All components of RAS are expressed locally in the eye.
\r\n\tIt is a relatively simple process and a standard tool in any industry. Because of the versatility of the titration techniques, nearly all aspects of society depend on various forms of titration to analyze key chemical compounds.
\r\n\tThe aims of this book is to provide the reader with an up-to-date coverage of experimental and theoretical aspects related to titration techniques used in environmental, pharmaceutical, biomedical and food sciences.
The prevalence of diabetes has been continuously increasing for the last few decades and it is being recognized as a worldwide epidemic [1]. Diabetic retinopathy (DR) is the most common diabetic microvascular complication, and despite recent advances in therapeutics and management, DR remains the leading cause of severe vision loss in people under age of sixty [2-4]. The prevalence of DR increases with duration of diabetes, and nearly all individuals with type 1 diabetes and more than 60% of those with type 2 have some form of retinopathy after 20 years [5-7].
Diabetic retinopathy (DR) is characterized by the development of progressive pathological changes in the retinal neuro-glial cells and microvasculature. The earlier hallmarks of diabetic retinopathy include breakdown of the blood-retinal barrier (BRB), loss of pericytes, thickening of basement membrane, and the formation of microaneuryms, which are outpouchings of capillaries [8]. BRB breakdown results in increased vascular permeability and leakage of fluid into the macula causing macular edema, another significant cause of vision loss in those with diabetes. With the progression of diabetic retinopathy, hemorrhage, macular edema, cotton wool spots, all signs of retinal ischemia, and hard exudates, the result of precipitation of lipoproteins and other circulating proteins through abnormally leaky retinal vessels become increasingly apparent. More severe and later stages of diabetic retinopathy, known as proliferative diabetic retinopathy (PDR), is characterized by pathological neovascularization. Vision loss can occur from vitreous hemorrhage or from tractional retinal detachment [8, 9].
Despite recent developments in the pharmacotherapy of DR, treatment options for patients with DR are still limited. Laser photocoagulation, the primary treatment option for patients with PDR, is still considered gold standard therapy for the treatment of PDR. Although this treatment slows the loss of vision in those with PDR, it does not represent a cure, and is in itself a cell destructive therapy. Corticosteroids and anti-VEGF agents have shown promising results with regard to prevention of neovascularization, but remain limited in use due to their short-duration effects. More importantly, none of these agents have been able to substitute for the durability and effectiveness of laser mediated panretinal photocoagulation in preventing vision loss in the late stages of DR.
The renin-angiotensin system (RAS) plays a vital role in the cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance, and in the sympathetic nerve system. Angiotensin II (Ang II), a peptide hormone of RAS, has been known to regulate a variety of hemodynamic physiological responses, including fluid homeostasis, renal function, and contraction of vascular smooth muscle [10]. In addition, Ang II is capable of inducing a multitude of non-hemodynamic effects, such as the induction of reactive oxygen species (ROS), cytokines, and the stimulation of collagen synthesis [11-14]. Most of the pathophysiological actions of Ang II are mediated via activation of Ang II type 1 receptors (AT1R), G protein–coupled receptors (GPCRs) that couple to many signaling molecules, including small G proteins, phospholipases, mitogen-activated protein (MAP) kinases, phosphatases, tyrosine kinases, NADPH oxidase, and transcription factors to stimulate vascular smooth muscle cell growth, inflammation, and fibrosis [11, 15, 16]. Dysregulation of RAS has been implicated in a number of major cardiovascular and metabolic diseases, including endothelial dysfunction, atherosclerosis, hypertension, renal disease, diabetic complications, stroke, myocardial infarction and congestive heart failure [17, 18]. RAS blockade produces beneficial cardiovascular and renal effects in numerous clinical trials [19-21].
Recent discoveries have revealed that the RAS hormonal signaling cascade is more complex than initially conceived with multiple enzymes, effector molecules, and receptors that coordinately regulate the effects of the RAS. Recent studies have identified additional peptides with important physiological and pathological roles, new enzymatic cascades that generate these peptides and more receptors and signaling pathways that mediate their function [22, 23].
Discovery of angiotensin-converting enzyme 2 (ACE2) has resulted in the establishment of a novel axis of the RAS involving ACE2/Ang-(1-7)/Mas [24-27]. ACE2, like ACE, is a zinc-metallopeptidase, exhibiting approximately 42% amino acid identity with ACE in its catalytic domain. However, unlike somatic ACE, ACE2 only contains a single catalytic site and functions as a carboxymonopeptidase, cleaving a single C-terminal residue from peptide substrates, thus ACE2 is able to cleave Ang II to form Ang (1-7). Ang (1-7), a biologically active component of the RAS [28-30] binds to a G-protein coupled receptor, Mas receptor [31], and plays a counter-regulatory role in the RAS by opposing the vascular and proliferative effects of Ang II [32]. A current view of RAS consists of at least two axis with counteracting biologic effects (Figure 1).
Schematic diagram depicting the key components of the Renin Angiotensin System. Angiotensinogen is cleaved by renin to form angiotensin I (Ang I). Angiotensin converting enzyme (ACE) converts Ang I into Angiotensin II (Ang II) the main effector peptide of the RAS. Ang II elicits is cellular effects by activating the main receptor, Angiotensin II receptor 1 (AT1R), as well as other receptors (not shown). Angiotensin II-converting enzyme 2 (ACE2), a recently discovered component of RAS, cleaves Ang II to form Angiotensin (1-7) (Ang 1-7), which activate Mas receptor to produce counteracting effects mediated by Ang II. All these components are expressed locally in various cell types in the eye, regulating metabolism, cell survival, and other local neuronal-vascular and immune-modulating functions in the retina.
This vasoprotective axis of RAS counteracts the traditional proliferative, fibrotic, proinflammatory and hypertrophic effects of the ACE/Ang II/AT1R axis of the RAS [24]. The importance of the vasodeleterious axis of the RAS [ACE/angiotensin II (Ang II)/ AT1R] in cardiovascular disease, as well as in diabetes and diabetic complications, is well established since ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are leading therapeutic strategies [20, 33-35]. However, the impact of the vasoprotective axis of the RAS remains poorly understood [24, 36-38]. The concept that shifting the balance of the RAS towards the vasodilatory axis by activation of ACE2 or its product, Ang-(1-7) is beneficial has been supported by many studies in cardiac, pulmonary, and vascular fibrosis [24, 39-43]. Indeed, ACE2/Ang-(1-7) activation is now considered to be a critical part of the beneficial actions of ACEi and ARB drugs [24, 36].
The classical (endocrine) RAS has been traditionally regarded as systemic hormonal system. Ang II is formed from liver-synthesized angiotensinogen via a series of proteolytic cleavage events. Circulating Ang II activates AT1 and AT2 receptors in various tissues, such as the brain, adrenal and vascular tissues to modulate cardiovascular and hydromineral homeostasis.
However, most components of RAS have also been identified in essentially every organ including kidney, heart, liver, brain, adipose tissue, reproductive tissue, hematopoietic tissue, immune cells and eye, and increasing evidence supports the existence of tissue- specific RAS that exerts diverse physiological effects locally and independently of circulating Ang II [44-46]. These tissue- specific paracrine, intracrine andautocrine actions of RAS may contribute to end-organ damage in many pathological conditions including diabetic complications and maybe the basis for the reported limited beneficial effects of RAS blockade.
Increasing evidence continues to implicate the involvement of the local renin-angiotensin-system (RAS) in retinal vascular dysfunctions. Various components of RAS have been detected in the different cell types of the eye (Table 1).
\n\t\t\t\tRAS components\n\t\t\t | \n\t\t\t\n\t\t\t\tRetinal Localization\n\t\t\t | \n\t\t\t\n\t\t\t\tReference\n\t\t\t | \n\t\t
Angiotensinogen | \n\t\t\tRetinal microvasculature, RGCs, RPE | \n\t\t\t[47, 48] | \n\t\t
Angiotensin I | \n\t\t\tAqueous, vitreous, and subretinal fluid | \n\t\t\t[49] | \n\t\t
Angiotensin II | \n\t\t\tAqueous, vitreous, and subretinal fluid, RGCs, retinal endothelial cells and photoreceptors | \n\t\t\t[49-51] | \n\t\t
Angiotensin 1-7 | \n\t\t\tMuller cells | \n\t\t\t[50] | \n\t\t
Renin | \n\t\t\tMuller cells and vitreous fluid | \n\t\t\t[52, 53] | \n\t\t
Renin receptor | \n\t\t\tRetinal microvasculature, microglia, astrocytes, RGCs, RPE | \n\t\t\t[54-58] | \n\t\t
ACE | \n\t\t\tMuller cells, RGCs, retinal endothelial cells, photoreceptors, and vitreous | \n\t\t\t[51, 59-61] | \n\t\t
ACE2 | \n\t\t\tRetina | \n\t\t\t[50] | \n\t\t
AT1R | \n\t\t\tMuller cells, retinal blood vessels, photoreceptors and RGCs | \n\t\t\t[50, 51] | \n\t\t
AT2R | \n\t\t\tMuller cells, nuclei of some inner, nuclear layer neurons, and ganglion cells | \n\t\t\t[50] | \n\t\t
Mas receptor | \n\t\t\tRGCs, retinal microvasculature, microglia, subset of astrocytes | \n\t\t\tunpublished results | \n\t\t
All components of RAS are expressed locally in the eye.
GC: retinal ganglion cells; RPE: retinal pigment epithelium.
Hyperglycemia has been shown to directly stimulate angiotensin gene expression via the hexominase pathway, thus contributing to increased Ang II synthesis [62]. Elevated levels of renin, prorenin, and Ang II have been found in patients with DR. In fact, ACE inhibitors and angiotensin receptor blockers (ARBs) have been shown to improve diabetes-induced vascular, neuronal, and glial dysfunction [61, 63-66]. Recent clinical studies have also clearly demonstrated the beneficial effects of RAS inhibition in both type 1 and type 2 diabetic patients with retinopathy [67-71]. Despite these positive outcomes, RAS blockers are not completely retinoprotective and retinopathy still progresses to more advanced stages. This could be attributed to the existence of local Ang II formation and that current therapeutic agents are unable to cross the blood-retina barrier (BRB) in a concentration sufficient to influence the local RAS in the eye. In addition, increasing evidence suggests that Ang II can be generated via multiple pathways, many of which may not be blocked by classic inhibitors of ACE [72-75]. Furthermore, additional components of RAS that contribute to end-organ damage, such as receptors for renin and prorenin (PRR), have been recently identified [76]. Activation of prorenin/PRR signaling pathway can initiate the RAS cascade independent of Ang II [76].
Ang II may contribute to development and progression of DR by several mechanisms. First, Ang II has been shown to increase VEGF expression directly via activation of AT1R signaling and indirectly by PCK activation [77] to enhance the role of VEGF induced vascular permeability and angiogenesis. Treatment with ACE inhibitors reduces vitreous levels of VEGF and attenuates VEGF-mediated BRB breakdown [78, 79]. Second, Ang II, mediated via AT1R, also contributes to diabetes-induced retinal inflammation by activation of nuclear factor-κβ signaling pathway within retinal endothelial cells [80, 81] leading to the release of inflammatory cytokines which perpetuates the inflammatory cycle. Pro-inflammatory cytokines, chemokines and other inflammatory mediators play an important role in the pathogenesis of DR [82, 83]. These lead to persistent low-grade inflammation, the adhesion of leukocytes to the retinal vasculature (leukostasis), breakdown of BRB and neovascularization with subsequent sub-retinal fibrosis or disciform scarring [84-88]. Third, Ang II may contribute to increased oxidative stress in diabetic retina. Ang II induces reactive oxygen species (ROS) production by activation of NADPH oxidases [89], which has been implicated in diabetic complications [90, 91]. Ang II also induces mitochondrial ROS production, which further stimulate of NADPH oxidases leading to vicious cycle and contributing tissue damage [92, 93].
Fourth, Ang II may also contribute to neuronal dysfunction induced by diabetes [94]. Receptors for Ang II are also expressed in the inner retinal neurons (Table 1). Ang II induced AT1R signaling may cause neuronal dysfunction by reducing the synaptophysin protein in the synaptic vesicles [94].
The discovery of ACE2- mediated degradation of Ang II into the protective peptide Ang 1-7 thereby negatively regulating the classic RAS, has instigated stimulated interest regarding the potential of ACE2 as a therapeutic target [88, 89], and strategies aimed at enhancing ACE2 action may have important therapeutic potential for cardiovascular disorders as well as for diabetic complications [40, 95-99]. Ang (1-7) has been shown to prevent diabetes-induced cardiovascular dysfunction [100] and nephropathy [101]. The protective effect of Ang 1-7 signaling is at least in part mediated by direct inhibition of diabetes-induced ROS production due to elevated NADPH oxidase activity [101, 102] and reduction in PPAR-gamma and catalase activities [102]. Adenovirus mediated gene delivery of human ACE2 in pancreas improved fasting blood glucose, beta-cell dysfunction and apoptosis occurring in type 2 diabetes mouse model [103]. The importance of ACE2 as a negative regulator of RAS in diabetic complications is supported by the facts that ACE2 deficiency exacerbates diabetic complications [104, 105] and enhancing ACE2 action counteracts the deleterious effects of Ang II and produces protective effects [96-99, 106].
We have previously shown that diabetes induced by STZ treatment in eNOS-/- mice results in more severe, accelerated retinopathy than diabetes in untreated eNOS+/+ animals [107]. Thus it became critical to compare retinal mRNA levels of the RAS genes in control and diabetic animals during the progression of diabetes. We observed significant (3-10 fold) increases in the mRNA levels of the vasodeleterious axis of the RAS (angiotensinogen, renin, pro/renin receptor, ACE and AT1 receptor subtypes) following STZ treatment (Figure 2) [108]. In contrast, there was ~ 30% reduction in ACE2 mRNA following an initial stimulatory response. As a result the ACE/ACE2 mRNA ratio was increased by 10-fold, while AT1R/Mas ratio was increased by 3-fold following one month of diabetes (Figure 2). These observations were our initial indication that DR is associated with a shifting balance of the retinal RAS towards vasodeleterious axis.
AAV vector expressing the secreted form of human ACE2 was constructed under the control of the chicken-beta-actin (CBA) promoter (Figure 3A). This secreted form of ACE2 has been previously characterized and shown to be active enzymatically [109]. Since Ang-(1-7) peptide contains only 7 amino acids and small peptides are usually difficult to express in mammalian cells, we designed an expression construct in which the Ang-(1-7) peptide is expressed as part of the secreted fusion GFP protein, and is subsequently cleaved upon secretion into the active peptide. Expression of the fusion sGFP-FC-Ang-(1-7) is under the control of the CBA promoter in the AAV vector (Figure 3A) and was confirmed by tranfecting HEK293 cells using this plasmid DNA (Figure 3B). To ensure that the fusion protein was indeed secreted, proteins isolated from the culture supernatants as well as cell lysates from transfected, sham-transfected or untransfected cells were analysized by western blotting (Figure 3B). Mass spectrometry analysis of Ang (1-7) peptide in supernatant samples of HEK293 cells transfected with the sGFP-FC-Ang-(1-7) plasmid DNA was also performed. The Ang-(1-7) peptide is detectable in supernatant isolated from cells transfected with sGFP-FC-Ang-(1-7) plasmid DNA, but not detectable in samples isolated from un-transfected cells, or cells transfected with the control plasmid expressing only the cytoplasmic GFP protein (data not shown). Intravitreal administration of AAV-Ang-(1-7) resulted in a robust transduction of retinal cells primarily within the inner retinal layer (Figure 3C-F). This was associated with an increase in both cellular and secreted Ang-(1-7) (Figure 3G-H). Similarly, ACE2 protein level was increased in the retina following transduction with AAV-ACE2 (Figure 3G).
Real-time RT-PCR analysis of retinal mRNA for renin-angiotensin system genes. Values represent fold difference compared to age matched non-diabetic retinal samples for each gene at each time point (14 day and 1 month after induced diabetes). DM: diabetic. NDM: non-diabetic. At least 4 eyes were analyzed at each time point. *p<0.01 (versus NDM group). (From [108] with permission of Mol. Therapy).
Construction and characterization of AAV vectors expressing ACE2 and Ang-(1-7).A: Maps of the AAV vector expressing the human ACE2 gene (hACE2) and the AAV vector expressing Ang-(1-7) gene. The Ang-(1-7) peptide is expressed as part of fusion protein, and cleaved in vivo upon secretion at the furin cleavage (FC) site. ITR: inverted terminal repeat; CBA: CMV- chicken-β-actin promoter. A control vector contains the coding region for the secreted GFP without the Ang-(1-7) peptide coding sequence. B: Expression and cleavage of the fusion protein. In cultured HEK293 cells transfected with the plasmid sGFP-FC-Ang-(1-7), or infected with AAV-sGFP-FC-Ang-(1-7), there was robust expression of GFP as expected. Proteins isolated from cell lysates contained a single protein band with molecular weight ~30 kd, as predicted for the precursor (fusion protein), but culture supernatants contained two protein bands (30kd and a 27kd), indicating that the secreted protein is cleaved at the furin cleavage site as predicted. C-F: Transduction of mouse retina with AAV vector expressing sGFP-FC-Ang-(1-7) and hACE2. A single intravitreal injection of 1μl AAV vector (109 vg/eye) resulted in efficient transduction of inner retinal cells, primarily retinal ganglion cells. C. Low magnification of cross section of a mouse eye that received AAV2-sGFP-FC-Ang-(1-7) injection. D. Higher magnification of the same eye. E. A retinal whole mount showing GFP expression. F. Higher magnification of the same retinal whole mount. G: Western blot of proteins isolated from an uninjected eye and an eye injected with AAV2-ACE2 (top) and AAV2-sGFP-FC-Ang-(1-7) (bottom) compared to a molecular weight standard (right lane). H: Ang-(1-7) peptide levels in the retina with and without AAV-sGFP-FC-Ang-(1-7) injection. There was more than a 10-fold increase in Ang-(1-7) peptide level detected by using an Ang-(1-7) specific EIA kit (Bachem, San Carlos, CA) in retinas receiving injection of AAV-sGFP-FC Ang-(1-7). PR: photoreceptor; OPL: outer plexiform layer; INL: inner nuclear layer; IPL: inner plexiform layer; RGC: retinal ganglion cells. (From [108] with permission of Mol. Therapy).
Diabetes induced more than a 5-fold increase in ACE activity in the retinas of eNOS-/- mice, whereas ACE2 activity was relatively unchanged (Figure 4A). AAV2-ACE2 injected retinas show more than a two-fold increase in ACE2 enzymatic activity (Figure 4A) and this is associated with a reduced level of Ang II and increased Ang-(1-7) peptide level (Figure 4B), but has only a marginal effect on ACE activity (Figure 4A). Injection of AAV2-Ang-(1-7) has no effect on ACE2 activity, but significantly decreased ACE activity (Figure 4A).
We also determined Ang II and Ang-(1-7) peptide levels using a commercial EIA kit (Bachem, San Carlos, CA). STZ induced diabetes resulted in more than a 2-fold increase in Ang II levels whereas the Ang-(1-7) level was unchanged in the retinas of eNOS-/- mice (Figure 4B). This increase of Ang II was completely normalized in retinas injected with AAV-ACE2 but was unchanged in retinas injected with AAV-Ang-(1-7) vector (Figure 4B).
ACE, ACE2 activities and angiotensin peptide levels in the mouse retina.A: ACE and ACE2 enzymatic activities and ACE/ACE2 ratios in non-diabetic (NDM), 1 month diabetic (1M DM), and 1 month diabeticeNOS-/- mouse retinas treated with AAV-ACE2/Ang-(1-7). Values are expressed as fold differences compared with age-matched non-diabetic group. *p<0.01 (versus untreated DM group, N=6/group). B: Ang II and Ang-(1-7) peptide levels in non-diabetic (NDM), 1 month diabetic (1M DM), and 1 month diabetic eNOS-/- retinas treated with AAV-ACE2/Ang-(1-7), measured by ELISA using a commercial kit. *p<0.01 (versus untreated DM group). Values represent fold difference compared with age-matched non-diabetic group. Three retinas were pooled for each measurement, each measurement was done in duplicates, and three separate pools were averaged for each group. (From [108] with permission of Mol. Therapy).
We investigated if elevated expression of retinal ACE2 or Ang-(1-7) would overcome the vasodeleterious effect of the ACE/AT1R axis and prevent the development of diabetes-induced retinopathy. Effects of increased ACE2 and Ang-(1-7) expression on retinal vascular permeability were evaluated by FITC-labeled albumin extravasations and quantified by measuring its fluorescence intensity in serial sections from non-diabetic, untreated, ACE2 treated diabetic eNOS-/- mice and Ang 1-7 treated diabetic eNOS-/- mice. Induction of diabetes for 2 month in eNOS-/- mice resulted in a 2-fold increase in vascular permeability. This pathophysiology was significantly reduced in diabetic retinas which received ACE2/Ang-(1-7) vector treatments (Figure 5), but not in the retinas receiving control vector containing the coding sequence for secreted GFP without Ang-(1-7) or ACE2 (data not shown).
Effects of ocular treatments with ACE2 and Ang-(1-7)-AAV2 on retinal vascular permeability in diabetic eNOS-/- mice. Retinal vascular permeability was evaluated by FITC-labeled albumin extravasations and quantified by measuring the fluorescence intensity in serial sections from eNOS-/- mice at 1 month after induced diabetes. Data are presented as mean ± SD from 6 eyes in each group. *p<0.01 (versus untreated DM group). NDM: non-diabetes; DM: diabetes. (From [108] with permission of Mol. Therapy).
Diabetes-induced ocular inflammation, as demonstrated by increased infiltrating CD45 positive macrophages and activation of CD11b positive microglial cells, was significantly reduced in eyes treated with ACE2 and Ang-(1-7) expression vectors (Figure 6).
Induction of diabetes for 2 month in eNOS-/- mice resulted in a >10-fold increase in the formation of acellular capillaries that was significantly reduced in diabetic retinas which received ACE2/Ang-(1-7) vector treatments (Figure 7). Furthermore, increasing the level of ACE2 also prevented basement membrane thickening in diabetic eNOS-/- retina (Figure 8).
Intravitreal administration of ACE2 or Ang-(1-7)-AAV reduces diabetes-induced ocular inflammation. A. Quantification of CD45positive inflammatory cells in the retinas from untreated non-diabetic, ACE2 treated and Ang-(1-7) treated diabetic eNOS-/- mouse retinas at 1 month after induced diabetes or the equivalent age in untreated controls. B. Quantification of CD11b positive inflammatory cells in the retinas from untreated non-diabetic, ACE2 treated and Ang-(1-7) treated diabetic eNOS-/- mouse retinas at 1 month after induced diabetes or the equivalent age in untreated controls. N=4 for each group. *p<0.01 (versus untreated DM group). (From [108] with permission of Mol. Therapy).
Evaluation of acellular capillary formation in untreated and AAV-ACE2/Ang-(1-7) treated retinas of diabetic mice. Treatments with ACE2 and Ang 1-7 vectors in the diabetic eNOS-/- mouse retinas reduced acellular capillaries. A: Representative images of trypsin-digested retinal vascular preparations from untreated non-diabetic eNOS-/-, ACE2 and Ang-(1-7) treated diabetic eNOS-/- mouse retinas (2 months after induced diabetes or the equivalent age in untreated controls. Arrows indicate the acellular capillaries. B. Quantitative measurements of acellular capillaries. The values on Y-axis represent the number of acellular capillaries per mm2 retina. NDM: non-diabetes; DM: diabetes. N=6. *p<0.01 (versus untreated DM group). (From [108] with permission of Mol. Therapy).
Transmission electron micrographs of retinal capillaries from a untreated 2 month diabetic eNOS-/- mouse eye (A), and an eye that received AAV-ACE2 treatment 2 weeks before STZ-induction of diabetes (B). CL: capillary lumen; En: endothelial cell; P: pericyte; * indicates the capillary basement membrane. Scale bar = 500nm. We have previously shown that the basement membranes of retinal capillaries from the diabetic eNOS-/- animals at two months after STZ induction of diabetes was significantly thicker than those from age-matched, non-diabetic animals [107]. The thickening of the basement membrane was prevented in the AAV-ACE2 treated eyes (73.81+17nm, versus 95.72+20 nm in untreated DM eye).
We also used STZ-induced diabetic SD rats as an additional animal model of diabetes to provide conceptual validation. We observed more than a 5-fold increase in the number of acellular capillaries in STZ-induced diabetic rat retinas at 14 month of diabetes. This increase was almost completely prevented by gene delivery of either ACE2 or Ang-(1-7) (Figure 9).
Diabetes and its complications are associated with increased oxidative stress. We assessed oxidative damage measuring the levels of thiobarbituric acid-reactive substances (TBARs, is a marker for oxidative damage [110]) in the retina). Diabetes induced a significant increase in TBARs (Figure 10A) in eNOS-/- mouse retinas (Figure 10A). This increase is completely prevented by AAV-ACE2 or Ang-(1-7) treatment. Similar results were also obtained in SD rat retinas (Figure 10B).
Evaluation of acellular capillary formation in untreated and ACE2/Ang-(1-7) AAV2 vector treated retinas of diabetic SD rats. (A) Representative images of trypsin-digested retinal vascular preparations from non-diabetic SD rat, untreated, ACE2 and Ang-(1-7) treated diabetic SD rat retinas (14 months after induced diabetes). (B) Quantitative measurements of acellular capillaries. Values on Y-axis represent the number of acellular capillaries per mm2of retina. NDM: non-diabetes; DM: diabetes. N=6. *p<0.01(versus untreated DM group). (From [108] with permission of Mol. Therapy).
TBARs levels in eNOS-/- mouse retinas (A) and SD rat retinas (B). Diabetes resulted in increased TBARs levels in both eNOS-/- mouse retinas at1 month of diabetes and SD rat retinas at 4 months of diabetes. These increases were prevented by AAV-ACE2/Ang-(1-7) treatments. NDM: non-diabetes; DM: diabetes. N=6/group. *p<0.01(vs untreated DM). (From [108] with permission of Mol. Therapy).
We demonstrate that all the genes within the RAS are expressed in the retina, consistent with various previous reports (reviewed in [111] and references therein), and the expression levels of genes in the vasoconstrictive arm of RAS (renin, ACE, AT1R) are highly elevated in diabetic retinas, whereas there is initial increase in the expression of genes in the vascodilative axis (ACE2 and MAS) earlier in diabetes that attenuate over time with the progression of diabetes, thus tipping the balance towards more vasoconstrictive, proinflammatory, hypertrophic effects of RAS mediated by ACE/Ang II/AT1R axis. This is associated with increased ACE activity and Ang II levels in diabetic retinas, whereas ACE2 activity and Ang-(1-7) levels are not significantly changed, while the mRNA levels for ACE2 and Mas receptor are reduced under these conditions.
Furthermore, we show that enhanced expression of either ACE2 or Ang-(1-7) via AAV vector mediated gene delivery in the retina prevents diabetes-induced retinal vascular permeability, thickening of basement membrane, retinal inflammation, formation of acellular capillaries, and oxidative damage in both mouse and rat models of diabetic retinopathy. More importantly, these beneficial effects occur in the absence of systemic control of glucose, blood pressure, which is elevated in eNOS-/- mice [107], and other diabetic complications [112], suggesting that local RAS activation plays a significant role of pathogenesis of diabetic retinopathy, and can be modulated locally to restore the balance between the two counter-acting arms by enhancing the ACE2/Ang-(1-7)/MAS axis. These observations provide conceptual support that enhancing ACE2/ Ang-(1-7) axis maybe an effective strategy for the treatment of DR.
Although various components of RAS have been detected in retina, our study is the first to examine the expression levels of all known RAS genes during the progression of diabetes in the eNOS-/- mice, which exhibit accelerated retinopathy [107]. We show that increased expression of genes in the vasoconstrictive, proinflammatory axis of RAS (ACE, AT1R, renin, renin receptor) occur early, 14 days after STZ-induced diabetes. We have previously shown that increased retinal vascular permeability and gliosis are already detectable at this time point in diabetic eNOS-/- mouse retina, suggesting that local hyperactivity of the deleterious axis (ACE/Ang II/AT1R) may contribute to these pathological changes. We also measured ACE and ACE2 activities in diabetic eNOS-/- mouse retina. In contrast to a previous report which showed that ACE enzyme activity was decreased, whereas ACE2 enzyme activity was increased in diabetic rat retinas [113], we found that ACE activity is highly increased in diabetic retinas, whereas ACE2 activity remains unchanged. This discrepancy may be due to the difference in animal models or the time points at which these assays were performed.
The importance of the vasodeleterious axis of the RAS (ACE/ Ang II/ AT1R) in cardiovascular disease, as well as in diabetes and diabetic complications, is well established since ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are leading therapeutic strategies [20, 33-35]. However, the impact of the vasoprotective axis of the RAS remains poorly understood, particularly in the eye. The concept that shifting the balance of the RAS towards the vasodilatory axis by activation of ACE2 or its product, Ang-(1-7) is beneficial has been supported by many studies in cardiac, pulmonary, and vascular fibrosis [24, 36-38]. We show that increased expression of either ACE2 or Ang-(1-7) is protective in both eNOS-/- mouse and rat models of diabetic retinopathy. However the action of ACE2 and Ang-(1-7) may be different. The protective effect of ACE2 may result from reduced Ang II, by catalyzing its conversion to Ang-(1-7), thus increasing the level of Ang-(1-7), or combination of both. Indeed, in the AAV-ACE2 treated retina diabetes-induced elevation of Ang II is reduced and this is associated with an increased level of Ang-(1-7). On other hand, the fact that increased Ang-(1-7) expressed from AAV vector in the retina is also protective and that the Ang II level remained high in AAV-Ang-(1-7) treated retinas suggest that Ang-(1-7) can produce physiological responses that direct counteract these of Ang II, consistent with well-established effects of Ang-(1-7) [114].
It is interesting to note that ACE2 over-expression resulted in reduced Ang II and increased Ang-(1-7) levels as expected, but has no effect on ACE activity. However, over-expression of Ang-(1-7) had no effect on endogenous ACE2 activity, but significantly reduced ACE activity. Paradoxically, despite reduced ACE activity in AAV-Ang-(1-7) treated retinas, Ang II levels remained high. It is possible that other enzymes/pathways may be involved in Ang II formation in addition to ACE. One such candidate is chymase, which has been detected in vascular systems and other tissues including eye [115]. Another candidate is the receptor for prorenin and renin (pro/renin). It has been recently demonstrated that binding of pro/renin to its receptor, pro/renin receptor (PRR), causes its prosegment to unfold, thereby activating prorenin so that it is able to generate angiotensin peptides that stimulate the Ang II-dependent pathway [76]. Considering the fact that retina contains high level of prorenin, and its level is further increased in patients with diabetic retinopathy [52], this pathway likely contributes to increased Ang II level under diabetic conditions. The existence of multiple pathways for Ang II formation at the tissue level may explain the limited beneficial effects of classic RAS blockers, and may also lend support for thtoe notion that enhancing the protective axis of RAS (ACE2/Ang-(1-7)/Mas) may represent a more effective strategy for treatment of diabetic retinopathy and other diabetic complications.
AAV vector mediated gene therapy for ocular diseases has been studied in animal models for more than a decade. Reports focusing on retinal therapy include a wide variety of retinal degenerative animal models of corresponding human retinopathies, as well as the therapeutic effects of AAV-vector mediated expression of neuroprotective, anti-apoptotic, and anti-angiogenic agents in the retina [116]. In view of recent clinical trials in which AAV delivered RPE65 gene led to restoration of vision in human patients and other reports on successful trials on treatment of ocular diseases and inherited immune deficiencies (reviewed in [117] and references therein), gene therapy has emerged as promising approach and may become a standard treatment option for a wide range of diseases in the future. In particular, when considering that the diabetic individual experience this serious ocular complication for decades, a therapeutic strategy that is long-lasting and does not require patient compliance is particularly desirable. Thus, the delivery of ACE2 and/or Ang-(1-7) could serve as a novel gene therapeutic target for DR in combination with existing strategies to control hyperglycemic and insulin resistance states.
All genes of the RAS are locally expressed in the retina, establishing the existence of an intrinsic retinal RAS. It is clear that the expression of genes of the vasoconstrictive/pro-inflammatory/ proliferative/fibrotic (i.e., vasodeleterious) axis (ACE/Ang II/AT1R) is highly elevated, while the vasoprotective axis [ACE2/Ang-(1-7)/Mas] is decreased in the diabetic retina. We have demonstrated that increased expression of ACE2 or Ang-(1-7), two key members of the vasoprotective axis, via AAV-mediated gene delivery to the retina attenuates diabetes-induced retinal vascular pathology. Moreover, these beneficial effects of gene transfer occur without influencing the systemic hyperglycemic status. Thus, strategies enhancing the protective ACE2/Ang-(1-7) axis of RAS could serve as a novel therapeutic target for DR.
Hyperactivity of RAS, resulting in elevated concentrations of the principal effector peptide Ang II, is central to pathways leading to increased vascular inflammation, oxidative stress, endothelial dysfunction and tissue remodeling in variety of conditions including heart failure, stroke, renal failure, diabetes and its associated complications including DR. As a result, RAS inhibitors are one of the first-line therapeutic agents for treating patients with cardiovascular diseases, metabolic syndrome, diabetes and diabetic complications. Ang II blockade has shown to be antiangiogenic [66, 118, 119], anti-inflammatory [120] and improves retinal function [65], and indeed Ang II blockade therapy for retinopathy is in several clinical trials [67, 68, 121]. Despite the clear beneficial effects of RAS blockers (ACE inhibitors [ACEi] and angiotensin receptor blockers [ARBs]) [70, 71, 122], end-organ damage still ensue in patients with diabetes. Overwhelming evidence now supports the notion thatactivation of RAS at tissue levels contributes to the development and progression of diabetic complications including DR, independent of circulating RAS regulation. However the precise molecular and cellular mechanisms as to how retinal RAS contributes to the development and progression of DR remain to be elucidated. Recent studies have also revealed the evolving complexity of RAS with a myriad cellular and intracellular pathways leading to formation of Ang II, as well as Ang II- independent signaling pathways resulting in hyperactivity of tissue RAS. The physiological implications of many of these components are still not well understood and new antagonists/agonists specific to these new components remain to be discovered. Nevertheless, our results clearly demonstrate that enhancing the protective axis of RAS (ACE2/Ang1-7/Mas) locally may be a better strategy for counteracting the effects of the pathological RAS activation than present systemic approaches. Furthermore, since AAV vector mediated gene delivery has been shown to be safe, and improve vision for extended periods of time after a single administration in several clinical trials, enhancing the endogenous protective axis of RAS (ACE2/Ang1-7/Mas) by local gene delivery, in combination with combination with existing strategies to control hyperglycemic and insulin resistance states may represent a better strategy for preventing and treating diabetic complications such as diabetic retinopathy.
Supported in part by grants from American Diabetes Association, American Heart Association, Research to Prevent Blindness, NIH grants EY021752 and EY021721.
The global production of crude steel exceeds 1869 million tonnes in the year 2019. Steelmaking viz. carbon steel and alloy steel is a multistep process where iron ore is the starting material used for iron making. Blast furnace iron making is mostly adopted by industries throughout the globe [1, 2]. Production of DRI for smelting in EAF is an alternative for iron ore reduction. There are several problems that persist with the economy of iron and ferroalloys production, and it depends upon three major factors viz. material, process, and product. The characteristics of ore minerals decide the process kinetics, and hence product quality and yield. There are several problems that still persist, as the following needs to be resolved.
Ore minerals: The quality of iron ore plays a significant role as the cost of raw ore attributes about 40% of the total production cost. The mined ore needs to be in the specified size range for individual furnace types, which is accomplished by crushing and sizing. The crushing and washing of bulk ore generate a substantial amount of fines viz. micro and macro fines, which cannot be fed directly into a furnace as it affects the porosity of charge burden. Moreover, it increases process cost comprising of agglomeration and heat treatment before extraction.
Gangue content: The excavated ore always includes gangue contents viz. alumina, silica, and magnesia along with alkali, sulfur, and phosphorus. The type and quantity of gangue affect the entire process kinetics in terms of metallic yield and quality. The primary ore needs to be upgraded through various separation techniques, i.e., physical, gravitational, etc. which is critical for high gangue amounts.
Mineral phases: The mineral phases present in the ore are of interest as the entire extraction process is dependent on the various minerals present in the parent ore. Minerals in the ore are detected as metal oxides, hydroxides, carbonates, and also associated with gangue as silicates, aluminates. The silicates and aluminates phases are not only difficult to reduce but also consume high flux and energy for which ores with high content of such phases are commonly discarded at the mines site itself. The decomposition of hydroxides and carbonates results in higher coke consumption. The presence of alkali not only affects the process but also has a high impact on refractory linings.
Process: With the increased demand for steel across the globe in the scenario of unaffordability of high grade ores, research on the applicability of fines, dust, and other industry by-products has become essential in order to control the depletion of earth minerals. These fines are agglomerated through pelletization, sintering, and briquetting routes, which has various drawbacks in terms of production rate, energy consumption, charging, and environmental impact. Ore and agglomerate must be of suitable for minimal transportation loss, high-temperature sustainability, and low disintegration rate. The porosity, density, and crushing strength of agglomerate must be adequate in order to achieve a higher reduction rate and metallic yield. If such properties are not in the predesigned range, it can cost higher and affect smooth operation by promoting fines generation and hinders Boudouard reaction.
The utilization of lean ore and wastes in iron making requires wide research and adopting new advanced technologies for quality production with time-saving operations.
It is not unusual to refer plasma as the fourth state of matter as it is an ionized gas comprised of molecules, atoms, ions (in their ground or in various excited states), electrons, and photons. Plasma possesses a unique property known as quasi-neutrality since plasma is electrically neutral. In contrast to an ordinary gas, plasma encloses free electric charges that are commonly produced from the gas itself by a variety of ionization processes. In a steady-state situation, the rate of ionization in the plasma is balanced by the rate of recombination. Depending upon the energy content of the plasma, the degree of ionization may be so high that virtually no neutral particles are left, i.e., the plasma becomes fully ionized [3, 4].
\nSince plasma is a broad topic as concerned, all together plasmas are classified into three main categories [5]:
CTE plasmas (complete thermodynamic equilibrium)
LTE plasmas (local thermodynamic equilibrium)
Non-LTE plasmas (nonlocal thermodynamic equilibrium)
Among the above three types, CTE plasmas are used for thermonuclear fusion experiments. The latter two types are used as laboratory plasmas and also implemented for industrial purposes like MINTEK, South Africa. Again according to density and energy, typical plasmas are categorized as shown in Figure 1.
\nTypical plasmas characterized by their energies and densities.
Plasmas generated by electron and photon belong to the nonlocal thermodynamic equilibrium category. LTE plasmas are also called as hot plasmas or thermal plasmas and non-LTE plasmas as cold plasmas or non-thermal plasmas. Based on temperature, plasmas are subcategorized into two groups, i.e., low-temperature plasma and high-temperature plasma. Plasmas with temperatures below 105°K or in other words, energies less than 10 eV per particle are to be called as low-temperature plasmas. Beyond this limit, it is said to be high-temperature plasma. It is also not unusual for plasma to be called as per its gas name, i.e., oxygen plasma, argon plasma, nitrogen plasma or argon-nitrogen plasma, etc.
\nPlasma chemistry refers to the thermodynamic characteristics of various plasma forming gases. Both monoatomic and diatomic gases like argon, helium, neon, nitrogen, oxygen, hydrogen, carbon monoxide, carbon dioxide, air, and a mixture of gases are used as plasma forming gases. The relation between energy and temperature of some commonly used monoatomic and diatomic gases are shown in Figure 2.
\nTemperature and energy relationship of various plasma gases.
The diatomic molecules require 90 to 200 kcal mole-1 to dissociate between 4000 to 10,000°K, while ionization requires 340 to 600 kcal mole-1 between 10,000 to 30,000°K [5]. The upper practical limit of flame temperature is about 3500°K, where molecules begin to dissociate, while the lower limit of plasma temperatures is about 10,000°K. As most laboratory plasmas are heated electrically, their temperatures will lie in the bottom end of the ionization curve, i.e., above 10,000°K for diatomic gases. For any process operating below 1000°K, an air-fuel flame (~2000°K) or an oxygen-fuel flame (~3000°K) will have a high percentage of energy available for the process. However, for the reaction occurring at 2500°K, only one-sixth of energy contained in an oxygen flame will be available, and rest must be either wasted or recovered in the expensive heat exchangers. On the other hand, a plasma flame composed of atomic nitrogen at 10,000°K would have more than 90% of its energy available above 2500°K. This high energy efficiency may more than offset the economic advantage that combustion energy over electrical energy; certainly, this advantage will increase as electrical energy becomes cheaper while fossil energy gets more expensive. Although by utilizing plasma high temperature can be achieved with the liberation of huge heat energy in a chemical reaction, plasma gases are generally not used as reactants in the reaction.
\nThermal arc plasmas are generated by striking an electric arc between two or more electrodes. They are characterized by high current densities (greater than 100 A/cm2) and are more luminous than other types of discharges, especially when operated at atmospheric pressure and above. Thermal arcs can be initiated in several ways. Two common methods are electrode contact, which produces a short circuit, or pre-ionization of the gap between electrodes by a high-frequency spark. The cathode must be heated beyond 3500 °K, at which point the thermionic emission of electrons begins, generating the charge carriers that create the plasma state [3]. Cold cathodes are cylindrical and made of heavily cooled copper, iron, or copper alloy while high-temperature cathodes are usually rod-shaped and made of thorium, tungsten, or graphite. Thermal arc plasma torches can operate in two modes, i.e., non-transferred and transferred arc. If the plasma torch having two electrodes designed in such a way that hot gas emerges through one electrode and then heated by the flame is called non-transferred. If there is only one electrode in the torch and material to be heated/melted acts as another electrode, then it is said to be transferred. The schematic of both transferred and non-transferred arc plasma torches are shown in Figure 3.
\nSchematic diagram of transferred and non-transferred plasma torches.
Schematic diagram of DC extended arc plasma reactor.
In the last two decades, plasma has claimed to be an emerging solution to numerous processes due to its unique features and hence implemented in various sectors [4, 6, 7, 8, 9, 10]. Plasma finds significant industrial applications viz. melting, smelting, smelting and reduction, remelting and refining, spark plasma sintering, surface modification, and surface coating.
\nAlthough there are a lot of many advantageous aspects behind the utilization of plasma, some of the important features are given in Table 1.
\n\nHigh efficiency\n | \nSince a huge amount of energy in the form of heat is available by utilization of plasma, high throughput can be achieved. | \n
\nLong-range of melting materials\n | \nSince high temperature can be achieved in a reaction by using plasma, almost all materials can be melted in this process. Although its commercial use to melt and process metals is well known, the method is less known as a method of melting glass. | \n
\nFeed capability\n | \nThis process is independent of the size, shape, and composition of feed material. | \n
\nTransient process\n | \nDue to the release of huge heat energy that a particular reaction requires at a specific temperature, plasma stands ahead of any other process to respond to the changes in a shorter period. | \n
\nHigh energy fluxes\n | \nHigher temperatures with extreme jet velocities and greater thermal conductivities of plasma gases are the key factors that result in high energy fluxes. Smaller furnace dimensions with high smelting capacity are a unique aspect of using plasma. | \n
\nIndependent energy source\n | \nThe flexibility of control over feed rate and power independently and input power is not limited by the electrical conductivity of feed material to be melted or smelted. Hence greater freedom of choice with respect to charge composition is available by using plasma. | \n
\nGas flow control\n | \nUnlike combustion systems, the gas flow rate, temperature, and energy input are not interdependent, and gas flow rate and temperature can be controlled separately irrespective of energy input. | \n
\nGas environment control\n | \nEnergy can be provided to the system with desired oxygen potential to ensure oxidizing, reducing, or inert gas conditions independently without taking temperature into account. | \n
\nElectrical energy-intensive process\n | \nMinimization of the usage of fossil fuel energy and conservation of fossil fuel can be made. | \n
\nHigh energy transfer to slag layer\n | \nPlasma jet is directed towards slag layer and significantly increases the metallization rate. | \n
\nPurity level in product\n | \nThe purity level of the final product through plasma processing is very high. | \n
Advantageous aspects of thermal plasma.
Many researchers investigated the applicability of plasma in iron and steel making [9, 11, 12]. In general, plasma is used as a heat source instead of reductant itself, as the percentage of the degree of reduction lags behind when utilized as a reductant. The selection of the type of plasma and preferred operating parameters, along with the type of reductant, is a crucial factor that needs to be considered sensibly in relation to the treating of material. The wrong choice can affect both troubleshooting and also processing costs.
\nCriteria for selection must be based on answering many questions, which comprises;
Type of reducing agent (carboneous or any other)
Type of plasma forming gas (inert, self-reducing, self-burning or helps in burning)
Type of process (melting, smelting or smelting reduction)
Process duration
Process environment (open-air, inert or vacuum)
Feed rate
Power control
The schematic diagram of 30 kW DC extended arc plasma reactor used for this study is shown in Figure 4 [13].
\nOn top of the reactor, the plasma torch is attached in the downward direction. The plasma torch contains a hollow cylindrical graphite crucible with 145 mm outer diameter, wall thickness 15 mm, and 300 mm high that serves as the anode. A hollow graphite rod of 400 mm long and 5 mm inner and 35 mm outer diameter serves as the cathode. The graphite rod end is tapered to a conical shape for superior electron emission. The hollow structure of the cathode has been designed to have provisions for gas flow. The material to be processed was placed in the anode crucible bed, and the arc was initiated by shorting the cathode and the crucible bottom wall (graphite plate). The arc length was increased by raising the cathode rod up suitably within the crucible to heat the charge placed in the crucible. The power supply and power control unit is designed to vary the necessary voltage and current, enabling easy and smooth control of experimental conditions. Voltage and current can be altered over a range of 0–100 V and 0–500 A, respectively. The gas supply unit facilitates plasma forming gases, i.e., oxygen, argon, nitrogen, methane, coke oven gas. Besides, the mixture of above gases can be utilized as plasma forming gas. Gas flow control consisting of digital indicators helps in not only measuring gas flow rate but also governing a suitable flow of gases as per experiment performed and stands as a key parameter. The gas flow rate can be varied from 0 to 15 LPM. Heat insulating materials are placed in between the steel casting and reaction chamber.
\nSeveral prerequisite steps have to be done before feeding samples into the reaction chamber. Initially, the crucible was cleaned in order to avoid any other material contained in the crucible to be reacted with samples. The hollow tapered graphite rod was fitted in such a way that it points towards the center of the reaction chamber. After checking no leakage in the crucible, it was placed in the space provided in steel casting. Bubble alumina was poured in spacing between the reaction chamber and reaction chamber that acts as a heat-insulating medium. The power supply was then provided, and proper arcing between cathode and anode was tested. The gas supply is then connected to the cathode passage, and plasma forming gas was purged into the reaction chamber for 1 minute to displace atmospheric air. After that, the power supply and plasma forming gas supply both supplied simultaneously, and the required voltage and current maintained. Then sample feed was poured into the hot reaction chamber as per our requirement.
\nThe present study demonstrates the plasma processing of three iron-bearing minerals viz. blue dust, siliceous type iron ore, and manganiferous iron ore.
\nBlue dust is the purest form of iron oxide mineral (hematite) abundantly available in many states of India. For the present study, blue dust of Koira origin, Odisha, India, was collected, which is in fine form (150 μ). The chemical analysis of blue dust is given in Table 2. The ore is mainly composed of Fe2O3, and XRD analysis also confirmed the presence of single mineral hematite.
\nConstituents | \nIn Wt. % | \n
---|---|
Fe2O3\n | \n96.87 | \n
SiO2\n | \n0.45 | \n
Al2O3\n | \n0.21 | \n
MgO | \nTrace | \n
LOI | \n1.48 | \n
Chemical composition of blue dust.
Plasma smelting operations were carried out for mixtures of blue dust and coke in argon and nitrogen ionizing atmosphere [14]. The coke percentage in charge mixture (500 gm) was varied from 5–20%. The plasma gas flow rate was maintained at 2.5 LPM.
\nThe highest recovery rate exceeding 86% was achieved for using nitrogen as plasma forming gas. The recovery rates in argon plasma are comparatively less than those of nitrogen plasma. It is because of the diatomicity of N2 gas, which liberates higher energy flux than the monoatomic gas Ar. The loss of Fe in the process involves loss accounted for in charging and splashing of metal droplets due to the high velocity of the plasma jet in the course of smelting. The loss of metal splashing is further minimized by adjustment of power input and controlling gas flow rate. The recovery rate attains 95% maximum in closed furnace type arrangements.
\nAs the gangue in blue dust is low, the metallization (Fe) occurs in the absence of complex slag phases. Blue dust with different carbon percentages (i.e., 5, 10, 12, 15, and 20) smelted by using nitrogen plasma shows the change of ferrite, ferrite-cementite to fully pearlite structure, which can be attributed to the Hull-Mehl model of pearlitic transformation [15]. The silica in blue dust in the high reducing atmosphere reduces into SiO, observed in smelting tests as fumes. The smelting duration for the conversion of Fe2O3 into Fe was 17 minutes, which is several hours in BF iron making. Moreover, blast furnace limits the direct charging of blue dust to avoid lowering the porosity of charge burden, which increases process cost and affects smooth operation.
\nTo use blue dust in BF, agglomeration and heat treatment are required. Although stiff vacuum extrusion briquetting avoids heat treatment, binder requirement is still essential. The cement and bentonite binder adds cost and also requires unnecessary slag generation and separation from the purest Fe2O3 ore.
\nThe direct smelting of blue dust in thermal plasma has several advantages over conventional processes in terms of cost-saving operation, purity level in hot metal, and high production rate. The production cost will be much less for industrial large scale furnace and by using cheap gases such as methane, coke oven gas, etc.
\nFor this study, partially reduced briquettes made from iron minerals were collected from an industry in the vicinity of Rourkela, Odisha, India. Briquettes upon solid state reduction at 1250°C are partially melted which hinders further reduction at higher temperatures. The industrial trial of such briquettes in mini BF suggested its infeasible use for iron making due to high FeO loss in slag. The chemical composition of the briquette sample is given in Table 3.
\nConstituents | \nIn Wt. % | \n
---|---|
FeT\n | \n72.2 | \n
SiO2\n | \n8.6 | \n
Al2O3\n | \n7.2 | \n
MgO | \n0.63 | \n
CaO | \n1.4 | \n
TiO2\n | \n0.4 | \n
Others | \n9.57 | \n
Chemical composition of briquette.
The amount of silica and alumina in the briquette is about 16% in cumulative. XRD analysis detected wustite (FeO), fayalite (Fe2SiO4), and hercynite (FeAl2O4) as major phases in the briquette sample. The presence of such phases suggests the high affinity of FeO towards silica and alumina for which low melting fayalite forms, melts early and hinders CO gas passage to the core. Partial melting of briquette also affects the furnace operation and increases flux addition, and hence increases the process cost.
\nHere, an attempt was made for the utilization of these briquettes for the value addition with maximized extraction [16]. Since plasma processing does not restrict the slag chemistry, briquettes were smelted with and without flux (CaO). Initial trials with flux addition targeting melilite slag (CaO-MgO-Al2O3-SiO2) improved Fe recovery in metal. For the CaO/SiO2 ratio in the range of 0.9–1.0, metallic yield exceeds 88%. The flow characteristics of such slag allow a better reduction in the slag layer where unreduced Fe-oxides are more promptly metalized.
\nAnother approach was aimed at the direct smelting of briquettes without adjustment of slag chemistry. Since the briquettes are composed of fayalite, additional coke was provided for the reduction of silicon along with iron. These briquettes were smelted for a longer period than previous slag practice. The metallic recovery was appreciably higher, i.e., exceeds 94% by using nitrogen as plasma forming gas.
\nPhase and microstructure evolution confirms the formation of the iron silicide (Fe3Si) phase in the alloy along with Fe. These ferrosilicon alloys can be used for deoxidation purposes, which is of greater value than metallic Fe.
\nThis study suggests that the utilization of silicate-based iron minerals are more suitable for ferrosilicon production rather than iron making. Although the energy consumption is a little higher for FeSi production from these briquettes, flux consumption and melting of excess slag can be eliminated. Moreover, the product (FeSi) cost puts importance on its feasible production.
\nManganiferous iron ore is the type of lean manganese ore containing a maximum about 10–15% of Mn. These are of less importance in ferromanganese production; however, reduction roasting and magnetic separation improve Mn/Fe ratio. The primary objective of such a process is to reduce Fe2O3 into Fe3O4, which easily separates as magnetic particles. However, the feasibility of the upgrading process becomes questionable when both iron and manganese oxides are in associated form, i.e., bixbyite (Fe, Mn)O3 mineral.
\nAs an alternative, these ores are subjected to smelting for obtaining FeMn alloy with low Mn content. It is a cost-saving operation, and smelting operations can be carried out even in BF. The complexity arises for such ores with high gangue amount, which affects the extraction kinetics by forming silicates, aluminates, and/or complex mixtures phases.
\nIn the present study, lean manganese ore was collected from Joda valley, Odisha, India. The ore is in fine form and is being discarded as waste at the mines site itself. The initial assessment of the ore through wet chemical analysis indicated that the ore contains about 17% of alumina and 9% of silica. The Mn content in the fines is about 12%, which falls into the manganiferous category. The reduction studies of such briquettes evidenced the formation of hercynite, galaxite, fayalite-manganon, and spessartine phases at different temperatures. These phases lower the reducibility of the ore and also deteriorate the physical and mechanical properties of the agglomerate.
\nHere an attempt was made to utilize these fines directly in thermal plasma, avoiding any agglomeration. Smelting of such ores by using other technologies results in poor Mn recovery (≈30%) and high FeO loss into slag; flux addition was essential.
\nThe smelting of ore with flux addition targeting melilite and mayenite slags in ionizing atmosphere improved Mn recovery and was 80% maximum. Although plasma arc provides high energy flux, the slag chemistry also governed the process kinetics. By adjusting slag chemistry to a too basic slag lowered the activity of silica and alumna; however, the formation of high melting silicate compounds such as dicalcium silicate and tricalcium silicate increases the viscosity of the slag. The flowability of such slag hinders carbon contact with metal oxides and hence lowers the reducibility.
\nIn the current scenario, ferromanganese production follows rich slag and discard slag practices. The rich slag retained in primary smelting (low fluxing) is further smelted in another step to produce silicomanganese or ferro-silicomanganese. In discard slag practices, the slag retained in primary smelting, which contains less than 15–30% MnO, is discarded.
\nThe present study refers to the discard slag practice followed by plasma smelting with the highly basic slagging operation. As the ore contains high alumina, primary smelting similar to rich slag practice will result in slag with alumina bearing compounds, which will be difficult to reduce in the secondary smelting for obtaining silicomanganese. Moreover, the cost of smelting these high melting compounds will increase reductant, energy consumption, and also lower the furnace refractory life cycle.
\nThe extraction of metals from these types of complex ores in single-stage smelting operation should be chosen in such a way that the slag can be used in secondary products such as cement.
\nIn iron making, coke is used as a heat source and reductant. The application of plasma in iron making lowers COX emission for being used as plasma as a heat source. The reducibility of metal oxides by solid carbon or CO gas is lower than that of H2. The use of methane as plasma forming gas is beneficial over argon or nitrogen from a cost perspective. However, ecofriendly gas emission in iron making is only possible through hydrogen plasma processing; the exit gas is water vapor, which reduces environmental pollution and will be much beneficial in impurity-free metal production [17, 18].
\nAt present, research projects are being carried out for hydrogen reduction of iron ore in a pilot-scale, such as HYBRIT [19]. The primary installation of such reactors costs high; continuous improvements are essential. The primary beneficiation of iron ores will improve the purity of iron ore, which in turn will reduce the cost of the process.
\nThe importance of plasma in iron making is discussed considering different types of ore minerals and its various aspects of processing. The freedom in size, composition, and smelting conditions required for complex ore minerals fits into the processing of iron ore in thermal plasma. The use of coke as a heat source in conventional iron making processes can be eliminated with the application of thermal plasma. The recovery rate and purity level in hot metal extracted from complex mines waste is noticeable higher by using thermal plasma. The future eco-friendly hydrogen plasma processing is of interest. Moreover, the use of hydrogen plasma can result in carbon-free metal/alloys, which can lower production costs by avoiding decarburization.
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\\n\\n4. CORRESPONDING AUTHOR'S WARRANTY
\\n\\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\\n\\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\\n\\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n5. TERMINATION
\\n\\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\\n\\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\\n\\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\\n\\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n\\nLast updated: 2020-11-27
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
\n\n\n\n
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). 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