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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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Endocannabinoids are small lipids that regulate normal behaviors, including pain reception [1] and feeding [2, 3]. Likewise, cannabinoids have therapeutic potential [4]. Endocannabinoids show a neuroprotective role against acute excitotoxicity [5] and facilitate functional recovery after brain injury [6]. They regulate human airway function and provide a means to treat respiratory pathologies [1]. Cannabinoids are widely used as recreational and psychoactive drugs and interact with other drugs of abuse, indicating the need to understand the endocannabinoid system and the neurobiological substrate of its mood-altering capacity [7, 8]. Furthermore, the endocannabinoid system is crucially involved in processes of learning and memory, for example, in the extinction of aversive memories [9]. Endocannabinoids influence synaptic transmission and different forms of short- and long-term plasticity [10–12]. They also influence growth and development such as synapse formation and neurogenesis. Other biological functions and human behaviors modulated by endocannabinoids include eating and anxiety [2, 3, 13].
\nA hallmark feature of endocannabinoids is their ability to serve as retrograde signaling molecules between activated postsynaptic principal neurons and presynaptic interneurons that express CB1R [10, 12, 14]. While the breadth of endocannabinoid function has become increasingly clear over the past years, we still have much to learn about their detailed signaling mechanisms.
\nOur understanding of the endocannabinoid system has significantly advanced in limbic system areas such as the hippocampus and the amygdala. However, the study of this signaling system in the olfactory pathway is still in its infancy. Recent work has started to shed light on the role of the endocannabinoid system in the olfactory pathway, specifically in the olfactory bulb as well as for its output to higher order olfactory centers and its centrifugal input [3, 15]. Here, we review the role of endocannabinoids as signaling molecules in activity-dependent regulation of dynamically changing neural networks in the limbic and olfactory system and the relevance of the endocannabinoid system for synaptic plasticity. We highlight the prospects for cannabinoid-based therapies in the treatment of various brain disorders such as epilepsy [16, 17]. An increased understanding of cannabinoid signaling may pave the way for developing cannabis-related substances as antiseizure medications.
\nEndocannabinoids are fatty acid-derived endogenous ligands for Gi/o-protein-coupled CB1Rs [11]. Endocannabinoids are synthesized from membrane lipids [18]. They can diffuse through cellular membranes and are thus able to activate receptors in the same manner as exogenously applied cannabinoids such as the plant-derived compound Δ9-tetrahydrocannabinol, THC, the bioactive ingredient of the drugs marijuana and hashish. Marijuana (cannabis) is a commonly abused illicit and recreational drug. The brain produces two endogenous cannabinoids, N-arachidonoylethanolamide (anandamide (AEA)) and 2-arachidonoylglycerol (2-AG). The two endocannabinoids bind to CB1R and have the same functional activity as marijuana. Based on the structural similarity between THC and endocannabinoids, THC is able to activate CB1R and, thereby, hijack this brain communication system. The evolutionary origin of this communication system rests with endogenously produced cannabinoids that bind and activate CB1R. The discovery of AEA and 2-AG occurred in the 1990s ([19–21], for review see [22]). It took another decade before the function of these two cannabinoids in brain signaling was discovered. It is now well known that endocannabinoids serve as retrograde messengers. Endocannabinoids diminish excitatory and inhibitory transmission. Numerous studies have established their function as retrograde signals in various brain regions: the hippocampus [23–28], cerebellum [29–31], neocortex [32, 33], amygdala [34, 35], and olfactory bulb [15]. Furthermore, in the mediobasal hypothalamus, retrograde endocannabinoid signaling represents a key mechanism under physiological and pathological conditions whereby gonadotropin-releasing hormone (GnRH) neurons control their excitatory GABAergic inputs [36, 37]. Endocannabinoid signaling is terminated by reuptake into neurons and glia. AEA is hydrolyzed enzymatically inside the cell by fatty acid amide hydrolase (FAAH), whereas 2-AG is hydrolyzed by monoacylglycerol lipase (MAGL) [38].
\nEndocannabinoids serve as important signaling molecules throughout the body including the nervous system [10, 12, 39–44]. Endocannabinoids play important roles in bodily processes during both health and disease [45–48]. Their role in bodily functions has been shown for vertebrates and invertebrates [48]. Pharmacological and physiological experiments in brain slices have described novel aspects of classic brain signaling mechanisms and/or revealed unknown mechanisms of cellular communication involving the endocannabinoid system [41, 49–51]. Endocannabinoids are involved in several forms of cellular signaling [49]. The most distinguishing feature of endocannabinoids is their ability to act as retrograde messengers in neural circuits as first shown in the hippocampus [10, 26, 52].
\nEndocannabinoids, together with their G-protein-coupled cannabinoid receptors, form the endocannabinoid system. This system also includes an associated biochemical machinery with endocannabinoid precursors, synthetic and degradative enzymes for these lipidic neurotransmitters, and transporters [10, 12, 14, 40]. Cannabinoid receptors exist in all normal brains and serve many essential brain functions when activated by their natural ligands. Two types of cannabinoid receptors, CB1 (CB1R) and CB2 receptors with 44% amino acid sequence homology, have been described [53, 54]. They are not homogeneously expressed throughout the body; rather, CB1R is the most abundant G-protein-coupled receptor in the brain [55]. In contrast, CB2R is found mainly in immune cells and peripheral tissues [54]. More recent evidence suggests that CB2R is also present in the brainstem, cortex, and cerebellar neurons and microglia [56, 57]. CB1R has a high level of expression in the brain [58, 59], with a particularly strong presence at presynaptic axons terminals [60, 61]. THC, the bioactive ingredient of the drugs marijuana and hashish [62], and other cannabis-derived drugs are potent activators of CB1R. These drugs artificially activate CB1R and act as exogenous cannabinoids. CB1R is found in normal brains and carries out critical brain functions [55, 58, 59] principally through a Gi/o-protein-coupled mechanism with CB1R.
\nEndocannabinoids mediate an unconventional type of neuronal communication, called DSI,
The main olfactory bulb offers an ideal platform for investigating how the endocannabinoid system modulates a functional neural network to achieve an integrated outcome. On the one side, the olfactory bulb directly receives sensory input from the nasal epithelium, and on the other side, it receives strong centrifugal cortical input that even outnumbers the cortical projections from the olfactory bulb. This structural organization makes the olfactory bulb preparation significantly different from the hippocampus, amygdala, neocortex, and cerebellum to address functional questions of CB1R modulation in the brain.
\nAs detailed below, new evidence demonstrates that CB1R-mediated retrograde signaling exists among olfactory bulb glomerular neurons such that endocannabinoids released from glomerular neurons function as retrograde messengers to control the excitability of presynaptic neurons and to regulate their transmitter release [15]. Endocannabinoids have a distinct effect on sensory input, that is, they are involved in gain control through regulating presynaptic inhibition. Another new work emphasizes the relevance of cortical feedback to the olfactory bulb as a means to control odor detection and establishes the relationship of food intake and olfactory processing [3]. The endocannabinoid system is a key player in these signaling pathways.
\nOdorants in the air that we breathe in activate olfactory receptor cells in the nasal epithelium. Each receptor cell sends an axon to the ipsilateral main olfactory bulb which serves as the first relay station in the central nervous system for processing olfactory sensory information. Cannabinoid receptors are expressed at high levels in the olfactory bulb, specifically in the input region, the glomerular layer [58, 63–65]. Furthermore, neurons in the glomerular layer are immunoreactive for enzymes that synthesize endocannabinoids [66–68]. Electrophysiological evidence has now established that the endocannabinoid system plays a functional role in regulating neuronal activity and signaling in olfactory bulb glomeruli [15].
\nThree types of neurons are housed in the glomerular layer of the main olfactory bulb, that is, these neurons have their cell bodies in the glomerular layer: periglomerular (PG), external tufted (eTC), and short-axon (SA) cells, reviewed in Ref. [49]. PG cells are neurochemically and functionally heterogeneous [69–71]. They are GABAergic, whereas SA cells express both GABA and dopamine and eTC cells are glutamatergic [71–73]. PG cells receive input from the olfactory nerve or dendrodendritic glutamatergic input from eTC or mitral cells, for example, as spontaneous bursts of excitatory postsynaptic currents (EPSCs) [70, 74, 75]. PG cells presynaptically inhibit olfactory receptor neurons through GABAergic transmission [76, 77]. eTC cells receive spontaneous bursts of inhibitory postsynaptic currents (sIPSCs) from PG cells at inhibitory GABAergic synapses as well as spontaneous glutamatergic EPSCs [77, 78]. Endocannabinoids are likely to be released by activated eTC cells in the glomerular layer.
\nMembrane properties of PG cells are potently regulated by cannabinoid drugs such as the CB1R antagonist AM251 and the potent CB1R agonist WIN 55,212-2 (WIN) [15, 49]. Cannabinoid receptors directly regulate PG cells since the effects of AM251 and WIN persist in the presence of ionotropic glutamate and GABAA receptor blockers (synaptic blockers: CNQX, APV, gabazine) [15], indicating that CB1R is expressed in PG cells. AM251 increases action potential firing of PG cells and triggers release of GABA. eTC cells are synaptic targets of PG cells such that CB1R-mediated effects on PG cells are affecting chemical synaptic transmission to eTC cells. CB1R is also expressed in eTC cells and may participate in modulating eTC cell activity.
\nCannabinoid drugs such as AM251 or WIN have no effect on membrane properties such as firing frequency or membrane potential in eTC cells [15, 49]. In the presence of synaptic blockers, cannabinoid drugs have a modest effect on eTC cells such that AM251 slightly increases the firing rate of eTC cells without membrane depolarization. WIN slightly decreases firing of eTC cells in synaptic blockers without a clear change in membrane potential. The effects of AM251 and WIN in the presence of synaptic blockers, that is, during pharmacological isolation of eTC cells, indicate that CB1R mediates a direct effect on eTC cells. The direct excitatory effect of AM251 is relatively weak and contrasted by strong GABAergic input from PG cells onto eTC cells, namely, the enhanced GABA release from PG cells. The strong inhibitory effect mediated by AM251 acting on PG cells overshadows the direct AM251-evoked excitation of eTC cells.
\nExperimental evidence indicates direct and indirect effects of cannabinoid drugs on glomerular neurons [15]. In order to determine if endocannabinoids are involved in retrograde signaling in the glomerular neural circuitry, that is, if DSI is present, eTC cells are activated by a 5 s depolarizing voltage step from a holding potential of −60 mV to 0 mV. In eTC cells DSI is visible as a decrease in the amplitude and frequency of sIPSCs. A single depolarizing step evokes a suppression of sIPSC area by ~40% of control which then gradually recovers. Projection or output neurons in the main olfactory bulb can show regular action potential firing or burst firing. eTC cells exhibit a distinct intrinsic bursting pattern [73]. In order to mimic their spontaneous rhythmic bursting, a train of depolarizing steps can be applied to an eTC cell which allows determining a possible functional role of DSI in olfactory glomeruli. A train of depolarizing steps results in a transient 60% reduction in sIPSC area (20 steps, 0.75 Hz). DSI can be completely eliminated in the presence of AM251, indicating that DSI is mediated by CB1R. eTC cells burst at a range from 0.5 to 6.5 Hz with a mean frequency of 2.7 bursts/s [73]. Depolarizing voltage pulses at 2 Hz (20 steps, pulse duration: 250 ms) evoke DSI as a reduction of sIPSCs in eTC cells, similar to the results obtained with voltage steps at 0.75 Hz to 0 mV. In eTC cells, single depolarizing voltage steps as well as a train of voltage steps evoke suppression of inhibition (DSI). The evidence suggests that spontaneous rhythmic bursting of eTC cells triggers the release of endocannabinoids which function as retrograde messengers to reduce GABA release from PG cells [15, 49]. This, in turn, regulates the activity of PG cell synaptic targets such as eTC cells.
\nThe results indicate that endocannabinoids regulate neuronal activity and signaling in olfactory bulb glomeruli and function in DSI through CB1R-mediated retrograde signaling among glomerular neurons [15, 49]. Endocannabinoids are synthesized and released from neuronal cell bodies as a result of cellular excitation [11]. Endocannabinoids in the olfactory bulb are likely to be synthesized and released from neurons that synapse with presynaptic cells, that is, PG cells, and receive feedback synaptic input from them. eTC cells could be a potential endocannabinoid source in the olfactory bulb which is supported by the fact that DSI is found in eTC cells. The extent of DSI in eTC cells is subject to the level of cellular activation, that is, voltage step duration and step number. DSI cannot be evoked with step durations of 1 s or less, while a step duration closer to 5 s evokes transient DSI. Likewise, increasing the number of number steps to more than three evokes strong DSI and inhibits sIPSCs. When eTC cells are activated and show rhythmic burst firing, endocannabinoids are released which in turn affects glomerular activity. Bursting is an intrinsic property of eTC cells [73, 78] and regulates the release of endocannabinoids from principal olfactory bulb neurons such as eTC cells. Bursting-induced endocannabinoid release may also occur also in other brain systems and represent a general phenomenon of endocannabinoid signaling.
\nRecently, the endocannabinoid system has been placed in a behavioral context by linking an internal metabolic state (hunger) to sensory perception and subsequent behavior, namely, food intake [3]. CB1 receptor-dependent control of excitatory drive from centrifugal feedback projections to the main olfactory bulb determines the efficiency of olfactory processes and food intake in fasted mice. This study focuses on neural processes deeper in the olfactory bulb, primarily involving those olfactory bulb neurons (GABAergic granule cells) that receive heavy CNS feedback rather than direct sensory input from the nasal epithelium. Given this structural organization of the main olfactory bulb, the authors integrate three separate neural components: sensory (olfactory) input, central processing in the main olfactory bulb, and behavioral output in terms of feeding in the overall framework of the internal state of the animal (hunger). Cortical feedback to the main olfactory bulb is a means to control odor detection. The relationship of food intake and olfactory processing implicates the endocannabinoid system as a key player in this signaling pathway. Thereby, the endocannabinoid system helps to resolve the old question of how the smell of a cookie makes us want to eat it and which brain mechanism allows us to find food more rapidly and reliably when we are hungry. CB1 receptor-dependent control of olfactory processes has a determinant role in coupling the internal state of hunger with the execution of the behavior such as increased food intake. THC has an effect on both olfactory detection thresholds and habituation, while the latter effect had no correlation to food intake. The authors suggest that enhancement of olfactory detection is likely the main mechanism linking (endo)cannabinoid signaling in the main olfactory bulb to increased food intake. Possibly, by reducing overall granule cell-mediated inhibition of mitral cells, the key output neurons of the main olfactory bulb, mitral cells become more sensitive and that would lower the odor detection threshold. The authors suggest that activation of CB1R on terminals of feedback cortical centrifugal glutamatergic neurons in the main olfactory bulb directly reduces the excitatory drive onto granule cells, thereby regulating mitral cell activity to increase odor detection and food intake [3]. However, other cellular mechanisms might come into play as well. These mechanisms could work in the peripheral input region of the main olfactory bulb rather than in the deeper granule cell layer. Also, glutamatergic input to the main olfactory bulb is not the only centrifugal input. Rather, other areas of the brain also provide feedback cortical projections with cholinergic, dopaminergic, serotonergic, or noradrenergic input [69, 79] and might be subject to CB1R modulation.
\nOur understanding of the endocannabinoid system has greatly benefited from studies of limbic system areas such as the hippocampus. Work in hippocampal slices first established the role of endocannabinoids as retrograde signaling molecules [26, 80]. One of the main functions of the hippocampus is to convert short-term memory into long-term memory [81]. A hippocampal formation exists in both hemispheres of the brain and is made up of the hippocampus, the dentate gyrus, and the parahippocampal gyrus. The hippocampus is composed of four regions called
Olfactory information is processed into long-term memory though the hippocampus. Sensory olfactory and synaptic information that is processed in the main olfactory bulb is sent to the piriform cortex and close to the orbital prefrontal cortex (PFC). The main olfactory bulb and these cortices project into the entorhinal cortex and the perirhinal area which relays the information through the perforant pathway to the hippocampus. Projections from the parahippocampal region extend to the piriform cortex, enabling a reciprocal and interconnected neural linkage [83].
\nNeural plasticity changes neuronal connectivity in the hippocampus. Through long-term potentiation and long-term depression (LTP), synaptic connections in the hippocampus are strengthened or weakened, respectively. Intracellular calcium release in postsynaptic neuron determines the level of neural plasticity. Receptors for CB1 are found throughout the hippocampus and are central to calcium-induced inhibition. The presence of the CB1R indicates that the hippocampus can be subject to depolarization-induced suppression of inhibition (DSI) which conversely affects the release of GABA from GABAergic neurons [10]. When endocannabinoids, 2-AG, and AEA are released by postsynaptic hippocampal neurons, GABAergic interneurons are inhibited, thus relieving principal neurons such as hippocampal pyramidal cells from inhibition [26]. This affects the information flow along the perforant pathway. The presence of more GABA increases the level of LTP and less GABA increases the amounts of long-term potentiation [26, 81] which affects memory production and learning. Unlike classical neurotransmitters, endocannabinoids can function as retrograde synaptic messengers. After release from postsynaptic neurons, they travel backward across synapses, activate CB1R on presynaptic axons, and suppress neurotransmitter release in order to modulate their inputs. The transient suppression of GABA-mediated transmission that follows depolarization of hippocampal pyramidal neurons is mediated by retrograde signaling through release of endogenous cannabinoids. Mechanistically, activation of CB1R inhibits presynaptic calcium channels through direct G-protein inhibition [27]. These synapses are unusual among brain synapses in that they use N- but not P/Q-type calcium channels for neurotransmitter release. A combination of patch-clamp electrophysiology in cultured hippocampal slices, calcium measurements, and flash photolysis of caged compounds, such as caged AEA, has allowed determining the temporal kinetics of the hippocampal endocannabinoid signaling cascade [15]. AEA and, by extension, other lipid signaling molecules do not simply serve long-term neuromodulatory functions but they are sufficiently fast to exert moment-to-moment control of synaptic transmission indicating that endocannabinoids are highly selective, rapid modulators of hippocampal inhibition.
\nThe amygdala is an almond-shaped nuclear structure located within the temporal lobe. It can be subdivided into three major nuclei: the basolateral nuclear complex, the central nucleus, and the medial nucleus. At the neuronal level, the emotional memory and emotional processes involve a brain network with limbic circuits including the amygdala, the medial PFC, and the anterior insula [84–87]. The amygdala is typically activated in response to emotional events, for example, dangerous situations by triggering and processing anger and fear [88]. Fear-conditioning experiments have delineated an amygdala-hippocampal-cortico-striatal circuit as a key brain circuit responsible for processing and storing fear-related memories and for coordinating fear-related behaviors [89, 90].
\nThe basolateral amygdala is a critical component in the learning of conditioned fear responses [91], emotional processing, and encoding of associative memories with an affective component [92–95]. Animals with lesions to the basolateral amygdala complex produce serious deficits in learning new fear responses in a number of different conditioning tasks [96–99].
\nHigh levels of CB1R expression in the amygdala are observed in adult, fetal, and neonatal brains [58, 100–103] including GABAergic axonal terminals of the amygdala [104]. Endocannabinoids are known to retrogradely activate presynaptic CB1 receptors and modulate the release of several neurotransmitters (glutamate and GABA) [7, 15, 105]. Endocannabinoids regulate anxiety- and depressive-like behaviors mostly
It was found that CB1R expression is sensitive to stressful experiences, as animals submitted to a fear-conditioning paradigm presented CB1R upregulation in the PFC [90, 120]. Exposure to shock or stressful environments leads to an increase in endocannabinoids [121] and increased endocannabinoid release [9, 122] in the amygdala. Therefore, CB1R was considered as being a significant modulator for amygdala responses in social emotional negative situations [87].
\nThe neuronal endocannabinoid system modulates synaptic transmission and plasticity
It has been reported that in the amygdala FAAH, the enzyme that degrades AEA aggravates stress, whereas AEA protects and helps with recovery from stress [126]. Exposure to stress rapidly mobilizes FAAH to deplete the available pool of AEA and increases neuronal excitability in the basolateral amygdala, an anxiety-mediating region [126]. When FAAH is genetically deleted and pharmacologically inhibited, stress-induced reductions in AEA are prevented. Along the same line, long-term fear extinction is facilitated when FAAH is inhibited suggesting that the restoration of AEA levels in the basolateral amygdala by blocking FAAH with drugs might be clinically relevant to treat traumatic stress disorders.
\nThe endocannabinoid system has become a major focus in the search for pharmacological interventions for fear extinction (for review see [91, 127, 128]). CB1R agonists and antagonists generate diverse cognitive effects and change extinction learning. CB1R is implicated in the sensory processing and learning. CB1R is expressed at high levels in the medial PFC, hippocampus, and basolateral amygdala. CB1R affects synaptic transmission and plasticity such as LTP in these brain areas.
\nImpairment of CB1R signaling affects the neuronal excitatory/inhibitory balance with effects on emotional function and anxiety- or depressive-like behaviors [129–132]. Drug use often starts during adolescence. During this time, the structure and function of the developing brain are particularly receptive to external stimuli such as cannabis. Adolescence is critical in the emergence of mental illness prior to its manifestation in adults but how does adolescent cannabis use affect brain development and function? Indeed, synaptic CB1R expression in adult mouse brain amygdala regions is downregulated by adolescent THC exposure, that is, it affects brain structure and function [133]. A recent study shows broad CB1R/b-arrestin2 co-expression in the medial PFC, amygdala, and hippocampus. This is paralleled by impairment of extracellular signal-regulated kinase signaling and elevation of vesicular glutamate transporter (VGluT1) at CB1R-expressing excitatory terminals in the medial PFC or vesicular GABA transporter (VGAT) at CB1R-expressing inhibitory terminals in the amygdala and hippocampus [132]. These alterations play a key role in the etiology of anxiety-like behaviors when occurring in the PFC, amygdala, and hippocampal circuits [129, 131].
\nEmotional dysfunction has been considered a hallmark of schizophrenia dating back to early days of research. Emotional disturbances in brain circuits, especially the amygdala, play a key part in symptoms of schizophrenia [134]. Adolescent cannabis use is an environmental risk to exacerbate cognitive and emotional behavioral abnormalities in individuals with genetic vulnerabilities [133].
\nDeficiency of CB1R signaling is associated with anxiety and persistence of negative memories [135]. Endocannabinoid-CB1R signaling is reduced with pharmacologic antagonists or genetic deletion [136–138]. Blockade of endocannabinoid-CB1R signaling with CB1R antagonists results in increased anxiety-like behaviors [135, 139] and also results in delayed and ineffective extinction of fearful memories in an animal model [9]. Administration of CB1R antagonist to healthy humans increases anxiety [140]. Indeed, anxiety is a main adverse effect in humans treated with a CB1R antagonist for metabolic disorder and obesity [141]. Patients, particularly those with prior depressive symptoms, exhibit increased depressive symptoms, including suicidality after treatment with CB1R antagonists [142].
\nEndocannabinoids are strongly linked to stress, fear, and anxiety, which has led to a growing interest in developing novel medication for anxiety and other psychological disorders targeting the endocannabinoid system [126]. Robusting endocannabinoid-CB1R signaling is vital for appropriate stress responses and for the maintenance of emotional homeostasis, particularly in the face of chronic stress. Understanding the underlying mechanisms of endocannabinoids in controlling stress, fear, and anxiety has grown considerably in recent years, with some targets already having been advanced to preliminary clinical trials in patients [126].
\nStudies highlighting the effects of endocannabinoids point to their neuroprotective role in the brain. Endocannabinoid-like compounds such as arachidonoyl serine (AraS), which has a similar structure to the endocannabinoid 2-AG, have been found to reduce lesion size following the induction of traumatic brain injury in mice [143]. Brain diseases have been shown to cause alterations to endocannabinoid synthesis. In Alzheimer’s disease, FAAH, the enzyme which terminates endocannabinoid signaling, is epigenetically regulated. Patients with late-onset Alzheimer’s disease, LOAD patients, display an increase in FAAH, whereas other components of the endocannabinoid system remain unchanged [144]. Another example of alteration of FAAH resulting in an increase in endocannabinoid system activation has been shown through application of an FAAH inhibitor. Use of the FAAH inhibitor, PF3845, in a mouse model helped to relieve traumatic brain injury-induced impairments including impairments of fine motor movement, hippocampus-dependent working memory, and anxiety-like behaviors. An FAAH inhibitor can result in the promotion of neuronal survival, attenuation of inflammation, and improvement of functional recovery following traumatic brain injury [145]. Traumatic brain injury is the leading cause of death in young people in the USA. Therefore, studies on FAAH potentially have great benefit to society in terms of treating traumatic brain injury.
\nThe endocannabinoid system has also been shown to be neuroprotective during neurological diseases such as Alzheimer’s disease, amyotrophic lateral sclerosis, and drug addiction. A role of endocannabinoids has been shown in Alzheimer’s disease when WIN 55,212-2, a CB1R agonist, was tested on the effect of the toxic peptide Aβ1–42 in cultured astrocytes. Peptide Aβ1–42 accumulates during Alzheimer’s disease causing cellular damage. Treatment with WIN 55,212-2 resulted in an increase in cellular viability of astrocytes and a decrease in inflammation [146]. An area of current investigation is the role of endocannabinoids as neuroprotectants in motor degeneration diseases. In one study, endocannabinoids played a neuroprotective role in amyotrophic lateral sclerosis [147]. In addition to endogenous cannabinoids assisting in ameliorating the effects of disease such as traumatic brain injury and neuropathic pain, research has also shown that endocannabinoids help to reduce the effects of drugs of abuse on the brain, in particular amphetamine abuse. THC, an exogenous form of cannabinoid, has been shown to reduce the neurotoxicity of methamphetamine by reducing the methamphetamine-induced overexpression of neuronal nitric oxide synthase in the caudate putamen [148].
\nEndocannabinoids have been shown to play a neuroprotective role in the limbic system. CB1R in both the hippocampus and amygdala is sufficient for synaptic and behavioral functions. In a study using conditional CB1R knockout mice, genetic restoration of wild-type CB1R function, specifically in dorsal telencephalic glutamatergic neurons, fully restored hippocampus-dependent neuroprotection from chemically induced epileptic-like seizures [149]. Dopamine receptor (D3 receptor) null mice have been shown to exhibit changes in levels of endocannabinoid and TRPV1 (transient receptor potential cation channel subfamily V member 1, also known as the capsaicin receptor and the vanilloid receptor 1), but not in CB1R in the hippocampus, nucleus accumbens, amygdala, and striatum. This change is related to less anxious-like behavior when mice underwent the elevated maze plus test. Hence, the endocannabinoid and endovanilloid systems may interact with dopamine receptors in order to produce normal responses to excitotoxic or anxiogenic stimuli [150]. Following exposure to foot shocks and situational reminders which mimic post-traumatic brain disorder in mice, treating mice with WIN 55,212-2, leads to normalization of CB1R upregulation in the PFC and CA1 of the hippocampus. Consequently, cannabinoids aid in emotional processing by preventing the distraction of foot shock followed by situation reminders [90].
\nThe endocannabinoid AEA has been shown to protect HT22 cells exposed to hydrogen peroxide. This occurs
Endocannabinoid action is needed for normal activation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK ½, ERK1/ERK2 subtypes) induced synaptic integrity in the hippocampus. This has been determined by treating hippocampal cells with endocannabinoid antagonist AM281, resulting in FAK and ERK ½ activation being blocked. The blocking of FAK and ERK ½ results in a decrease in synaptic markers. These results support the notion that the endocannabinoid system is the key for the integrity and maintenance of synapses in the hippocampus [152]. Endocannabinoid signaling can be modulated not only through direct activation of CB1 receptors but also through inhibition of endocannabinoid transport and FAAH, two mechanisms of endocannabinoid inactivation. Dual modulation of endocannabinoid transport and the enzyme FAAH results in protection against excitotoxicity. When hippocampal slices are exposed to excitotoxic insult and then treated with endocannabinoid transport blocker AM404 and FAAH blocker AM374, neuroprotection occurs against cytoskeleton damage and a decrease of synaptic decline. Likewise, the blockers protect against behavioral impairment and memory impairment characteristic of excitotoxic insult [153]. In the hippocampus THC has been shown to protect neurons from excitotoxicity. Both WIN 55122, a full CB1R agonist, and THC, a partial CB1R agonist, elicit a neuroprotective effect on rat hippocampal cells when the cells are excitotoxically stimulated to mimic disease-generated excitotoxic neuronal death [154]. CB1R also plays a role in neural progenitor proliferation and neurogenesis induced by excitotoxicity. During excitotoxicity the brain will attempt to repair damage by stimulating neural progenitor cells. When CB1R is inhibited in the hippocampus, both basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF), key factors in neural progenitor stimulation, are blocked [155]. Excitotoxicity results in an increase in CB1R-positive and bFGF-positive cells, which proceeds neural progenitor cell proliferation. These results point to the importance of the endocannabinoid system in cellular regeneration from excitotoxic cellular damage in the hippocampus [155]. The endocannabinoid N-arachidonoyldopamine (NADA) has been shown to exert a neuroprotective effect in response to excitotoxic neuronal damage [156]. The neuronal damage occurs
Additionally, endocannabinoids have been shown to be neuroprotective in other disorders and anatomical systems such as obesity, endocannabinoid deficiency syndrome, and anti-inflammation. The endocannabinoid system has a direct relation with obesity because rimonabant (SR141716, trade names Acomplia, Zimulti), an anorectic anti-obesity drug, is an inverse agonist for CB1R. Rimonabant is a selective CB1 receptor blocker that was originally approved for use but has been withdrawn from the market because of potentially negative side effects. Since rimonabant has been shown to be an anti-obesity drug by inactivating the endocannabinoid system, it can be argued that the endocannabinoid system when activated can assist with weight gain, an issue faced by people experiencing weight-compromising diseases including cancer and people facing food absorption diseases including Crohn’s disease [157]. The endocannabinoid system can potentially be used in clinical interventions. A growing area of research documents the “endocannabinoid deficiency syndrome” which is linked to migraine, fibromyalgia, irritable bowel syndrome, and psychological disorders [158]. Activation of nuclear receptor protein peroxisome proliferator-activated receptor-gamma has been shown to play a key role in the neuroprotective anti-inflammatory role of 2-AG in the brain [159].
\nEndocannabinoids and their receptors are expressed through the central nervous system and immune system suggesting a critical functional role for endocannabinoids in the operation of these systems. Activation of the endocannabinoid system is directly related to bodily recovery from a disease state such that endocannabinoids play a neuroprotective role in the nervous and immune system. This neuroprotective effect can be seen specifically in response to neurological disorders and injury such as Alzheimer’s disease and traumatic brain injury. Likewise, endocannabinoids show neuroprotective effects following spinal cord injury. These data suggest that the endocannabinoid system as a neuroprotective agent has the potential for new therapeutic interventions during diseases of the nervous system and immune system.
\nThis work was supported in part by grants from NIH (MD007597) and NSF (IOS-1355034) to TH. PTA was supported through The Advanced Research Training Corps: A Novel Initiative for URM Students, NIH-NIGMS [GM101997].
\nFrom the public health and socioeconomic standpoints, schistosomiasis is a parasitic disease with significant prevalence in most developing countries, and it is the second-largest neglected disease in the world [1, 2, 3]. Schistosomiasis is caused by digenean trematodes belonging to the genus
The number of people living in risk areas, which cover 78 countries in tropical and subtropical regions, is greater than 700 million [5, 6]. Transmission is high or moderate in 52 of these countries (World Health Organization, 2021). More specifically,
Schistosomiasis is characterized by two phases: acute and chronic. Symptoms of acute illness include myalgia, abdominal pain, diarrhea, fatigue, fever, and, in the case of urogenital schistosomiasis, hematuria. Diarrhea occurs in patients with a greater parasite load; abdominal pain is diffuse. In chronic intestinal schistosomiasis, symptoms are more severe. Over time, patients have diarrhea with the presence of blood in stool, anemia, and retention of eggs in the anal region, not to mention hepatosplenomegaly due to egg deposition in the liver. Hepatosplenomegaly causes granuloma (Figure 2) and occurs in around 10% of patients, who present periportal fibrosis with portal hypertension, ascites, and gastrointestinal varices with bleeding [12, 13]. As for urogenital schistosomiasis, it affects the urogenital system so severely that it causes fibrosis in the bladder and ureter, calcification in the urinary tract, and kidney dysfunction. The greatest concern about this urogenital disease is that it causes bladder cancer and sterility, and, in the chronic phase, patients have bladder injury [2].
Slides of (a) mouse liver infected with
The differences in schistosomiasis pathology are due to parameters such as oviposition, granuloma size, and modeling of interleukins, which depend on the parasite load, host’s immunological profile (that is, the host’s ability to respond to the parasite, whether the parasite is in the form of schistosomula, adult worms, or eggs), and parasite virulence and infectivity [14]. Therefore, the parasite and host interact in a co-evolutionary and complex way (interplay) that interferes with disease transmission potential and pathology [2].
Worm maturation requires that host-derived signals be translated, to generate adaptive and innate immune responses. Much research is still needed to unravel the interrelationship of
When it comes to schistosomiasis, egg antigens are the major problem: they are antigenic structures that secrete various toxic substances, the main one being SEA (Soluble Eggs Antigens). These toxic substances elicit the complex and multifactorial response in the mammalian host’s innate immune system [15]. The acute condition of the disease is characterized by the lesion around the eggs, with the release of interferon-ɣ and IL-10 by macrophages and IL-12 by dendritic cells [12]. Later, another eggshell protein, ɷ-1, is internalized in dendritic cells, directing the Th2 response and lowering IL-12 secretion [16]. However, this does not occur in infections caused by
Thus, these parasites activate the immune system and form the highly organized granuloma that is wrapped by the Th2 immune cells, namely macrophages, eosinophils, and cells that secrete cytokines of numerous types, including IL-2, IL-4, IL-13, and IL-5, which are surrounded by stromal cells and fibroblasts. In the case of
During infection with
In the infection period, there is a balance between the Th2 and Th1 responses. The Th2 anti-inflammatory effects control the immunopathology caused by the Th1 response [18]. In
The Th2 response is crucial for granuloma maintenance and host survival. Proteins such as Cyclophilin A and lysophosphatidylserine (LPS), excreted from worms, can modulate the dendritic cell function, causing IL-10 to expand and activating regulatory T cells. The role of small fatty acid chains (SFACs) excreted by worms in regulating immune response is not yet known, but LPS and SCFA can modify the TLR2 signaling pathway in dendritic cells, altering maturation and regulatory T cell activation [15]. In children infected with
Several studies have reported that the host’s immune response plays a role in PZQ effectiveness. Studies using 0-, 1-, and 3-day
The WHO has planned strategies to control schistosomiasis through PZQ administration in endemic areas where the disease is highly prevalent, mainly in Africa, in regions such as the Nile Delta, Côte d’Ivoire, Mayuge District, and Uganda. These strategies have shown that the prevalence of morbidity due to
Nevertheless, the greatest PZQ-R has been detected in parasite strains maintained in the laboratory. After the passage of
PZQ has a series of pharmacological and pharmaceutical limitations that are often disregarded because the effectiveness of oral, single-dose treatment has cure rates between 50 and 90%, whether for single- or mixed-species infections [13, 23, 24]. Regarding pharmacology, PZQ exhibits suboptimal pharmacokinetics with high intra- and inter-individual variability and extensive first-pass hepatic metabolism, which results in low oral bioavailability [25]. The PZQ mechanism of action is still poorly understood, but it seems to affect Ca2+ absorption through calcium channel opening, which interferes with muscle contraction and leads to antigens being present in the tegument [26]. Furthermore, PZQ is only effective against adult parasites; that is, it has no antiparasitic action against schistosomula. Thus, even during treatment, immature parasites develop into mature adult worms and continue to generate morbidity in reinfected patients [27, 28]. Schistosomiasis treatment with PZQ alone increases the possibility of resistance and hence treatment failure, especially in areas where infection occurs massively [13, 29]. Academically, resistance to any drug is defined as hereditary sensitivity acquired by a living organism; that is, it is transmitted between generations [9].
One of the consequences of PZQ-R is the increasing reproduction rate of parasites that survive treatment with PZQ. One of the possible explanations for this fact is that parasites have drug-resistant alleles, which are passed from generation to generation and are related to virulence [2].
Moreover, intergeneric, interspecies, and intraspecies interactions may occur because hosts are usually infected with more than one
Even the same parasite species have distinct lineages presenting greater or lesser infectivity and transmission in different endemic regions of Africa. This is due to genetic mutations caused by several factors, including environmental changes in both geographic regions and PZQ-R [30], which promote epigenetic changes in the parasite. Epigenetics is related to changes in gene expression while the DNA sequence remains unaltered. Epigenetics is one of the main regulatory systems of post-translational modifications (PTMs) in histones, which are proteins that form a unit called nucleosome [31].
In eukaryotes, chromatin is made up of genomic DNA (gDNA), RNA, and proteins. The main proteins are called histones, which are divided into isoforms. The main isoforms are H2A, H2B, H3, and H4, which form octamers around gDNA, consisting of two dimers, H3-H4 and H2A-H2B. At physiological pH, histones bear a positive charge and interact with the negative charge on gDNA, thereby constituting the basic unit called nucleosome, which closes the DNA structure. The nucleosome structure allows the terminal carbon and nitrogen tails (C-t and N-t, respectively) of these proteins to undergo PTMs [31]. The PTMs of these proteins include lysine acetylation and methylation (K), serine/threonine phosphorylation (Ser/Thr), and ubiquitination, among others. These PTMs are covalent modifications, and their set is called the “histone code” [32], with more than one PTM occurring in a histone molecule.
Metabolic alterations and environmental changes (nutritional deprivation, temperature, and chemical agents) generate a stressful environment for living organisms. The stress mechanism is activated and causes activation of other regulatory mechanisms, including gene transcription, which generates an “epigenetic memory” in response to stress. This mechanism has been detected in
Studies have been carried out to understand how the molecular relationship between parasites and hosts works. Genome integrity is essential for host cells, organisms, and species survival. Thus, errors in genome checkpoints trigger cellular apoptosis, to eliminate the altered cell. However, pathogens can alter these pathways by manipulating both chromatin repair and cell signaling pathways. For this to happen, pathogens produce genotoxins and oncoproteins that modify the host’s epigenetic programs; that is, DNA expression, which consequently influences metabolism by altering the proteins that will be expressed. For this reason, pathogens are called epigenators. Some intracellular parasites such as
Some studies are being carried out on
The
Given that the parasite can act as an epigenator, to modify the host’s immune response to the disease, it is extremely important to know how chromatin epigenetic regulation occurs upon changes in temperature, pH, osmolarity, and physical and biochemical signals in
With respect to
New drugs or vaccines against schistosomiasis must be discovered—
Research aimed at discovering a vaccine against schistosomiasis involves selecting possible parasite antigens that are expressed in the intra-mammalian stages. These antigens activate the host’s immune system, forming memory cells. Reaction of immunoglobulins IgA, IgG, and IgM excreted by immune system cells is analyzed by the Enzyme-linked Immunosorbent Assay (ELISA) reaction with antigens from
As for the discovery of new drugs, it involves substances that act against tegumentary proteins or proteins that are linked to parasite metabolism. The initial tests on the investigated substances are called
Scheme for discovering new drugs to treat schistosomiasis. The discovery of a new medication for schistosomiasis takes a long time, 10 years or more. The steps involve
After the first
“In 2016, Science ranked the schistosomiasis vaccine as one of the 10 vaccines that urgently need to be developed to make a significant impact on reducing the global burden of diseases.” In 2013, a meeting with 70 experts from the Bill and Melinda Gates Foundation considered that an effective vaccine against schistosomiasis should reduce the parasite load and pathology caused by eggs by 75%; in other words, granulomas in the liver and urogenital tract should be reduced. In addition, an effective vaccine should elicit adaptive immune response and be effective against the three main
New vaccines are developed by using recombinant proteins, and their effectiveness is tested by verifying whether they generate an immune response when applied to mammals. For the schistosomiasis vaccine, the recombinant protein system has proteins that are part of the surface of the parasite and that are secreted by it. These proteins have previously been selected by proteomics and transcriptome and analyzed
Scheme for discovering schistosomiasis vaccine. Vaccine development involves several steps including
Developing a vaccine, which does not need to be 100% effective against schistosomiasis, will ensure that patients are not reinfected with the parasite, especially in endemic areas where morbidity is high. If this goal is reached, disease control is achieved [11]. However, discovering a vaccine is difficult because the parasite can escape the host’s immune system [53]. This escape can occur through epigenetic changes in the parasite genome [40, 54, 55]. Additionally, the parasite can act as an epigenitor, interfering with the expression of proteins linked to the vertebrate host’s immune system through genotoxins, also called bioactive molecules. Genotoxins can be enzymes or inhibitors that modify histone PTM, causing a balance between resisting reinfection and controlling the immune response (e.g., in relation to eggs retained in the liver) after treatment with PZQ [13].
The possibility that
Vaccines that are being tested in humans include Sh28GST (Bilvax-Phase III), which offers 30–60% protection; Smp80 (phase I), which offers 30–70% protection; Smp14 (phase I), which offers 50–68% protection; and SmTPS1 and Sm-TSP-2 (phase I), which offer 65–69% protection [56, 57].
Techniques for producing vaccines with recombinant proteins are described below for further understanding of their tests. As an example, we will mention a vaccine that is in the test phase and which is based on the parasite protein p80, called calpain. The parasite protein p80 is present in the inner membrane of the tegument of adult worms and other
Preclinical trials with many types of the Sm-p80-based vaccine, tested in mice infected with
After vaccination and infection with cercariae, the livers of the mice and baboons were removed, and transcriptome was performed by using RNAseq. This technique is used for sequencing and expression analysis of the mRNA set. In the case described here, this technique was used to analyze which host genes linked to the immune system would be active during the development of protection due to vaccination. RNAseq analysis of mouse liver showed high expression of genes linked to coding of innate immune response proteins; inflammatory cytokines such as IL-1, IL-15, IL-18, and the TNF superfamily; interferon; and complement factors. In addition, high IL-27 levels, related to IL-12 involved in CD4+ T cell proliferation and genes related to adaptive immune response, were detected. In baboon liver, expression of mRNA related to the Th1 immune response was identified. This was associated with differentiation and development of T cells, which are memory cells of paramount importance for immune response in the presence of parasite. CD8 and humoral responses with B cell differentiation were also detected [59].
When applied to mice, the vaccine mentioned above provided promising results with high IgM, IgA, and IgG levels and protection for up to 60 weeks after it was administered. At the end of the experiments, the recombinant vaccine showed between 30% and 70% protection. The next test, carried out on baboons, provided around 50% protection and 100% reduction in eggs in the liver and intestine, which should prevent disease transmission [56, 59]. The same vaccine was also administered to hamsters and baboons infected with
For
Tetrapanin proteins (TSP) are transmembrane proteins of the tegument detected at all stages of the parasite life cycle. TSP is exposed to the host’s immune system. The main TSP is Sm-TSP-2, which has been used for testing vaccine development. In animal models, the recombinant Sm-TSP-2 vaccine protected the animals and decreased the parasite load and eggs in the liver. The neutralization response of the animals to the vaccine involved IgG1, IgG2 Abs., and IgG3. Later, a study was carried out with the recombinant vaccine, Recombinant Sm-TSP-2 vaccine formulated on aluminum hydroxide adjuvant (Sm-TSP-2/Al), in infected volunteers from non-endemic areas. The volunteers responded with increased IgG production. Projects encouraged by the Sabin Institute and in support of schistosomiasis vaccines have been launched, and a new recombinant vaccine, called Sm-TSP-2/Alhydrogel, is in phase 2 clinical trials in Brazil and the USA [57].
Another vaccine, still in pre-clinical testing for
The 14-kDa protein FABP is located in the basal part of the tegument and intestinal epithelium of all the stages of the parasite life cycle, including eggs. Because
Molecules that alter the parasite tegument structure must be considered as possible new drugs because the tegument is essential for parasite survival in mammalian hosts: indeed, the tegument plays an important role in evading immune response and acquiring nutrients from the host [53].
To date, no new molecule has reached the clinical screening phase, but several studies are in the preclinical and
Some drugs are administered to treat schistosomiasis. One example is metrifonate, which has been used to treat urogenital schistosomiasis. Nevertheless, this drug requires that several doses be administered, and it has several side effects. Another drug is Oltipraz, which acts against
The association of anthelmintic drugs with antimalarials is advantageous for research aimed at discovering combinations that eliminate not only the adult stage of the parasite but also schistosomula. Drug combinations are an alternative to treatment with PZQ monotherapy [62].
Concomitant administration of OXA and PZQ to treat
Drugs used for malaria treatment have been tested in association with PZQ in pre-clinical trials. The combination that reduced the parasite load and the number of eggs went on to the clinical phase in endemic regions of Africa and Asia, where transmission and reinfection rates are high. Various combinations have been administered to patients infected with
Mefloquine (MFQ), an antimalarial drug, has been considered the best
Despite the importance of PZQ monotherapy, this drug does not treat granulomas caused by eggs in the liver. Therefore, in addition to PZQ-resistant parasite strains, changes in liver histopathology are a problem in patients with chronic disease, especially in areas where reinfection occurs [62].
Recently, researchers have studied extracts of substances of plant origin, but most studies are in the
Among medicinal plants with high schistosomicidal activity,
Due to their anti- and pro-fibrotic function, small molecules, called microRNAs (miRNAs), have been researched for schistosomiasis treatment. miRNAs are small RNAs that are not translated into proteins. They contain around 70 nucleotides and are important for cellular homeostasis: they are involved in the post-transcriptional regulation of one-third of the protein-coding genes and hence participate in the activation or inhibition of cellular processes. miRNAs have been the target of research into the therapy of diseases such as cancer, diabetes, viral diseases, and other metabolic diseases. Through molecular biology techniques, they can be detected in tissues, plasma, serum, and biological fluids. These techniques include Polymerase Chain Reaction, Microarrays, and RNA Sequencing, which together amplify nucleotides and sequence them in order to discover their sequences [66]. Therefore, several miRNAs are being studied for the therapy of diseases such as solid tumors and hematopoietic diseases. Examples of such miRNAs include MiR-34 and MRX34 (the liposomal miR-34a mimic), which are in the phase I preclinical trials [67].
Along with the genotoxins produced by the parasites, which alter the host’s immune response [35], vertebrate host miRNAs play a role in the parasite-host relationship, so they have been studied as biomarkers for schistosomiasis detection and hepatic fibrosis gene therapy. Such studies are in the preclinical trial phase. Initial research has shown that miR-21 and miR-96 are involved in regulating the immune response and hence hepatic granuloma by regulation of the TGF β/SMAD pathway, linked to collagen formation. Therefore, they have a pro-fibrotic function, in contrast to miR-203-3p, which is anti-fibrotic. In the case of schistosomiasis, there are miRNAs that characterize liver changes and hepatosplenomegaly progression. Among these miRNAs, we can mention MiR-223: the serum of mice infected with
In view of what has been explained, the development of new vaccines for schistosomiasis is more advanced than the development of new drugs against this disease. As judged from the time that PZQ , the only drug of choice, has been used, developing new substances that are active against the parasite is difficult. When it comes to evading the host’s immune response,
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Sustained rapid expansion in North America, followed by local expansion in Europe and Asia, has made cruising a global industry, with 365 ships and estimated sales of $37.8 US billion (CIN, 2017). This global development has been fueled by innovation and introduction of market changing resident ships appealing to the mass traveler which were quickly matched by competitors, establishment of industry and port marketing organizations, awareness of cruising as a vacation option, and availability of suitable port and berthing facilities. When these four conditions coexisted the industry experienced rapid growth. Since 1966, the cruise industry has developed from a Miami-centered industry to a global industry centered in North America, Europe, Asia, and Australia/New Zealand. Given the high cost of state-of-the-art ships, their deployment is a good indication of industry’s confidence in market growth. This chapter chronicles the development of the Asian cruise industry from 1994 through 2017. Data from Cruise Industry News Annual Reports (CIN) and Berlitz Complete Guide to Cruising and Cruise Ships (Ward) are examined and conclusions are drawn.",book:{id:"6950",slug:"education-human-rights-and-peace-in-sustainable-development",title:"Education, Human Rights and Peace in Sustainable Development",fullTitle:"Education, Human Rights and Peace in Sustainable Development"},signatures:"Andrew O. Coggins",authors:[{id:"229658",title:"Prof.",name:"Andrew",middleName:null,surname:"Coggins Jr",slug:"andrew-coggins-jr",fullName:"Andrew Coggins Jr"}]},{id:"72435",title:"Police Education in the United Kingdom: Challenges and Future Directions",slug:"police-education-in-the-united-kingdom-challenges-and-future-directions",totalDownloads:1132,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"This chapter outlines the historical development of police education in the United Kingdom, more precisely in England and Wales, and highlights new strategies and planning for the professional development of the police. There is a plethora of research carried out regarding professionalism in policing to meet the needs and challenges of the twenty-first century. Considering the recent developments in police education and training, this chapter mainly discusses three newly introduced routes for recruitment and education of police constables under the Policing Education Qualifications Framework (PEQF), namely Police Constable Degree Apprenticeship (PCDA), Degree Holder Entry Programme (DHEP), and Pre-Join Degree (PJD). Higher education institutions (HEIs), in partnership with the police forces, are providing professional qualifications for policing as a graduate level profession. Though they have made remarkable progress in developing police education programmes, they are facing various challenges in implementing the qualification framework. This chapter also explores pedagogical aspects of police education including the effectiveness and contrast between different forms of teaching and learning. While featuring the challenges and prospects of the new police education programmes, this chapter also outlines different aspects of partnership for delivering these professional qualification programmes.",book:{id:"6950",slug:"education-human-rights-and-peace-in-sustainable-development",title:"Education, Human Rights and Peace in Sustainable Development",fullTitle:"Education, Human Rights and Peace in Sustainable Development"},signatures:"M. Mahruf C. Shohel, Gias Uddin, Julian Parker-McLeod and Daniel Silverstone",authors:[{id:"94099",title:"Dr.",name:"M. Mahruf C.",middleName:null,surname:"Shohel",slug:"m.-mahruf-c.-shohel",fullName:"M. Mahruf C. Shohel"},{id:"319810",title:"Mr.",name:"Gias",middleName:null,surname:"Uddin",slug:"gias-uddin",fullName:"Gias Uddin"},{id:"321004",title:"Dr.",name:"Julian",middleName:null,surname:"Parker-McLeod",slug:"julian-parker-mcleod",fullName:"Julian Parker-McLeod"},{id:"321005",title:"Dr.",name:"Daniel",middleName:null,surname:"Silverstone",slug:"daniel-silverstone",fullName:"Daniel Silverstone"}]},{id:"73702",title:"Approaches to Analysis of Interstate Cooperation",slug:"approaches-to-analysis-of-interstate-cooperation",totalDownloads:643,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"At the present day cultural diplomacy plays a rather important role in the development of international relations and world politics. This concept is receiving increasing attention from various countries, international and non-governmental organizations and other actors. This trend exists due to a number of reasons, such as the desire of states to create a positive image of their country, the expansion of international cooperation, changes in the global and domestic political situation, the protection of national interests, the prevention of conflicts between states, etc. Cultural diplomacy, beyond historical precedents, consists of a relatively new practice of a country’s foreign policy, which has traditionally focused on trade and security and defense issues. It is true that in European countries there are institutions of cultural foreign relations since the beginning of the century, but in the last decade the issues, related to the projection of the international image of countries, have become more important.",book:{id:"6950",slug:"education-human-rights-and-peace-in-sustainable-development",title:"Education, Human Rights and Peace in Sustainable Development",fullTitle:"Education, Human Rights and Peace in Sustainable Development"},signatures:"Alexander Rozanov, Maria Ivanchenko, Alexandra Baranova, Elena N. Antonova, Mikhail Smirnov, Olga Belyaeva, Maria Ilicheva, Ludmila Ilicheva, Maria Krotovskaya, Tatiana Grabovich, Zaru Utekova, Dmitry Medvedev, Natalya Ogneva, Furat Al-Mutairi, Elvira Shishlo, Amina Surpkelova, Irina Kopachevskaya, Irina Sokurova, Yulia Borisova, Fernando Joao, Artyom Pakulskikh, Polina Chernova, Alexandra Khramova, Oksana Gryuk, Jesus Yaniz Gonzalez, Valentina Komleva, Alina Papsheva and Arkadi Bessonov",authors:[{id:"233092",title:"Dr.",name:"Alexander",middleName:null,surname:"Rozanov",slug:"alexander-rozanov",fullName:"Alexander Rozanov"},{id:"312194",title:"Prof.",name:"Valentina",middleName:"Vycheslavovna",surname:"Komleva",slug:"valentina-komleva",fullName:"Valentina Komleva"},{id:"312195",title:"Ms.",name:"Alexandra",middleName:null,surname:"Baranova",slug:"alexandra-baranova",fullName:"Alexandra Baranova"},{id:"312196",title:"Dr.",name:"Furat",middleName:null,surname:"Al Mutairi",slug:"furat-al-mutairi",fullName:"Furat Al Mutairi"},{id:"312197",title:"Ms.",name:"Maria",middleName:null,surname:"Ivanchenko",slug:"maria-ivanchenko",fullName:"Maria Ivanchenko"},{id:"312198",title:"Associate Prof.",name:"Arkadi",middleName:null,surname:"Bessonov",slug:"arkadi-bessonov",fullName:"Arkadi Bessonov"},{id:"312199",title:"Ms.",name:"Alina",middleName:null,surname:"Papsheva",slug:"alina-papsheva",fullName:"Alina Papsheva"},{id:"312200",title:"Prof.",name:"Ludmila",middleName:null,surname:"Ilicheva",slug:"ludmila-ilicheva",fullName:"Ludmila Ilicheva"},{id:"312201",title:"Ph.D. Student",name:"Aleksandra",middleName:null,surname:"Khramova",slug:"aleksandra-khramova",fullName:"Aleksandra Khramova"},{id:"316768",title:"Dr.",name:"Maria",middleName:null,surname:"Ilicheva",slug:"maria-ilicheva",fullName:"Maria Ilicheva"},{id:"317753",title:"Dr.",name:"Oksana",middleName:null,surname:"Gryuk",slug:"oksana-gryuk",fullName:"Oksana Gryuk"}]},{id:"71206",title:"Uprising and Human Rights Abuses in Southern Cameroon-Ambazonia",slug:"uprising-and-human-rights-abuses-in-southern-cameroon-ambazonia",totalDownloads:951,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"In 2016, lawyers, teachers and students in the two Anglophone regions initially led demonstrations and strikes, which eventually involved a wider section of the population. This mobilization was against their marginalization by the Francophone-dominated government in which they were chronically under-represented in all aspects of national life: political appointments and professional training and had been treated as second-class citizens since their reunification. They argued that their vibrant economic and political institutions had been completely erased, and their education and judicial systems had been undermined and degraded. Activists spread videos that show security forces abusing human rights (by suppressing peaceful gatherings, beating, harassing, arresting and killing protesters, burning their houses, schools and hospitals) in order to produce a counter-narrative to the ‘official story’ that main-stream media had been producing. We collected and analyzed 30 videos to better appreciate the human rights abuses. The videos provide information that cannot be provided by other types of data. They are used as ‘proofs of facts’ and they contain much more visual information on bodily movement and acoustic data. The videos show appalling images not just of how French-speaking soldiers tortured Anglophones but also their inability to communicate with them adequately although they share the same country.",book:{id:"6950",slug:"education-human-rights-and-peace-in-sustainable-development",title:"Education, Human Rights and Peace in Sustainable Development",fullTitle:"Education, Human Rights and Peace in Sustainable Development"},signatures:"Nanche Billa Robert",authors:[{id:"285893",title:"Dr.",name:"Nanche Billa",middleName:null,surname:"Robert",slug:"nanche-billa-robert",fullName:"Nanche Billa Robert"}]},{id:"72097",title:"Towards Global Peace and Sustainability: Role of Education in Peace-Building in the Great Lakes Region of Sub-Saharan Africa",slug:"towards-global-peace-and-sustainability-role-of-education-in-peace-building-in-the-great-lakes-regio",totalDownloads:683,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The Great Lakes Region of sub-Saharan Africa is well known for being volatile and turbulent in terms of peace and stability. For over 60 years, almost all countries in the region have experienced some kind of political and social turmoil such as civil war, coup de tat, and genocides. In 1960, the first democratically elected Congolese prime minister was assassinated. There were unprecedented social and political havoc in a nearby “other Congo” characterized by power struggle between various political and ethnic factions in the post-independence Congo Brazzaville. In Burundi and Rwanda, ethnic tensions between the Tutsi and Hutu engulfed the developmental dreams of nationalist freedom fighters until 2015. Though arguably stable, Tanzania has experienced its own share of socio-political messy including the 1998 Mwembechai and 2001 Pemba massacres. Efforts to build a sense of sustainable peace and development based on mutual understanding and socio-political harmony has brought limited success. In all these countries, the missing link in building sustainable peace and security has been a lack of education. The chapter intends to fill this gap by critically analyzing the potential role of basic education, especially pre-primary and early grades education, in sustainable peace-building in the sub-Saharan context.",book:{id:"6950",slug:"education-human-rights-and-peace-in-sustainable-development",title:"Education, Human Rights and Peace in Sustainable Development",fullTitle:"Education, Human Rights and Peace in Sustainable Development"},signatures:"Laurent Gabriel Ndijuye and Pambas Basil Tandika",authors:[{id:"301740",title:"Dr.",name:"Laurent Gabriel",middleName:null,surname:"Ndijuye",slug:"laurent-gabriel-ndijuye",fullName:"Laurent Gabriel Ndijuye"},{id:"319403",title:"Dr.",name:"Pambas Basilius",middleName:null,surname:"Tandika",slug:"pambas-basilius-tandika",fullName:"Pambas Basilius Tandika"}]}],onlineFirstChaptersFilter:{topicId:"476",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"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:"July 20th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:14,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. Dr. Chen\\'s research interests include bioactive compounds, chromatography techniques, in vitro culture, medicinal plants, phytochemicals, and plant biotechnology. He has published more than ninety scientific papers and serves as an editorial board member for Plant Methods, Biomolecules, and International Journal of Molecular Sciences.",institutionString:"National University of Kaohsiung",institution:{name:"National University of Kaohsiung",institutionURL:null,country:{name:"Taiwan"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:16,paginationItems:[{id:"82135",title:"Carotenoids in Cassava (Manihot esculenta Crantz)",doi:"10.5772/intechopen.105210",signatures:"Lovina I. Udoh, Josephine U. Agogbua, Eberechi R. Keyagha and Itorobong I. Nkanga",slug:"carotenoids-in-cassava-manihot-esculenta-crantz",totalDownloads:15,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Carotenoids - New Perspectives and Application",coverURL:"https://cdn.intechopen.com/books/images_new/10836.jpg",subseries:{id:"13",title:"Plant Physiology"}}},{id:"82112",title:"Comparative Senescence and Lifespan",doi:"10.5772/intechopen.105137",signatures:"Hassan M. Heshmati",slug:"comparative-senescence-and-lifespan",totalDownloads:17,totalCrossrefCites:0,totalDimensionsCites:0,authors:[{name:"Hassan M.",surname:"Heshmati"}],book:{title:"Mechanisms and Management of Senescence",coverURL:"https://cdn.intechopen.com/books/images_new/10935.jpg",subseries:{id:"11",title:"Cell Physiology"}}},{id:"81796",title:"Apoptosis-Related Diseases and Peroxisomes",doi:"10.5772/intechopen.105052",signatures:"Meimei Wang, Yakun Liu, Ni Chen, Juan Wang and Ye Zhao",slug:"apoptosis-related-diseases-and-peroxisomes",totalDownloads:11,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"The Metabolic Role of Peroxisome in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/10837.jpg",subseries:{id:"11",title:"Cell Physiology"}}},{id:"81723",title:"Peroxisomal Modulation as Therapeutic Alternative for Tackling Multiple Cancers",doi:"10.5772/intechopen.104873",signatures:"Shazia Usmani, Shadma Wahab, Abdul Hafeez, Shabana Khatoon and Syed Misbahul Hasan",slug:"peroxisomal-modulation-as-therapeutic-alternative-for-tackling-multiple-cancers",totalDownloads:12,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"The Metabolic Role of Peroxisome in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/10837.jpg",subseries:{id:"11",title:"Cell Physiology"}}}]},overviewPagePublishedBooks:{paginationCount:14,paginationItems:[{type:"book",id:"7264",title:"Calcium and Signal Transduction",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7264.jpg",slug:"calcium-and-signal-transduction",publishedDate:"October 24th 2018",editedByType:"Edited by",bookSignature:"John N. 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The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",annualVolume:11403,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"Tzallas",fullName:"Alexandros Tzallas",profilePictureURL:"https://mts.intechopen.com/storage/users/5886/images/system/5886.png",institutionString:"University of Ioannina, Greece & Imperial College London",institution:{name:"University of Ioannina",institutionURL:null,country:{name:"Greece"}}},{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",fullName:"Lulu Wang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRX6kQAG/Profile_Picture_1630329584194",institutionString:"Shenzhen Technology University",institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}},{id:"225387",title:"Prof.",name:"Reda R.",middleName:"R.",surname:"Gharieb",fullName:"Reda R. Gharieb",profilePictureURL:"https://mts.intechopen.com/storage/users/225387/images/system/225387.jpg",institutionString:"Assiut University",institution:{name:"Assiut University",institutionURL:null,country:{name:"Egypt"}}}]},{id:"8",title:"Bioinspired Technology and Biomechanics",keywords:"Bioinspired Systems, Biomechanics, Assistive Technology, Rehabilitation",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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Valarmathi",profilePictureURL:"https://mts.intechopen.com/storage/users/69697/images/system/69697.jpg",institutionString:"Religen Inc. | A Life Science Company, United States of America",institution:null},{id:"205081",title:"Dr.",name:"Marco",middleName:"Vinícius",surname:"Chaud",fullName:"Marco Chaud",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSDGeQAO/Profile_Picture_1622624307737",institutionString:null,institution:{name:"Universidade de Sorocaba",institutionURL:null,country:{name:"Brazil"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/337893",hash:"",query:{},params:{id:"337893"},fullPath:"/profiles/337893",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()