",isbn:"978-1-83968-760-0",printIsbn:"978-1-83968-759-4",pdfIsbn:"978-1-83968-761-7",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"cc49d6034d85f8f2e2890c6acc3cc629",bookSignature:"Dr. Abhijit Biswas",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10285.jpg",keywords:"Mott Insulators, Semi Metals, Polycrystals, Single Crystals, Electronic Properties, Magnetic Properties, PLD, MBE, Topological Insulators, Topological Hall Effect, Devices Applications, Catalysis",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 9th 2020",dateEndSecondStepPublish:"October 7th 2020",dateEndThirdStepPublish:"December 6th 2020",dateEndFourthStepPublish:"February 24th 2021",dateEndFifthStepPublish:"April 25th 2021",remainingDaysToSecondStep:"5 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher in the field of tailoring metal oxide crystal surfaces and growth as well as engineering of thin films for various emergent phenomena and energy applications. Dr. Biswas received his Ph.D. from POSTECH, South Korea.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"194151",title:"Dr.",name:"Abhijit",middleName:null,surname:"Biswas",slug:"abhijit-biswas",fullName:"Abhijit Biswas",profilePictureURL:"https://mts.intechopen.com/storage/users/194151/images/system/194151.png",biography:"Dr. Abhijit Biswas is a research associate at the Indian Institute of Science Education and Research (IISER) Pune, in India. His research goal is to design and synthesize highest quality epitaxial heterostructures and superlattices, to play with their internal degrees of freedom to exploit the structure–property relationships, in order to find the next-generation multi-functional materials, in view of applications and of fundamental interest. His current research interest ranges from growth of novel perovskite oxides to non-oxides epitaxial films, down to its ultra-thin limit, to observe unforeseeable phenomena. He is also engaged in the growth of high quality epitaxial layered carbides and two-dimensional non-oxide thin films, to exploit the strain, dimension, and quantum confinement effect. His recent work also includes the metal-insulator transitions and magneto-transport phenomena in strong spin-orbit coupled epitaxial perovskite oxide thin films by reducing dimensionality as well as strain engineering. He is also extremely interested in the various energy related environment friendly future technological applications of thin films. In his early research career, he had also extensively worked on the tailoring of metal oxide crystal surfaces to obtain the atomic flatness with single terminating layer. Currently, he is also serving as a reviewer of several reputed peer-review journals.\nDr. Biswas received his B.Sc. in Physics from Kalyani University, followed by M.Sc in Physics (specialization in experimental condensed matter physics) from Indian Institute of Technology (IIT), Bombay. His Ph.D., also in experimental condensed matter physics, was awarded by POSTECH, South Korea for his work on the transport phenomena in perovskite oxide thin films. 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1. Introduction
After food intake, blood glucose levels rise and insulin is released by the pancreas to maintain homeostasis. In the diabetic state, the absence or deficient action of insulin in target tissues is the cause of hyperglycemia and abnormalities in the metabolism of proteins, fats and carbohydrates. In addition, chronic hyperglycemia, characteristic of diabetes, is responsible for organic dysfunction, being eyes, kidneys, nervous system, heart and blood vessels the most important affected organs. Diabetes mellitus (DM) is a heterogeneous dysregulation of carbohydrate metabolism, characterized by chronic hyperglycemia resulting from impaired glucose metabolism and the subsequent increase in blood serum glucose concentration. The pathogenic equation for DM presents a complex interrelation of metabolic, genetic and environmental factors, as well as inflammatory mediators. Among the latter, it is mostly unclear whether they reflect the disease process or are simply signs of systemic or local responses to the disease [1].
DM affects about 26 million individuals in America and at least 250 million people worldwide (World Health Organization), causing about 5% of all deaths. Besides, the number of affected people is expected to duplicate by 2030 unless urgent measures are taken [2, 3]. Every day, 200 children under 14 years are affected by type 1 diabetes, and this number increases by 3 per cent each year, whereas the analogous increment for preschool children reaches 6 per cent [4]. All these data point out the epidemic character of DM.
2. Animal models for the study of diabetes
Rats and mice are animals commonly used for studying the effects of diabetes. Type 2 DM can be induced in animal models through dietary modification such as the administration of sucrose, fructose, high fat diet and glucose infusion or through genetic manipulation such as db/db mice, ob/ob mice, Goto-Kakizaki rats, Zucker diabetic rats and BHE rats [5].
On the other hand, type 1 diabetes can be replicated in animal models through genetic modifications, i.e. non obese diabetic mice (NOD), which spontaneously develop type 1 diabetes in a manner similar to humans [6]. Other animal models genetically selected are the Bio Breeding rats (BB), in which the pancreatic islets are under the attack of immune T cells, B cells, macrophages and natural killer cells. At approximately 12 weeks of age, these diabetic rats present weight loss, polyuria, polyphagia, hyperglycemia and insulinopenia. As in humans, if these rats are not treated with exogenous insulin, ketoacidosis becomes severe and fatal [7]. Another way to obtain experimental animals with type 1 diabetes is through the administration of chemicals such as alloxan or streptozotocin [8-10]. In our laboratory, we have shown that treatment with streptozotocin causes alterations in biliary excretion during the first seven days post-injection of the drug, becoming normalized 10 days after injection [10, 11]. This is the reason why studies of liver function during streptozotocin-induced diabetic state should be performed fifteen day after injection of the drug. In our work, streptozotocin-induced diabetes (SID) was induced by a single dose of streptozotocin (STZ) (60mg/kg body weight, i.p., in 50 mM citrate buffer, pH 4.5). Control rats were injected with vehicle alone. Fifteen days after STZ injection, a time when the toxic effect of the drug on the liver has disappeared [9, 10], serum glucose levels were tested by means of the glucose oxidase method (Wiener Lab., Rosario, Argentina) in samples obtained from diabetic and control animals. Successful induction of diabetes was defined as a blood glucose level of > 13.2 mmol/l. Between 10 and 12 A.M. the rats were weighed, anesthetized with sodium pentobarbital solution (50 mg/kg body weight, i.p.) and euthanatized. Blood was obtained by cardiac puncture and plasma was separated by centrifugation. Livers were promptly removed and hepatic tissue was either processed for immunohistochemical studies or frozen in liquid nitrogen and stored at −70 °C until analytical assays were performed.
3. Diabetes and inflammation
Inflammation represents a protective response to the control of infections and promotes tissues repair, but it can also contribute to local tissue damage in a broad spectrum of inflammatory disorders. The inflammatory responses are associated with variations of a wide array of plasma proteins and pro-inflammatory cytokines. The acute-phase response is a systemic reaction in which a number of changes in plasma protein concentrations, termed acute-phase proteins, may increase or decrease in response to inflammation [12]. Modifications in the plasma concentration of acute-phase proteins are largely dependent on their biosynthesis in the liver and changes in their production are influenced by the effect of pro-inflammatory cytokines such as IL-1, IL-6 and tumor necrosis factor alpha (TNF-α) on the hepatocytes. These cytokines are produced during the inflammatory process and they are the main stimulators of acute-phase proteins and other markers of chronic inflammation commonly detected in cardiovascular diseases, diabetes mellitus, osteoarthritis, and rheumatoid arthritis [13, 14].
Chronic hyperglycemia can directly promote an inflammatory state where the increase in cytokines can lead to destruction of the pancreatic beta cells and dysfunction of the endocrine pancreas in diabetes type 1 and 2. [15]. There is evidence that autocrine insulin exerts protective anti-apoptotic effects on beta cells and that it inhibits the suppressor of cytokine signaling (SOCS), which is induced by various cytokines and lead to apoptosis of the beta cell [16]. Commonly, DM type 1 and type 2 are considered inflammatory processes [17, 18] as there is a significant increase in interleukin (IL) IL-6, IL-18, IL-1 and TNF-α in blood of patients with this disease [19, 20].
Futhermore, chemokines (ligands 2 and 5 chemokines CCL2, CCL5 and CX3CL1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule -1 (VCAM-1) and nuclear transcription factor κB (NFκB) are involved in the development and progression of the disease [21, 22]. In this connection, we have demonstrated that hyperglycemia increases the production of hydroxyl radical in the liver of streptozotocin-induced diabetic rats [23]. In addition, the increase in oxidative stress induced by hyperglycemia and inflammation conduces to development of associated diseases such as diabetic nephropathy [17, 21].
The role for pro-inflammatory cytokines in regulating insulin action and glucose homeostasis and their function in type 2 diabetes has been suggested by several lines of evidence. High TNF-α levels are related to the pathophysiology of insulin resistance and type 2 diabetes [24]. The mechanisms that govern the association between the increased synthesis of inflammatory factors and type 2 diabetes are still being elucidated. In macrophages, adipocytes, antigen-presenting B-cells, dendritic cells, and Kupffer cells in the liver, a number of germline-encoded pattern recognition receptors (PRRs), such as the toll-like receptors (TLR), are activated upon ligand binding with conserved structural motifs that are either specific patterns of microbial components (eg, bacterial lipopolysaccharide [LPS]) or nutritional factors (eg, free fatty acids [FFAs]) [25]. Binding to PRRs gives rise to inflammatory responses by mediating downstream transcriptional events that activate nuclear factor-κB (NFκB) and activator protein-1 (AP-1) and their pathways [26]. Upon activation, these intra-cytoplasmic molecular cascades up-regulate the transcription of pro-inflammatory cytokine genes and, consequently, the synthesis of acute-phase inflammatory mediators and activation of c-Jun N-terminal kinase (JNK) and inhibitor of NFκB kinase-β (IKK). In liver and adipose tissue, these two molecules can inactivate the first target of the insulin receptor (INSR), IRS-1, thereby reducing downstream signaling towards metabolic outcomes [27]. Recent data have revealed that the plasma concentration of inflammatory mediators, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), is increased in the insulin resistant states of obesity and type 2 diabetes, raising questions about the mechanisms underlying inflammation in these two conditions. Increased concentrations of TNF-α and IL-6, associated with obesity and type 2 diabetes, might interfere with insulin action by suppressing insulin signal transduction. This might interfere with the anti-inflammatory effect of insulin, which in turn might promote inflammation [13].
4. Nitric oxide in TNF-α pathways and apoptosis
As stated above, one of the main cytokines released in these inflammatory processes is TNF-α, which can activate signaling pathways associated with cell survival, apoptosis, inflammatory response and cell differentiation. The induction of the responses mediated by TNF-α occurs through the binding of the cytokine to the receptors TNF-R1 and TNF-R2. Both receptors may mediate cell death, however, TNF-R1 has a death domain while TNF-R2 does not, but it would enhance the cytotoxic effects of TNF-R1. TNF-α is produced primarily by cells of the immune system, such as macrophages and lymphocytes in response to inflammation and infection [28, 29]. The binding of TNF-α to TNF-R1 can promote the activation of NFκB or initiate the activation of caspases, which play a major role in the execution of programmed cell death or apoptosis (Figure 1) [30]. NFκB stimulates the expression of genes encoding cytokines (e.g. TNF-α, IL-1, IL-6, IL-2, IL-12, INF-γ and CM-CSF), cell adhesion molecules (CAMs), chemokine receptors and inducible enzymes (e.g., COX-2, iNOS). It also increases the expression of molecules involved in regulating cell proliferation, apoptosis and cell cycle progression, such as the cellular inhibitor of apoptosis protein 1 and 2 (c-IAP1 and c-IAP2), TNF-receptor-associated factor 1 and 2 (TRAF-1 and TRAF-2), B-cell lymphocyte/leukemia-2 (Bcl-2), Fas, c-myc and cyclin D1 [31, 32]. It was found that high levels of glucose can cause apoptosis, in part, through activation of NFκB [33]. Other authors have shown that high glucose levels activate protein kinase C (PKC) pathway and reactive oxygen species (ROS) [34-36]. Furthermore, cytokines and bacterial pathogens can activate iNOS and generate large concentrations of NO, through activation of nuclear transcription factors [37].
4.1. Hepatic expression of TNF-α and TNF-R1, NFκB activity and iNOS expression
We analyzed the hepatic levels of TNF-α and its receptor TNF-R1 by western blot. As shown in Figure 2 (A and B), hepatic levels of TNF-α and TNF-R1 of the diabetic group were higher than those of the control animals (120 % and 300 %, respectively).
We performed inhibition studies of NO production using a preferential inhibitor of iNOS enzyme, aminoguanidine (AG). Fifteen days after the onset of diabetes, a group of rats was separated into different groups and received injections of AG. The groups were as follows: Control group, injected with the vehicle citrate buffer only, and receiving AG in isotonic saline i.p. (100 mg/kg body weight) once a day, beginning 3 days before euthanized (Control +AG) [38], Diabetic group receiving AG i.p. (100 mg/kg body weight) once a day, beginning 3 days before euthanized (SID+AG). The whole study lasted one month. Six animals from each group (Control+AG and SID+AG) were euthanatized and the samples were promptly processed. We examined the expression of iNOS in liver cytosolic fraction by western blot in all experimental groups. Immunoblot analysis followed by quantitative densitometry from six separate animal sets revealed that iNOS increased by 500% (p<0.05) in SID rats compared to the control group (Figure 2 D). Treatment of SID rats with AG markedly decreased the cytosolic protein levels of iNOS, thus reaching the control value.
We also determined the role of TNF-α using ENBREL® (etanercept), a dimeric fusion protein that binds to TNF-α and decreases its role in disorders mediated by excess of TNF-α. Etanercept mimics the inhibitory effects of naturally occurring soluble TNF-α receptors but has a greatly extended half-life in the bloodstream, and therefore a more profound and long-lasting biologic effect than a naturally occurring soluble TNF-R1 [39]. Etanercept was administered to 6 rats from each group (Control-a-TNF-α and SID-a-TNF-α) in a dose of 8 mg/Kg bw/day twice a week for 15 days.
Figure 1.
Schematic mechanisms of NFκB activation induced by TNF-α signaling pathways.
Administration of etanercept or AG also produced a significant attenuation of both TNF-α and TNF-R1 when compared to SID, reaching the control values (Figures 2A and 2B). Also, in Figure 2 C we show that the increase of TNF-α levels in the liver of streptozotocin-induced diabetic rats leads to a marked up-regulation of the NFκB pathway. The high levels of TNF-α due to blood glucose levels increased iNOS expression leading to a high production of NO (see Figure 2 D). Similar findings have been reported in different tissues by other authors [40, 41]. Moreover, we observed that the treatment with etanercept, which blocks TNF-α, leads to a decrease in the expression of iNOS which is increased in the diabetic state. It has been shown that high concentrations of glucose cause an increase in the expression of iNOS induced by cytokines [42] in rat tissues. Consistently, high glucose concentrations do not increase iNOS in the absence of TNF-α [43]. The inhibition of iNOS with a selective inhibitor such as aminoguanidine, also reduced the production of TNF-α, thus evidencing an interaction between TNF-α pathway and the activity of iNOS.
Figure 2.
Hepatic TNF-α (Panel A) and TNF-R1 expression (Panel B), NFκB activity (Panel C) and iNOS expression (Panel D). The results obtained for all experimental groups are shown as follows: Lane 1: Control Control group of animals injected with sodium citrate vehicle; Lane 2: Control+a-TNF-α: Etanercept (8 mg/ kg body weight, i.p.) was administered once a day, twice a week, in saline solution starting 15 days after injection of sodium citrate vehicle and for 15 days; Lane 3: Control+AG: Aminoguanidine (100 mg/ kg body weight, i.p.), was administered once a day, in saline solution starting 15 days after injection of sodium citrate vehicle and for 3 days before euthanasia; Lane 4: SID: Streptozotocin (STZ)-Induced Diabetic rats received an i.p. injection of STZ 60 mg/kg body weight; Lane 5: SID+a-TNF-α: Etanercept (8 mg/ kg body weight, i.p.) was administered once a day, twice a week, in saline solution starting 15 days after injection of STZ and for 15 days Lane 6: SID+AG: Aminoguanidine (100 mg/ kg body weight, i.p.) was administered, once a day, in saline solution starting 15 days after injection of STZ and for 3 days before euthanasia. Immunoblot analysis of TNF-α (Panel A) and TNF-R1 (Panel B) in total liver lysate. Typical examples of Western blots are shown in top panel for each experimental group. The accompanying bars represent the densitometric analysis of the blots as percentage change from six separate animal sets, expressed as arbitrary units considering control as 100%. Data are expressed as means ± SE. Panel C: NFκB activity is showed as follow: Lane 1: Control; Lane 2: Control+a-TNF-α; Lane 3: Control+AG; Lane 4: SID; Lane 5: SID+a-TNF-α; Lane 6: SID+AG.*p<0.05 vs Control; †p<0.05 vs SID. Panel D: Immunoblot analysis of iNOS expression in total liver lysate. Effect of the treatments on each experimental group described above. Typical examples of Western blots are shown in top panel for each experimental group. The accompanying bars represent the densitometric analysis of the blots expressed as percentage change from six separate animal sets. Data are expressed as means ± SE. *p<0.05 vs Control; †p<0.05 vs SID.
4.2. Apoptosis induced by TNF-α
Binding of death receptors to their ligands results in the formation of an intracellular death domain (DISC: death-inducing signal complex) generated by the recruitment of two molecules: the death domain-associated TNF-R1 (TRADD: Tumor necrosis factor receptor type 1-associated death domain protein) and protein-associated death domain Fas (FADD: Fas-Associated protein with Death Domain). This complex also recruits procaspase-8 protein, which is activated by proteolysis. Releasing of the active fragment caspase-8 induces the activation of other caspases in the cytosol [44]. Thus, the DISC complex is responsible for the activation of the caspase cascade leading to apoptosis and/or activation of the kinase signaling pathway involved in apoptosis and JNK (c-Jun N- terminal kinase), resulting in the expression of genes through NFκB or AP-1 (activator protein-1) [45, 46]. The activation of caspase-8 that was induced by activation of the death receptor is followed by excision of Bid protein generating an active fragment of 15 kDa, truncated Bid (Bid-t). Bid-t protein is translocated into the mitochondria and interacts with other proteins of the Bcl2 family (Bax and Bak) and induces the release of apoptogenic factors such as SMAC (second mitochondria-derived activator of caspases) / DIABLO (direct IAP protein with low pI), AIF (apoptosis inducing factor) and the release of cytochrome c into the cytosol forming the apoptosome complex with APAF-1 and procaspase-9. In the apoptosome, procaspase-9 is proteolysed to its mature form, which then activates effector caspase-3, ultimately leading to apoptosis [47, 48].
We performed studies in STZ-induced diabetic rats of both, expression of activated caspase-8 and its activity in liver cytosolic fraction. We observed a substantial increase in activated caspase-8 in the diabetic state (Figure 3 A). Administration of etanercept or AG showed a reduction of both activated caspase-8 expression and its activity as compared to STZ-diabetic rats. We also examined the expression of t-Bid in cytosolic fraction and in liver mitochondrial fraction by western blot in all experimental groups. Immunoblot analysis followed by quantitative densitometry revealed that mitochondrial t-Bid protein levels increased by approximately 50% (p<0.05) in STZ-diabetic rats when compared to the control group (Figure 3 B). Administration of etanercept or AG produced a significant attenuation of Bid-t in the mitochondrial fraction when compared to SID. According to that described by other authors in different tissues [49, 50] the anti–TNF-α (etanercept) treatment was demonstrated to produce a declination in the response of receptor TNF-R1 to TNF-α (diminished activated caspase-8 expression and activity and mitochondrial protein t-Bid, as compared to SID group). Treatment with the iNOS-inhibitor showed a significant decrease of activated caspase-8 expression and activity when compared to STZ-induced diabetic rats (Figure 3 A). Also, we evaluated the activation of c-Jun N-terminal kinase (JNK), a member of the family of the mitogen-activated protein kinases (MAPK). The administration of both etanercept and AG prevents the hyperglycemia-induced phosphorylation of JNK (Figure 3 C).
Figure 3.
Panel A: Activated Caspase-8 expression and activity in diabetic liver: Protein immunoblot analysis and fluorometric assessment of activity of casapase-8 were performed in cytosolic fraction. Activities represented as bars are shown in arbitrary units. Data are expressed as means ± SE for at least six rats per experimental group. Panel B: Immunoblotting of cytosolic BID and t-BID expression in mitochondria-enriched fractions of diabetic liver and effect of different treatments in experimental groups as was described in Figure 2. Typical examples of Western blots are shown for cytosolic BID and mitochondrial t-BID in top panel for each experimental group. The accompanying bars represent the densitometric analysis of the blots for t-BID expressed as percentage change from six separate animal sets. Data are expressed as mean ± S.E. *p<0.05 vs Control; †p<0.05 vs SID. Panel C: Western blot analysis of p-JNK in the liver tissue of diabetic animals and effect of different treatments. Typical examples of Western blots are shown in: Lane 1: Control; Lane 2: Control+a-TNF-α, Lane 3: Control+AG, Lane 4: SID, Lane 5: SID+a-TNF-α, Lane 6: SID+AG. The accompanying bars represent the densitometric analysis of the blots expressed as percentage from six separate animal sets. Data are expressed as means ± SE. *p<0.05 vs Control; †p<0.05 vs SID.
Figure 4.
Panel A: Caspase-3 activity in diabetic rats and effect of the different treatments: Caspase-3 activity was fluorometrically determined. The bars represent activity expressed as arbitrary units. Data are expressed as means ± SE for at least six rats per experimental group. *p<0.05 vs Control; †p<0.05 vs SID. Panel B: Effect of NO and TNF-α on liver apoptosis of diabetics rats: Bars of apoptotic index (AI) represent the percentage of apoptotic cells scored at least 1000 hepatocytes per field in 10 fields of tissue sections at a magnification of 400X. Data are expressed as means ± SE for at least six rats per experimental group. *p<0.05 vs Control; †p<0.05 vs SID. Panel C: TUNEL assay: A representative TUNEL assay was performed on liver slides from the Control group, Control+a-TNF- α, Control+AG, SID, SID+a-TNF-α and SID+AG groups.
An early study had demonstrated that the activation of JNK is associated with increased TNF-induced apoptosis in hepatocytes [51]. In this connection, our results demonstrate that diabetes leads to the activation of JNK, inducing an increase of the apoptotic index. Moreover, we demonstrated that the decrease of TNF-α levels by etanercept treatment seems to completely abolish the observed activation of JNK induced by the diabetic state, thus leading to a decrease of apoptosis (Figures 3 and 4). We assessed apoptotic cell death by determining caspase-3 activity and performing TUNEL assays. There was a significant increase in caspase-3 activity in SID rats when compared to the control group (p<0.05). The administration of etanercept or AG to SID rats significantly decreases caspase-3 activity as compared to SID rats (p<0.05) (Figure 4 A). Figure 4 B shows Apoptotic Index (AI) expressed as a percentage. Apoptotic cells were identified in all experimental groups. Typical features of apoptosis, such as cellular shrinking with cytoplasmatic acidophilia, condensation and margination of chromatin were corroborated by hematoxylin-eosin staining. The diabetic state significantly increased the AI when compared to the control group (p<0.05), while treatments with etanercept or AG significantly attenuated this increment when compared to SID group (p<0.05), even reaching the control values (Figure 4 B). In Figure 4 C a representative TUNEL assay for Control, SID, SID+etanercept and SID+AG is showed. TUNEL–positive signal is maximal in the SID group and it is clear that after the different treatments there is a significant reduction of TUNEL-positive cells.
Our results clearly show that in the liver of STZ-induced diabetic rats there is an enlargement of caspase-3 activity with the consequent increase in the AI.
5. Diabetes, inflammation and liver apoptosis
Several studies have shown that TNF-α may be involved in viral hepatitis, alcoholic hepatitis, ischemia/reperfusion liver injury, and fulminant hepatic failure. In human disease, serum levels of TNF-α and hepatic TNF-receptors are frequently increased [52]. A research paper recently published by our group demonstrates that the diabetic state induces an increase of TNF-α and its receptor TNF-R1 in the liver [43]. Data presented in this work show that the increase of TNF-α levels in the liver of streptozotocin-induced diabetic rats leads to a marked up-regulation of the NFκB pathway. NFκB is one of the key transcription factors involved in triggering the cascade of events that allow inflammation and different research groups have demonstrated its activation in the diabetic liver [53, 54]. The expression of iNOS is closely related to stimulation of NFκB, whose recognition sites have been identified in the promoter region of the gene encoding for iNOS.
In the liver of diabetic rats we found an increase of TNF-α due to increased expression of iNOS which led to a high production of NO [43]. Similar results have been reported in different tissues by other authors [40, 41]. In our work, we observed that the treatment with etanercept, which blocks TNF-α, leads to a decrease in the expression of iNOS which is increased in the diabetic state. Furthermore, etanercept treatment reduces the production of NO in the liver of streptozotocin-induced diabetic rats. It has been shown that high concentrations of glucose cause an increase in the expression of iNOS induced by cytokines [42] in rat tissues. Consistent with this, high glucose concentrations do not increase iNOS in the absence of TNF-α [43]. The inhibition of iNOS with a selective inhibitor such as aminoguanidine also reduced the production of TNF-α, thus demonstrating an interaction between TNF-α pathway and the activity of iNOS.
Figure 5 depicts a summary of the apoptotic mechanisms occurring through TNF-α pathway in the liver in the diabetic state.
Figure 5.
Proposed scheme for the mechanism involved in TNF-α- induced apoptosis in liver disease induced by diabetes type 1. In the diabetic state, hepatic TNF-α elevation induces activation of NFκB, caspase-8 and JNK, thus leading to an increased apoptotic rate.
6. Conclusion
The relevance of the present chapter is to provide further knowledge on the mechanisms underlying the disease process in the liver during an inflammatory process such as type 1 diabetes. The regulation of hepatic TNF-α level and iNOS activity in the diabetic state could be therapeutically relevant for the improvement or delay of the hepatic complications of chronic hyperglycemia.
Acknowledgments
This work was supported by research grants from CONICET. We especially wish to thank PhD Cecilia Basiglio for English revision.
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Ronco and Cristina E.\nCarnovale",authors:[{id:"158464",title:"Ph.D.",name:"Cristina",middleName:null,surname:"Carnovale",fullName:"Cristina Carnovale",slug:"cristina-carnovale",email:"ccarnova@fbioyf.unr.edu.ar",position:null,institution:{name:"National University of Rosario",institutionURL:null,country:{name:"Argentina"}}},{id:"166123",title:"Dr.",name:"Paola",middleName:null,surname:"Ingaramo",fullName:"Paola Ingaramo",slug:"paola-ingaramo",email:"paolaingar@gmail.com",position:null,institution:null},{id:"166124",title:"Dr.",name:"Daniel",middleName:null,surname:"Francés",fullName:"Daniel Francés",slug:"daniel-frances",email:"danieleafrances@hotmail.com",position:null,institution:null},{id:"166125",title:"Dr.",name:"M. Teresa",middleName:null,surname:"Ronco",fullName:"M. Teresa Ronco",slug:"m.-teresa-ronco",email:"tereronco@hotmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction ",level:"1"},{id:"sec_2",title:"2. Animal models for the study of diabetes ",level:"1"},{id:"sec_3",title:"3. Diabetes and inflammation",level:"1"},{id:"sec_4",title:"4. Nitric oxide in TNF-α pathways and apoptosis",level:"1"},{id:"sec_4_2",title:"4.1. Hepatic expression of TNF-α and TNF-R1, NFκB activity and iNOS expression",level:"2"},{id:"sec_5_2",title:"4.2. Apoptosis induced by TNF-α",level:"2"},{id:"sec_7",title:"5. Diabetes, inflammation and liver apoptosis",level:"1"},{id:"sec_8",title:"6. Conclusion ",level:"1"},{id:"sec_9",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Pietropaolo M, Barinas-Mitchell E, Kuller LH. The heterogeneity of diabetes: unraveling a dispute: is systemic inflammation related to islet autoimmunity? Diabetes 2007; 56 (5) 1189-1197'},{id:"B2",body:'Kasuga M. Insulin resistance and pancreatic beta cell failure. J.Clin.Invest 2006; 116 (7) 1756-1760'},{id:"B3",body:'Wild S, Roglic G, Green A et al. 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Biochem.Pharmacol. 2006; 72 (9) 1090-1101'},{id:"B52",body:'Ding WX, Yin XM. Dissection of the multiple mechanisms of TNF-alpha-induced apoptosis in liver injury. J.Cell Mol.Med. 2004; 8 (4) 445-454'},{id:"B53",body:'Boden G, She P, Mozzoli M et al. Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kappaB pathway in rat liver. Diabetes 2005; 54 (12) 3458-3465'},{id:"B54",body:'Romagnoli M, Gomez-Cabrera MC, Perrelli MG et al. Xanthine oxidase-induced oxidative stress causes activation of NF-kappaB and inflammation in the liver of type I diabetic rats. Free Radic.Biol.Med. 2010; 49 (2) 171-177'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Paola I. Ingaramo",address:null,affiliation:'
Institute of Experimental Physiology, (CONICET), Faculty of Biochemical and Pharmaceutical Sciences (National University of Rosario), Rosario, Argentina
'},{corresp:null,contributorFullName:"Daniel E. Francés",address:null,affiliation:'
Institute of Experimental Physiology, (CONICET), Faculty of Biochemical and Pharmaceutical Sciences (National University of Rosario), Rosario, Argentina
'},{corresp:null,contributorFullName:"María T. Ronco",address:null,affiliation:'
Institute of Experimental Physiology, (CONICET), Faculty of Biochemical and Pharmaceutical Sciences (National University of Rosario), Rosario, Argentina
'},{corresp:"yes",contributorFullName:"Cristina E. Carnovale",address:"ccarnova@fbioyf.unr.edu.ar",affiliation:'
Institute of Experimental Physiology, (CONICET), Faculty of Biochemical and Pharmaceutical Sciences (National University of Rosario), Rosario, Argentina
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1. Introduction
The chapter analyzes the sources of computer visualization metaphors and human-machine interaction. The metaphor essence consists of interpretation and experience of the phenomena of one sort in terms of the phenomena of other sort.
A metaphor is the main idea of forming the types of visualization views, interfaces, and scenarios of visualization output and interaction with it.
Metaphor sources are objects of the surrounding world, scientific ideas, ideas derived from literature, folklore, sci-fi cinema, computer games, etc.
Metaphorization is based on interaction structures of source and target domains. In the process of metaphorization, some objects of target domain are structured on an example of objects of target domain, and there is a metaphorical mapping (projection) of one domain onto another. That is how the metaphor can be understood as a map from source domain onto target domain, and this map is strictly structured [1]. Metaphor ideas are often based on real life as well as on abstract scientific ideas. Worth mentioning are such examples of pre-computer era visualization as cartography, engineering graphics, and Cartesian coordinates, which played a crucial role in the development of modern civilization. Cartesian coordinates were the basis for the idea of computer graphics during the first period of its development. The use of new ideas is connected with developing the means for human-computer interaction. It is in this field that such metaphors as a light button and light button menu appeared. The most well-known and still popular desktop metaphor is also connected with interfaces intended to provide interaction in office work computerization. The desktop metaphor is almost entirely based on office work realities. However, there is a double-click, which can be called a magic feature and is unparalleled in real life. Further, such magic features were added in a whole range of metaphors used in computer visualization systems. The emergence of virtual reality as an environment for computer visualization made the use of metaphors relevant. Conditions inherent to virtual reality are somewhat similar to magic and science fiction. That is why fairy tales and sci-fi in literature and cinema may become an interesting source of new metaphors.
Below we shall discuss the main ideas of pre-computer visualization, the potentials of metaphors based on real-life phenomena and on scientific ideas. Then we shall analyze the potentials of fairy tales as sources of metaphors. We shall also provide several examples of metaphors based on science fiction and discuss the evolution of visualization from a comic book to immersive cinema.
2. Global visualization metaphors
The concept of metaphors is popular in publications on computer visualization and human-computer interaction. One may reveal the following two cases of using this concept:
A metaphor as the basic idea of data presentation, the idea of convergence of entities of a computer system, and a source domain.
A metaphor as the idea of interaction with the [virtual] environment created by computer systems.
The following hierarchy of computer metaphors is considered:
Global metaphors of design
Basic visualization and interface metaphors
Local metaphors
Global metaphors map the main design idea. For example, considering the world as a “super office.” (The whole world is an office, and all the men and women are merely clerks in it).
Let us consider global visualization metaphors. These ideas depend on global events and changes in society, art, and science. We are interested in global metaphors that have a visual (“pre-computer” and computer) representation. These ideas formed the basics of cartography, engineering drawings, and function graphs on the Cartesian plane.
We review the interference of metaphorical ideas and the challenges facing economy, science, and education in the past and now.
Modern cartography is the result of geography development and a prerequisite for the Age of Exploration. The use of the Mercator projection and the grid of parallels and meridians in the modern age is a great achievement in the visualization of geographical and navigation data.
Variations of geographical metaphors are used now in data visualization and software visualization systems.
Engineering drawing is the product of the Industrial Revolution, its prerequisite and an important tool. Multiple views and projections, a set of rules depicting product features, compile a certain explicit code.
Engineering drawing in the form of CAD systems is an integral part of computer tools of modern engineers.
One of the most powerful visualization ideas of the modern age is the idea to draw function graphs in Cartesian coordinates. The idea of function reflects rather abstract concepts, but due to graph drawings, even very young students may become familiar with them.
2D and 3D graph drawings are the bases of modern scientific visualization and an important part of data and software visualization [2].
3. Computer metaphors
For a start, let us revise the way things were in the field of human-computer interface before the emergence of visual metaphors. In those times software engineers (who comprised the basic quota of users all over the world) still remembered working with bulky computer consoles. Command-line interface prevailed in interactive systems. For instance, text editing commands included operation indication, the number of source line (sometimes the number of a symbol in the line as well), and (if necessary) the new text for correction or pasting. Such an interface, although it required from the user to keep in mind a continuously changing text, and despite occasional mishaps with saving the changes, was tolerable enough for professionals. Graphic displays gave a new impetus to human-computer interaction. Along with the tools of data visualization, program interface tools came into use. Based on that, light buttons (an output primitive used to emulate a functional key) and light button menu came into exploitation. With their help one could easily interact both with the program’s system and with the user’s program.
The mass arrival of personal computers simply could not have happened without the emergence of visual interaction tools, new devices, and brand-new concepts of interface organization with the user, for example, the concept of direct manipulation.
The concept of direct manipulation was suggested in the early 1980s by Professor B. Shneiderman, a famous expert in the field of computational sciences, who combined and analyzed new trends in organizing the interface. Currently, this concept prevails in interface design.
B. Shneiderman determined the following features of an interface created on the basis of the direct manipulation concept:
Continuous depiction of the object of interest
Physical actions (manipulations with the mouse, joystick, touch screen, etc.) or using a functional keyboard instead of commands with complex syntax
Quick operations, divisible into steps and allowing resets, with an instantly visible effect on the object of interest
The essence of this approach to interface creation is in making the user perceive their activity as direct manipulation with the objects displayed on the screen, rather than as a dialog with the computer regarding these objects. Instead of using command language to describe operations with objects, the user manipulates visible perceptions of these objects on the screen.
The interface metaphor is considered as the basic idea of convergence and similarity between model objects of an applied field and interactive objects. The role of an interface metaphor is to facilitate better understanding of interaction semantics, as well as to provide a visual idea of dialog objects and define the set of user manipulations with them.
The interface metaphor in this respect is seen as the basis of the semiotic system, which in turn underlies the interactive language. With the help of this language, the user forms their task and achieves the solution by means of a computer. The interface metaphor does not only help describe abstractions but also structures the understanding of a new applied field and defines objects of the interactive [visual] language [3].
The most recent global metaphor is the basis of modern computerization. For a variety of economic and social reasons, people at the end of the twentieth century understood the world around them not as a workshop where employees work but as an office where clerks and managers spend their time. The cornerstone of a desktop metaphor success is tightly linked with this change in the awareness of the world. Results of modern computerization (and the desktop metaphor) reflect global ideas of modern “postindustrial” world. However, “office” interfaces generate office activity techniques in such “non-office” domains as medicine or education. This often involves non grata effects.
Originally, this metaphor was offered for office automation systems, but then its use was expanded for operating systems interfaces. These ideas were linked with end-user programming, as the means for office clerks and managers to simplify their work using computers.
The desktop metaphor became the most frequent practice in the 1990s. This metaphor is in many respects the basis of modern visual interfaces. The success of a desktop metaphor, undoubtedly, is connected not only (and not so much) with the natural figurativeness of icons that are [not always] clear to users but with logicality and systematic nature of all activities within visual environments based on this metaphor.
The formula of a desktop metaphor is described in [1]. Apart from borrowing office work realities, this metaphor has a “magic” idea: all actions within the system are made by means of double-clicking on icons.
Significantly, desktop metaphor extensions toward an office desk metaphor, office space metaphor, and a filing cabinet metaphor were not very successful, despite interesting solutions and the use of several magic features.
4. Fairy tales and science fiction as a source for metaphors
By providing calculation results, visualization ensures interpretation and analysis of the acquired data. The following subfields of computer visualization can be distinguished: scientific visualization, software visualization, and information visualization. Scientific visualization presupposes using the means of computer graphics and human-computer interaction to provide data on objects, processes, and phenomena, modeled in scientific calculations. Software visualization means a combination of methods of using graphics and human-computer interaction tools used for better understanding of phenomena and for efficient exploitation of the software, as well as for specification and presentation of software objects in the process of program creation. The term information visualization relates to visual description and presentation of abstract information acquired as a result of gathering and processing data of different types and functions.
Typically, scientific visualization uses traditional (pre-computer) methods of displaying mathematical, physical, chemical, biological, and other models (e.g., two-dimensional and three-dimensional function graphs). Sometimes the imagery natural and/or typical for a given application is also used, for example, molecule presentations in modeling chemical processes. Traditional imagery, sometimes borrowed from the pre-computer static graphics, is also used in information visualization. One may conclude that the use of metaphors in scientific and information visualization is limited.
Computer metaphors became most widely used in software visualization systems. These metaphors are based on objects and phenomena of the real world or on models derived from specific branches of science. Among these metaphors the most popular are spatial metaphors: the city metaphor or the landscape metaphor and their variations in particular. Spatial (three-dimensional) metaphors are actively applied in developing presentation views in visualization systems used for monitoring, testing, and debugging parallel and distributed programs, as well as programs for processing events and providing reactions to them. These metaphors are widely used in the systems based on virtual reality [4, 5, 6, 7].
Using a city metaphor presupposes structuring the input data by means of internal city structure containing separate blocks, streets, and buildings. The naturalness of metaphors causes both simplicity of orientation in space and navigation ease. In software visualization systems within a city or a landscape, metaphor transport arteries are often used to represent control flows and data flows, as well as various connections between objects and program components. When using these metaphors in the systems based on virtual reality, a flight over the city is possible. There are examples of software visualization systems based on an extended city/building/room metaphor with the use of teleportation for immediate relocation between city districts or buildings representing different elements of a big software complex.
A cosmic metaphor in its modern sense, with a heliocentric worldview, is chosen as an idea for a visual programming medium. At the same time, parts of the entities of the program are represented as planets, their satellites, rings (like the rings of Saturn), and other elements of outer space. It seems that in the case of virtual reality application, the most archaic 3D version of a geocentric model may be more convenient, with the Earth represented as being flat and celestial bodies located on hemispheres covering the flat Earth [8].
Based on scientific views, a molecule metaphor in particular can be used to visualize performance traces and graphs for parallel programs. This metaphor provides representation view of a large volume of structured data. Interpreting a physical molecule (particle) metaphor and its modifications is generally simple and natural, although it requires certain (basic) knowledge of physics from the user. Moving and navigation can be executed by means of flying around the molecule (or a set of particles). This means, a molecule metaphor, in the same way as a city/landscape metaphor, includes some magic or fantastic features.
The paper [9] describes the original brain metaphor, which is used for animated representation of a parallel program performance. The idea of visualizing brain activity when presenting it with some stimuli is transferred onto a program or an application’s performance visualization (activating procedures and functions, input/output, etc.). Let us note that this metaphor does not have any magic features; possibly, this is what hampers perception of a large volume of information based on it.
Currently the idea of gamification has been gaining popularity. It implies the use of computer game ideas in non-gaming fields of application. When developing software visualization systems, this approach presupposes creating tools that provide software engineers with an interface similar to that of computer games. The paper [5] discusses a software visualization system based on virtual reality with the use of virtual reality. A city metaphor is the basic metaphor for this system. However, both the imagery and the method of interaction in the system strongly resemble popular computer games.
Gamification in software visualization system development based on virtual reality is also mentioned in the paper [10]. An environment based on virtual reality is described, which should provide work with the structures of a program code using city metaphors and cosmic metaphors for visualization, navigation, and program code data transfer in an interactive mode. Games have been released that have demonstrated the potential of gamification for the purposes of enhancing the understanding of structural dependencies and code modularization.
Thus, everyday reality, scientific ideas, and modern computer games serve as sources for metaphors. Further, we shall look at fairy tales and science fiction, where objects with magic features are used and characters have magic abilities, as sources. Magic ideas described in fantasy novels or in literary processed folklore fairy tales are the most functional and consequently the most useful ones for our purposes.
An important issue when forming scientific and, in particular, computer metaphors is the question of where to find the source [11, 12]. The description of the constructive procedure of searching and/or generating interface metaphors is presented in [13]. This multistage procedure provides (among other things) the consideration of application domains, user tasks, and user characteristics.
Interest to “magic” in connection with HCI and interface metaphors has been shown in the early 1990s. Significant attention has been given to the concept of “magic features.” This concept in the context of HCI was introduced for the first time by [14].
The issue of magic and magic features as a source for metaphors when developing interactive visual software complexes is also discussed in the paper [15] (see also [16]).
The word “magic” is very popular as part of metaphoric names for interface techniques, for example, a “magic lens,” a “magic mirror,” a “magic lancet,” etc. In [17] a number of specific examples from stage magic are presented, and application of its principles and techniques in human interface design is discussed. The article [18] is devoted to sources of metaphor for tangible user interfaces. Authors suppose magic and paranormal phenomena could be a fruitful place to look for new metaphors for tangible user interfaces. Also, voodoo magic is considered an interesting idea for interfaces with virtual objects. In [19] Voodoo doll technique is used as a two-handed interaction technique for manipulating objects at a distance in immersive virtual environments.
Ideas for interface metaphor design, linked with magic fairy tales, fantasy, and science fiction novels, are described in a number of articles. In [20], for example, the magic metaphor of a flying carpet is mentioned, but in [21] the metaphor of a magic carpet is realized, for instance, moving in the virtual reality environment. In [22, 23, 24, 25, 26], the ways of using a “magic wand” are described. A magic wand is considered a manipulation metaphor to form an interface in systems with elements of virtual reality. Interesting ideas of wonder objects (e.g., a magic mirror) were proposed (and realized in prototype versions) for storytelling in modern museums [27]. In [28] an information system using a city metaphor is described. In this system, magic/fantastic opportunities are used on a regular basis. Among these opportunities there is “tunneling through space” presenting the typical adoption from science fiction. Rooms with “magic windows” may also be considered as a magic (science fiction) feature. A “magic window” is an interesting expansion of a well-known information wall metaphor.
Here we consider fantastic magic features, selecting the samples that are fruitful for interface and visualization metaphors.
Magic transport: In fairy tales and science fiction novels, one can find:
Teleportation—an instant movement by means of verbal influence (spell) or by means of manipulations with any objects or uses of such devices as teleports
A rather slow movement by means of magic transport. A magic transfer may take place both for subjects and for (animated and inanimate) objects of magic
Magic navigation means: An example is a milestone with a magic legend or a magic clew, following which one may reach Fairyland.
Magic communication means: An example is a magic mirror tuned on an interesting character for his/her protection or observation.
Magic (additional to normal) opportunities for manipulations with objects, processes, and even natural phenomena. In some options a superpower, invincibility, etc. Generally speaking, one can use the term “magic power” (or “superpower”). These manipulations and powers may be executed through spells and objective magic, as well as through the universal manipulator, a magic wand.
One can set out the general class of magic objects as objects possessing “magic properties.” Thus, magic expansion of usual functionality is possible (for example, seven-league boots), as well as attributing additional, unusual in real life functions to objects (for example, Aladdin’s magic lamp used to summon, activate and neutralize magic beings). For the purpose of magic objects used as manipulators, transport and communication means one can also use the term “magic tools.”
Magic transformations of objects: As an example, one may consider the construction of palaces by the Genie in the Arabic fairy tale or the transformation a pumpkin into the carriage for Cinderella.
Similarly to magic objects, magic subjects may be set out, i.e., evil, good, or neutral (with respect to the characters) magicians possessing superpowers. (As an option—magic anthropomorphic beings, e.g., fairies, gnomes, trolls, genies, etc.)
Magic transformations of persons: In fairy tales such transformations may be spontaneous, unexpected for the characters, or they may result from magic actions (some magic spells or manipulations). These transformations can be carried out in view of sympathetic magic (i.e., magic based on a certain similarity).
Our attention was focused on two “magic-fantastic” metaphors from the novels (and also the films) about Harry Potter. These are speaking and moving portraits and the Marauder’s Map, which even showed people’s movements on it. In this case, portraits of dead people are the active objects. They may address the living characters of the novel without requests and even move from one portrait frame to another to pay visits to each other. The map continuously traces and shows the location of the person under observation.
There are many active, anthropomorphic, and speaking characters in fairy tales and in science fiction novels such as Golem, robots of K. Capek and I. Asimov, and so on. Similarly, there are numerous variations of magic/fantastic means of navigation and search both in fairy tales and in fantasy.
In these magic metaphors, visual characteristics are not as important as spontaneous activity inherent to generated objects and subjects. Spontaneous activity can be considered the means of imitating reasonable behavior. Of importance is also the character’s existence independently of users, imitating reasonable behavior. In sci-fi and popular scientific literature and films such active computer, “subjects” appeared several decades ago. In modern computer practice, agents who are active under their own initiative frequently cause irritation. We started our research of active intellectual agents to understand what, why, and where active intellectual agents have to do.
The idea of an “active” map showing a real landscape and movements of objects was considered. The “activity” of a map can be connected to events, in the same way as in navigating systems: moving around, turning, crossing, and so on; but “activity” can also be spontaneous, connected with time events. Another idea that may be possible is the development of an “active” scheme of a protected apartment or territory. In this case tracking systems and “highlighting” persons may be necessary. Movements of all characters without exception may be shown on the scheme, and labels will allow identification. In the context of the given ideas, it may be noted that works in this direction, on the basis of such systems as GPS, are underway and there are examples of interactive maps serving as guide advisers. Moreover, now it is easy to develop speaking anthropomorphic avatar agents, and there are many examples of such implementations.
We have decided to link the idea of active agents based on a metaphor of a speaking portrait with the expert system. The point is that an active agent with its (possibly) importunate activity is authorized only in the case of teaching systems. The logic of project development led us to the following idea of an “active textbook.” This textbook has to be able to analyze the student’s behavior in the process of studying, for example, the time of reading, manipulations with the text, and so on. Based on these analyses, the “active textbook” may detail teaching material, search new data sources, or turn to other things. The analysis of a user behavior may be accomplished at a syntactic level (at a level of operations with a mouse and a keyboard, eye tracking, etc.) and on a semantic one (monitoring opened files or sites, running applications, recording events, etc.). Such analysis and elements of programming by demonstrations will allow our system to learn how to teach in the process of its use and to operate in the given direction “independently.” It is also possible to supply the system with adviser functions. The system will be like an intelligent human adviser and will not impose its opinion but provide recommendations and solutions. This human-like behavior may be provided by psychologically driven slowdowns in the system’s activity.
Expansion of a city metaphor used in software visualization systems is suggested by means of adding active agents by inputting parameters into certain functions and methods. The agents can move around the city, determining the locations where they are used and changed and the way the process of algorithm work plays out. This way, an extended metaphor creates such additional properties as the opportunity to observe software objects inside buildings or rooms, reflecting particular entities while active agents move around the city.
In visualization systems based on virtual reality environments, there are such tasks where complex manipulations with objects are necessary, for example, pulling something out, cutting, or zooming in. As a metaphor of the tool for such tasks, first of all, the idea of a magic wand comes into designer’s mind. However, a magic wand does not have differentiated actions and hence requires the means to change operating modes. In specialized systems, it is more natural to use specialized “magic tools.” For example, in medical information system as manipulator’s metaphor, the idea of a “magic lancet” is offered. The lancet allows to “dissect” this or that organism area for profound exploration. When “dissecting” any human organism object, all physical changes are visualized, as if we did it in a reality. In case of a combination of a “magic lancet” metaphor with a three-dimensional model of a human body, one may obtain the virtual model of operations, and a prototype system of information visualization for medical purposes is in progress now. Systems based on this metaphor may be used, for example, to teach surgery [29].
Science fiction may be an implicit source of metaphors used to control visual objects in virtual reality environments. Thus, for instance, the paper [30] describes an environment for an experiment studying psychological states in virtual environments. A user has to manipulate cubes to compose a given pattern. These cubes in the virtual environments are “caught” with a special trap, in which an antigravity movement mode to a necessary point or a cube rotation mode may be activated. When using a special command, the cube rises over the virtual table and flies in the location set by the user.
Our preliminary research shows the applicability of “magic” metaphors for tasks in interactive systems and systems based on virtual reality environments. For example, the search of metaphors for movements in virtual environments may require magic transportation techniques, such as teleports and flights of various types (the flying carpet, the flying ship, Roc, a winged horse). Metaphors of intellectual agents-informants may also be based on magic means of navigation.
In fairy tales and science fiction novels, one can find a lot of magic phenomena, such as magic knowledge, war magic, fulfillments of desires, telepathy and thought-reading, etc. But we do not know for sure yet, whether these features are useful for metaphor search. However, for a choice of metaphors for manipulations with objects and processes in virtual environments, “the war magic” may be of interest. War magic is connected with transferring the events taking place in the magical world into reality. For example, any variations of “magic chess,” where games with chess pieces are transferred into land battles, or the “naval” military magic where models of fight in a vat of water are transferred into sea battles. One may find these ideas (partially close to voodoo magic) in a number of folk and literary fairy tales.
Note that folk fairy tales are governed by rigorous logic of plot development and a choice of characters. By the way, in literary fairy tales and fantasy novels, this logic is also typically observed.
Analysis shows that exotic “magic” metaphors may be used to form any interface features. However, implementation of interactive systems on their basis may be both complex and contradictory. Magic metaphors are frequently transformed into abstract interface opportunities, losing the appreciable connection with initial ideas. For example, in case of a speaking portrait metaphor, the anthropopathy of an agent turned out to be unnecessary. But it is necessary to endow it with the function of a magic assistant/conductor into the world of knowledge. Of course, the transmuted abstractness of metaphors is an advantage rather than a defect of their use. In the systems created, for example, for office automation or for end-user programming, the presence of magic interface manuals may appear as a distracting or even irritating factor. However, using such “magic features” as automatic return of electronic analogs of paper documents on their place at the end of processing may be carried out without any special warnings even for non-expert users. Such features are well-conformed to common sense of clerks and do not demand unnecessary efforts during operations. Infringement of magic logic due to any absurd ideas or too farfetched subjective likeness may lead to serious mistakes. Sharp criticism of interface metaphors as such is connected with the infringement of magic logic in the early version of Apple’s interface (using the trash can metaphor to eject disks) [14].
5. Metaphors for systems based on virtual reality
Virtual reality environments were initially used for aviation and space simulation training systems. They gained widespread use in entertainment systems and computer games. They are also used in medicine and psychology for therapeutic purposes. We are interested in virtual reality as a basis for computer visualization systems development. The imagery used in virtual reality systems can be adopted from the imagery inherent to a certain computer model. However, for software visualization, systems based on virtual reality metaphors are typically used. Such systems can benefit from (or even require) fairy tale features described above. In this respect, we are interested in interface metaphors which are applied in virtual reality.
The role of interface metaphor is to promote the best understanding of interaction semantics and to determine the visual representation of dialog objects and a set of user manipulations with them. A metaphor, considered as a basis of the sign system, in turn underlies a dialog language. A user articulates the problem with the help of this language and achieves solution from the computer. The metaphor helps to describe abstraction and provide structural understanding of a new applied area but also assigns dialog [visual] language objects. Interface metaphors may be considered a special case of scientific metaphor used for generating new or additional senses to understand new facts and phenomena.
Virtual reality is characterized by a set of specific states, above all, presence, involving a human perceiving themselves inside a virtual environment with various features. Due to experiencing presence, a person finds themselves in situations similar to those of fairy tales and science fiction, even if no magic metaphors were applied (e.g., finding oneself inside a brain or a molecule). In such conditions, the use of magic features described above is reasonable, both for navigation and movement in a virtual environment and for interaction with the objects of this environment.
A project of a virtual environment designed for modeling visual search in large space may use either emerging magic signs or talking objects to facilitate user navigation. In virtual reality systems, a magic wand may be useful as an interface metaphor to point at objects and interact with them. The idea of teleportation is interesting in virtual reality systems for movement organization, as it provides the possibility of instant movement to a new virtual scene.
6. The butterfly effect
Interesting metaphors may be adopted from science fiction works. Thus, a time machine metaphor and a butterfly effect metaphor were used in a project of an environment for adjusting parallel programs dealing with software visualization systems [31].
One may consider time as an axis that is analogous to traditional spatial axes. And the event stream may be depicted along this axis. Any change in this stream may break the whole chain of cause-and-effect relations. In this case, the idea of traveling in time in both directions seems to be natural. One may consider a set of parallel processes as consistent streams of events flowing and changing along this time axis. In this case, effects of an event in the process cause a reaction, affecting both the process in which it has occurred and other processes. It is possible to correct errors by going back in time along the axis and interfering with the sequence of events at the moment. This approach can be described as the “time machine” metaphor. Note that the use of the time machine metaphor does not require any knowledge of the source (science fiction novels). We have developed a prototype of a visualization component for a parallel process control and representation system. This system can be used for debugging parallel programs. We use 3D imagery to visualize processes. Processes are represented by color cylinders connected with each other by thin “threads” (similarly to visual representations in the VisuaLinda system [32]). Globules representing data move along these threads. The states of processes are depicted by colors. A user may navigate along the time axis and change the processes’ states. The time machine metaphor may be considered similar to a traditional record player metaphor. However, in the case of a time machine, there is a possibility of event changes described by the well-known butterfly effect metaphor, which is connected with the situation when a small change of initial conditions causes significant and often unpredictable effects.
A time machine metaphor seemed promising for software visualization of parallel computing. However, after analyzing its implementation, this impression may change. In this case further development of fully fledged debugging and visualization facilities for parallel programs is needed, for example, trapping events, online visualization, and other tools similar to those implemented in the debuggers of the 1990s, such as [33, 34]. These metaphors may also be applied in the systems of software visualization based on virtual reality [31].
7. Visualization texts: From interactive comics to motion pictures with immersion
Present-day comics and manga may be described in terms of visual texts. You can describe rich and complex languages of pictorial art based on natural imagery, but in this case, the task of a detailed language description is rather complex and often uncertain. One can also describe complex and weakly formalizable dynamic languages of cinema and animation. Similarly, one can define graphical texts associated with computer visualization. The examples of those visualization texts are:
Isolated displays
Dynamic, logically related shot changes with the inclusion of interaction
Animations also with the inclusion of interaction
The goal of visualization is to leverage the existing scientific methods by providing new scientific insight into visual methods. Virtual reality environments are actively used to practice leaping into a new quality of cognitive visualization. Virtual environments are characterized by such features as egocentric points of view and user-centered, often multisensory, interactions. Virtual reality environments are dynamic, rather than static. The user’s experience of the virtual world may combine a visual channel with auditory or haptic feedback. Immersion and sense of presence (the feeling of “being there”) are factors which define virtual reality. The sense of presence distinguishes virtual reality from “traditional” 3D computer graphics. Users “immersed” in virtual reality control the graphics output. Users may also participate in adaptive control of the application system. The essence of virtual reality is in the interaction between the user and the virtual environment. The interpretation principle for graphical texts was formulated as follows: interpretation of such texts is possible only if the “readers” of the text have external information. This principle is similar to the principle of intuitive use. The interpretation principle is very important in the case of visualization based on virtual reality.
One may consider the evolution from comic-like visualization methods to controlled animation-like movies and from these movies to full insight and controlled immersion processes. In its own right, visualization languages of virtual reality may be considered; however, a visualization language in the case of “immersion movies” becomes much more complicated and needs further description. It appears that a new quality of visualization can be achieved primarily through the following media:
Immersion in virtual reality
Creation of an interactive “movie”
Presence of a controlled and modifiable “screen story” (“movie” script)
The language of this script is the language of visualization description (and possibly of visualization depiction—in the case of visual languages). The languages have to support history tracing, including visualization and interaction traces and fixing insight experiences. Examples of “immersion movies” will be used in computer visualization systems.
8. Conclusion
The issue of finding the sources arouses a whole range of questions. First, an assessment of metaphor applicability is necessary both for the given applications and for a specific task. When assessing the applicability of a metaphor, one should evaluate the way this metaphor can depict the features of a certain application, for which the visualization system is built. However, imaging precision does not necessarily guarantee success for the system. For example, a brain metaphor, precisely depicting the work of a parallel program, is not very convenient in terms of perception, which strongly hampers visualization perception. Magic features are useful in addition to the complex of computer metaphors but are not sufficient. There are examples when a metaphor, for various reasons, was not successful even after introducing these features. Gamification is an interesting idea. However, the question remains whether game components risk distracting the user from their intellectual activity by putting them into a silly, playful mood. Distraction from the main task may also be caused by the magic features of metaphors, especially in environments based on virtual reality. When using virtual reality, one should also analyze the potential user states in terms of increasing or decreasing performance. All these thoughts show that research of substantial user groups is necessary. It is worth noting that in case of software visualization, this research is relevant, as there is a considerable number of tasks and a significant number of experts.
\n',keywords:"computer metaphor, visualization, human-computer interface, fairy tales, magic features, fantasy",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/70097.pdf",chapterXML:"https://mts.intechopen.com/source/xml/70097.xml",downloadPdfUrl:"/chapter/pdf-download/70097",previewPdfUrl:"/chapter/pdf-preview/70097",totalDownloads:248,totalViews:0,totalCrossrefCites:0,dateSubmitted:"May 22nd 2019",dateReviewed:"September 30th 2019",datePrePublished:"November 22nd 2019",datePublished:"June 17th 2020",dateFinished:null,readingETA:"0",abstract:"This chapter is devoted to finding sources for metaphors of computer visualization and human-computer interaction. Computer metaphor is considered the basic idea for the development of interfaces, visualization views, and scenarios of visualization and interaction. Global metaphors map the main design idea. These ideas depend on global events and changes in society, art, and science. In the “pre-computer” era, such ideas formed the basics of cartography, engineering drawings, and drawing function graphs on the Cartesian plane. When designing visualization and interactive systems, computer metaphors use “magic features” beside analogies with daily life. Nowadays ideas of visualization are often based on “gamification.” This approach presupposes creating tools that provide software engineers with an interface similar to that of computer games. In this chapter, ideas drawn upon fairy tales, science fiction books, fantasy films, and other similar spheres are considered as sources of computer metaphors. Such metaphors are very interesting when designing visualization systems based on virtual reality.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/70097",risUrl:"/chapter/ris/70097",signatures:"Vladimir L. Averbukh",book:{id:"7311",title:"Cognitive and Intermedial Semiotics",subtitle:null,fullTitle:"Cognitive and Intermedial Semiotics",slug:"cognitive-and-intermedial-semiotics",publishedDate:"June 17th 2020",bookSignature:"Marta Silvera-Roig and Asunción López-Varela Azcárate",coverURL:"https://cdn.intechopen.com/books/images_new/7311.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"302728",title:"Dr.",name:"Marta",middleName:null,surname:"Silvera-Roig",slug:"marta-silvera-roig",fullName:"Marta Silvera-Roig"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"135209",title:"Prof.",name:"Vladimir",middleName:null,surname:"Averbukh",fullName:"Vladimir Averbukh",slug:"vladimir-averbukh",email:"averbukh@imm.uran.ru",position:null,institution:{name:"Institute of Mathematics and Mechanics",institutionURL:null,country:{name:"Russia"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Global visualization metaphors",level:"1"},{id:"sec_3",title:"3. Computer metaphors",level:"1"},{id:"sec_4",title:"4. Fairy tales and science fiction as a source for metaphors",level:"1"},{id:"sec_5",title:"5. Metaphors for systems based on virtual reality",level:"1"},{id:"sec_6",title:"6. The butterfly effect",level:"1"},{id:"sec_7",title:"7. Visualization texts: From interactive comics to motion pictures with immersion",level:"1"},{id:"sec_8",title:"8. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Averbukh VL. Semiotic analysis of computer visualization. In: Interdisciplinary Approaches to Semiotics. Rijeka, Croatia: InTech; 2017. pp. 97-133'},{id:"B2",body:'Averbukh V. Global visualization metaphors. In: Abstracts of 2nd Conference and Exhibition on Semiotics and Visual Communication. Lemesos, Cyprus: University of Technology; 2015. p. 2015'},{id:"B3",body:'Shneiderman B. Direct manipulation: A step beyond programming languages (abstract only). ACM SIGSOC Bulletin. 1982;13(2-3):143'},{id:"B4",body:'Romano S, Capece N, Erra U, Scanniello G, Lanza M. On the use of virtual reality in software visualization: The case of the city metaphor. Information and Software Technology. 2019;114:92-106'},{id:"B5",body:'Merino L, Ghafari M, Anslow C, Nierstrasz O. CityVR: Gameful software visualization. In: IEEE International Conference on Software Maintenance and Evolution (ICSME TD Track). 2017. pp. 633-637'},{id:"B6",body:'Vincur J, Navrat P, Polasek I. VR City: Software analysis in virtual reality environment. In: 2017 IEEE International Conference on Software Quality. Reliability and Security Companion. IEEE; 2017. pp. 509-516'},{id:"B7",body:'Schreiber A, Misiak M. Visualizing software architectures in virtual reality with an island metaphor. In: Chen J, Fragomeni G, editors. Virtual, Augmented and Mixed Reality: Interaction, Navigation, Visualization, Embodiment, and Simulation. VAMR 2018. Vol. 10909 of Lecture Notes in Computer Science. Springer; 2018. pp. 168-182'},{id:"B8",body:'Averbukh V, Averbukh N, Vasev P, Gvozdarev I, Levchuk G, Melkozerov L, et al. Metaphors for software visualization systems based on virtual reality. In: De Paolis L, Bourdot P, editors. Augmented Reality, Virtual Reality, and Computer Graphics. AVR 2019. Vol. 11613 of Lecture Notes in Computer Science. Springer; 2019. pp. 60-70'},{id:"B9",body:'Palepu VK, Jones JA. Visualizing constituent behaviors within executions. In: Proceedings of the 1st Working Conference on Software Visualization (VISSOFT). IEEE Computer Society. 2013. p. 4'},{id:"B10",body:'Oberhauser R, Carsten L. Gamified virtual reality for program code structure comprehension. The International Journal of Virtual Reality. 2017;17(02):7988'},{id:"B11",body:'Averbukh VL. The origins of computer metaphors. 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In search of the ‘magic carpet’: Design and experimentation of a bimanual 3D navigation Interface. Journal of Visual Languages and Computing. 1999;10:3-17'},{id:"B22",body:'Ciger J, Gutierrez M, Vexo F, Thalmann D. The magic wand. In: Proceedings of the 19th Spring Conference on Computer Graphics Budmerice, Slovakia SESSION: Virtual Reality. 2003. pp. 119-124'},{id:"B23",body:'Metaphor Design KK. Case study of an animated programming environment. In: Proceedings of the 1995 Computer Game Developer Conference April. Santa Clara, California. 1995. p. 241'},{id:"B24",body:'de Sousa AMF, Morimoto CH. 5* magic wand: An RGBD camera-based 5 DoF user interface for 3D interaction. In: 2015 XVII Symposium on Virtual and Augmented Reality. IEEE; 2015. pp. 15-22. DOI: 10.1109/svr.2015.10'},{id:"B25",body:'Henschke M, Gedeon T, Jones R, Caldwell S, Zhu D. Wands are magic: A comparison of devices used in 3D pointing interfaces. 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In: Proceedings of “Augmented and Mixed Reality. Designing and Developing Virtual and Augmented Environments” Conference. Vol. 8525 of Lecture Notes in Computer Science. Crete. 2014. pp. 131-138'},{id:"B31",body:'Averbukh VL, Bakhterev MO, Manakov DV. Evaluations of visualization metaphors and views in the context of execution traces and call graphs. Scientific Visualization. 2017;9(5):1-18. Available from: http://sv-journal.org/2017-5/01/index.php?lang=en'},{id:"B32",body:'Koike H, Takada T, Masui T. VisuaLinda: A framework for visualizing parallel Linda programs. In: Proceeding 1997 IEEE Symposium on Visual Languages. IEEE; 1997. pp. 174-178'},{id:"B33",body:'Hood R. The p2d2 project: Building a portable distributed debugger. In: Proceedings of the SIGMETRICS Symposium on Parallel and Distributed Tools. 1996. pp. 127-136'},{id:"B34",body:'May J, Berman F. Retargetability and extensibility in a parallel debugger. Journal of Parallel and Distributed Computing. 1996;35(2):142-155'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Vladimir L. Averbukh",address:"averbukh@imm.uran.ru",affiliation:'
Krasovskii Institute of Mathematics and Mechanics UrB RAS, Ural Federal University, Yekaterinburg, Russia
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Prokineticin‐2 is a peptide hormone, which exists as both a circulating hormone system and a local paracrine‐signaling mechanism within various tissues including the brain, kidney, and adipose. It acts on the G‐protein‐coupled receptors (GPCRs) PKR1 and PKR2. The role of prokineticin‐2 in the central nervous system is the control of food intake. Its anorexigenic effect is at least partly through the hypothalamic melanocortin system. Prokineticin‐2 also prevents adipose tissue expansion by limiting preadipocyte proliferation and differentiation capacity. Prokineticin‐2 signaling is important for insulin capillary passages. It also regulates heart and kidney development and function. Here, we discuss a new obesity peptide prokineticin signaling in central regulation of food intake, adipocyte tissue development, and cardiovascular function. Prokineticin may play a key role in the association between obesity and cardiovascular diseases. 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