 20 years. Nevertheless, terms such as exosomes and microparticles are still present in the literature, but it is important to note that this classification is based on biogenesis, which is rather difficult to assess. It is therefore more optimal to classify EVs based on their other characteristics, such as size, density, origin etc. Each isolation and characterization techniques have their advantages and disadvantages and influences the properties of the EVs studied. Choosing the best combination, albeit of different isolation techniques, along with the characterization of EVs, is of utmost importance to achieve good data quality. In addition, the limitations of the methods used in both isolation and characterization must be considered. In the rapidly developing field of EVs research, variations of existing methods, as well as new technologies, are emerging that enable more precise isolation and characterization of EVs. EVs from platelets, monocytes and endothelial cells play a crucial role in vascular dysfunction, which is a causal factor in the disturbance of hemostasis and the development of thrombosis. Platelet and monocyte EVs are involved in the increased adhesiveness of endothelial cells and the increased interaction of leukocytes with the endothelium. Platelet, monocyte and endothelial EVs carry procoagulant molecules, such as TF, and modulate the expression of coagulation molecules in endothelial cells. Research on EVs in APS is very heterogeneous, due to the lack of standardization of isolation and characterization methods, all of which limits solid findings and conclusions. In addition to the technological challenges, EVs in APS are difficult to study because of the puzzling nature of APS. It is a chronic disease with a complex clinical spectrum due to many different features and symptoms (e.g. hypertension, thrombocytopenia). Patients with APS receive lifelong treatment with anticoagulants, and the actual acute phase is practically impossible to monitor. However, in view of the data on EVs in APS, a trend towards elevated total endothelial and platelet EV levels can be observed, suggesting an activated endothelium, even in the absence of an acute event. The results of the study of sEVs suggest that smaller vesicle populations may also play a role in the pathogenesis of APS. It appears that in patients with APS, levels of sEVs and different medium/large EVs are elevated. Further research is needed to confirm this in a larger number of patients as well as determine their functionality in APS. Data on increased levels of endothelial EVs in APS is supported by
The authors declare no conflict of interest.
Idiopathic Pulmonary Fibrosis (IPF) is the most common type of Idiopathic Interstitial Pneumonia. It is more prevalent in men, and its incidence increases with age, especially beyond the fifth decade [1]. Its incidence is estimated to be 3–9 cases per 100,000 per year in the western hemisphere [2]. As per a systematic review, the prevalence is estimated to be 0.5–27.9/100,000 [3]. Although newer therapies such as Pirfenidone and Nintedanib are available to slow the progression of the disease, the mortality and prognosis remain dismal, comparable to that of certain malignancies [4]. A key consideration has been the lack of optimal understanding of the pathophysiological mechanisms underlying the disease process, as interventions can then be targeted to modify the disease process and achieve better outcomes for the patients [4]. In a genetically susceptible individual, many risk factors have been proposed [1]. One such factor that has been closely associated with IPF is Gastroesophageal reflux disease (GERD) [1]. Their association has been hypothesized, studied, and targeted therapeutically. However, its role as a causative and aggravating factor has not yet been crystallized. Our chapter aims to review the association of GERD with IPF, its alleged role in causing or promoting lung injury, the effect of GERD therapy on IPF, recommendations from clinical guidelines, and the direction for future research.
GERD is a disease caused by reflux of stomach contents into the esophagus and beyond, causing troublesome symptoms and complications [5]. It causes esophageal and stomach symptoms characterized by chest pain, nausea, bloating, heartburn, and regurgitation. It can also cause extraesophageal symptoms such as throat pain, burning, lump in the throat, the sensation of needing to clear the throat, hoarseness of voice, cough, wheezing, bronchospasm, etc. [5, 6]. Importantly not all reflux events are symptomatic as there could be non-acid reflux [5, 6, 7].
Prevalence of GERD is very common in the western world, with North American estimates being 18.1–27.8% [8]. Europe, similarly, has a prevalence of up to 25% [8]. In a United Kingdom general practice database, IPF was much more likely to be associated with a diagnosis of GERD (65%) or use of anti-reflux therapy (71%) when compared to controls [4, 7, 9]. The prevalence of erosive esophagitis and hiatal hernia, both of which are associated with increased reflux, is also much higher in pulmonary fibrosis patients when compared to the general population [8, 10]. Hence there is a strong epidemiological association between these two disease entities.
GERD occurs commonly as a result of increased frequency of transient lower esophageal sphincter relaxations (TLESRs), which are defined as brief moments of lower esophageal sphincter tone inhibition that are independent of a swallow [11]. Other pathophysiological mechanisms implicated in the causation of GERD are reduced lower esophageal sphincter (LES) pressure, reduced upper esophageal sphincter pressure, reduced esophageal motility, Hiatal hernias, which distorts the gastroesophageal junctional anatomy, impairment of esophageal clearance, and sluggish gastric emptying [4, 5, 7]. A combination of these factors leads to the reflux establishing contact with mucosa in the upper gastrointestinal tract, pharynx, tracheobronchial tree, and lungs, causing extra esophageal symptoms as previously described [4, 5, 7].
Evaluation of GERD can be made by direct visual examination by esophagogastroduodenoscopy (EGD). The chief advantage is that the mucosa can be visualized directly and is helpful in the diagnosis of possible complications of GERD, including Barret’s esophagitis, esophagitis, gastritis, gastric and esophageal stricture, and malignancy. However, pH monitoring better evaluates reflux, wherein a pH measuring probe is placed in the esophagus [5]. The primary measurement is the amount of time spent with a pH less than 4.0 [5]. However, it has its inherent limitations, as non-acid reflux cannot be measured and can remain totally asymptomatic. This limitation has been overcome by the placement of channels that measure impedance. Liquid reflux has low impedance and high conductance, while gaseous reflux, such as belching, has high impedance with low conductance [12]. Combined 24-hr multichannel intraluminal impedance-pH monitoring (MII-pH) are available to determine the amount of refluxate, its proximal extent, and/or the presence of both acid and weakly acidic reflux [7, 13]. The chief metric when using MII-pH is the “Total number of refluxes” (Pathological when more than 80 and normal if less than 40 in a 24-hour period) and esophageal “Acid exposure time (AET)” as the percentage of time with pH less than 4.0 in the distal esophagus [14]. The use of MII-pH in GERD associated with extra esophageal disease, particularly in IPF, is rather novel and promising to help illuminate the pathophysiological mechanisms between the two diseases [15]. It is noteworthy that IPF belongs to a group of diseases that are only possibly or likely associated with GERD, and its role is only speculated [7]. The use and application of MII-pH for the study of extraesophageal diseases and symptoms has not been as productive as for typical GERD [7].
The relationship between IPF and GERD is quite intriguing. The epidemiological association suggests that there appear to be plausible biological and mechanical factors underlying this pathophysiology.
It is suggested that GERD is associated with decreased upper and lower esophageal sphincter tone (hypotensive esophagogastric junction) with or without increased frequency of transient lower esophageal sphincter relaxations (TLESRs), leading to increased refluxate with an associated micro-aspiration of the gastric contents into the trachea and lungs [16, 17, 18]. Contrary to this proposed theory, it has been proposed that lung fibrosis causes decreased lung compliance along with lower lung elasticity, resulting in increased negative intrathoracic pressure during inspiration that is transmitted to the mediastinal structures, including the esophagus and its sphincters [17]. This causes increased transient lower esophageal sphincter relaxations (TLESRs) with lower and upper esophageal sphincters [17]. There is also a pressure gradient across the diaphragm in respiratory diseases like IPF, which may promote these favorable refluxate mechanisms, especially during coughing, increased respiratory excursions during exacerbations, and may potentially be further aggravated by hypoxia/hypercapnia, medications like antacids, glucocorticoids, and obstructive sleep apnea/hypopnea syndromes [19]. Hiatal hernia alters the physical and physiologic function of the lower esophageal sphincter, thereby promoting reflux [20, 21, 22]. Furthermore, it has been proposed that esophageal dysmotility may contribute to reflux [23, 24]. Ultimately, the result of these phenomena is that the gastric refluxate, which contains both acidic and non-acidic contents, leads to delayed esophageal clearance and micro-aspiration in the tracheobronchial tree injure the pulmonary parenchyma consisting of both alveolar and interstitial components [4, 7, 19]. The healing of this injury eventually occurs by fibrosis, and the pulmonary remodeling that ensues culminates in a distorted fibrotic architecture [4, 7].
Many studies have been performed to provide evidence and study the relationship between GERD and IPF. Most of these studies have limitations and often conclude with contradictory results. Therefore, evidence has shown a co-existence and/or association between IPF and GERD. However, causality has yet to be determined [4, 7, 25].
Gao et al. conducted a study involving 69 IPF patients, 62 healthy volunteers, and 88 IPF negative GERD patients. The prevalence of GERD was high in patients with IPF, and in relation to their comparator group showed the variable presence of esophageal dysmotility and decreased lower and upper esophageal sphincter pressure. IPF patients also had increased reflux events proximally and impaired bolus transit time [16]. Raghu et al. studied 65 patients with IPF who were subjected to 24-h pH monitoring and esophageal manometry with a comparison group of 133 asthmatic patients and symptoms of GERD. The prevalence of abnormal gastroesophageal reflux in IPF patients was high at 87%, with 76% and 63% demonstrating abnormal distal and proximal esophageal acid exposures, respectively; a finding higher than within the comparison group [18]. The study also showed that the presence of GERD was not always symptomatic, and there was no correlation with IPF severity [18]. This was further confirmed in a study involving 28 patients with histologically confirmed IPF using hypopharyngeal multichannel intraluminal impedance (HMII) [26]. HMII used a specialized impedance catheter to directly measure laryngopharyngeal reflux (LPR) and full column reflux (reflux 2 cm distal to the upper esophageal sphincter). The study included 16 males and 12 females with a mean age of 60.4 years (range, 41–78) and a BMI of 28.4 (range, 21.1–38.1), respectively. Abnormal proximal exposure was present in 54% (15/28) of patients. This latter group was more likely to have a defective lower esophageal sphincter (LES) compared with those without (93% vs. 75%). Fourteen patients (56%) had abnormal esophageal motility, including aperistaltic esophagus (n = 9), suggesting that this may be common in this patient population [26].GERD was noted to be highly prevalent at more than 70% in patients with IPF; abnormal proximal reflux events such as LPR and full column reflux were also quite common despite a frequently negative DeMeester score (It is a composite of six different parameters which measures acid exposure giving a pH score used to diagnose GERD), suggesting that nonacid reflux (25% of patients) is prevalent in this patient population [26]. A high rate of esophageal mucosal injury and a longer acid clearance time was also noted [26].67–76% of the systematic review demonstrated abnormal esophageal acid exposure off PPI treatment [27].
In another study conducted by Savarino et al. [28], 40 IPF patients were studied alongside 40 non-IPF ILD patients and 50 healthy volunteers, who served as controls. Patients were off reflux therapy and underwent a High-resolution Lung CT scan (HRCT) and pH-impedance monitoring. Patients with IPF had significantly increased esophageal acid exposure, the number of acidic, weakly acidic, and proximal reflux events relative to the comparison groups. Pulmonary fibrosis HRCT scores correlated well with reflux episodes in both the distal and proximal esophagus. Patients with IPF had more bile acids and pepsin (p < 0.03) in bronchoalveolar lavage fluid (62% and 67%, respectively) and saliva (61% and 68%, respectively) relative to the comparison groups [28]. Gavini et al. conducted an elegant study involving 45 pre-transplants patients with IPF who had received pulmonary function tests within the last 3 months. Patients were off reflux therapy and had no reflux surgery. They measured GER on multichannel intraluminal impedance and pH study (MII-pH). Six pH/acid reflux parameters with corresponding MII/bolus reflux measures were prespecified. Multivariate analyses were applied using forward stepwise logistic regression. Severe pulmonary dysfunction was defined using diffusion capacity for carbon monoxide (DLCO) ≤40%. Abnormal total reflux episodes and prolonged bolus clearance time (OR = 1.21 p = 0.05), but not the refluxate pH values, were significantly associated with pulmonary dysfunction severity on univariate and multivariate analyses [29]. Overall, it appears that esophageal dysmotility, the total number of acidic, weakly acidic, and non-acidic refluxes with prolonged bolus clearance time, appear to impact the underlying lung pathology.
Animal and human studies have shown that the presence of gastric contents (pepsin, bile acids, gastric acid) via microaspiration in bronchoalveolar lavage (BAL) fluid can cause tissue damage and inflammatory infiltrate [28, 30, 31, 32, 33, 34, 35]. Histologically presence of thickened alveolar walls, collagen deposition in the interstitium, epithelial-mesenchymal transition, and presence of various fibrogenic factors has been found [28, 34, 35]. The latter consists of TGF-beta, NFκB, Farnesoid X receptor, and others. TGF-beta can be induced by gastric contents, leading to fibroblast proliferation and fibroproliferative changes [4, 7].
There has been a long-standing interest in the use of anti-secretory therapy/anti-reflux surgery in IPF patients, given that GERD has been thought of as having a relationship with IPF [4, 7]. While it is not unreasonable to give anti-secretory therapy to patients with symptomatic GERD patients, it has certainly been hard to objectively justify the use in all patients with IPF, some of whom may not have any reflux or reflux with non-acidic gastric contents [36]. This has indeed been a recommendation from international guidelines, albeit it was a week level of recommendation [37]. As per literature, PPIs are the most frequently used medications, and further discussion will relate henceforth to PPI.
PPIs are known for increasing the pH of gastric acid; a mechanism thought to prevent microaspiration of acidic contents into the lung and hence potentially protect against acid-induced pneumonitis [37]. In vitro studies show that PPIs like Esomeprazole have pleiotropic effects, can inhibit expression of pro-inflammatory molecules like vascular cell adhesion molecule-1, inducible nitric oxide synthase, tumor necrosis factor-alpha (TNF-α), and interleukins (IL-1β and IL-6), and exhibit antioxidant and anti-fibrotic properties by downregulation of profibrotic proteins including receptors for transforming growth factor β (TGFβ), fibronectin and matrix metalloproteinases (MMPs) [38, 39]. They may also inhibit apoptosis of pneumocytes expressing Surfactant (SP-C) [38, 39]. Retrospective studies have also demonstrated that PPIs may prolong transplant-free survival of IPF patients [38, 39].
However, PPIs are not without risks. They have been shown to alter the microbiome of the respiratory tract and increase the risk of pneumonia [17]. Furthermore, they increase the risk of micronutrient deficiencies like Vitamin B12, cause dementia,
Anti-reflux surgery is an important therapeutic option in patients with GERD. Nissen fundoplication and Laparoscopic anti-reflux surgery (LARS) are the two most performed surgeries, both of which are generally safe in IPF [4, 14]. Lee JS et al. reported a retrospective cohort of 204 IPF patients consisting of individuals with symptoms of GERD (34%), a history of GERD (45%), reported use of GERD medications (47%), and Nissen fundoplication (5%). After the multivariate adjustment, the use of GERD medication was associated with a lower radiologic fibrotic score. It was also an independent predictor of longer survival time in patients with IPF [41]. Lee JS et al. also reported the combined results of 3 prospectively collected randomized controlled trial data, including 242 patients only from the placebo arm. Although the data came from RCTs, this was not an RCT. Of the total 242 patients, 124 patients were taking PPI/H2RA, and 118 patients were not taking any antisecretory therapy. In IPF, a slower decline in Forced vital capacity (FVC) has shown a correlation with improved survival time in IPF [42]. The study showed that there was a slower decline in FVC in the PPI/H2RA group, which was statistically significant. Also, there were fewer acute exacerbations in the PPI/H2RA group, and this result did not contribute to the slower decline in FVC. However, there was no change in mortality, presumably due to the follow-up period not being sufficient. This study result generated an interesting hypothesis that the use of PPI/H2RA could slow disease progression [43].
Furthermore, Fidler et al. conducted a systematic review and meta-analysis, studying the effect of pharmacological therapy of GERD in IPF patients, which showed a significant improvement in IPF related survival (adjusted risk: HR 0.45) but no effect on all-cause mortality. There was a change in progression-free survival, FVC, acute exacerbation, and other Pulmonary function test parameters. In patients with FVC less than 70% of predicted, there was an increase in pulmonary infection, which was significant as this is a known side effect of PPI affecting patients with more advanced disease [44]. It follows from this discussion that the studies once again have small numbers, mostly observational, and hence have limitations providing poor or limited quality of evidence [44].
In a randomized controlled trial, Raghu et al. analyzed data from 27 patients who underwent Laparoscopic anti-reflux surgery (LARS) and 20 patients who did not undergo surgery with FVC measurement at 48 weeks as the endpoint in an intention to treat analysis. All patients had abnormal acid GER with a confirmed DeMeester score of ≥14·7; measured by 24-h pH monitoring and preserved forced vital capacity (FVC) of more than 50%. Patients were allowed to use Nintedanib and Pirfenidone. Patients in the surgery group had a slower decline in FVC, which was not statistically significant at 48 weeks in the non-surgery group (p = 0·28)}. Acute exacerbation of IPF, hospitalization for respiratory etiology, and mortality were also less in the surgical group, however not to statistical significance [45].
GERD has been known to be co-existent with many Pulmonary disorders such as Systemic Sclerosis, Chronic obstructive pulmonary disease (COPD), Bronchial Asthma, IPF, Bronchiectasis, Aspiration Pneumonia, Lung transplant complications such as Bronchiolitis obliterans (BOS), etc. [6]. These plethora’s of lung conditions being associated with GERD are likely due to the shared common genetic embryological and developmental origin of the two organ systems from the foregut [6, 60]. In addition, they share the intrathoracic cavity and also have the same vagal innervation [6, 60]. As such, two predominant theories are in vogue, the “Refluxate theory” and the “Reflux theory,” which attempt to explain the disease mechanisms with their common origin and development as background. The “Refluxate theory,” as previously described, implicates acid reflux from the GI tract and its micro-aspiration into the Respiratory tree, causing physicochemical damage to the latter culminating in fibrosis [6]. The “Reflex theory” pertains to the reflex increase in bronchoconstriction and airway resistance in response to the presence of acid in the esophagus and respiratory tree [6]. Furthermore, as discussed previously, the presence of pulmonary fibrosis may aggravate the gastroesophageal reflux due to decreased compliance, elasticity, and need for increased negative intrathoracic pressure generated during inspiration, causing increased gradient across thoracic and abdominal compartments [6]. Hence there is possibly a bidirectional relationship between the two organ systems, as depicted in Figure 1. A Summary of the studies that evaluated the role of antireflux therapy and surgery in the management of IPF is available in Table 1.
The bidirectional relationship between IPF and GERD.
Authors | Year | Study type | Anti-reflux therapy type | Population size | Outcomes |
---|---|---|---|---|---|
Cantu et al. [46] | 2004 | Retrospective cohort study | Fundoplication | 457 |
|
Raghu et al. [18] | 2006 | Case series | PPIs | 4 |
|
Linden et al. [47] | 2006 | Retrospective cohort study | Fundoplication | 45 |
|
Lee et al. [41] | 2011 | Retrospective cohort study | PPIs–H2RAs | 204 |
|
Fisichella et al. [48] | 2011 | Prospective study | LARS | 39 |
|
Noth et al. [10] | 2012 | Retrospective cohort study | PPIs–H2RAs | 74 |
|
Raghu et al. [49] | 2016 | Retrospective cohort study | LARS | 27 |
|
Lee et al. [43] | 2013 | Post hoc analysis of RCTs | PPIs–H2RAs | 242 |
|
Ghebremariam et al. [38] | 2015 | A retrospective analysis from 2 databases | PPIs | 215 |
|
Raghu et al. [37] | 2015 | Post hoc analysis of RCTs | PPIs–H2RAs | 1061 |
|
Kreuter et al. [50] | 2016 | PPIs–H2RAs | 624 |
| |
Lee et al. [51] | 2016 | Retrospective cohort study | PPIs | 786 |
|
Kreuter et al. [52] | 2016 | Retrospective cohort study | PPIs | 272 |
|
Elkstrom et al. [53] | 2016 | Prospective population-based study | PPIs–H2RAs | 462 |
|
Kulkarni et al. [54] | 2016 | Retrospective cohort study | PPIs–H2RAs | 284 |
|
Raghu et al. [55] | 2016 | Retrospective cohort study | LARS | 27 |
|
Kreuter et al. [56] | 2017 | Post hoc analysis of RCTs | PPIs–H2Ras | 632 |
|
Restivo et al. [57] | 2017 | Population-based study | PPIs–H2RAs | 6797 |
|
Raghu et al. [45] | 2018 | A prospective randomized controlled study | LARS | 58 |
|
Costabel et al. [58] | 2018 | PPIs–H2RAs | 406 |
| |
Helen et al. [59] | 2019 | A retrospective analysis from 1 database | PPIs–H2RAs | 587 |
|
Summary of the studies that evaluated the role of antireflux therapy and surgery in the management of IPF.
Abbreviations: BOS: bronchitis obliterans syndrome; PPIs: proton pump inhibitors; PFT: pulmonary function tests; H2RAs: H2 receptor antagonists; LARS: laparoscopic anti-reflux surgery; GERD: gastroesophageal reflux disease; IPF: idiopathic pulmonary fibrosis; DLCO: diffusion lung capacity for carbon monoxide; BALF: bronchoalveolar lavage fluid; RCTs: randomized controlled trials; FVC: forced vital capacity; ILD: interstitial lung disease; CI: confidence interval; HR: hazard ratio.
Studies designed to test the relationships between the two diseases entities have several limitations. They are mostly retrospective, have small sample sizes, with poorly defined inclusion and exclusion criteria, resulting in many confounders. While these limitations can be addressed partially by conducting prospective studies, randomized controlled data with a large sample size will remain elusive due to the prolonged time required for a disease process like IPF takes to evolve and manifest [25]. Besides, diseases like IPF are not clearly recognizable early, and GERD with non-acid reflux or poorly acidic reflux may not manifest with classic symptoms [6, 25], hence denying the opportunity for early recognition and follow up. Hence, our reliance on smaller case-controlled studies with a few well-conducted meta-analyses has only revealed an association between GERD and IPF, far from the nine causality criteria propounded by “Hill” [61, 62]. Although not ruling out causality, a weak association between the two diseases still needs to be viewed with an abundance of caution as the effects of residual confounding generate sufficient bias to prevent a robust causal inference from these types of studies [62]. Although such challenges will limit future studies, investigating therapeutic interventions like LARS and PPIs along with disease-modifying therapies like Nintedanib and Pirfenidone may improve outcomes for our IPF patients [25].
The large database-based clinical studies with robust timestamping of initiation of each disease entity will be helpful in establishing a temporal relationship. A machine learning model development is the need of the hour to answer this clinical question.
The co-existence of IPF and GERD is very common. There is likely a bidirectional pathophysiological relationship between the two disease entities. Although there is no causality established, current guidelines do recommend therapy with PPI in all patients with IPF. There remain many important challenges to the study of these coexisting conditions, and it may not be possible to obtain robust data establishing causality. Nevertheless, an attempt can be made to further conduct well-designed interventional studies to benefit patients in need.
Kristina Kardum Cvitan, Author Service Manager, IntechOpen.
The authors declare no conflict of interest.
As this section deals with legal issues pertaining to the rights of individual Authors and IntechOpen, for the avoidance of doubt, each category of publication is dealt with separately. Consequently, much of the information, for example definition of terms used, is repeated to ensure that there can be no misunderstanding of the policies that apply to each category.
",metaTitle:"Copyright Policy",metaDescription:"Copyright is the term used to describe the rights related to the publication and distribution of original works. Most importantly from a publisher's perspective, copyright governs how authors, publishers and the general public can use, publish and distribute publications.",metaKeywords:null,canonicalURL:"/page/copyright-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
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\\n\\nHOW COPYRIGHT WORKS WITH OPEN ACCESS LICENSES?
\\n\\nAgreement samples are listed here for the convenience of prospective Authors:
\\n\\nDEFINITIONS
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\\n\\nIntechOpen - Registered publisher with office at 5 Princes Gate Court, London, SW7 2QJ - UNITED KINGDOM
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\\n\\nVideo Lecture – an audiovisual recording of a lecture or a speech given by a Lecturer, recorded, edited, owned and published by IntechOpen.
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\\n\\nAll Works published on the IntechOpen platform and in print are licensed under a Creative Commons Attribution 3.0 Unported and Creative Commons 4.0 International License, a license which allows for the broadest possible reuse of published material.
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The CC BY 3.0 and CC BY 4.0 license permits Works to be freely shared in any medium or format, as well as the reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as the source Work is cited and its Authors are acknowledged in the following manner:
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\\n\\nPolicy last updated: 2016-06-08
\\n"}]'},components:[{type:"htmlEditorComponent",content:'Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
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\n\nHOW COPYRIGHT WORKS WITH OPEN ACCESS LICENSES?
\n\nAgreement samples are listed here for the convenience of prospective Authors:
\n\nDEFINITIONS
\n\nThe following definitions apply in this Copyright Policy:
\n\nAuthor - in order to be identified as an Author, three criteria must be met: (i) Substantial contribution to the conception or design of the Work, or the acquisition, analysis, or interpretation of data for the Work; (ii) Participation in drafting or revising the Work; (iii) Approval of the final version of the Work to be published.
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\n\nCompilation - a collection of Works distributed in a Book that IntechOpen has selected, and for which the coordination of the preparation, arrangement and publication has been the responsibility of IntechOpen. Any Work included is accepted in its entirety in unmodified form and is published with one or more other contributions, each constituting a separate and independent Work, but which together are assembled into a collective whole.
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\n\nIntechOpen - Registered publisher with office at 5 Princes Gate Court, London, SW7 2QJ - UNITED KINGDOM
\n\nIntechOpen platform - IntechOpen website www.intechopen.com whose main purpose is to host Monographs in the format of Book Chapters, Long Form Monographs, Compacts, Conference Proceedings, Scientific Journals and Videos.
\n\nVideo Lecture – an audiovisual recording of a lecture or a speech given by a Lecturer, recorded, edited, owned and published by IntechOpen.
\n\nTERMS
\n\nAll Works published on the IntechOpen platform and in print are licensed under a Creative Commons Attribution 3.0 Unported and Creative Commons 4.0 International License, a license which allows for the broadest possible reuse of published material.
\n\nCopyright on the individual Works belongs to the specific Author, subject to an agreement with IntechOpen. The Creative Common license is granted to all others to:
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\n\nAll Works are published under the CC BY 3.0 and CC BY 4.0 license. However, please note that book Chapters may fall under a different CC license, depending on their publication date as indicated in the table below:
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LICENSE | \n\t\t\tUSED FROM - | \n\t\t\tUP TO - | \n\t\t
\n\t\t\t Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported (CC BY-NC-SA 3.0) \n\t\t\t | \n\t\t\t1 July 2005 (2005-07-01) | \n\t\t\t3 October 2011 (2011-10-03) | \n\t\t
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The CC BY 3.0 and CC BY 4.0 license permits Works to be freely shared in any medium or format, as well as the reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as the source Work is cited and its Authors are acknowledged in the following manner:
\n\nContent reuse:
\n\n© {year} {authors' full names}. Originally published in {short citation} under {license version} license. Available from: {DOI}
\n\nContent adaptation & reuse:
\n\n© {year} {authors' full names}. Adapted from {short citation}; originally published under {license version} license. Available from: {DOI}
\n\nReposting & sharing:
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\n\nRepublishing – More about Attribution Policy can be found here.
\n\nThe same principles apply to Works published under the CC BY-NC-SA 3.0 license, with the caveats that (1) the content may not be used for commercial purposes, and (2) derivative works building on this content must be distributed under the same license. The restrictions contained in these license terms may, however, be waived by the copyright holder(s). Users wishing to circumvent any of the license terms are required to obtain explicit permission to do so from the copyright holder(s).
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\n\nAll rights to Books and Journals and all other compilations published on the IntechOpen platform and in print are reserved by IntechOpen.
\n\nThe copyright to Books, Journals and other compilations is subject to separate copyright from those that exist in the included Works.
\n\nAll Long Form Monographs/Compacts are licensed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license granted to all others.
\n\nCopyright to the individual Works (Chapters) belongs to their specific Authors, subject to an agreement with IntechOpen and the Creative Common license granted to all others to:
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\n\nNonCommercial - The use of the material for commercial purposes is prohibited. Commercial rights are reserved to IntechOpen or its licensees.
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\n\nContent reuse:
\n\n© {year} {authors' full names}. Originally published in {short citation} under {license version} license. Available from: {DOI}
\n\nContent adaptation & reuse:
\n\n© {year} {authors' full names}. Adapted from {short citation}; originally published under {license version} license. Available from: {DOI}
\n\nReposting & sharing:
\n\nOriginally published in {full citation}. Available from: {DOI}
\n\nAll Book cover design elements, as well as Video image graphics are subject to copyright by IntechOpen.
\n\nEvery reproduction of a front cover image must be accompanied by an appropriate Copyright Notice displayed adjacent to the image. The exact Copyright Notice depends on who the Author of a particular cover image is. Users wishing to reproduce cover images should contact permissions@intechopen.com.
\n\nAll Video Lectures under IntechOpen's production are subject to copyright and are property of IntechOpen, unless defined otherwise, and are licensed under the Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. This grants all others the right to:
\n\nShare — copy and redistribute the material in any medium or format
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\n\nAll software used on the IntechOpen platform, any used during the publishing process, and the copyright in the code constituting such software, is the property of IntechOpen or its software suppliers. As such, it may not be downloaded or copied without permission.
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\n\nPolicy last updated: 2016-06-08
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"396",title:"Dr.",name:"Vedran",middleName:null,surname:"Kordic",slug:"vedran-kordic",fullName:"Vedran Kordic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/396/images/7281_n.png",biography:"After obtaining his Master's degree in Mechanical Engineering he continued his education at the Vienna University of Technology where he obtained his PhD degree in 2004. He worked as a researcher at the Automation and Control Institute, Faculty of Electrical Engineering, Vienna University of Technology until 2008. 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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. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. He has contributed in stochastic estimation of control area especially, in the Multiple Target Tracking and Interactive Multiple Model (IMM) research, Ball & Beam Control Problem, Robotics, Levitation Control. He has contributed in developing Algorithms for Fingerprint Matching, Computer Vision and Face Recognition. He has been supervising Pattern Recognition, Formal Languages and Distributed Processing projects for several years. He has reviewed many books on Management, Computer Science. Currently, he is an active and permanent reviewer for many international conferences and symposia and the program committee member for many international conferences.\nIn teaching he has taught the core computer science subjects like, Digital Design, Real Time Embedded System Programming, Operating Systems, Software Engineering, Data Structures, Databases, Compiler Construction. 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Stress is any adverse environmental condition that hampers proper growth of plant. Abiotic stress creates adverse effect on multiple procedures of morphology, biochemistry and physiology that are directly connected with growth and yield of plant. Abiotic stress are quantitative trait hence genes linked to these traits can be identified and used to select desirable alleles responsible for tolerance in plant. Plants can initiate a number of molecular, cellular and physiological modifications to react to and adapt to abiotic stress. Crop productivity is significantly affected by drought, salinity and cold. Abiotic stress reduce water availability to plant roots by increasing water soluble salts in soil and plants suffer from increased osmotic pressure outside the root. Physiological changes include lowering of leaf osmotic potential, water potential and relative water content, creation of nutritional imbalance, enhancing relative stress injury or one or more combination of these factors. Morphological and biochemical changes include changes in root and shoot length, number of leaves, secondary metabolite (glycine betaine, proline, MDA, abscisic acid) accumulation in plant, source and sink ratio. Proposed chapter will concentrate on enhancing plant response to abiotic stress and contemporary breeding application to increasing stress tolerance.",book:{id:"9345",slug:"sustainable-crop-production",title:"Sustainable Crop Production",fullTitle:"Sustainable Crop Production"},signatures:"Summy Yadav, Payal Modi, Akanksha Dave, Akdasbanu Vijapura, Disha Patel and Mohini Patel",authors:[{id:"186963",title:"Dr.",name:"Summy",middleName:null,surname:"Yadav",slug:"summy-yadav",fullName:"Summy Yadav"},{id:"308004",title:"Ms.",name:"Payal",middleName:null,surname:"Modi",slug:"payal-modi",fullName:"Payal Modi"},{id:"308005",title:"Ms.",name:"Akanksha",middleName:null,surname:"Dave",slug:"akanksha-dave",fullName:"Akanksha Dave"},{id:"308006",title:"Ms.",name:"Akdasbanu",middleName:null,surname:"Vijapara",slug:"akdasbanu-vijapara",fullName:"Akdasbanu Vijapara"},{id:"308007",title:"Ms.",name:"Disha",middleName:null,surname:"Patel",slug:"disha-patel",fullName:"Disha Patel"},{id:"308008",title:"Ms.",name:"Mohini",middleName:null,surname:"Patel",slug:"mohini-patel",fullName:"Mohini Patel"}]},{id:"45540",doi:"10.5772/56621",title:"Genes and QTLs for Rice Grain Quality Improvement",slug:"genes-and-qtls-for-rice-grain-quality-improvement",totalDownloads:3768,totalCrossrefCites:21,totalDimensionsCites:49,abstract:null,book:{id:"3554",slug:"rice-germplasm-genetics-and-improvement",title:"Rice",fullTitle:"Rice - Germplasm, Genetics and Improvement"},signatures:"Jinsong Bao",authors:[{id:"52135",title:"Dr.",name:"Jinsong",middleName:null,surname:"Bao",slug:"jinsong-bao",fullName:"Jinsong Bao"}]}],mostDownloadedChaptersLast30Days:[{id:"70658",title:"Factors Affecting Yield of Crops",slug:"factors-affecting-yield-of-crops",totalDownloads:4150,totalCrossrefCites:31,totalDimensionsCites:45,abstract:"A good understanding of dynamics involved in food production is critical for the improvement of food security. It has been demonstrated that an increase in crop yields significantly reduces poverty. Yield, the mass of harvest crop product in a specific area, is influenced by several factors. These factors are grouped in three basic categories known as technological (agricultural practices, managerial decision, etc.), biological (diseases, insects, pests, weeds) and environmental (climatic condition, soil fertility, topography, water quality, etc.). These factors account for yield differences from one region to another worldwide. The current chapter will discuss each of these three basic factors as well as providing some recommendations for overcoming them. In addition, it will provide the importance of climate-smart agriculture in the increase of crop yields while facilitating the achievement of crop production in safe environment. This goes in line with the second goal of 2030 Agenda for Sustainable Development of United Nations in transforming our world formulated as end hunger, achieve food security, improve nutrition and promote sustainable agriculture.",book:{id:"8153",slug:"agronomy-climate-change-food-security",title:"Agronomy",fullTitle:"Agronomy - Climate Change & Food Security"},signatures:"Tandzi Ngoune Liliane and Mutengwa Shelton Charles",authors:[{id:"313819",title:"Dr.",name:"Liliane",middleName:null,surname:"Tandzi",slug:"liliane-tandzi",fullName:"Liliane Tandzi"},{id:"314316",title:"Prof.",name:"Charles Shelton",middleName:null,surname:"Mutengwa",slug:"charles-shelton-mutengwa",fullName:"Charles Shelton Mutengwa"}]},{id:"40178",title:"Molecular Markers and Marker-Assisted Breeding in Plants",slug:"molecular-markers-and-marker-assisted-breeding-in-plants",totalDownloads:23130,totalCrossrefCites:85,totalDimensionsCites:153,abstract:null,book:{id:"3060",slug:"plant-breeding-from-laboratories-to-fields",title:"Plant Breeding from Laboratories to Fields",fullTitle:"Plant Breeding from Laboratories to Fields"},signatures:"Guo-Liang Jiang",authors:[{id:"158810",title:"Dr.",name:"Guo-Liang",middleName:null,surname:"Jiang",slug:"guo-liang-jiang",fullName:"Guo-Liang Jiang"}]},{id:"60074",title:"Pollen Germination in vitro",slug:"pollen-germination-in-vitro",totalDownloads:2812,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Pollen germination in vitro is a reliable method to test the pollen viability. It also addresses many basic questions in sexual reproduction and particularly useful in wide hybridization. Many pollen germination medium ranging from simple sugars to complex one having vitamins, growth regulators, etc. in addition to various minerals have been standardized to germinate pollen artificially. The different media, successful pollen germination methods, procedures from pollen germination studies with wheat, rye, brinjal, pigeonpea and its wild relatives are discussed.",book:{id:"6659",slug:"pollination-in-plants",title:"Pollination in Plants",fullTitle:"Pollination in Plants"},signatures:"Jayaprakash P",authors:[{id:"235465",title:"Dr.",name:"Jayaprakash",middleName:null,surname:"P",slug:"jayaprakash-p",fullName:"Jayaprakash P"}]},{id:"62376",title:"Genotype × Environment Interaction: A Prerequisite for Tomato Variety Development",slug:"genotype-environment-interaction-a-prerequisite-for-tomato-variety-development",totalDownloads:2339,totalCrossrefCites:2,totalDimensionsCites:7,abstract:"Tomato (Solanum lycopersicum L.) is the second most important vegetable crop in the world due to its high level of nutrition particularly in vitamins and antioxidants. It is grown in several ecologies of the world due to its adaptability and ease of cultivation. Besides field conditions, tomatoes are grown in controlled environments which range from hydroponics and simple high tunnel structures to highly automated screen houses in advanced countries. However, the yield and quality of the fruits are highly influenced by the environment. This results in unpredictable performances in different growing environments in terms of quality, a phenomenon known as genotype by environment (G × E) interaction which confounds selection efficiency. Various approaches are employed by plant breeders to evaluate and address the challenges posed by genotype by environment interaction. This chapter discusses various field and controlled environments for growing tomatoes and the effect of these environments on the performance of the crop. The various types of genotype × environment interactions and their effect of the tomato plant are discussed. Finally, efforts are made to suggest ways and methods of mitigating the confounding effects of genotype × environment interaction including statistical approaches.",book:{id:"6422",slug:"recent-advances-in-tomato-breeding-and-production",title:"Recent Advances in Tomato Breeding and Production",fullTitle:"Recent Advances in Tomato Breeding and Production"},signatures:"Michael Kwabena Osei, Benjamin Annor, Joseph Adjebeng-\nDanquah, Agyemang Danquah, Eric Danquah, Essie Blay and Hans\nAdu-Dapaah",authors:[{id:"204223",title:"Dr.",name:"Agyemang",middleName:null,surname:"Danquah",slug:"agyemang-danquah",fullName:"Agyemang Danquah"},{id:"217531",title:"M.Sc.",name:"Michael Kwabena",middleName:null,surname:"Osei",slug:"michael-kwabena-osei",fullName:"Michael Kwabena Osei"},{id:"217760",title:"Dr.",name:"Joseph",middleName:null,surname:"Adjebeng-Danquah",slug:"joseph-adjebeng-danquah",fullName:"Joseph Adjebeng-Danquah"},{id:"217768",title:"MSc.",name:"Benjamin",middleName:null,surname:"Annor",slug:"benjamin-annor",fullName:"Benjamin Annor"},{id:"247378",title:"Dr.",name:"Eric Y.",middleName:null,surname:"Danquah",slug:"eric-y.-danquah",fullName:"Eric Y. Danquah"},{id:"248095",title:"Prof.",name:"Essie",middleName:null,surname:"Blay",slug:"essie-blay",fullName:"Essie Blay"},{id:"248096",title:"Prof.",name:"Hans",middleName:null,surname:"Adu-Dapaah",slug:"hans-adu-dapaah",fullName:"Hans Adu-Dapaah"}]},{id:"45153",title:"Irrigation of Sandy Soils, Basics and Scheduling",slug:"irrigation-of-sandy-soils-basics-and-scheduling",totalDownloads:5638,totalCrossrefCites:5,totalDimensionsCites:11,abstract:null,book:{id:"3357",slug:"crop-production",title:"Crop Production",fullTitle:"Crop Production"},signatures:"Mohamed S. Alhammadi and Ali M. Al-Shrouf",authors:[{id:"78245",title:"Dr.",name:"Mohamed",middleName:"Salman",surname:"Alhammadi",slug:"mohamed-alhammadi",fullName:"Mohamed Alhammadi"},{id:"159904",title:"Mr.",name:"Ali",middleName:null,surname:"Al-Shrouf",slug:"ali-al-shrouf",fullName:"Ali Al-Shrouf"}]}],onlineFirstChaptersFilter:{topicId:"29",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:140,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,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:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",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. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"August 2nd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:33,editor:{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"}}},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:42,paginationItems:[{id:"82914",title:"Glance on the Critical Role of IL-23 Receptor Gene Variations in Inflammation-Induced Carcinogenesis",doi:"10.5772/intechopen.105049",signatures:"Mohammed El-Gedamy",slug:"glance-on-the-critical-role-of-il-23-receptor-gene-variations-in-inflammation-induced-carcinogenesis",totalDownloads:12,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}},{id:"82875",title:"Lipidomics as a Tool in the Diagnosis and Clinical Therapy",doi:"10.5772/intechopen.105857",signatures:"María Elizbeth Alvarez Sánchez, Erick Nolasco Ontiveros, Rodrigo Arreola, Adriana Montserrat Espinosa González, Ana María García Bores, Roberto Eduardo López Urrutia, Ignacio Peñalosa Castro, María del Socorro Sánchez Correa and Edgar Antonio Estrella Parra",slug:"lipidomics-as-a-tool-in-the-diagnosis-and-clinical-therapy",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fatty Acids - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11669.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82440",title:"Lipid Metabolism and Associated Molecular Signaling Events in Autoimmune Disease",doi:"10.5772/intechopen.105746",signatures:"Mohan Vanditha, Sonu Das and Mathew John",slug:"lipid-metabolism-and-associated-molecular-signaling-events-in-autoimmune-disease",totalDownloads:17,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fatty Acids - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11669.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82483",title:"Oxidative Stress in Cardiovascular Diseases",doi:"10.5772/intechopen.105891",signatures:"Laura Mourino-Alvarez, Tamara Sastre-Oliva, Nerea Corbacho-Alonso and Maria G. Barderas",slug:"oxidative-stress-in-cardiovascular-diseases",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Importance of Oxidative Stress and Antioxidant System in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/11671.jpg",subseries:{id:"15",title:"Chemical Biology"}}}]},overviewPagePublishedBooks:{paginationCount:33,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:{name:"Kobe College",institutionURL:null,country:{name:"Japan"}}}]},{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. 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The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. This series is intended for doctors, engineers, and scientists involved in biomedical engineering or those wanting to start working in this field.",coverUrl:"https://cdn.intechopen.com/series/covers/7.jpg",latestPublicationDate:"August 3rd, 2022",hasOnlineFirst:!0,numberOfOpenTopics:3,numberOfPublishedChapters:107,numberOfPublishedBooks:12,editor:{id:"50150",title:"Prof.",name:"Robert",middleName:null,surname:"Koprowski",fullName:"Robert Koprowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTYNQA4/Profile_Picture_1630478535317",biography:"Robert Koprowski, MD (1997), PhD (2003), Habilitation (2015), is an employee of the University of Silesia, Poland, Institute of Computer Science, Department of Biomedical Computer Systems. For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},subseries:[{id:"7",title:"Bioinformatics and Medical Informatics",keywords:"Biomedical Data, Drug Discovery, Clinical Diagnostics, Decoding Human Genome, AI in Personalized Medicine, Disease-prevention Strategies, Big Data Analysis in Medicine",scope:"Bioinformatics aims to help understand the functioning of the mechanisms of living organisms through the construction and use of quantitative tools. The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",annualVolume:11403,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"Tzallas",fullName:"Alexandros Tzallas",profilePictureURL:"https://mts.intechopen.com/storage/users/5886/images/system/5886.png",institutionString:"University of Ioannina, Greece & Imperial College London",institution:{name:"University of Ioannina",institutionURL:null,country:{name:"Greece"}}},{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",fullName:"Lulu Wang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRX6kQAG/Profile_Picture_1630329584194",institutionString:"Shenzhen Technology University",institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}},{id:"225387",title:"Prof.",name:"Reda R.",middleName:"R.",surname:"Gharieb",fullName:"Reda R. Gharieb",profilePictureURL:"https://mts.intechopen.com/storage/users/225387/images/system/225387.jpg",institutionString:"Assiut University",institution:{name:"Assiut University",institutionURL:null,country:{name:"Egypt"}}}]},{id:"8",title:"Bioinspired Technology and Biomechanics",keywords:"Bioinspired Systems, Biomechanics, Assistive Technology, Rehabilitation",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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