\r\n\tAn update on clinical manifestations, their assessment, monitoring, and imagiology, including peripheral arthritis, enthesopathy, and extra-articular findings, and, the differential diagnosis with other diseases which evolves with axial and peripheral calcifications will be provided.
\r\n\r\n\t
\r\n\tAn important component of this book must be dedicated to the more recent treatments namely with biologic therapies but focusing also on new small molecule inhibitors and experimental therapies.
The significance of hyperglycemia-induced endothelial damage is underlined by its pathogenic role in diabetes complications and the associated costs of diabetes management. The global prevalence of diabetes among adults over 18 years of age has risen from 4.7% in 1980 to 8.5% in 2014 with a steep increase over the age of 50, reaching the peak prevalence of 25% above 80 years of age [1, 2]. The (direct and indirect) medical costs for patients with diabetes are double the amount compared to expenses for nondiabetic individuals and three times higher in case of cardiovascular diseases such as myocardial infarction or stroke [3]. Currently, diabetes-related healthcare expenditure accounts for 10% of the total healthcare costs and it is estimated to increase by 70% over the next 25 years leading to a serious societal and economic burden [4]. Diabetes complications are responsible for the majority of the associated costs and excess costs gradually increase with the duration of the disease leading to substantially higher expenses after 8–10 years [3, 5]. Hyperglycemia-induced endothelial dysfunction is the major contributor to the development of vascular disease in diabetes mellitus [6]. While insulin resistance may be present in patients with no increase in plasma glucose level and it may contribute to endothelial dysfunction, the major pathway that is responsible for endothelial damage is glucose-induced oxidative stress in diabetes [6, 7].
\nEndothelial dysfunction is a pathological state of the endothelium and can be defined as an aberration of the normal endothelial function of vascular relaxation, blood clotting and immune function. In general, it means impaired endothelium-dependent vasodilation as a result of imbalance between vasodilating and vasoconstricting substances produced by (or acting on) the endothelium. Endothelial dysfunction can be a significant predictor of coronary artery disease and atherosclerosis and it increases the risk of stroke and heart attack [8]. In basic science and in clinical research, endothelial function is commonly assessed by the use of the acetylcholine-mediated vasodilatation test or by flow-mediated vasodilation, and this methodology is considered the ‘gold standard’ at this moment [8, 9]. Endothelial dysfunction is primarily responsible for the impaired vasorelaxation in diabetes but it is closely followed by the development of vascular smooth muscle cell dysfunction [10, 11]. Impaired relaxation may be caused by diminished production or increased destruction of vasodilating factors or impaired response to them in diabetes. Oxidative stress is considered as one of the major underlying mechanisms, which leads to endothelial dysfunction in hyperglycemia, since the therapeutic supplementation of antioxidants or antioxidant enzymes can restore the endothelium-dependent vasodilation in experimental models of diabetes [10].
\nGlucose-induced damage is apparently controversial: glucose is a major source of energy and a small increase in blood glucose, which has no obvious ill effect on the short term, can cause serious long-term complications in diabetes. Glucose uptake is noninsulin dependent in endothelial cells and it occurs via GLUT1 (glucose transporter 1), thus high blood glucose level results in similarly high intracellular glucose concentration in endothelial cells [12, 13]. Endothelial cells have few mitochondria and primarily use glycolysis to produce ATP molecules, which suggests low oxygen consumption and relatively low level of oxidant production [14]. Furthermore, higher glucose concentration would allow even higher rate of anaerobic metabolism to produce the necessary amount of ATP and limit aerobic metabolism, oxygen consumption and reactive oxygen species (ROS) production in the cells. Still, hyperglycemia is associated with the activation of various ROS-producing pathways and increased oxidant production in endothelial cells [15, 16]. Oxidants play a significant role in the destruction of nitric oxide and other signaling molecules and result in impaired vasoreactivity [10, 17, 18]. Inflammatory pathways may be implicated in the early stages of the injury and they are typically involved in the later stages of the disease and contribute to oxidant production and inflammatory cytokine secretion, which can also change the vascular function [19]. Oxidative stress also induces DNA damage that triggers endothelial cell senescence that might have an impact on vascular function in the later stages of the injury [20]. There are approximately 2–10 trillion (2–10 × 1012) endothelial cells in the human body and they form the endothelial surface of 500 m2 of blood vessels and require constant renewal [21, 22, 23]. Mostly, the resident stem cells (located in the vessel wall) take part in the repair processes but also circulating progenitor cells that arise from the bone marrow are involved in the process [22]. In diabetes, endothelial cell turnover is impaired and it might be a consequence of accelerated aging or reduced renewal of cells [24, 25]. While ROS-mediated injury dominates in the earlier stages of hyperglycemia-induced damage, cell senescence and impairment of endothelial cell turnover may play the leading part in the later stages.
\nHyperglycemia induces damage in a select cell population in the body, including mainly the mesangial cells in the kidney, neurons and Schwann cells in peripheral nerves and a subset of endothelial cells: only the microvascular and the arterial endothelial cells show impairment [26]. Interestingly, this dichotomy in the vulnerability is often preserved in
Differences in glucose uptake may be partially responsible for the susceptibility: most cells tightly regulate the glucose transport rate and prevent the unrestricted uptake, but endothelial and mesangial cells are unable to decrease the transport rate [29, 30]. Glucose overload induces a gradual increase in the mitochondrial membrane potential and the elevated protonic potential increases the superoxide generation by the respiratory chain [31]. The mitochondrial membrane potential is regulated by uncoupling proteins in the cells: these channels release excess protons from the intermembrane space to the matrix and protect against mitochondrial hyperpolarization. Endothelial cells express uncoupling protein 2 (UCP2) and its transport capacity is controlled by oxidative stress: high levels of oxidants open the channel, whereas the absence of oxidants closes the channel [32, 33]. In venous endothelial cells, hyperglycemia upregulates the expression of UCP2 and it effectively protects against mitochondrial hyperpolarization and ROS production [34, 35]. This process does not work in microvascular endothelial cells: there is no change in UCP2 expression in response to elevated glucose concentration resulting in mitochondrial hyperpolarization with a simultaneous rise in mitochondrial superoxide generation [35]. In many cases, endothelial cells were found to produce excess levels of mitochondrial oxidants in response to hyperglycemia only in the presence of pro-inflammatory cytokines, suggesting further mechanisms to be involved in the hyperglycemia-induced cell-damaging processes but the potential implication of inflammatory pathways has not been clarified [36].
\nAt cellular level, hyperglycemic damage occurs within a few days and induces compensatory and repair mechanisms that may have consequences in the cell population. Vascular endothelium covers a huge surface in the body and possesses a huge capacity to compensate for any damage that occurs over longer periods, thus changes in vascular function may occur with a delay.
\nIn experimental models, glucose levels are often above 20–30 mmol/L and vascular dysfunction develops over weeks or within a few months [37]. The development of hyperglycemia-induced endothelial cell damage is neither instantaneous
On the other hand, diabetic vascular complications occur after years of hyperglycemic exposure and poor glycemic control accelerates the development of the disease [40, 41]. Although complications usually first appear some years after clinical diagnosis, retinopathy and nephropathy were often present (in 10–37% of patients) at the time of clinical diagnosis or within the first year after diagnosis [42]. Glucose levels that induce endothelial damage are moderately elevated in most patients due to improved diabetes care and diabetes self-management education and support (DSME/S) [43, 44].
\nEndothelial cell senescence and reduced proliferation are the dominant features in diabetes, still pathological proliferation of blood vessels occurs in diabetic retinopathy [45]. This controversy is explained by the fact that progressive retinal angiogenesis is preceded by a series of events that is characterized by reduced cell proliferation and stimulates neovascularization in the retina [45]. Proliferative diabetic retinopathy is not the primary pathogenic response to hyperglycemia but a compensatory response to retinal hypoxia. Diabetic retinopathy starts with the loss of two cell types of the retinal capillaries: the endothelial cells and the vessel supporting pericytes and the earliest pathologic signs are acellular, nonperfused capillary segments in the retina [45]. Pericyte loss may precede the endothelial damage in the retina and it is caused by angiotensin II overexpression induced by oxidative stress in diabetes. However, the increased number of migrating pericytes and loss of pericytes from the straight parts of capillaries may also occur as a result of hypoxia, and thus might be a consequence of prior endothelial damage. On the other hand, the loss of pericytes results in reduced proliferation of stalk endothelial cells leading to fewer phalanx cells and promotes hypoxia in the retina. Hypoxia is the main stimulus of uncontrolled proliferation in diabetic vessels and both angiotensin II and vascular endothelial growth factor (VEGF) are involved in the neovascularization. In the pathological angiogenesis, not only the retinal endothelial cells take part but also the bone marrow-derived progenitor cells that may explain how enhanced proliferation capacity replaces the cell loss at the later stage.
\nGlucose-induced endothelial damage is not only caused by constantly high glucose concentration but also by transiently elevated glucose levels. In experimental models, damage induced by intermittent high glucose is comparable or more severe than the injury induced by constantly high glucose concentration. Glucose levels studied in most experimental models are often much higher than the values that cause irreversible damage in humans on the long term and result in accelerated progression of diabetic complications.
\nDiagnostic criteria for diabetes are based on the relationship between plasma glucose values and the risk of diabetes-specific microvascular complications: blood glucose concentration that causes diabetic vascular damage has been empirically determined and diagnostic criteria were established. The World Health Organization (WHO) introduced new diagnostic criteria in 1980, which were globally accepted, but had to lower the cut-off values for diabetes in 1999 since growing body of evidence supported the development of complications at lower blood glucose levels [46, 47]. The updated threshold values has raised considerable dispute and are often criticized for not preventing complications but further lowering has not been achieved because of the risk of hypoglycemia. The definition of hyperglycemia is challenging, since blood glucose values show a physiological increase after a meal and this calls for separate normal values for fasting, postprandial and random blood glucose levels. Still, it is evident that “high” glucose levels that induce damage in endothelial cells in the long term are very close to the normal blood glucose values, less than a twofold increase in the blood glucose level triggers injury in the cells. In the past, osmotic damage was presumed to play a pathogenic role in glucose-induced cellular injury but the minor changes in osmolality rule out this possibility. In healthy human subjects, the rise in blood glucose levels after a meal typically reaches or goes beyond these values, making the definition of hyperglycemia rather confusing [48]. From the pathogenic viewpoint of hyperglycemia, absolute cut-off values cannot be established to separate normoglycemic and hyperglycemic concentration ranges.
\nWhile earlier studies confirmed that the risk of cardiovascular complications corresponds to the average increase in glucose level (measured as glycated hemoglobin, HbA1c), more recent studies also found independent associations with the postprandial peaks [49]. These results highly suggest the action of secondary mediators that are rather induced by the fluctuations in blood glucose (glycemic variability) than by an absolute increase. Experimental models confirmed that glycemic swings caused at least as severe tissue damage as constant hyperglycemia, and persistence of high-glucose memory was postulated in cells and animals that were exposed to normoglycemic conditions following a hyperglycemic exposure [50, 51, 52]. Endothelial cells when returned to normal glucose concentration after exposure to high glucose showed increased ROS production and activation of poly(ADP-ribose) polymerase (PARP) even a week following the normalization of the glucose level and in this respect they showed similar characteristics to cells maintained at high glucose [52]. The persistence of oxidative stress in endothelial cells
Blockade of the early changes has been confirmed to prevent or slow down the progression of complications but the reversal at a later phase may not be achieved by glycemic control [53]. Benefits of intensive glucose control can be detected after 3 years of treatment if no retinopathy or mild disease is present at the start of the treatment strategy in type 1 diabetes [54]. The importance of blocking the glucose-induced damage early on in type 2 diabetes has been confirmed by the results of the United Kingdom Prospective Diabetes Study (UKPDS) [41]. On the other hand, there is little benefit of strict glucose control if established cardiovascular disease is already present at the start of the treatment regimen [53]. Similarly, in diabetic rats, a 6-month long period of good glycemic control following 2 months of poor glycemic control results in significantly reduced progression, whereas no benefit is observed on retinopathy if good glycemic control was started after 6 months of poor glycemic control: both nitrosative stress and tissue damage were similarly advanced as with 12 months of poor glycemic control [55, 56]. These suggest that the processes started by hyperglycemia may be partially reversed if normoglycemia follows a shorter period of high glucose exposure. It is still unclear whether the detrimental effects of transient hyperglycemia is buffered within the individual cells or it is the entire population of endothelial cells that compensate for the changes and the reason why progressive damage occurs following an extended hyperglycemic period is the loss of the renewal capacity of the cells.
\nThe mechanism of high glucose memory is still obscure and little is known about the pathways involved. Hyperglycemia modifies the metabolism of the cells and is suspected to induce various downstream pathways or molecules that are responsible for maintaining the tissue damaging actions. Oxidative stress pathways act as executors of tissue damage but the linkage between hyperglycemia and the sustained activation of oxidative pathways still remains rather elusive.
\nAlterations in the metabolome in diabetes are suspected to maintain the metabolic changes for extended periods even if there is little change in the expression profile of proteins [57]. Excess glucose load induces changes in a series of metabolite levels and the normalization of these levels may not occur as rapidly as glucose lowering. Apart from glucose, the concentrations of glucose-1-phosphate, lactate, glucosamine, mannose, mannosamine, hydroxybutyrate and glyoxalate also elevate in the plasma in diabetes [58]. All of the above intermediates and the increased fatty acids increase the tricarboxylic acid (TCA) cycle flux in the cells. Perturbation of the TCA cycle flux is also supported by other metabolomics studies in diabetes [59]. Associations between diabetes risk and the plasma levels of branched chain (BCAA, isoleucine, leucine and valine) and aromatic (phenylalanine, tyrosine) amino acids have been found suggesting that the changes not only involve the carbohydrate and lipid metabolism but also the catabolism of proteins and amino acids [60]. Catabolism of BCAAs provides intermediates for the TCA cycle and potentially drives the TCA flux. Apart from the systemic changes that affect the milieu of the cells, specific changes of amino acid levels have been observed in endothelial cells: hyperglycemia increases the concentration of alanine, proline, glycine, serine and glutamine within the cells and induces elevation of the aminoadipate, cystathionine and hypotaurine levels [61]. Whether these changes are only markers of hyperglycemia or they play a pathogenic role in oxidative stress induction is still undetermined.
\nChanges in glucose metabolism are presumed to be directly responsible for provoking oxidant production in endothelial cells. Endothelial cells predominantly use glucose as energy source and rely on glycolysis to generate ATP molecules [14]. Glycolytic flux exceeds the rate of oxidative phosphorylation (OXPHOS) by two orders of magnitude in endothelial cells
The metabolic balance between glycolysis and OXPHOS is controlled by nutrients (the ATP and NADH output) via Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) in the cells. SIRT1 is a NAD+-dependent histone deacetylase enzyme that regulates energy homeostasis via gene expression changes induced by deacetylating a variety of histone proteins, transcription factors and coregulators [67]. The activity of SIRT1 is primarily controlled by NAD+ abundance and NAD+/NADH ratio. AMPK is a master sensor of the energy level in the cells: it detects the cellular ATP concentration and is activated by a decrease in the ATP level. There is a complex interplay between AMPK and SIRT1: the two enzymes indirectly activate each other. Activated SIRT1 deacetylates LKB1 (tumor suppressor liver kinase B1) that phosphorylates and activates AMPK [68, 69], whereas AMPK activates SIRT1 by increasing the NAD+/NADH ratio either by inducing the NAD+ biosynthesis enzyme NamPRT (nicotinamide phosphoribosyltransferase) or by a NamPRT-independent mechanism [70]. Thus, caloric restriction activates both AMPK and SIRT1, whereas both enzymes are suppressed if energy sources are abundant like in hyperglycemia [71, 72]. In caloric restriction, SIRT1 deacetylates and activates peroxisome proliferation activating receptor-γ (PPAR-γ) coactivator 1-α (PGC-1) and forkhead box O1 protein 1 (FOXO1) and leads to glucose sparing: suppressed glycolysis and increased mitochondrial activity and they also activate gluconeogenesis [73, 74]. On the other hand, in hyperglycemia, the activity of AMPK and SIRT1 is suppressed and it results in enhanced glycolysis, inhibition of gluconeogenesis and decreased mitochondrial biogenesis and OXPHOS [73].
\nOverload of glycolysis and the pentose phosphate pathway are the initial steps that trigger alternate pathways of glucose metabolism (Figure 1). Prior perturbation of mitochondrial metabolism (TCA cycle overload and impaired OXPHOS) is highly possible since inhibition of mitochondrial superoxide generation prevents the activation of the above pathways but the exact mechanism that initiates these events is unknown [26]. The high glycolytic input and low OXPHOS capacity may gradually block the main metabolic steps and shunt the metabolism to alternative pathways. These include the methylglyoxal, hexosamine and polyol pathways: dihydroxyacetone phosphate (DHAP) is diverted to the methylglyoxal pathway and leads to protein kinase C (PKC) activation, and fructose-6-phosphate (F6P) increases the flux through the hexosamine pathway and excess glucose enters the polyol pathway when converted to sorbitol [66, 75]. Suppressed expression of the gluconeogenetic enzyme glucose-6-phosphate dehydrogenase (G6PDH) prevents shunting of glucose to the pentose phosphate pathway that further increases the glycolytic load [76, 77]. All these processes lead to ROS production and the generation of advanced glycation end products (AGEs), the products of nonenzymatic glycation and oxidation of proteins and lipids that accumulate in diabetes. AGEs signal through the receptor of AGE (RAGE), a cell surface receptor that is also activated by the damage-associated molecular patterns (DAMP) HMGB1 (high-mobility group box 1) and S100 proteins [78]. RAGE activates nuclear factor kappa B (NF-κB) and controls several inflammatory genes, thus links hyperglycemia to inflammation. Since RAGE itself is upregulated by NF-κB, inflammation is maintained by positive feedback in hyperglycemia as AGEs, the ligands are continuously produced.
\nHyperglycemia-induced ROS-producing pathways in the cytoplasm. AGEs: advanced glycation end-products; G6PDH: glucose-6-phosphate dehydrogenase; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GSH/GSSG: reduced/oxidized glutathione; NAD+/NADH: nicotinamide adenine dinucleotide; NADP+/NADPH: nicotinamide adenine dinucleotide phosphate and ROS: reactive oxygen species.
Interestingly, hyperglycemia induces a long-lasting suppression in SIRT1 and AMPK activity in endothelial cells: the activity of both enzymes remains low weeks after the normalization of glucose level following a week long hyperglycemia [68]. Thus, SIRT1 and AMPK have been implicated in glucose memory since restoration of their activity reduces the ROS production and PARP activity in the cells.
\nOne further molecule that possibly takes part in the maintenance of oxidative stress in hyperglycemic endothelial cells is p66SHC (66-kDa Src homology 2 domain-containing protein) [79]. p66SHC is induced by hyperglycemia and it contributes to oxidative stress and endothelial damage. Genetic ablation of p66SHC reduces the oxidative stress in diabetic animals, protects against vascular dysfunction and blocks the progression of nephropathy [79, 80]. p66SHC is a redox enzyme that associates with 70 kDa heat shock protein (Hsp70) and localizes within the intermembrane space in the mitochondria. Upon oxidative stress, p66SHC is released from the complex and transfers electrons from the electron transfer chain (from cytochrome c specifically) to oxygen and produces hydrogen peroxide (H2O2) [81]. Under basal conditions, p66SHC is also present as an inactive enzyme in the cytoplasm where it becomes activated via phosphorylation in response to cellular stress and translocates to the mitochondria. The active p66SHC diverts a fraction of the mitochondrial electron flow between complexes III and IV to produce ROS instead of water and is involved in the opening of the permeability transition pore during apoptosis. In hyperglycemia, p66SHC may function as a shunt pathway if complex IV activity is impaired. The activity of p66SHC is also regulated by acetylation: it is a direct target of SIRT1 and diminished SIRT1 activity increases the acetylation and activity of p66SHC in hyperglycemia [82]. Furthermore, acetylation of p66SHC promotes the phosphorylation-mediated activation of the protein, and since the acetylation-resistant p66SHC isoform partially protects against the vascular impairment, it may play a pathogenic role in diabetic vascular dysfunction. The linkage to SIRT1 and the protection associated with the loss of p66SHC suggest that p66SHC make a substantial contribution to oxidative stress in diabetes and it may represent the key target of SIRT1.
\nWith the growth of our knowledge about glucose-induced cellular damage and the various molecules and pathways involved in the process, the pathomechanism of glucose-induced damage has become inexplicable. In an effort to explain the puzzling complexity of the cellular events, Michael Brownlee introduced a unifying hypothesis in which he placed the events in an integrating linear model [26]. In the unifying mechanism, mitochondrial superoxide generation is placed in center stage followed by all other ROS-producing pathways as secondary events. As the contribution of mitochondrial energy production seems negligible in endothelial cells, this proposition was a striking novelty at first, but it renders the series of events logically based on a wealth of scientific results. First of all, the unifying framework assumes that the main ROS-producing mechanisms implicated in hyperglycemic cellular damage are interrelated and a common pathway is responsible for their activation [75]. Secondly, the overload of glycolysis rather occurs as a single downstream perturbation of metabolism that leaves behind glycolytic intermediates than by multiple blockades of glycolytic enzymes in response to excess glucose input. Thus, inhibition of a downstream step of glucose catabolism in the mitochondria might be responsible for the activation of the ROS-producing shunt pathways in the cytoplasm. The observation that prevention of mitochondrial superoxide generation inhibits the cytoplasmic ROS production pathways (PKC activation, sorbitol accumulation and AGE production) also supported the assumption that mitochondrial damage precedes the glycolytic impairment [83].
\nThe exact nature of hyperglycemic perturbation of mitochondrial metabolism remains enigmatic, and it is still debatable whether superoxide itself or the steps leading to its increased production is the triggering event of glucose-induced damage. High TCA flux and elevated glycolytic pyruvate input were detected in hyperglycemia and these may serve as inducers of mitochondrial ROS production but might also be the consequences of dysfunctional OXPHOS [83]. Various pharmacological interventions that reduce the mitochondrial ROS production effectively inhibit the hyperglycemic damage [26, 38, 75]. Higher flux through the electron transport chain is expected to reduce the accumulation of glycolytic intermediates and prevent the activation of oxidative stress pathways but only some of the interventions increased the electron transport (e.g. uncoupling agents and proteins), whereas others (e.g. antioxidants) did not change it or severely reduced it (complex II inhibition). Also, the increased electron flow may induce a proportional rise in superoxide generation by the electron transport chain if electron leakage is unaffected. Furthermore, endothelial cells, in which the mitochondrial DNA is selectively depleted (rho zero cells) and lacks a functional electron transport chain, fail to activate PKC, the polyol and hexosamine pathways and they do not produce AGEs, though their mitochondrial metabolism is impaired and they are expected to accumulate glycolytic intermediates [26]. These observations led to the proposition that mitochondrial superoxide generated by the electron transport chain is responsible for the initiation of hyperglycemic endothelial damage [26, 83, 84].
\nMitochondria produce superoxide nonenzymatically via multiple respiratory complexes in the electron transport chain and enzymatically via the mitochondrial xanthine oxidase [85, 86, 87]. The nonenzymatic production of superoxide occurs when a single electron is directly transferred to oxygen by prosthetic groups of the respiratory complexes or by reduced coenzymes that act as soluble electron carriers. The electron transport chain may leak electrons to oxygen and it is the main source of superoxide in hyperglycemia. Mitochondrial monoamine oxidase (MAO) and p66SHC also produce H2O2 within the mitochondria that may contribute to oxidative stress in hyperglycemia [88].
\nMolecular oxygen is biradical; it has two unpaired electrons in the outer orbitals, which makes it chemically reactive. In the ground state, the unpaired electrons are arranged in the triplet state, and as a result of spin restrictions, molecular oxygen is not highly reactive: it can only react with one electron at a time. If one of the unpaired electrons is excited and changes its spin (oxygen goes from the triplet state to the short-lived singlet state), it will become a powerful oxidant that is highly reactive [86]. The reduction of oxygen by one electron at a time produces superoxide (O2•−) anion that might be converted to hydrogen peroxide (either spontaneously or through a reaction catalyzed by superoxide dismutase), which may be fully reduced to water or partially reduced to hydroxyl radical (OH•). In addition, superoxide may react with other radicals including nitric oxide (NO•) and form peroxynitrite (ONOO•−), another very powerful oxidant. The respiratory components are thermodynamically capable of transferring one electron to oxygen and form superoxide in the highly reducing environment of the mitochondria, since the standard reduction potential of oxygen to superoxide is −0.160 V and the respiratory chain incorporates components with standard reduction potentials between −0.32 V (NAD(P)H) and +0.39 V (cytochrome a3 in Complex IV) [86].
\nIn the respiratory chain, electrons move along the electron transport chain going from donor to acceptor molecules until they are transferred to molecular oxygen (the standard reduction potential of oxygen/H2O couple is +0.82 V), while the generated free energy is used to synthesize ATP from ADP and inorganic phosphate. Respiratory Complex I transfers electrons from NADH and Complex II from FADH2 to coenzyme Q (CoQ, ubiquinone), which is the substrate of Complex III. Complex III transfers electrons from reduced CoQ to cytochrome C, which is used by Complex IV to reduce oxygen into water. The step-by-step transfer of electrons allows the free energy to be released in small increments. The energy released as electrons flow through the respiratory chain is converted into a H+ gradient through the inner mitochondrial membrane: protons are transported from the mitochondrial matrix to the intermembrane space (by Complexes I, III and IV) and a proton concentration gradient forms across the inner mitochondrial membrane [89]. Since the mitochondrial outer membrane is freely permeable to protons, the pH of the mitochondrial matrix is higher (the proton concentration is lower) than that of the intermembrane space and the cytosol. An electric potential (mitochondrial membrane potential) of 140–160 mV is formed across the inner membrane by pumping of positively charged protons outward from the matrix, which becomes negatively charged [90]. Thus, free energy released during the oxidation of NADH or FADH2 is converted to an electric potential and a proton concentration gradient—collectively, the proton-motive force—and this energy is used by ATP synthase (Complex V) for ATP generation via the chemiosmotic coupling [91]. While the majority of oxygen molecules are used for water formation during the above processes, superoxide is generated at an estimated rate of 0.1–2% of oxygen consumption under normal respiration (State 3) and physiological operation of the respiratory chain [85, 88].
\nThe electron transport chain may produce superoxide by multiple mechanisms but electron leakage before Complex III is suspected to represent the main source of superoxide in hyperglycemic endothelial cells [26, 83]. Complexes I and III are the respiratory complexes that are capable to produce large amounts of superoxide under certain conditions (Figure 2). Complex I may produce superoxide by two mechanisms: (1) the reduced flavin mononucleotide (FMN) center can transfer electrons to oxygen instead of CoQ when the NADH/NAD+ ratio is high (and the CoQ binding site is blocked or the CoQ pool is mostly reduced) and (2) by reverse electron transfer (RET) from the CoQ binding site if there is high electron supply from Complex II and the electrons are forced back to Complex I instead of proceeding to Complex III (by a reduced CoQ pool and high proton-motive force) [85, 92]. In Complex III, superoxide is produced from the semiquinone anionic state of CoQ (semiubiquinone) by directly reacting with oxygen instead of completing the Q-cycle [85, 93]. Reduced CoQ diffuses through the bilipid layer of the membrane to its binding site in Complex III and transfers the electrons to the iron-sulfur protein (Rieske protein) in two steps that produce a semiquinone intermediate state of CoQ after the first electron transfer, which is the source of superoxide. In the presence of respiratory inhibitors, Complex I may produce the highest amount of superoxide, especially through RET, but the contribution of Complexes I and III to superoxide production is unknown in healthy mitochondria [86]. Superoxide is also produced in the matrix by other enzymes that interact with the NADH pool and by enzymes connected to the inner membrane CoQ pool. These include α-ketoglutarate dehydrogenase that may produce superoxide if its substrate (α-ketoglutarate) concentration and the NADH/NAD+ ratio increase in the matrix. In the membrane, α-glycerophosphate dehydrogenase may produce superoxide partly via RET and Complex II, which transfer electrons from succinate to CoQ, is also suspected to generate some superoxide [85].
\nOxidant production by the mitochondrial electron transport chain. CoQ: coenzyme Q, ubiquinone; Cyt C: cytochrome C; FAD+/FADH2: flavin adenine dinucleotide; H2O2: hydrogen peroxide; MnSOD: manganese-dependent superoxide dismutase; NO•: nitric oxide; O2•−: superoxide, ONOO•−: peroxynitrite; PARP: poly(ADP-ribose) polymerase; p66SHC: 66-kDa Src homology 2 domain-containing protein; SQR: sulfide:quinone oxidoreductase and UCP: uncoupling protein.
In hyperglycemic endothelial cells, the increased production of superoxide originates from the reduced CoQ pool before Complex III [75, 83]. The high electron donor input from glycolysis and the TCA cycle may increase the membrane potential and inhibit the electron transfer at Complex III, thus increase the concentration of reduced and free radical intermediates of CoQ. Superoxide generation may occur as direct ‘leakage’ of electrons to oxygen, as a result of the longer half-life of CoQ intermediates in the lipid bilayer and bound to Complex III or via RET through Complex I. Superoxide generation is also promoted by the increased membrane potential and proton concentration gradient through the inner membrane [31, 35, 83, 94]. Superoxide production was found to increase exponentially above 140 mV with the increase of the mitochondrial membrane potential [95]. Since with the generation of each superoxide molecule one electron is lost compared to the number of protons, superoxide production per se may increase the membrane potential and the proton gradient or might be responsible for the maintenance of the elevated membrane potential. Furthermore, the proton and charge transfer of Complexes III and IV are disproportional since Complex III picks up two protons from the matrix side of the inner membrane (the negatively charged N-face) and releases four protons to the intermembrane space side (positively charged P-face), whereas Complex IV abstracts four protons from the matrix and releases two protons to the intermembrane space per transfer of two electrons. Thus, Complex III transfers four protons but only two positive charges, whereas Complex IV transfers two protons and four positive charges [89, 96], which may lead to an increase in the membrane potential if there is a mismatch between the activity of the two complexes. Also, while it is possible to generate considerably higher membrane potential than the physiological value, since the proton-motive force is sufficient to generate about 240 mV, the proton permeability of biological membranes increases above 130 mV; thus, the higher values are associated with energy loss [95]. To optimize the energy efficiency, OXPHOS is tightly regulated by the ATP concentration (or ATP/ADP ratio) in the matrix: high ATP concentration in the matrix allosterically inhibits Complex IV of the respiratory chain and decreases the mitochondrial membrane potential [97]. Complex IV has a low reserve capacity and it may represent the major controlling site of respiration and mitochondrial ATP synthesis [95]. This immediate regulation is supplemented by the phosphorylation-mediated regulation of respiratory complexes, which transmit the extramitochondrial and extracellular stimuli to adapt OXPHOS to stress conditions [95]. Phosphorylation sites were detected in all respiratory complexes and there is a growing list of stress factors that may induce phosphorylation of the complexes or mitochondrial hyperpolarization that might be associated with the adaptive process. This is how inflammatory cytokines may affect superoxide generation in diabetes.
\nHyperglycemia-induced mitochondrial superoxide production is a functional change of the respiratory chain; no difference is detectable in the assembly or the relative amounts of the respiratory complexes in the early phases of the injury [26, 35]. At later stages, changes in the expression or assembly of some components of the respiratory chain may occur and these are typically associated with impaired functionality [98, 99]. The glucose-induced changes in the mitochondrial superoxide production are reversible: normalization of the membrane potential suppresses the ROS production in endothelial cells [26, 35, 83, 94, 100]. While elevated mitochondrial membrane potential is detectable in endothelial cells exposed to high glucose concentration, the overexpression of either uncoupling protein 1 (UCP1) or uncoupling protein 2 (UCP2) normalizes the membrane potential and reduces the ROS production [26, 35, 83]. The function of UCP2 is regulated by ROS itself: the proton conductance of the protein is controlled by glutathionylation, and if ROS is present, it increases the proton leakage, whereas in the absence of ROS, the channel closes, thus this feedback may control the mitochondrial potential and the ROS production simultaneously [32, 33]. Furthermore, hydrogen sulfide donors that normalize the mitochondrial potential by electron supplementation via sulfide:quinone oxidoreductase (SQR) also inhibit the superoxide generation induced by hyperglycemia [94, 100].
\nThe mitochondrial matrix possesses antioxidant enzymes to defend against oxidative damage. Manganese-dependent superoxide dismutase (MnSOD, also known as superoxide dismutase 2 (SOD2)) is the mitochondrial enzyme that neutralizes superoxide produced by the respiratory chain and converts it to H2O2. Since functional mitochondria constantly produce ROS, it is necessary to scavenge oxygen radicals. The importance of MnSOD is underlined by the fact that MnSOD-deficient mice exhibit extensive mitochondrial injury and only survive for less than 3 weeks [101]. Mutations associated with reduced activity of MnSOD accelerate diabetic nephropathy and neuropathy [102, 103, 104]. On the other hand, overexpression of MnSOD prevents hyperglycemic injury in endothelial cells, suggesting that the respiratory chain is the source of oxidants in hyperglycemia [26, 83]. The amount of superoxide produced by the respiratory chain may not be excessively higher in hyperglycemia, since the overexpression of the MnSOD can efficiently scavenge the oxidants or low amounts of mitochondria-targeted antioxidants are able to neutralize ROS in hyperglycemia [26, 38, 83].
\nIn cells exposed to hyperglycemia, mitochondrial ROS production activates various mechanisms to reduce the oxidant production. This includes immediate responses that may control the mitochondrial potential in the short term and also longer term responses that may protect against the increase of the mitochondrial potential, but these mostly reduce the energy efficiency of OXPHOS. Hyperglycemia and ROS production activate the uncoupling proteins in the mitochondrial inner membrane that allow higher proton transfer from the intermembrane space to the matrix without coupled ATP production [32, 33]. This activity not only reduces the mitochondrial membrane potential but also decreases the amount of ATP generated in the mitochondria.
\nHyperglycemia also increases the consumption of hydrogen sulfide, an inorganic substrate of the mitochondria that can act as an endogenous electron donor [105, 106, 107]. Since H2S oxidation may provide electrons to CoQ without the additional protons, it can reduce the mitochondrial potential and promote ATP synthesis; thus, H2S may represent an alternative energy source that is used in small quantities or function as a buffer to control the mitochondrial potential. Hyperglycemia reduces the mitochondrial H2S pool and the plasma concentration of H2S, and it may deplete the buffering capacity of H2S in the mitochondria [94, 108, 109].
\nThese immediate reactions are supplemented with the morphological changes of mitochondria. Mitochondria are dynamically changing organelles in the cells: they may form long tubes that cross the whole length of the cell or short rods that are as long as wide or any length in between. Mitochondria continuously change their shape by fusion (elongation) and fission (fragmentation) and they move along microtubular tracks within the cells. This process is believed to help maintain functional mitochondria; it allows rapid redistribution of mitochondrial proteins and may help the elimination of dysfunctional parts or proteins. Hyperglycemia stimulates the fission of mitochondria that can reduce the mitochondrial membrane potential but also helps dissociate the respiratory complexes and decrease the chance of assembly of various proteins within a complex [110, 111, 112, 113, 114]. Altogether, it results in partly assembled respiratory complexes and higher superoxide production that will reduce the energy efficiency of mitochondria [98, 99]. Mitochondrial fission is a later process induced by high glucose exposure, and it occurs only after the superoxide production is induced. Mitochondrial ROS production plays an active role in the initiation of fragmentation, since administration of a mitochondrial scavenger prevents the hyperglycemia-induced fission of mitochondria [113]. Blocking of mitochondrial fission will also restore the acetylcholine-mediated eNOS (endothelial nitric oxide synthase) phosphorylation and cGMP response in hyperglycemic endothelial cells, suggesting that the vascular impairment is partly caused by mitochondrial fission itself [114].
\nMitochondrial ROS production results in DNA damage in the mitochondria that activates the mitochondrial DNA repair enzymes [115]. Oxidative DNA damage activates poly(ADP-ribose) polymerase 1 (PARP1) in the mitochondria similar to the situation in the nucleus [116]. PARP1 adds ADP-ribose polymers (PARs) to the mitochondrial base excision repair (BER) enzymes, exo/endonuclease G (EXOG) and DNA polymerase gamma (Polγ) and affects the mitochondrial DNA repair [116]. Activation of mitochondrial PARP1, as opposed to nuclear PARP1, may decrease the DNA repair and slow down the mitochondrial biogenesis. Integrity of the mitochondrial DNA (mtDNA) also relies on mitochondrial transcription factor A (TFAM), a protein that may act as a physical shield of the mitochondrial DNA, since it forms histone-like structures with mtDNA and is present in large amounts in mitochondria (~900 molecules for each mtDNA). Apart from protecting the DNA from damaging agents, it tightly binds to heavily damaged DNA parts, blocks the transcription and may promote the repair of affected sites [115]. TFAM is also implicated in mitochondrial biogenesis and the maintenance of stable mtDNA copy number. In diabetic retinas, the level of TFAM is reduced, and it decreases the mitochondrial biogenesis that can lead to fewer mitochondria and less efficient OXPHOS [117].
\nOxidant production will also induce several changes in the function of proteins that may be associated with cellular injury and result in altered cell metabolism, senescence and vascular dysfunction. Oxidative stress leads to oxidative DNA damage and DNA strand breaks that activates the predominantly nuclear PARP1 and may lead to ATP depletion and necrosis or apoptosis [118]. However, the level of PARP activation is mostly lower than to induce cell death; it results in higher NAD+ consumption and changes in the PARylation pattern of proteins [50]. The higher NAD+ utilization and decreased mitochondrial output may decrease the nuclear and cytoplasmic NAD+ concentrations and by reducing the amount of substrate for SIRT1 (another NAD+-dependent enzyme), it will block the deacetylation of proteins [67, 68, 82]. A third posttranslational modification that changes in hyperglycemia is protein S-sulfhydration (or persulfidation), a reaction between H2S and reactive cysteine residues [119]. Protein S-sulfhydration is a highly prevalent modification that typically increases the activity of target proteins. The antioxidant master regulator Nrf2 (nuclear factor E2-related factor 2) transcription factor is also activated by H2S via sulfhydration of its key controller, Kelch-like erythroid cell-derived protein with Cap ‘n’ collar (CNC) homology (ECH)-associated protein 1 (Keap1) [120, 121]. A further target is ATP synthase in the respiratory chain: H2S increases cellular bioenergetics via S-sulfhydration of Complex V [122]. Since hyperglycemia reduces the H2S level in the cells and plasma, it will also decrease the protein S-sulfhydration and results in lower Nrf2 activity and OXPHOS efficiency [108, 109]. All these changes contribute to the dysfunction of proteins in hyperglycemia and promote cellular dysfunction.
\nThere are further changes in the cellular metabolism that reduce the ATP output, which include diminished glucose uptake, blockage of anaerobic metabolism and inappropriate assembly of mitochondrial respiratory complexes. High extracellular glucose immediately stimulates glucose uptake, but decreases the glucose transport over longer term in endothelial cells [123, 124]. Downregulation of GLUT1 glucose transporter is responsible for the diminished glucose uptake, and it may contribute to the low ATP output. Hyperglycemia reduces the activity of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) via PARylation and reduces the anaerobic glucose metabolism [125]. Aerobic metabolism is also decreased by mitochondrial fragmentation and disassembly of mitochondrial respiratory complexes that develop over longer exposure to hyperglycemia [93, 99, 113]. Altogether these changes reduce the ATP generation in the cells and block the anaerobic compensation for the diminished mitochondrial activity.
\nOxidative stress will induce DNA strand breaks in the mitochondria and promote mutations and senescence of endothelial cells. Accelerated aging of endothelial cells and the lack of endothelial progenitor cells decrease the functional endothelial cell pool in hyperglycemia [126]. The number of bone marrow-derived progenitor cells is lower in the circulation in diabetes and the progenitor cells possess diminished proliferation capacity [24, 127]. It will reduce the resupply of endothelial cells and may place extra workload on the pre-existing vascular endothelium extending the exposure to glucose, inflammatory mediators and oxidants.
\nVascular dysfunction is characterized by inappropriate relaxation in response to acetylcholine, which is mediated by endothelial nitric oxide (NO) [128, 129, 130, 131]. NO is synthesized from the guanidinium group of L-arginine by eNOS via a NADPH-dependent reaction. Mitochondrial superoxide may interact with NO, which leads to a loss of bioavailable NO, and form peroxynitrite (ONOO−), a very reactive radical that activates PARP1 [132, 133, 134]. Furthermore, tetrahydrobiopterin (the pteridine cofactor of eNOS) is an essential regulator of the enzyme: when tetrahydrobiopterin availability is inadequate, it becomes ‘uncoupled’ and produces superoxide, using molecular oxygen as substrate, instead of NO [135]. Tetrahydrobiopterin levels are lower in animal models of diabetes and tetrahydrobiopterin supplementation restores the vascular relaxation in these models suggesting a pathogenic role in diabetes [136, 137]. Another key element of vascular dysfunction is the reduced H2S bioavailability in diabetes. H2S and NO interact at multiple levels: H2S stimulates eNOS expression and activity, promotes the action of NO by maintaining a reduced soluble guanylate cyclase (sGC) and by inhibition of the vascular cGMP phosphodiesterase (PDE5) and prolongs the half-life of cGMP [138, 139, 140]. Increased mitochondrial H2S consumption and its diminished concentration in hyperglycemic endothelial cells inhibit the NO-dependent vasodilation and contribute to vascular damage in diabetes.
\nGlycemic control has been the main therapeutic modality for prevention and treatment of hyperglycemic injury and diabetes complications. However, recent studies confirmed that glycemic control provides limited protection against the cardiovascular events, and adjunct therapy is necessary to reduce the risk of complications. Previous efforts found aldose reductase (a key enzyme of the polyol pathway) to serve as potential drug target and found that inhibition of aldose reductase may prevent the pathological changes that occur in response to high sorbitol levels [141]. The results of the clinical trials were less impressive than expected from preclinical studies, still the first aldose reductase inhibitor has been marketed in Asia for the treatment of diabetes complications [142].
\nFollowing the discovery that mitochondrial superoxide is responsible for the induction of all ROS-producing pathways in hyperglycemic endothelial cells, an intense search began for mitochondrial drug targets and inhibitors of mitochondrial superoxide generation [26, 83, 84]. Mitochondria-specific targeting moieties have been developed and linked to antioxidants or superoxide dismutase (SOD) mimetics [143, 144]. The majority of these molecules use the triphenylphosphonium (TPP) targeting group and attain 100- to 500-fold accumulation in the mitochondria [145, 146]. Both the mitochondria-targeted ubiquinol (MitoQ) and piperidine nitroxide TEMPO (mitoTEMPO) proved beneficial in diabetes models [147, 148, 149]. Overexpression of MnSOD was found to protect against diabetic retinopathy in a transgenic model, but long-term delivery of MnSOD is unresolved in humans [150].
\nWhile no protein target has been identified, various phenotypic screens were performed, which allowed the target-agnostic discovery of potential drug candidates [38, 151]. In cell-based models, paroxetine emerged as a mitochondrial free radical scavenger and glucocorticoid steroids as UCP2 inducers in hyperglycemic endothelial cells [35, 38]. In another screen, which also used multiple assay variables as output and examined the OXPHOS-associated gene expression, the antihelmintic drug mebendazole and the Chinese herbal medicine deoxysappanone B emerged as inhibitors of mitochondrial ROS production [151]. The protective effect of all of these drugs might be a direct consequence of the normalization of the mitochondrial membrane potential or free radical scavenging.
\nThe mitochondrial antioxidant effect of select microtubular drugs, which was independently confirmed by the previous two studies, might be related to their mitochondrial fusion promoting effect, since excessive mitochondrial fission and fragmentation occur in hyperglycemia [38, 151]. To identify compounds that promote mitochondrial fusion, a separate phenotypic screening program was conducted [152]. This study identified hydrazone M1, a small molecule that restore the mitochondrial network in cells but its efficacy has not been tested in diabetes [152, 153]. Also, compounds that block the mitochondrial fission are expected to improve the mitochondrial function and reduce the mitochondrial ROS production in hyperglycemia, but these inhibitors (mitochondrial division inhibitor-1 (mdivi-1), dynasore, P110 and 15-oxospiramilactone) have not been tested in diabetes [154, 155].
\nIn another effort to identify compounds that reduce the mitochondrial ROS production but do not interfere with energy production, isolated mitochondria were used for high throughput screening and hit compounds were selected based on a dual output of ROS production and respiration rate [156, 157]. CN-POBS (N-cyclohexyl-4-(4-nitrophenoxy)benzenesulfonamide) was identified as a selective inhibitor of ROS production by the ubiquinone-binding site of complex I, and S3QELs (“sequels,” selective suppressors of site IIIOQ electron leak) were found to act as inhibitors of the outer ubiquinone-binding site similar to terpestacin [156, 157, 158]. Unfortunately, there are no data about their action against hyperglycemia-induced ROS production. Statins also block the mitochondrial ROS production but they simultaneously reduce the mitochondrial respiration and may cause toxicity [38, 151]. A further inhibitor of mitochondrial respiration is H2S, a known inhibitor of complex IV, that turns out to act as stimulator of mitochondrial metabolism at low concentrations via electron donation [106]. H2S supplementation either using sodium sulfide or mitochondria-targeted donor molecules inhibits the hyperglycemia-induced ROS production and endothelial dysfunction at low concentrations [35, 94]. Long-term administration of H2S is effective against diabetic nephropathy and retinopathy in animal models [159, 160].
\nFinally, many of the currently used anti-diabetic medications also possess mitochondrial targets and they might be partly responsible for their beneficial effects on endothelial cells and the vasculature. The biguanide metformin apart from activating AMPK also acts as a mild and transient inhibitor of respiratory complex I [161]. The sulfonylurea glibenclamide inhibits the mitochondrial ATP-sensitive potassium channel (mitoKATP), decreases the mitochondrial membrane potential and ROS production and increases the respiration rate [162, 163]. Thiazolidinediones (TZDs) also possess a specific mitochondrial target (mTOT, mitochondrial target of TZDs), which comprise a recently identified protein complex. TZDs bind to a pyruvate carrier complex in the mitochondria and modulate the pyruvate entry into the mitochondria that may explain their antioxidant effect [164]. The discovery of these novel mitochondrial targets is expected to promote target-based drug discovery efforts and may provide new compounds in the upcoming years.
\nEndothelial cells exposed to oxidative stress and the proinflammatory environment undergo accelerated aging in hyperglycemia, thus stimulation of cell replacement with fresh endothelial cells may help restore the vascular function [126]. While it is difficult to estimate the exact number of endothelial cells, a reduction of progenitor cell count and functionality was detected in diabetes, and it is expected to result in a decreased number of functional endothelial cells in the vasculature [24, 127]. Even in the retina, where neovascularization (proliferative diabetic retinopathy) is the characteristic event, progenitor cell therapy is expected to cause improvement and treat the ischemic vascular abnormalities [165]. Currently, it is difficult to predict which treatment strategy will prove effective in diabetes, but probably the drug-induced enhancement of progenitor cell potency has the highest translational potential in diabetes [166, 167]. Drugs that were suggested for progenitor cell enhancement include statins, losartan (angiotensin II receptor antagonist), aliskiren (direct renin inhibitor), hydrogen sulfide, thymosin β4 and the CXCR4 (C-X-C chemokine receptor type 4) antagonist plerixafor (AMD3100, 1,1-[1,4-Phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane) [167]. As some of these drugs are in use in diabetic patients, an evaluation of the effect of these compounds on diabetic progenitor cells might be available in the near future [168]. If mobilization and enhancement of endothelial progenitor cells are achieved, it could help the endothelial recovery in the vasculature in diabetic patients, which may lead to an extension of indication of these drugs.
\nReversible changes occur in the early phase of hyperglycemic injury that might be pharmacologically targetable. Blocking the high glucose-induced mitochondrial superoxide production represents the major goal in endothelial cells, but it does not provide a drug target that can be directly assessed [169, 170]. The involvement of mitochondria in the pathogenesis of various diseases intensified the interest in druggable targets and promoted selective delivery of compounds to the mitochondria [146]. Normalization of the mitochondrial membrane potential or administration of mitochondria-specific free radical scavengers reverses the adverse effects of hyperglycemia and may present experimental therapeutic approaches in diabetes [16, 38, 100]. Early administration of mitochondrial antioxidants or drugs that restore the mitochondrial metabolism is expected to prevent the later changes that occur in diabetes.
\nThe later stages of hyperglycemic injury also include morphological changes and impaired assembly of the respiratory complexes that necessitate different treatment strategies. Mitochondrial fusion promoting drugs might represent promising approaches in this phase of diabetes complications but their efficacy has not been tested in diabetes [152, 153]. Alternatively, stimulation of the endothelial progenitor cells to help replace the senescent endothelial cells may prove beneficial in diabetes [126].
\nAltogether, advancement in our understanding of glucose-induced cellular and mitochondrial damage and identification of new drug targets are expected to provide novel strategies in diabetes treatment.
\nD.G. received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme under the grant agreement number 628100.
\nParticipation can be described as a process by which communities work together towards change [1]. More specifically, participation can be seen as the “
In recent decades, there has been growing attention to community and stakeholder participation touching a wide range of applications such as watershed, ecosystem or forest management, agricultural development, environmental governance, and land use planning [3], and for assessing community and environmental needs, especially in the context of development projects [1, 5]. This growing interest in participatory processes is also reflected in a range of international agreements. Already in 1992, more than 150 states agreed at the Rio Conference on Environment and Development (UNCED) that environmental issues are best handled with the participation of all concerned citizens [6]. Other agreements calling for public participation include, for example, the Earth Summit, the European Landscape Convention, the Aarhus Convention, and the European Water Framework Directive [3].
Participatory approaches’ purposes can vary, ranging from providing information and collecting inputs from stakeholders to negotiation and solving a problem or strengthening local capacity. Although participatory approaches did not originate as a method for research, they can also be used to produce detailed narratives of a certain topic in an interactive and collaborative manner, promoting learning and generating research data through a process of “guided discovery” [4]. Due to its application in diverse contexts for several decades, participation has acquired an ideological, social, political and methodological meaning, giving rise to a wide range of interpretations [5].
In this context, this chapter first provides an overview about the different types of participation, including their advantages and limitations (Subchapter 2). Subchapter 3 goes more into detail about the participatory processes related to natural hazard risk management, while Subchapter 4 provides examples of participatory approaches adopted specifically within the Interreg Alpine Space project GreenRisk4ALPs [7]. Finally, some recommendations are given (Subchapter 5).
Participatory mechanisms vary greatly in form and aims, ranging from traditional (e.g. public meetings) to more innovative approaches (e.g. consensus conferences) and from instruments that collect responses of participants operating alone (e.g. surveys) to those involving participants interacting in groups (e.g. focus groups) [8]. The degree of participation can also vary, spanning from participants as passive recipients of information to engaging them in decision-making processes [9]. Moreover, also the people invited to participate vary: participatory approaches can be generally divided into methods with stakeholder involvement and methods with the involvement of the general public [10]. The distinction between public participation and stakeholder engagement is reflected in academic literature where stakeholders and citizens or the general public represent clearly differentiated entities [11, 12]. Stakeholders often represent sectorial or focused interests and shared preferences on a specific issue, while the general public generally represents the public good [12].
A necessary early step to be able to describe but also implement participatory methods is the definition and identification of stakeholders to involve [13, 14]. To achieve fair and socially representative processes, criteria have been developed. In the environmental field for instance, these criteria include classifications such as in individuals, groups and organizations who are affected by or can affect an environmental management issue and who may be interested in or impacted by it [11, 12, 15]. The practitioner is therefore required to investigate all the complex societal structures to determine who achieves the “stakeholder status” for the specific issue to be addressed within the engagement process [12].
Typologies have also been developed to classify the variety of existing participatory approaches. They can be based on different criteria: for instance, they can classify the different degrees of participation [16], the objectives for which participation is used or the direction of the communication flow [17]. These classifications can be used
Among these typologies, one often-cited classification for assessing community participation that has been used for over 50 years, is Arnstein’s ladder [16]. The ladder mainly refers to citizens as the main actors to engage, but it can be adapted for other contexts. It consists of eight rungs representing a continuum of increasing stakeholder involvement ranging from “Non-participation” and passive dissemination of information (“Tokenism”) to active engagement (“Citizen Power”).
The ladder has been used in practice and academia and was adapted or integrated throughout the years. For example, the pyramid adapted from Arnstein shown in Figure 1 clarifies the increase in participation rights with each rung, but also shows that the obligation to assume responsibility for those increasingly involved at the same time [19]. Participatory processes are therefore more than pure communication processes; they are based on a mutual working relationship - the initiator or sponsor of the process is dependent on those involved and vice versa [19].
Adapted “ladder of participation” [
Within participatory approaches we can distinguish between two different phases. One is the participation of stakeholders within a research process, which aims towards solving practical problems by scientific methods and standards [20]. This participation phase, developing concrete solutions and measures for problem solving, must be planned before formulation and implementation of a specific policy output is approached. It is intended to ensure that state-of-the-art knowledge and innovative science-based information should be sufficiently included into the measures and solutions. The second phase is the participation of stakeholders within the formulation and implementation of a specific policy output. Here, participation should lead to decisions regarding the selection of concrete measures and solutions within a political program. Of course, both phases might be linked to each other or not.
Participation within the research process builds on the co-production models for scientific knowledge transfer. Here, researchers, experts, non-academic stakeholders and policymakers interact and influence the production and use of scientific knowledge [21]. The co-production models accept the fundamental differences between practice and science. Whereas science relies on the scientific truth and logic based on empirical evidence, political actors follow the principles of political rationality, which is based on interests, power and political ideologies [20]. Due to this different logic, doing research based on a participatory approach and in transdisciplinary teams is often recognized as a time and labor intensive process for all participants [22]. Additionally, the lack of training (for working in such team structures), the length of the participation in the research process and even competing disciplinary working cultures are further challenges [23, 24, 25]. In research projects, in which resources are very limited [26], neither transdisciplinary concepts of “mode 3 knowledge production” [27] nor concepts of “collaboratively framing the problem” [23] are easily able to bridge the world of science and the world of practice. Similarly, actors from practice may not be expected to be able to work while adhering to scientific methods and standards [28].
Another common criticism to participatory approaches is that participation of divergent stakeholder groups in knowledge transfer leads often to discourses dominated by the most powerful one [29], and that, therefore, those stakeholders suppress minority interests systematically [30]. Different authors [31, 32, 33] argue that participation has to be understood as an arena of negotiation on of interests due to unbalanced power relations of stakeholders by means of strategic rationality. It needs to be noted that in complex and coupled human-natural systems, like sustainability, practical problems cannot be easily solved by involving non-academic stakeholders into the research process [33, 34, 35]. However, involving stakeholders into the research might be of high relevance for defining practical problems and related research topics or for data collection.
Participation of stakeholders within the formulation and implementation of a specific policy output is traditionally connected to trying to implement measures and solutions for practical problems within the particular political programs, by using a mixture of regulative, financial and informational instruments [35]. This might be based on the state-of-the-art scientific knowledge (also with participation of non-academic stakeholders) or not. Undoubtedly, participation of different stakeholder groups ensures more legitimation for decisions and measures [23]. This may be secured by the exchange of information, expressing opinions or articulating interests and has the potential to influence the outcome [36]. This potential influence depends on the degree of co-determination of stakeholders, ranging from pure information provision to participation in decision making processes [37].
Depending on the degree of co-determination of involved stakeholders and on the complexity of mutual conflicts, it is still a challenge for any layperson participating in the process to have a realistic opportunity of finding a sufficient solution for its own problem and conflict. Indeed, participatory approaches are based on the principle of collaboration between conflicting parties, but this does not mean that those parties will abandon their objectives. At this point, a good reason for shifting one’s own interests towards a compromise is needed. Therefore, neither sophisticated (communication, mediation or moderation) techniques of experts nor the experience in the group building processes (by round tables) are enough for solving the current conflicts easily [38].
To conclude, there is no unique best way for designing and managing a participatory process: the chosen approach must reflect the specifics of the given situation and the needs of the parties involved. Moreover, several approaches can also be used simultaneously [3, 39].
Mountain areas face multiple challenges connected to the coexistence of natural hazards and the high presence of settlements in limited available space (i.e., valley bottoms). Natural hazards can affect society in various ways, impacting different stakeholders at different levels by directly damaging infrastructure or causing fatalities or indirectly by causing economic losses. Especially in the European Alps, the number of potentially exposed people is increasing, and the characteristics of natural hazards are changing due to climate change, modifying the different components of risk and posing increasing challenges to Alpine societies (see chapter [40] of this book).
Decision-making addressing complex and dynamic environmental challenges such as natural hazard risk management (NHRM) therefore requires flexible and transparent approaches embracing a diversity of knowledge and values. Rapidly changing risks are not manageable by one public institution alone or by a single discipline. The risk influencing factors are so vast and inter-dependent that many disciplines and institutions are required to deal with natural hazard and risk management. Therefore, integrated risk management is a joint responsibility of public institutions at different levels (e.g., national, regional and local) and of the private sector. Without combining participatory approaches in NHRM with strong financial, informational and regulative instruments, the success in reaching risk reduction targets will be limited, especially in protective forest management [41].
The importance of participatory approaches in the planning phase of (protective) forest management activities to achieve a sustainable use of this resource has been acknowledged by several authors and institutions such as the UN and the EU [42, 43, 44]. Integrating various stakeholders allows for the increase of public acceptance of policy decisions and to build an inclusive platform for constructive discussion. These aspects are even more important when dealing with forests and their management due to the multitude of conflicting interests and demands that are related to them [45, 46].
In addition to strong or weaker country specific regulative instruments affecting natural hazard management, for example, forest, flood protection or civil protection acts, many authorities increasingly prefer financial and informational instruments for solving practical issues. This is because regulative instruments and their rigorous implementation encounter resistance by recipients, especially in protective forest management [37, 47, 48]. However, even the usage of financial and informational instruments does not always lead to sufficient solutions to solving issues related to protective forests (e.g., sufficient regeneration, adequate forest maintenance or restoration). This deficiency can be overcome by newer participatory approaches that include all relevant stakeholders such as mountain farmers, outdoor recreationists or hunters, who have considerable influence on helping to reach the targets of protective forest policies [37, 47, 48]. Therefore, participatory approaches should be understood as an additional political instrument for involving important stakeholder groups into the policy making process.
This subchapter provides an overview on the participatory approaches and the scientific methods behind them that were developed and applied within the GreenRisk4ALPs project, spanning from expert consultation and developing new science-based knowledge to stakeholder integration and the transfer of knowledge into practice.
Within the framework of GreenRisk4ALPs, stakeholder network analyses were carried out in six Pilot Action Regions (PARs) as a first step to identify the relevant stakeholders to be included in the following activities. This section presents the outcomes for the Austrian PAR (municipalities of Vals and Gries am Brenner, Tyrol). The analysis consisted in the identification of the different administrative levels (local, regional, national) responsible for ecosystem-based NHRM and related topics.
Although the Austrian PAR covers an area of only 105 km2 (which is approximately in size to about one third of Munich), a total of 36 stakeholder groups dealing with NHRM were identified. Of these, 30% are located at the federal level (Austria), 25% at the state level (Tyrol), 10% in the political district (Innsbruck Land), and another 30% at the municipal level. Three points were taken particularly into account in the initial identification of these stakeholder groups, which were also relevant in the following activities (e.g., round tables, surveys, interviews or expert workshops):
Some institutions have a hierarchical departmental structure (superior and subordinate departments) within their organization. For instance, the Landesforstdirektion Tirol (Tyrolean Forest Service) is subdivided into several departments and groups as well as in the Bezirksforstinspektionen (forestry offices at district level). When identifying relevant stakeholders, the umbrella organization (Landesforstdirektion), a subordinate department (Bezirksforstinspektion) or all experts of the respective institution that are somehow connected to the topic can be considered, depending on the question.
Some stakeholders are organized at the federal level, but are fragmented into regional bodies, where they are also partly incorporated into regional institutions. For example, the Federal Agency for Water Management is an organizational unit within the Ministry of Agriculture, Regions and Tourism (BMLRT), which is located in Vienna. The operational offices, however, are at the Hydrographic Service of the Federal States or in the administrative building of the districts.
In terms of stakeholder groups, a distinction must be made between government institutions, non-governmental organizations, companies, associations, voluntary aid organizations, landowners and pure user groups (e.g., tourists). Of course, the power positions as well as decision-making and influence potentials of the different groups vary considerably.
It is therefore obvious that the understanding of administrative and official structures has the highest priority, as (not only) in Austria the distribution of responsibilities and competences is not always clear, which can lead to difficulties in fully identifying the relevant stakeholders.
After the most important stakeholders related to the project-relevant topics had been identified and listed, a network of their representatives was established (see Figure 2). This network helped to understand which stakeholders are in direct contact with other stakeholders, which stakeholders are possibly in a competitive relationship, or which had to be introduced among each other. This graphical representation of the stakeholders’ network helped to decide which stakeholders ultimately needed to be brought together to participate in the project. Here, the analysis unit is the relationship between two entities and not the entity itself, considering that the networks consist of connections measured through communications or exchanges among actors [49, 50]. Analyzing the stakeholder network allowed us to highlight strengths and weaknesses of social structures, providing relevant information to improve the governance processes. These results are useful whenever institutional stakeholders are involved in a participatory process aiming at a consensual agreement and to overcome possible conflicts of interests.
Network of actors involved in (ecosystem-based) natural hazard risk management: Exchange of information, influences and financial streams exemplified by the Austrian GreenRisk4ALPs pilot action regions.
More details about the stakeholder analyses conducted in the other PARs can be found in the GreenRisk4ALPs project report ‘Actors and networks for ecosystem-based risk management for the Alpine Space’ [50].
The following is a (chronologically sorted) summary of the events, site inspections, meetings, etc. that were held to achieve the best possible integration and participation of the relevant stakeholders in terms of the project objectives.
As a kick-off for the stakeholder involvement process in the project, the mayors of the two municipalities that constitute the Austrian PAR were interviewed. A detailed questionnaire was answered by these political decision-makers and evaluated [50]. The questionnaires primarily served to summarize past natural hazard events and to identify expected future challenges in natural hazard and protective forest management.
Based on the identification of stakeholders carried out in the network analysis, the was presented to a wider audience, which was introduced to the project objectives. Important issues (e.g., where the overpopulation of game is severely damaging protective forests locally) were addressed. During a lively discussion on the current status and the urgent challenges in the region, several topics were defined for further investigation within the framework of GreenRisk4ALPs, one of which was addressed in [51]. During this discussion, representatives of the stakeholder groups also recommended to include additional relevant actors. These stakeholders had already been identified in the stakeholder network analysis and therefore only needed to be contacted.
The site inspection resulted from the lively discussion at the second round table. The focus was on the massive impairment of specific protective forests caused by the high population of game and a prominent rock face from which boulders regularly endanger infrastructure. The present stakeholders showed great interest and the need to communicate the most pressing challenges of the community.
After controversial discussions about the general conflict between forest and game management, contact was made with the Tyrolean Hunters’ Association. An interesting exchange on highly relevant topics (e.g., browsing) took place. It was highlighted that the interests of various stakeholders naturally differ and that this can also influence the setting of objectives and goals of the project.
The expert round table had the aim to discuss and critically examine various modeling results generated within the framework of GreenRisk4ALPs with experts from various disciplines. Representatives from forest and natural hazard management were invited, most of them were already familiar with the project or had previously worked together. For various reasons, three stakeholders (more than half) canceled the meeting at short notice. This experience highlights the challenges underling participatory approaches. Nevertheless, the discussion was very lively and the questions and technical input from the experts showed that the constant involvement of stakeholders is highly relevant for adaptations in every step of the project.
Stakeholders from all relevant areas were invited to a hybrid event (both online and on-site) at the end of the project [52]. The decision support tools developed in the project - which were based on stakeholder inputs, among others - were presented to practitioners, policy makers, scientists and to the general public. Finally, the extent to which stakeholders and practitioners can practically use new findings and tools from science was discussed. The indispensable feedback from practitioners and the realization by scientists that there is still a long way to go to understand the gaps that exist in practice were important discussion points during this final GreenRisk4ALPs event.
As noted from the previous paragraphs, a lively participation was quickly achieved at the beginning of the project. Helpful follow-up events involving additional stakeholders and the definition and concretization of local objectives in the context of the project GreenRisk4ALPs could be generated.
Within the GreenRisk4ALPs project, further analyses regarding stakeholders were conducted to better plan the participatory processes and to pinpoint potential actors’ interests and possible conflicts between them. In this context, conflicts were defined as a result of different interests in ecosystem services (ES), which cannot be fulfilled simultaneously [20].
Ecosystem services are “the benefits people obtain from ecosystems” [53]. In regard to NHRM in the Alpine Space we used an ES classification with four classes [53]: (i) regulating services such as green prevention measures entailing the maintenance, afforestation or reforestation of protective forests; (ii) provisioning services such as wood or game provision; (iii) supporting services such as biodiversity or habitats; and (iv) cultural services such as outdoor recreation, esthetics of cultural landscapes or tourism.
Out of these four classes we selected 12 ES relevant for NHRM in the Alpine Space [54]. They provided a first link to individual or collective actors that might be affected by the ES provision. This ES perspective builds up necessarily on actors who have a stake in the issue of NHRM. This NHRM issue is linked to the achievement of their goals, objectives or conditions to which specific ES can contribute [55]. In this context, actors can be divided in two groups: users and regulators. Users can be defined as the actors who benefit from ES and, for instance, include protective forest owners, hunters, environmental actors and citizens. Regulators on the other hand include different levels of the administrative system and subordinate agencies (e.g., state agency for agriculture or forestry). Both, users and regulators can benefit or influence ES in different ways: (i) by direct use, primarily by harvesting, consuming and even producing services [56] or (ii) by indirect influence exerted through the decision-making system (for instance by elections) [57]. Governmental actors themselves are responsible (by their mandate) for the public task of managing, maintaining, restoring or distributing ES related to natural hazards risks. These tasks become constitutive for the social role of regulators and link them to various collective actors, whose specific goals, objectives or conditions result in a variety of ES-related interests. Regulator’s influence is visible directly in the ecosystems and their services or indirectly as a consequence of changing the behavior of users (which is more frequent), that is, by providing subsidies for forest management or enforcing regulations on hazard zone plans. Normally, regulators receive their mandate as a result of formal institutional settings [58]. The social role which an actor has influences the formation of its interests and limits the available sources and/or political instruments to enforce the own interests in decision making processes.
Figure 3 shows the area affected by three natural hazards, snow avalanches, rockfall and shallow landslides, and reflects the ES approach adapted for the GreenRisk4ALPs project. It reveals the two different social roles of actors – user (red) and regulator (blue) - and possible ways of actors’ influence on NHRM. The role of science is not visualized but it includes the provision of innovative NHRM strategies to regulators and/or users. They can accept (or reject) the scientific information and, after merging it with their existing knowledge and experiences, new knowledge emerges [59], which is used to enforce their own interests.
Stakeholder (actor) roles in natural hazard risk management.
Building up on the information gained from the stakeholder analysis, roundtables with local experts were organized in the framework of the project. Among the different roundtables, a series of workshops was organized, applying a specific method developed within the project, the Rapid Risk management Appraisal (RRA).
The RRA is a participatory tool which aims to identify the strengths and the points for improvement in the field of NHRM in the different PARs for the implementation of future risk reduction measures. Consequently, this tool aims at supporting municipalities to increase their resilience to natural disasters.
The RRA makes use of local knowledge through the involvement of local experts in a short (few hours to half-day), collaborative workshop. This way, qualitative information as well as detailed knowledge on local particularities can be collected in a short time frame within a group setting. The personal information exchange which takes place through such a participatory approach also fosters mutual learning and information exchange among experts with a diverse technical background. The results gained from this participatory exercise can serve as a starting point for a more in-depth analysis, providing also a more specific direction in which to focus the detailed spatially explicit risk assessment and scientific research in general.
The selection of participants to the RRA workshop aimed to provide both technical and applied expertise within the field of risk management (e.g. geology department, torrent and avalanche control experts, but also foresters, civil protection engineers, land use planners and municipality technicians). Moreover, the technical expertise covered a range of gravitational natural hazards addressed by the project.
The RRA approach follows a series of steps, adapted from the ISO standard 31,000 for risk management [60]. The standard focuses on providing guidelines for the management of risks. Although it mainly addresses organizations and industries, it can be customized and applied to different activities, including decision-making at all levels. ISO31000 is here applied as a general framework to guide the collection of information and the discussion during the workshop. The three steps are the following: risk identification (1), risk analysis (2), and risk evaluation (3).
This step aims at identifying the two natural hazards which are the most relevant from a risk perspective for each PAR. Thus, the focus of this step is discussing about damage and losses that the different hazards have caused in the past and which are likely to cause in the future. The indirect consequences caused by such events (i.e., impact on reputation, interruption of activities) are also addressed. Consequently, this step provides information about the general sensitivity to natural hazards starting from the lessons we can learn from the past and moving on to potential and future risks. Maps are also used to visualize the areas mentioned by the different experts. If available, maps can include past natural hazard events or hazard zone plans.
The risk management analysis step builds on the previous discussion and represents the core of the RRA. The aim of this step is therefore to analyze risk management practices in place in the PAR, related to the two previously selected natural hazards. In order to cover all the risk management activities, questions are structures following the Integrated Risk Management cycle steps [61]. The adopted measures should therefore cover the preparedness, the response and the recovery phases [62].
The selected questions, which constitute this step of the RRA are divided in eight categories and are listed in the GreenRisk4ALPs project report “Preparation for risk analysis and strategy workshops” [63]. Each of the questions is presented together with three possible answers which correspond to different scenarios of expert satisfaction. The first scenario describes the case in which the participants perceive the specific risk management practice as a best practice or if they are highly satisfied with its quality or implementation. On the contrary, the third scenario, foresees a low expert satisfaction and ample room for improvement. The second scenario provides the intermediate or average case, where experts see space for desirable improvements. Along with the three scenarios, discussion points such as concrete best practice examples from the European Alps are listed to provide existent examples or comparisons to which experts could refer to during the discussion. The different experts are asked to answer and discuss each question in detail, explaining how each risk management-related-practice functions in their PAR, considering the differences and similarities for the selected natural hazards. Finally, experts are asked to come to an agreement and to select one of the three proposed scenarios.
Furthermore, different scores are attributed to the three scenarios. The maximum number of points is assigned to the best practice scenario (scenario one); on the contrary, the least is given in case some points are missing and an improvement is considered as necessary (scenario three). The full answer, the selected scenarios and the respective points are all recorded and used in the risk management evaluation step. An example of a question, the scenarios and respective discussion points are provided below (Figure 4).
An example of a question of the RRA, including scenarios on which the experts should agree on, and possible discussion points attributed to each scenario. On the left also the points assigned to each scenario are reported.
The points assigned in the previous steps are used to generate a spider chart. For this scope, the assigned points are inserted in an Excel Sheet and the average for each category is then calculated.
The spider chart, called here
Example of a risk management profile. A spider chart that allows to compare the risk management capacities in place related to different natural hazards.
The spider chart is presented and discussed with the participants as a final step of the workshop. By presenting the Risk Management Profile, the participants receive an immediate picture which summarizes the risk management practices addressed during the half-a-day RRA workshop. This way, the strengths in risk management can be underlined and entrance points for improvement can be summarized.
Finally, after the execution of the RRA workshops in the different study areas, the results from different PARs are compared, considering not only the profile but also the full recorded answers. Best practices or strengths which arise from the analysis of the results of one PAR could be transferred or proposed to PARs presenting specific weaknesses. This way, one PAR can learn from the risk management of the others and a more successful ecosystem-based strategy can be proposed. In particular, the final results of the RRA activity are presented in the respective project report [64].
The involvement of local actors in participatory processes can be placed on different rungs or steps of the participation ladder or pyramid (Subchapter 2, Figure 1); therefore, different levels of participation were achieved throughout the project.
Since the project focused primarily on the modeling of natural hazards and on the respective risk identification, many activities described in the previous sections belong to the consultation level of participation. Participants were asked to bring in questions and criticism to provide a solid basis and knowledge for the development of project tools (see also chapters [65, 66] of this book).
On the other hand, participatory processes such as the Rapid Risk management Appraisal belong to the Participation rung of the pyramid. Participants were indeed asked to actively support the process, bringing in their own ideas and perception on current risk management practices and on potential ways to improve them in the future.
A higher level of participation (e.g., Empowerment) can be achieved beyond the project if the local experts involved practically try to improve risk management practices using the RRA or other project outputs.
As previously highlighted in the introduction, environmental issues are best dealt with by involving affected citizens and stakeholders [6]. In the stakeholder analysis and involvement in the project GreenRisk4ALPs, not all citizens or the entire public were involved [10], but - as described in Subchapter 3 - all relevant public institutions and private stakeholders at different levels were considered. The example of the Austrian Pilot Action Region was used to outline what a stakeholder network analysis in this region might look like and which special characteristics might have to be considered.
In a stakeholder network analysis, it is important to become familiar with the administrative and political structures in the region of interest. This is particularly challenging in a country such as Austria, where the division of administration and legislation differs between the different federal states.
In the implementation of stakeholder involvement (e.g., roundtables or interviews), it is essential that stakeholders are not given the impression that they are being pitted against each other. Such situations were also relevant during the GreenRisk4ALPs project. Even if all possible stakeholders should not be brought together at the same table from the beginning, it is important that all stakeholders who are somehow identified as relevant are involved during a project. In this context, clear, unambiguous and comprehensive communication is essential. This is how results can be successfully achieved in projects with the need for stakeholder involvement. It should be considered that transparent and integrative processes are the central prerequisite for implementing research results in practice, for any necessary political solution strategies, and for the implementation of transnational management programs [19].
If new methods are developed during a project, they can ideally be applied and tested during stakeholder involvement activities. A good example is the development and application of the Rapid Risk management Appraisal, which could contribute to the potential generation of risk management plans in the context of specially tailored workshops. The Protective Forest Assessment Tool (FAT) was also a GreenRisk4ALPs development [67, 68], which can offer stakeholders a tool for decision-making in NHRM. The development of the tool was influenced by critical feedback from the involved stakeholders throughout the project, which is evidence that the involvement of stakeholders from the beginning allowed to respond and to tailor the outputs to their needs.
We thank all the stakeholders who dedicated their expertise and time. This work was conducted in the context of the GreenRisk4ALPs project (ASP635), which has been financed by Interreg Alpine Space programme, one of the 15 transnational cooperation programs covering the whole of the European Union (EU) in the framework of European Regional policy.
The authors declare no conflict of interest.
IntechOpen aims to ensure that original material is published while at the same time giving significant freedom to our Authors. To that end we maintain a flexible Copyright Policy guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
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\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
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\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
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\n\nLast updated: 2020-11-27
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In general, the pyrolysis types are classified base on heating rate mainly either fast or slow pyrolysis. The characteristic and properties of wood vinegar are primarily influenced by the type of carbonaceous feedstocks as well as the production techniques. Wood vinegar is a complex mixture of polar and non-polar chemicals with various molecular weights and compositions. Its major constituent is water (80–90%). Some physical properties; such as pH, specific gravity, dissolved tar content are, respectively, within the range of 2–4, 1.005–1.016 g/mL, 0.23–0.89% wt, and color, odor and transparency have been reported. In addition, the degree of oBrix was ranged between 1.7 and 6.6. Besides water, the chemical compositions of wood vinegars consisted of acetic acid with the largest component (30.45–70.60 mg.mL−1). A high number of phenol derivatives have been found and those in higher concentrations were 4-propyl-2-methoxyphenol (5–11 mg.mL−1) followed by 2-methylphenol (2–4 mg.mL−1). Wood vinegar has been regarded as a natural product, which claimed to be capable in several fields of application. In agriculture, wood vinegar has been used in vegetable cropping in order to combat disease, pest control, improve growth and fruit quality, seed germination accelerator as well as herbicide. In pharmaceutical and medical applications, it is used for the preparation of detoxification pad while in veterinary and animal production, incorporation of the wood vinegar in feed could promote acidity in large intestine to inhibit growth of enteropathogenic microbes. In food processing, wood vinegar has a characteristic smoke flavor, and also exhibits microbial growth inhibition. In addition, several investigators reported that bio-oil and wood vinegar obtained from fast pyrolysis and carbonization showed a high potential on organic wood preservative. In summary, the wood vinegar prepared from the tropical wood and/or biomass waste is widely beneficial. 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It is the conversion of forested land to non-forested land by humans. Deforestation occurs when a land dominated by naturally occurring trees is converted to provide certain services in response to the human demand. The indiscriminate felling of trees has resulted in a reduction of 3.16% in the global forest cover from 1990 to 2015. Although India has seen an increment in the total forest cover of ca. 1%, still there are certain regions in the country that have sought a decrease in the forest cover. The main reasons attributed to the reduction in forest cover are shifting cultivation, rotational felling, other biotic pressures, diversion of forest lands for developmental activities, etc. Continuous illicit cutting of trees has impacted the microclimatic conditions, hydrological cycle, soil quality, biodiversity, etc. of the country, thereby making the country more vulnerable for any uneventful happening. Sustainable forest management practices, alternatives for shifting cultivation, promotion of plantation outside the forest and the usage of certified forest products, etc. are some of the measures that can be adopted to curb the rate of deforestation.",book:{id:"7629",slug:"forest-degradation-around-the-world",title:"Forest Degradation Around the World",fullTitle:"Forest Degradation Around the World"},signatures:"Rima Kumari, Ayan Banerjee, Rahul Kumar, Amit Kumar, Purabi Saikia and Mohammed Latif Khan",authors:[{id:"276688",title:"Prof.",name:"Mohammed Latif",middleName:null,surname:"Khan",slug:"mohammed-latif-khan",fullName:"Mohammed Latif Khan"},{id:"279797",title:"Dr.",name:"Purabi",middleName:null,surname:"Saikia",slug:"purabi-saikia",fullName:"Purabi Saikia"},{id:"279806",title:"MSc.",name:"Rima",middleName:null,surname:"Kumari",slug:"rima-kumari",fullName:"Rima Kumari"},{id:"279807",title:"BSc.",name:"Ayan",middleName:null,surname:"Banerjee",slug:"ayan-banerjee",fullName:"Ayan Banerjee"},{id:"285660",title:"Dr.",name:"Amit",middleName:null,surname:"Kumar",slug:"amit-kumar",fullName:"Amit Kumar"},{id:"285661",title:"Dr.",name:"Rahul",middleName:null,surname:"Kumar",slug:"rahul-kumar",fullName:"Rahul Kumar"}]},{id:"45219",doi:"10.5772/56279",title:"Potential Future Ranges of Tree Species in the Alps",slug:"potential-future-ranges-of-tree-species-in-the-alps",totalDownloads:4918,totalCrossrefCites:3,totalDimensionsCites:16,abstract:null,book:{id:"3403",slug:"management-strategies-to-adapt-alpine-space-forests-to-climate-change-risks",title:"Management Strategies to Adapt Alpine Space Forests to Climate Change Risks",fullTitle:"Management Strategies to Adapt Alpine Space Forests to Climate Change Risks"},signatures:"Niklaus E. Zimmermann, Robert Jandl, Marc Hanewinkel, Georges\nKunstler, Christian Kölling, Patrizia Gasparini, Andrej Breznikar,\nEliane S. Meier, Signe Normand, Ulrich Ulmer, Thomas\nGschwandtner, Holger Veit, Maria Naumann, Wolfgang Falk, Karl\nMellert, Maria Rizzo, Mitja Skudnik and Achilleas Psomas",authors:[{id:"165202",title:"Prof.",name:"Niklaus",middleName:"E.",surname:"Zimmermann",slug:"niklaus-zimmermann",fullName:"Niklaus Zimmermann"}]}],mostDownloadedChaptersLast30Days:[{id:"31959",title:"Structure, Diversity, Threats and Conservation of Tropical Forests",slug:"structure-diversity-threats-and-conservation-of-tropical-forests",totalDownloads:8044,totalCrossrefCites:2,totalDimensionsCites:5,abstract:null,book:{id:"902",slug:"tropical-forests",title:"Tropical Forests",fullTitle:"Tropical Forests"},signatures:"Madhugiri Nageswara-Rao, Jaya R. Soneji and Padmini Sudarshana",authors:[{id:"79318",title:"Dr.",name:"Padmini",middleName:null,surname:"Sudarshana",slug:"padmini-sudarshana",fullName:"Padmini Sudarshana"},{id:"120847",title:"Dr.",name:"Madhugiri",middleName:null,surname:"Nageswara-Rao",slug:"madhugiri-nageswara-rao",fullName:"Madhugiri Nageswara-Rao"},{id:"120848",title:"Dr.",name:"Jaya",middleName:null,surname:"Soneji",slug:"jaya-soneji",fullName:"Jaya Soneji"}]},{id:"66710",title:"Deforestation in India: Consequences and Sustainable Solutions",slug:"deforestation-in-india-consequences-and-sustainable-solutions",totalDownloads:2063,totalCrossrefCites:13,totalDimensionsCites:17,abstract:"Deforestation is one of the most pressing environmental issues that the world is facing currently. It is the conversion of forested land to non-forested land by humans. Deforestation occurs when a land dominated by naturally occurring trees is converted to provide certain services in response to the human demand. The indiscriminate felling of trees has resulted in a reduction of 3.16% in the global forest cover from 1990 to 2015. Although India has seen an increment in the total forest cover of ca. 1%, still there are certain regions in the country that have sought a decrease in the forest cover. The main reasons attributed to the reduction in forest cover are shifting cultivation, rotational felling, other biotic pressures, diversion of forest lands for developmental activities, etc. Continuous illicit cutting of trees has impacted the microclimatic conditions, hydrological cycle, soil quality, biodiversity, etc. of the country, thereby making the country more vulnerable for any uneventful happening. Sustainable forest management practices, alternatives for shifting cultivation, promotion of plantation outside the forest and the usage of certified forest products, etc. are some of the measures that can be adopted to curb the rate of deforestation.",book:{id:"7629",slug:"forest-degradation-around-the-world",title:"Forest Degradation Around the World",fullTitle:"Forest Degradation Around the World"},signatures:"Rima Kumari, Ayan Banerjee, Rahul Kumar, Amit Kumar, Purabi Saikia and Mohammed Latif Khan",authors:[{id:"276688",title:"Prof.",name:"Mohammed Latif",middleName:null,surname:"Khan",slug:"mohammed-latif-khan",fullName:"Mohammed Latif Khan"},{id:"279797",title:"Dr.",name:"Purabi",middleName:null,surname:"Saikia",slug:"purabi-saikia",fullName:"Purabi Saikia"},{id:"279806",title:"MSc.",name:"Rima",middleName:null,surname:"Kumari",slug:"rima-kumari",fullName:"Rima Kumari"},{id:"279807",title:"BSc.",name:"Ayan",middleName:null,surname:"Banerjee",slug:"ayan-banerjee",fullName:"Ayan Banerjee"},{id:"285660",title:"Dr.",name:"Amit",middleName:null,surname:"Kumar",slug:"amit-kumar",fullName:"Amit Kumar"},{id:"285661",title:"Dr.",name:"Rahul",middleName:null,surname:"Kumar",slug:"rahul-kumar",fullName:"Rahul Kumar"}]},{id:"68528",title:"Forest Biodiversity and Deforestation in Bangladesh: The Latest Update",slug:"forest-biodiversity-and-deforestation-in-bangladesh-the-latest-update",totalDownloads:1553,totalCrossrefCites:4,totalDimensionsCites:13,abstract:"Located in the Indo-Burma biodiversity hotspot, Bangladesh is a tropical country in Southeast Asia and a transitional point for flora and fauna between the Indo-Himalayan and Indo-Chinese subregions. About 11% land area (1,429,000 hectares) of the country is covered with four major forest types: mixed-evergreen forests, deciduous forests, mangrove forests, and freshwater swamp forests. Though Bangladesh is a small and densely populated country, it is the home of 1952 species of invertebrates, 653 fish, 50 amphibians, 147 reptiles, 566 birds, and 127 mammalian species of which many of them are globally threatened. We have discussed the latest status of all the major vertebrate groups in this chapter. Thirty-one species of vertebrates have gone extinct from Bangladesh over the last century. Many of the species are facing continuous threat of extinction due to deforestation and degradation of habitat caused by various anthropogenic activities. In this chapter, we are going to discuss about the current management and conservation practices and issues related to the forests and wildlife of Bangladesh.",book:{id:"7629",slug:"forest-degradation-around-the-world",title:"Forest Degradation Around the World",fullTitle:"Forest Degradation Around the World"},signatures:"Ahm Ali Reza and Md. Kamrul Hasan",authors:[{id:"281012",title:"Dr.",name:"Md. Kamrul",middleName:null,surname:"Hasan",slug:"md.-kamrul-hasan",fullName:"Md. Kamrul Hasan"},{id:"302258",title:"Dr.",name:"AHM Ali",middleName:null,surname:"Reza",slug:"ahm-ali-reza",fullName:"AHM Ali Reza"}]},{id:"61747",title:"Physicochemistry and Utilization of Wood Vinegar from Carbonization of Tropical Biomass Waste",slug:"physicochemistry-and-utilization-of-wood-vinegar-from-carbonization-of-tropical-biomass-waste",totalDownloads:2183,totalCrossrefCites:9,totalDimensionsCites:19,abstract:"Pyroligneous acid also called wood vinegar is an aqueous liquid produced from pyrolysis of lignocellulose waste and biomass. In general, the pyrolysis types are classified base on heating rate mainly either fast or slow pyrolysis. The characteristic and properties of wood vinegar are primarily influenced by the type of carbonaceous feedstocks as well as the production techniques. Wood vinegar is a complex mixture of polar and non-polar chemicals with various molecular weights and compositions. Its major constituent is water (80–90%). Some physical properties; such as pH, specific gravity, dissolved tar content are, respectively, within the range of 2–4, 1.005–1.016 g/mL, 0.23–0.89% wt, and color, odor and transparency have been reported. In addition, the degree of oBrix was ranged between 1.7 and 6.6. Besides water, the chemical compositions of wood vinegars consisted of acetic acid with the largest component (30.45–70.60 mg.mL−1). A high number of phenol derivatives have been found and those in higher concentrations were 4-propyl-2-methoxyphenol (5–11 mg.mL−1) followed by 2-methylphenol (2–4 mg.mL−1). Wood vinegar has been regarded as a natural product, which claimed to be capable in several fields of application. In agriculture, wood vinegar has been used in vegetable cropping in order to combat disease, pest control, improve growth and fruit quality, seed germination accelerator as well as herbicide. In pharmaceutical and medical applications, it is used for the preparation of detoxification pad while in veterinary and animal production, incorporation of the wood vinegar in feed could promote acidity in large intestine to inhibit growth of enteropathogenic microbes. In food processing, wood vinegar has a characteristic smoke flavor, and also exhibits microbial growth inhibition. In addition, several investigators reported that bio-oil and wood vinegar obtained from fast pyrolysis and carbonization showed a high potential on organic wood preservative. In summary, the wood vinegar prepared from the tropical wood and/or biomass waste is widely beneficial. The chapter attempts to provide essential knowledge relevant to physicochemical characteristics of wood vinegar and its applications.",book:{id:"6370",slug:"tropical-forests-new-edition",title:"Tropical Forests",fullTitle:"Tropical Forests - New Edition"},signatures:"Yongyuth Theapparat, Ausa Chandumpai and Damrongsak\nFaroongsarng",authors:[{id:"219997",title:"Dr.",name:"Yongyuth",middleName:null,surname:"Theapparat",slug:"yongyuth-theapparat",fullName:"Yongyuth Theapparat"},{id:"226821",title:"Dr.",name:"Ausa",middleName:null,surname:"Chandumpai",slug:"ausa-chandumpai",fullName:"Ausa Chandumpai"},{id:"398427",title:"Dr.",name:"Damrongsak",middleName:null,surname:"Faroongsarng",slug:"damrongsak-faroongsarng",fullName:"Damrongsak Faroongsarng"}]},{id:"54603",title:"Methodological Considerations in the Study of Earthworms in Forest Ecosystems",slug:"methodological-considerations-in-the-study-of-earthworms-in-forest-ecosystems",totalDownloads:1808,totalCrossrefCites:0,totalDimensionsCites:5,abstract:"Decades of studies have shown that soil macrofauna, especially earthworms, play dominant engineering roles in soils, affecting physical, chemical, and biological components of ecosystems. Quantifying these effects would allow crucial improvement in biogeochemical budgets and modeling, predicting response of land use and disturbance, and could be applied to bioremediation efforts. Effective methods of manipulating earthworm communities in the field are needed to accompany laboratory microcosm studies to calculate their net function in natural systems and to isolate specific mechanisms. This chapter reviews laboratory and field methods for enumerating and manipulating earthworm populations, as well as approaches toward quantifying their influences on soil processes and biogeochemical cycling.",book:{id:"5539",slug:"forest-ecology-and-conservation",title:"Forest Ecology and Conservation",fullTitle:"Forest Ecology and Conservation"},signatures:"Dylan Rhea-Fournier and Grizelle González",authors:[{id:"82355",title:"Dr.",name:"Grizelle",middleName:null,surname:"Gonzalez",slug:"grizelle-gonzalez",fullName:"Grizelle Gonzalez"},{id:"194800",title:"M.Sc.",name:"Dylan",middleName:null,surname:"Rhea-Fournier",slug:"dylan-rhea-fournier",fullName:"Dylan Rhea-Fournier"}]}],onlineFirstChaptersFilter:{topicId:"138",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:320,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:133,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:17,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{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"}}}},{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"}}}}]},series:{item:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261",scope:"Modern physiology requires a comprehensive understanding of the integration of tissues and organs throughout the mammalian body, including the cooperation between structure and function at the cellular and molecular levels governed by gene and protein expression. While a daunting task, learning is facilitated by identifying common and effective signaling pathways mediated by a variety of factors employed by nature to preserve and sustain homeostatic life. \r\nAs a leading example, the cellular interaction between intracellular concentration of Ca+2 increases, and changes in plasma membrane potential is integral for coordinating blood flow, governing the exocytosis of neurotransmitters, and modulating gene expression and cell effector secretory functions. Furthermore, in this manner, understanding the systemic interaction between the cardiovascular and nervous systems has become more important than ever as human populations' life prolongation, aging and mechanisms of cellular oxidative signaling are utilised for sustaining life. \r\nAltogether, physiological research enables our identification of distinct and precise points of transition from health to the development of multimorbidity throughout the inevitable aging disorders (e.g., diabetes, hypertension, chronic kidney disease, heart failure, peptic ulcer, inflammatory bowel disease, age-related macular degeneration, cancer). With consideration of all organ systems (e.g., brain, heart, lung, gut, skeletal and smooth muscle, liver, pancreas, kidney, eye) and the interactions thereof, this Physiology Series will address the goals of resolving (1) Aging physiology and chronic disease progression (2) Examination of key cellular pathways as they relate to calcium, oxidative stress, and electrical signaling, and (3) how changes in plasma membrane produced by lipid peroxidation products can affect aging physiology, covering new research in the area of cell, human, plant and animal physiology.",coverUrl:"https://cdn.intechopen.com/series/covers/10.jpg",latestPublicationDate:"June 20th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:11,editor:{id:"35854",title:"Prof.",name:"Tomasz",middleName:null,surname:"Brzozowski",slug:"tomasz-brzozowski",fullName:"Tomasz Brzozowski",profilePictureURL:"https://mts.intechopen.com/storage/users/35854/images/system/35854.jpg",biography:"Prof. Dr. Thomas Brzozowski works as a professor of Human Physiology and is currently Chairman at the Department of Physiology and is V-Dean of the Medical Faculty at Jagiellonian University Medical College, Cracow, Poland. His primary area of interest is physiology and pathophysiology of the gastrointestinal (GI) tract, with the major focus on the mechanism of GI mucosal defense, protection, and ulcer healing. He was a postdoctoral NIH fellow at the University of California and the Gastroenterology VA Medical Center, Irvine, Long Beach, CA, USA, and at the Gastroenterology Clinics Erlangen-Nuremberg and Munster in Germany. He has published 290 original articles in some of the most prestigious scientific journals and seven book chapters on the pathophysiology of the GI tract, gastroprotection, ulcer healing, drug therapy of peptic ulcers, hormonal regulation of the gut, and inflammatory bowel disease.",institutionString:null,institution:{name:"Jagiellonian University",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"10",title:"Animal Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/10.jpg",isOpenForSubmission:!0,editor:{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},{id:"11",title:"Cell Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/11.jpg",isOpenForSubmission:!0,editor:{id:"133493",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",profilePictureURL:"https://mts.intechopen.com/storage/users/133493/images/3091_n.jpg",biography:"Prof. Dr. Angel Catalá \r\nShort Biography Angel Catalá was born in Rodeo (San Juan, Argentina). He studied \r\nchemistry at the Universidad Nacional de La Plata, Argentina, where received aPh.D. degree in chemistry (Biological Branch) in 1965. From\r\n1964 to 1974, he worked as Assistant in Biochemistry at the School of MedicineUniversidad Nacional de La Plata, Argentina. From 1974 to 1976, he was a Fellowof the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor oBiochemistry at the Universidad Nacional de La Plata, Argentina. He is Member ofthe National Research Council (CONICET), Argentina, and Argentine Society foBiochemistry and Molecular Biology (SAIB). His laboratory has been interested for manyears in the lipid peroxidation of biological membranes from various tissues and different species. Professor Catalá has directed twelve doctoral theses, publishedover 100 papers in peer reviewed journals, several chapters in books andtwelve edited books. Angel Catalá received awards at the 40th InternationaConference Biochemistry of Lipids 1999: Dijon (France). W inner of the Bimbo PanAmerican Nutrition, Food Science and Technology Award 2006 and 2012, South AmericaHuman Nutrition, Professional Category. 2006 award in pharmacology, Bernardo\r\nHoussay, in recognition of his meritorious works of research. Angel Catalá belongto the Editorial Board of Journal of lipids, International Review of Biophysical ChemistryFrontiers in Membrane Physiology and Biophysics, World Journal oExperimental Medicine and Biochemistry Research International, W orld Journal oBiological Chemistry, Oxidative Medicine and Cellular Longevity, Diabetes and thePancreas, International Journal of Chronic Diseases & Therapy, International Journal oNutrition, Co-Editor of The Open Biology Journal.",institutionString:null,institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}},editorTwo:null,editorThree:null},{id:"12",title:"Human Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/12.jpg",isOpenForSubmission:!0,editor:{id:"195829",title:"Prof.",name:"Kunihiro",middleName:null,surname:"Sakuma",slug:"kunihiro-sakuma",fullName:"Kunihiro Sakuma",profilePictureURL:"https://mts.intechopen.com/storage/users/195829/images/system/195829.jpg",biography:"Professor Kunihiro Sakuma, Ph.D., currently works in the Institute for Liberal Arts at the Tokyo Institute of Technology. He is a physiologist working in the field of skeletal muscle. He was awarded his sports science diploma in 1995 by the University of Tsukuba and began his scientific work at the Department of Physiology, Aichi Human Service Center, focusing on the molecular mechanism of congenital muscular dystrophy and normal muscle regeneration. His interest later turned to the molecular mechanism and attenuating strategy of sarcopenia (age-related muscle atrophy). His opinion is to attenuate sarcopenia by improving autophagic defects using nutrient- and pharmaceutical-based treatments.",institutionString:null,institution:{name:"Tokyo Institute of Technology",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"331519",title:"Dr.",name:"Kotomi",middleName:null,surname:"Sakai",slug:"kotomi-sakai",fullName:"Kotomi Sakai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000031QtFXQA0/Profile_Picture_1637053227318",biography:"Senior researcher Kotomi Sakai, Ph.D., MPH, works at the Research Organization of Science and Technology in Ritsumeikan University. She is a researcher in the geriatric rehabilitation and public health field. She received Ph.D. from Nihon University and MPH from St.Luke’s International University. Her main research interest is sarcopenia in older adults, especially its association with nutritional status. Additionally, to understand how to maintain and improve physical function in older adults, to conduct studies about the mechanism of sarcopenia and determine when possible interventions are needed.",institutionString:null,institution:{name:"Ritsumeikan University",institutionURL:null,country:{name:"Japan"}}},editorThree:null},{id:"13",title:"Plant Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/13.jpg",isOpenForSubmission:!0,editor:{id:"332229",title:"Prof.",name:"Jen-Tsung",middleName:null,surname:"Chen",slug:"jen-tsung-chen",fullName:"Jen-Tsung Chen",profilePictureURL:"https://mts.intechopen.com/storage/users/332229/images/system/332229.png",biography:"Dr. Jen-Tsung Chen is currently a professor at the National University of Kaohsiung, Taiwan. He teaches cell biology, genomics, proteomics, medicinal plant biotechnology, and plant tissue culture. 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Bucak",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/196707/images/system/196707.png",biography:"Mustafa Numan Bucak received a bachelor’s degree from the Veterinary Faculty, Ankara University, Turkey, where he also obtained a Ph.D. in Sperm Cryobiology. He is an academic staff member of the Department of Reproduction and Artificial Insemination, Selçuk University, Turkey. He manages several studies on sperms and embryos and is an editorial board member for several international journals. His studies include sperm cryobiology, in vitro fertilization, and embryo production in animals.",institutionString:"Selçuk University, Faculty of Veterinary Medicine",institution:null},{id:"90846",title:"Prof.",name:"Yusuf",middleName:null,surname:"Bozkurt",slug:"yusuf-bozkurt",fullName:"Yusuf Bozkurt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/90846/images/system/90846.jpg",biography:"Yusuf Bozkurt has a BSc, MSc, and Ph.D. from Ankara University, Turkey. He is currently a Professor of Biotechnology of Reproduction in the field of Aquaculture, İskenderun Technical University, Turkey. His research interests include reproductive biology and biotechnology with an emphasis on cryo-conservation. He is on the editorial board of several international peer-reviewed journals and has published many papers. Additionally, he has participated in many international and national congresses, seminars, and workshops with oral and poster presentations. He is an active member of many local and international organizations.",institutionString:"İskenderun Technical University",institution:{name:"İskenderun Technical University",country:{name:"Turkey"}}},{id:"61139",title:"Dr.",name:"Sergey",middleName:null,surname:"Tkachev",slug:"sergey-tkachev",fullName:"Sergey Tkachev",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61139/images/system/61139.png",biography:"Dr. Sergey Tkachev is a senior research scientist at the Institute of Fundamental Medicine and Biology, Kazan Federal University, Russia, and at the Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia. He received his Ph.D. in Molecular Biology with his thesis “Genetic variability of the tick-borne encephalitis virus in natural foci of Novosibirsk city and its suburbs.” His primary field is molecular virology with research emphasis on vector-borne viruses, especially tick-borne encephalitis virus, Kemerovo virus and Omsk hemorrhagic fever virus, rabies virus, molecular genetics, biology, and epidemiology of virus pathogens.",institutionString:"Russian Academy of Sciences",institution:{name:"Russian Academy of Sciences",country:{name:"Russia"}}},{id:"310962",title:"Dr.",name:"Amlan",middleName:"Kumar",surname:"Patra",slug:"amlan-patra",fullName:"Amlan Patra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/310962/images/system/310962.jpg",biography:"Amlan K. Patra, FRSB, obtained a Ph.D. in Animal Nutrition from Indian Veterinary Research Institute, India, in 2002. He is currently an associate professor at West Bengal University of Animal and Fishery Sciences. He has more than twenty years of research and teaching experience. He held previous positions at the American Institute for Goat Research, The Ohio State University, Columbus, USA, and Free University of Berlin, Germany. His research focuses on animal nutrition, particularly ruminants and poultry nutrition, gastrointestinal electrophysiology, meta-analysis and modeling in nutrition, and livestock–environment interaction. He has authored around 175 articles in journals, book chapters, and proceedings. Dr. Patra serves on the editorial boards of several reputed journals.",institutionString:null,institution:{name:"West Bengal University of Animal and Fishery Sciences",country:{name:"India"}}},{id:"53998",title:"Prof.",name:"László",middleName:null,surname:"Babinszky",slug:"laszlo-babinszky",fullName:"László Babinszky",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/53998/images/system/53998.png",biography:"László Babinszky is Professor Emeritus, Department of Animal Nutrition Physiology, University of Debrecen, Hungary. He has also worked in the Department of Animal Nutrition, University of Wageningen, Netherlands; the Institute for Livestock Feeding and Nutrition (IVVO), Lelystad, Netherlands; the Agricultural University of Vienna (BOKU); the Institute for Animal Breeding and Nutrition, Austria; and the Oscar Kellner Research Institute for Animal Nutrition, Rostock, Germany. In 1992, Dr. Babinszky obtained a Ph.D. in Animal Nutrition from the University of Wageningen. His main research areas are swine and poultry nutrition. He has authored more than 300 publications (papers, book chapters) and edited four books and fourteen international conference proceedings.",institutionString:"University of Debrecen",institution:{name:"University of Debrecen",country:{name:"Hungary"}}},{id:"201830",title:"Dr.",name:"Fernando",middleName:"Sanchez",surname:"Davila",slug:"fernando-davila",fullName:"Fernando Davila",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201830/images/5017_n.jpg",biography:"I am a professor at UANL since 1988. My research lines are the development of reproductive techniques in small ruminants. We also conducted research on sexual and social behavior in males.\nI am Mexican and study my professional career as an engineer in agriculture and animal science at UANL. Then take a masters degree in science in Germany (Animal breeding). Take a doctorate in animal science at the UANL.",institutionString:null,institution:{name:"Universidad Autónoma de Nuevo León",country:{name:"Mexico"}}},{id:"309250",title:"Dr.",name:"Miguel",middleName:null,surname:"Quaresma",slug:"miguel-quaresma",fullName:"Miguel Quaresma",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309250/images/9059_n.jpg",biography:"Miguel Nuno Pinheiro Quaresma was born on May 26, 1974 in Dili, Timor Island. He is married with two children: a boy and a girl, and he is a resident in Vila Real, Portugal. He graduated in Veterinary Medicine in August 1998 and obtained his Ph.D. degree in Veterinary Sciences -Clinical Area in February 2015, both from the University of Trás-os-Montes e Alto Douro. He is currently enrolled in the Alternative Residency of the European College of Animal Reproduction. He works as a Senior Clinician at the Veterinary Teaching Hospital of UTAD (HVUTAD) with a role in clinical activity in the area of livestock and equine species as well as to support teaching and research in related areas. He teaches as an Invited Professor in Reproduction Medicine I and II of the Master\\'s in Veterinary Medicine degree at UTAD. Currently, he holds the position of Chairman of the Portuguese Buiatrics Association. He is a member of the Consultive Group on Production Animals of the OMV. He has 19 publications in indexed international journals (ISIS), as well as over 60 publications and oral presentations in both Portuguese and international journals and congresses.",institutionString:"University of Trás-os-Montes and Alto Douro",institution:{name:"University of Trás-os-Montes and Alto Douro",country:{name:"Portugal"}}},{id:"38652",title:"Prof.",name:"Rita",middleName:null,surname:"Payan-Carreira",slug:"rita-payan-carreira",fullName:"Rita Payan-Carreira",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRiFPQA0/Profile_Picture_1614601496313",biography:"Rita Payan Carreira earned her Veterinary Degree from the Faculty of Veterinary Medicine in Lisbon, Portugal, in 1985. She obtained her Ph.D. in Veterinary Sciences from the University of Trás-os-Montes e Alto Douro, Portugal. After almost 32 years of teaching at the University of Trás-os-Montes and Alto Douro, she recently moved to the University of Évora, Department of Veterinary Medicine, where she teaches in the field of Animal Reproduction and Clinics. Her primary research areas include the molecular markers of the endometrial cycle and the embryo–maternal interaction, including oxidative stress and the reproductive physiology and disorders of sexual development, besides the molecular determinants of male and female fertility. She often supervises students preparing their master's or doctoral theses. She is also a frequent referee for various journals.",institutionString:null,institution:{name:"University of Évora",country:{name:"Portugal"}}},{id:"283019",title:"Dr.",name:"Oudessa",middleName:null,surname:"Kerro Dego",slug:"oudessa-kerro-dego",fullName:"Oudessa Kerro Dego",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/283019/images/system/283019.png",biography:"Dr. Kerro Dego is a veterinary microbiologist with training in veterinary medicine, microbiology, and anatomic pathology. Dr. Kerro Dego is an assistant professor of dairy health in the department of animal science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. He received his D.V.M. (1997), M.S. (2002), and Ph.D. (2008) degrees in Veterinary Medicine, Animal Pathology and Veterinary Microbiology from College of Veterinary Medicine, Addis Ababa University, Ethiopia; College of Veterinary Medicine, Utrecht University, the Netherlands and Western College of Veterinary Medicine, University of Saskatchewan, Canada respectively. He did his Postdoctoral training in microbial pathogenesis (2009 - 2015) in the Department of Animal Science, the University of Tennessee, Institute of Agriculture, Knoxville, Tennessee. Dr. Kerro Dego’s research focuses on the prevention and control of infectious diseases of farm animals, particularly mastitis, improving dairy food safety, and mitigation of antimicrobial resistance. Dr. Kerro Dego has extensive experience in studying the pathogenesis of bacterial infections, identification of virulence factors, and vaccine development and efficacy testing against major bacterial mastitis pathogens. Dr. Kerro Dego conducted numerous controlled experimental and field vaccine efficacy studies, vaccination, and evaluation of immunological responses in several species of animals, including rodents (mice) and large animals (bovine and ovine).",institutionString:"University of Tennessee at Knoxville",institution:{name:"University of Tennessee at Knoxville",country:{name:"United States of America"}}},{id:"251314",title:"Dr.",name:"Juan Carlos",middleName:null,surname:"Gardón",slug:"juan-carlos-gardon",fullName:"Juan Carlos Gardón",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/251314/images/system/251314.jpeg",biography:"Juan Carlos Gardón Poggi received University degree from the Faculty of Agrarian Science in Argentina, in 1983. Also he received Masters Degree and PhD from Córdoba University, Spain. He is currently a Professor at the Catholic University of Valencia San Vicente Mártir, at the Department of Medicine and Animal Surgery. He teaches diverse courses in the field of Animal Reproduction and he is the Director of the Veterinary Farm. He also participates in academic postgraduate activities at the Veterinary Faculty of Murcia University, Spain. His research areas include animal physiology, physiology and biotechnology of reproduction either in males or females, the study of gametes under in vitro conditions and the use of ultrasound as a complement to physiological studies and development of applied biotechnologies. Routinely, he supervises students preparing their doctoral, master thesis or final degree projects.",institutionString:"Catholic University of Valencia San Vicente Mártir, Spain",institution:{name:"Valencia Catholic University Saint Vincent Martyr",country:{name:"Spain"}}},{id:"125292",title:"Dr.",name:"Katy",middleName:null,surname:"Satué Ambrojo",slug:"katy-satue-ambrojo",fullName:"Katy Satué Ambrojo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/125292/images/system/125292.jpeg",biography:"Katy Satué Ambrojo received her Veterinary Medicine degree, Master degree in Equine Technology and doctorate in Veterinary Medicine from the Faculty of Veterinary, CEU-Cardenal Herrera University in Valencia, Spain. She is a Full Professor at the Department of Medicine and Animal Surgery at the same University. She developed her research activity in the field of Endocrinology, Hematology, Biochemistry and Immunology of horses. She is a scientific reviewer of several international journals : American Journal of Obstetrics and Gynecology, Comparative Clinical Pathology, Veterinary Clinical Pathology, Journal of Equine Veterinary Science, Reproduction in Domestic Animals, Research Veterinary Science, Brazilian Journal of Medical and Biological Research, Livestock Production Science and Theriogenology. Since 2014, she has been the Head of the Clinical Analysis Laboratory of the Hospital Clínico Veterinario from the Faculty of Veterinary, CEU-Cardenal Herrera University.",institutionString:"CEU-Cardenal Herrera University",institution:{name:"CEU Cardinal Herrera University",country:{name:"Spain"}}},{id:"309529",title:"Dr.",name:"Albert",middleName:null,surname:"Rizvanov",slug:"albert-rizvanov",fullName:"Albert Rizvanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/309529/images/9189_n.jpg",biography:'Albert A. Rizvanov is a Professor and Director of the Center for Precision and Regenerative Medicine at the Institute of Fundamental Medicine and Biology, Kazan Federal University (KFU), Russia. He is the Head of the Center of Excellence “Regenerative Medicine” and Vice-Director of Strategic Academic Unit \\"Translational 7P Medicine\\". Albert completed his Ph.D. at the University of Nevada, Reno, USA and Dr.Sci. at KFU. He is a corresponding member of the Tatarstan Academy of Sciences, Russian Federation. Albert is an author of more than 300 peer-reviewed journal articles and 22 patents. He has supervised 11 Ph.D. and 2 Dr.Sci. dissertations. Albert is the Head of the Dissertation Committee on Biochemistry, Microbiology, and Genetics at KFU.\nORCID https://orcid.org/0000-0002-9427-5739\nWebsite https://kpfu.ru/Albert.Rizvanov?p_lang=2',institutionString:"Kazan Federal University",institution:{name:"Kazan Federal University",country:{name:"Russia"}}},{id:"210551",title:"Dr.",name:"Arbab",middleName:null,surname:"Sikandar",slug:"arbab-sikandar",fullName:"Arbab Sikandar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210551/images/system/210551.jpg",biography:"Dr. Arbab Sikandar, PhD, M. Phil, DVM was born on April 05, 1981. He is currently working at the College of Veterinary & Animal Sciences as an Assistant Professor. He previously worked as a lecturer at the same University. \nHe is a Member/Secretory of Ethics committee (No. CVAS-9377 dated 18-04-18), Member of the QEC committee CVAS, Jhang (Regr/Gen/69/873, dated 26-10-2017), Member, Board of studies of Department of Basic Sciences (No. CVAS. 2851 Dated. 12-04-13, and No. CVAS, 9024 dated 20/11/17), Member of Academic Committee, CVAS, Jhang (No. CVAS/2004, Dated, 25-08-12), Member of the technical committee (No. CVAS/ 4085, dated 20,03, 2010 till 2016).\n\nDr. Arbab Sikandar contributed in five days hands-on-training on Histopathology at the Department of Pathology, UVAS from 12-16 June 2017. He received a Certificate of appreciation for contributions for Popularization of Science and Technology in the Society on 17-11-15. He was the resource person in the lecture series- ‘scientific writing’ at the Department of Anatomy and Histology, UVAS, Lahore on 29th October 2015. He won a full fellowship as a principal candidate for the year 2015 in the field of Agriculture, EICA, Egypt with ref. to the Notification No. 12(11) ACS/Egypt/2014 from 10 July 2015 to 25th September 2015.; he received a grant of Rs. 55000/- as research incentives from Director, Advanced Studies and Research, UVAS, Lahore upon publications of research papers in IF Journals (DR/215, dated 19-5-2014.. He obtained his PhD by winning a HEC Pakistan indigenous Scholarship, ‘Ph.D. fellowship for 5000 scholars – Phase II’ (2av1-147), 17-6/HEC/HRD/IS-II/12, November 15, 2012. \n\nDr. Sikandar is a member of numerous societies: Registered Veterinary Medical Practitioner (life member) and Registered Veterinary Medical Faculty of Pakistan Veterinary Medical Council. The Registration code of PVMC is RVMP/4298 and RVMF/ 0102.; Life member of the University of Veterinary and Animal Sciences, Lahore, Alumni Association with S# 664, dated: 6-4-12. ; Member 'Vets Care Organization Pakistan” with Reference No. VCO-605-149, dated 05-04-06. :Member 'Vet Crescent” (Society of Animal Health and Production), UVAS, Lahore.",institutionString:"University of Veterinary & Animal Science",institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}},{id:"311663",title:"Dr.",name:"Prasanna",middleName:null,surname:"Pal",slug:"prasanna-pal",fullName:"Prasanna Pal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311663/images/13261_n.jpg",biography:null,institutionString:null,institution:{name:"National Dairy Research Institute",country:{name:"India"}}},{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",country:{name:"United Kingdom"}}},{id:"283315",title:"Prof.",name:"Samir",middleName:null,surname:"El-Gendy",slug:"samir-el-gendy",fullName:"Samir El-Gendy",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRduYQAS/Profile_Picture_1606215849748",biography:"Samir El-Gendy is a Professor of anatomy and embryology at the faculty of veterinary medicine, Alexandria University, Egypt. Samir obtained his PhD in veterinary science in 2007 from the faculty of veterinary medicine, Alexandria University and has been a professor since 2017. Samir is an author on 24 articles at Scopus and 12 articles within local journals and 2 books/book chapters. His research focuses on applied anatomy, imaging techniques and computed tomography. Samir worked as a member of different local projects on E-learning and he is a board member of the African Association of Veterinary Anatomists and of anatomy societies and as an associated author at local and international journals. Orcid: https://orcid.org/0000-0002-6180-389X",institutionString:null,institution:{name:"Alexandria University",country:{name:"Egypt"}}},{id:"246149",title:"Dr.",name:"Valentina",middleName:null,surname:"Kubale",slug:"valentina-kubale",fullName:"Valentina Kubale",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246149/images/system/246149.jpg",biography:"Valentina Kubale is Associate Professor of Veterinary Medicine at the Veterinary Faculty, University of Ljubljana, Slovenia. Since graduating from the Veterinary faculty she obtained her PhD in 2007, performed collaboration with the Department of Pharmacology, University of Copenhagen, Denmark. She continued as a post-doctoral fellow at the University of Copenhagen with a Lundbeck foundation fellowship. She is the editor of three books and author/coauthor of 23 articles in peer-reviewed scientific journals, 16 book chapters, and 68 communications at scientific congresses. Since 2008 she has been the Editor Assistant for the Slovenian Veterinary Research journal. She is a member of Slovenian Biochemical Society, The Endocrine Society, European Association of Veterinary Anatomists and Society for Laboratory Animals, where she is board member.",institutionString:"University of Ljubljana",institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",biography:"Dr. Fonseca-Alves earned his DVM from Federal University of Goias – UFG in 2008. He completed an internship in small animal internal medicine at UPIS university in 2011, earned his MSc in 2013 and PhD in 2015 both in Veterinary Medicine at Sao Paulo State University – UNESP. Dr. Fonseca-Alves currently serves as an Assistant Professor at Paulista University – UNIP teaching small animal internal medicine.",institutionString:null,institution:{name:"Universidade Paulista",country:{name:"Brazil"}}},{id:"245306",title:"Dr.",name:"María Luz",middleName:null,surname:"Garcia Pardo",slug:"maria-luz-garcia-pardo",fullName:"María Luz Garcia Pardo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/245306/images/system/245306.png",biography:"María de la Luz García Pardo is an agricultural engineer from Universitat Politècnica de València, Spain. She has a Ph.D. in Animal Genetics. Currently, she is a lecturer at the Agrofood Technology Department of Miguel Hernández University, Spain. Her research is focused on genetics and reproduction in rabbits. The major goal of her research is the genetics of litter size through novel methods such as selection by the environmental sensibility of litter size, with forays into the field of animal welfare by analysing the impact on the susceptibility to diseases and stress of the does. Details of her publications can be found at https://orcid.org/0000-0001-9504-8290.",institutionString:null,institution:{name:"Miguel Hernandez University",country:{name:"Spain"}}},{id:"350704",title:"M.Sc.",name:"Camila",middleName:"Silva Costa",surname:"Ferreira",slug:"camila-ferreira",fullName:"Camila Ferreira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/350704/images/17280_n.jpg",biography:"Graduated in Veterinary Medicine at the Fluminense Federal University, specialist in Equine Reproduction at the Brazilian Veterinary Institute (IBVET) and Master in Clinical Veterinary Medicine and Animal Reproduction at the Fluminense Federal University. She has experience in analyzing zootechnical indices in dairy cattle and organizing events related to Veterinary Medicine through extension grants. I have experience in the field of diagnostic imaging and animal reproduction in veterinary medicine through monitoring and scientific initiation scholarships. I worked at the Equus Central Reproduction Equine located in Santo Antônio de Jesus – BA in the 2016/2017 breeding season. I am currently a doctoral student with a scholarship from CAPES of the Postgraduate Program in Veterinary Medicine (Pathology and Clinical Sciences) at the Federal Rural University of Rio de Janeiro (UFRRJ) with a research project with an emphasis on equine endometritis.",institutionString:null,institution:null},{id:"41319",title:"Prof.",name:"Lung-Kwang",middleName:null,surname:"Pan",slug:"lung-kwang-pan",fullName:"Lung-Kwang Pan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41319/images/84_n.jpg",biography:null,institutionString:null,institution:null},{id:"201721",title:"Dr.",name:"Beatrice",middleName:null,surname:"Funiciello",slug:"beatrice-funiciello",fullName:"Beatrice Funiciello",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/201721/images/11089_n.jpg",biography:"Graduated from the University of Milan in 2011, my post-graduate education included CertAVP modules mainly on equines (dermatology and internal medicine) and a few on small animal (dermatology and anaesthesia) at the University of Liverpool. After a general CertAVP (2015) I gained the designated Certificate in Veterinary Dermatology (2017) after taking the synoptic examination and then applied for the RCVS ADvanced Practitioner status. After that, I completed the Postgraduate Diploma in Veterinary Professional Studies at the University of Liverpool (2018). My main area of work is cross-species veterinary dermatology.",institutionString:null,institution:null},{id:"291226",title:"Dr.",name:"Monica",middleName:null,surname:"Cassel",slug:"monica-cassel",fullName:"Monica Cassel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/291226/images/8232_n.jpg",biography:'Degree in Biological Sciences at the Federal University of Mato Grosso with scholarship for Scientific Initiation by FAPEMAT (2008/1) and CNPq (2008/2-2009/2): Project \\"Histological evidence of reproductive activity in lizards of the Manso region, Chapada dos Guimarães, Mato Grosso, Brazil\\". Master\\\'s degree in Ecology and Biodiversity Conservation at Federal University of Mato Grosso with a scholarship by CAPES/REUNI program: Project \\"Reproductive biology of Melanorivulus punctatus\\". PhD\\\'s degree in Science (Cell and Tissue Biology Area) \n at University of Sao Paulo with scholarship granted by FAPESP; Project \\"Development of morphofunctional changes in ovary of Astyanax altiparanae Garutti & Britski, 2000 (Teleostei, Characidae)\\". She has experience in Reproduction of vertebrates and Morphology, with emphasis in Cellular Biology and Histology. 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