Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\n
Throughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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In this new context of variability and climatic changes, these ecosystems undergo notable modifications amplified by domestic uses of which it was subjected to. Indeed the ecosystems render diverse services to humanity from their composition and structure but the tolerable levels are unknown. The preservation of these ecosystemic services needs a clear understanding of their complexity. The role of research is not only to characterise the ecosystems but also to clearly define the tolerable usage levels. Their characterisation proves to be important not only for the local populations that use it but also for the conservation of biodiversity. Hence, the measurement, management and protection of ecosystems need innovative and diverse methods. For all these reasons, the aim of this book is to bring out a general view on the function of ecosystems, modelling, sampling strategies, invading species, the response of organisms to modifications, the carbon dynamics, the mathematical models and theories that can be applied in diverse conditions.",isbn:null,printIsbn:"978-953-51-0572-5",pdfIsbn:"978-953-51-5289-7",doi:"10.5772/2276",price:139,priceEur:155,priceUsd:179,slug:"diversity-of-ecosystems",numberOfPages:498,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"ee698d03ccce547bc8cdb4f13ebb2822",bookSignature:"Mahamane Ali",publishedDate:"April 27th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/1850.jpg",numberOfDownloads:46825,numberOfWosCitations:74,numberOfCrossrefCitations:22,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:86,numberOfDimensionsCitationsByBook:2,hasAltmetrics:0,numberOfTotalCitations:182,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 10th 2011",dateEndSecondStepPublish:"June 7th 2011",dateEndThirdStepPublish:"October 12th 2011",dateEndFourthStepPublish:"November 11th 2011",dateEndFifthStepPublish:"March 10th 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"103960",title:"Prof.",name:"Mahamane",middleName:null,surname:"Ali",slug:"mahamane-ali",fullName:"Mahamane Ali",profilePictureURL:"https://mts.intechopen.com/storage/users/103960/images/system/103960.jpg",biography:"Prof. Ali Mahamane is a Lecturer at Abdou Moumouni University (Niger). He was born in 1964 at Kendadji, Tillabéri, Niger. He got his first degree in Agricultural Sciences from the Abdou Moumouni University and later specialised in Arid Regions Forestry (ENGREF, Montpellier, France). He pursued his studies at the University of Ouagadougou, Burkina Faso where he obtained his M. Phil in 1997. In 2000, he got a tenure appointment at the Faculty of Sciences at Abdou Moumouni University. He registered for his Ph. D thesis at the Université Libre de Bruxelles, Belgium in April 2005. He published more than 38 Scientifics articles both in national and international journals. He is National Coordinator of UNDESERT Project (Understanding and combating desertification to mitigate its impact on ecosystem services). \nPresently Ali Mahamane is Deputy Vice Chancellor and Dean of Faculty of Sciences and Technics at the University of Maradi (Niger).",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Abdou Moumouni University",institutionURL:null,country:{name:"Niger"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"841",title:"Biodiversity",slug:"environmental-sciences-ecology-biodiversity"}],chapters:[{id:"36220",title:"Macrofaunistic Diversity in Vallisneria americana Michx. in a Tropical Wetland, Southern Gulf of Mexico",doi:"10.5772/35331",slug:"macrofaunistic-diversity-in-vallisneria-americana-michx-in-a-tropical-wetland-southern-gulf-of-mex",totalDownloads:2486,totalCrossrefCites:0,totalDimensionsCites:3,hasAltmetrics:0,abstract:null,signatures:"Alberto J. 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1. Introduction
Carbon is one of the most abundant elements found in nature. It is also one of the elements that form the fundamental building blocks of life on earth. Carbon, in solid, liquid and gaseous forms, is a major contributor in many human activities. Solid forms of carbon have a diverse phase diagram ranging from very soft graphitic to very hard diamond structures. These forms are produced through various processes ranging from coking to crystalline condensation from gaseous precursors. These diverse processes and the variables that define them lead to many different forms of solid carbon including coke, carbon blacks, graphitized carbon, pyrocarbon, glossy carbon, active carbon, diamond, fullerenes, carbon fibers and the newest identified form- carbon nanotubes. Carbon nanotubes (CNTs) are one of the most elegant arrangements of solid carbon that are elongated structures of C60 molecules (also known as fullerenes (Kroto, 1987; Kroto et al., 1985)). CNTs were first observed by Baker et al. in the 1970s (Baker et al., 1972;, 1973; Oberlin et al., 1976). However, these findings did not spark as much interest in the scientific community as that sparked by the re-discovery of CNTs by Iijima(Iijima, 1991). For the last two decades carbon nanotubes and their remarkable properties have been extensively studied and different synthesis methods have been developed for their production.
Carbon nanotubes can be classified by the number of concentric walls. A single wall carbon nanotube (SWNT) can be visualized as a flat graphene sheet of fullerene (C60) molecules rolled up to make a seamless cylinder. C60 molecules are tiny spherical structures (diameter of ~ 7 Å) of 60 carbon atoms connected together forming 20 hexagons and 12 pentagons. Two halves of the fullerene molecule can be visualized to form the end caps of the nanotube. SWNTs exhibit extraordinary physical properties including very high thermal (1750-5800 W/m-k) and electrical conductivity (resistivity equals ~ 10-6 Ω-m) in the axial direction (Hone et al., 1999; Thess et al., 1996) and equally remarkable structural properties such as high Young’s modulus (1054 GPa) (Yu et al., 2000). A multi wall carbon nanotube (MWNT) can be visualized as a structure with concentric cylinders of increasing diameters with correspondingly larger hemispherical end caps terminating them at each end. MWNTs are more commonly found in products of synthesis than the SWNTs. SWNTs are produced by carefully controlling the condensation process. Diameters of SWNTs are, typically a few nanometers, and those of MWNTs are generally of tens of nanometers. Another classification of CNTs is based on the orientation of the hexagonal (six-member carbon ring) in a honeycomb lattice with respect to the axis of the nanotube. Three possible structures include armchair, zigzag and chiral, as shown in figure 1. Armchair and zigzag structures are achiral, that is, their mirror image is identical to the original object. On the other hand, chiral structures exhibit spiral symmetry, whose mirror images cannot be superimposed on the original one.
Figure 1.
Various configurations of carbon nanotubes (a) Armchair, ( b) Zigzag and (c) Chiral
Catalytic synthesis of carbon nanotubes is typically a multiple length-scale multi-step process in which carbon is deposited in solid form. This conversion occurs at the nano scale via endothermic reactions occurring at surface of catalyst nano-particle. Therefore, a synthesis reactor generally consists of three essential components: (i) source of gaseous carbon (ii) source of heat and (iii) catalyst particles that provide the reaction sites. A mixture of carbon containing gaseous precursor species at appropriate temperature is maintained throughout the reactor. The size of the reactor defines the largest scale. The catalyst is added either in a form of nano-scale depositions on a substrate or freely floating nano-particle aerosol embedded in the bulk phase. In the past, carbon nanotubes have been produced using methods such as plasma arc discharge, pulsed laser vaporization (PLV), chemical vapor deposition (CVD), Plasma Enhanced (PECVD) and hydrocarbon flame synthesis. Schematic representation of these synthesis processes is shown in figure 2.
Iijima (Iijima, 1991) used the arc discharge method for production of CNTs. The process involved condensation of carbon atoms generated from evaporation of a solid carbon source. In this method, high electric current (~50 - 120 A) is passed through graphite electrodes placed at a distance of approximately 1 mm in the synthesis chamber that causes material from the cathode to sublimate and the nanotubes to form on the anode. The arc discharge process is difficult to control because of the very high temperature (~3200 K) in the electrode gap. The method is also cost and energy intensive and unwanted byproducts such as polyhedron graphite particles contaminate the relatively low yield of CNTs.
In the pulsed laser vaporization or laser ablation method, a high energy laser is directed to ablate a carbon target that contains some nickel and cobalt in a tube furnace, at the temperature of ~ 1400 K. A flow of inert gas is passed through the chamber to carry the CNTs downstream, to a collector surface. Single walled carbon nanotubes, mostly in the form of ropes, at a 1- 10g scale have been formed by this method. The CNTs formed by the laser ablation method are of a higher quality than those produced by the arc discharge method. However, the production rate is low, and the pulsed laser vaporization or laser ablation method is both capital and energy intensive.
The chemical deposition method (CVD) is an alternative method in which CNTs are grown using catalysis. This method involves decomposition of a hydrocarbon gas over a transition metal catalyst and initiation of CNT synthesis by some of the resulting carbon atoms. CVD growth mechanism generally involves the dissociation of hydrocarbon molecules and saturation of carbon atoms in the catalyst metal nano-particles. The precipitation of carbon from the saturated metal particles leads to the formation of carbon nanotubes. Use of catalysis reduces the need for high temperatures. Hydrogen from the decomposition process, and supplemented by that carried with the bulk phase, contributes to the activation and reactivation of the catalytic surface. The CVD method has a better CNT yield and is potentially scalable to commercial manufacturing.
Figure 2.
Schematic representation of methods used for carbon nanotube synthesis (a) Arc discharge (b) Chemical vapor deposition (c) Laser ablation (d) hydrocarbon flames
Hydrocarbon flames provide a unique combination of the chemical and catalytic factors that are conducive to initiation and growth of carbon nanotubes. Gases (CO, CH4, C2H2, C2H4 and C2H6) present in the post flame environment form a diverse source of gaseous carbon. The chemical energy released in the form of heat in the flame supports the endothermic carbon deposition reactions. Catalysts in appropriate form (substrate or aerosol) provide the reaction sites for deposition of solid carbon. Growth mechanisms similar to those observed in the CVD process govern the growth of nanotubes in flames. The geometry and characteristics of the catalysts play an important role in the structural properties of the carbon nanotubes. Flames are scalable and are commercially used for the production of solid carbon forms such carbon black and printing ink. Appropriately tailored flame conditions may provide an ideal environment for growth of CNTs on a large commercial scale.
The rest of this chapter summarizes the mechanisms of carbon nanotubes formation in flames followed by a summary of the types of flame configurations and chemistry that have been used in the synthesis process. The process parameters such as equivalence ratio, temperature, pressure are discussed next. Computational models for exploring the parameter space for optimization of the synthesis process are discussed next and the chapter ends with a few comments about future trends.
2. Mechanism of carbon nanotube formation in a catalytic synthesis process
The inception and growth mechanisms of CNTs have been studied extensively but a consensus on a single mechanism has not emerged. In fact, more than one mechanism may be involved in the inception and growth of CNTs depending on the specifics of the gaseous precursors, catalysts and operating parameters. One of the most popular descriptions involves the carbon dissolution-diffusion-precipitation mechanism proposed by (Baker et al., 1972). Catalytic nano-particles from transitional metal/metal alloys (e.g. Fe, Ni, and Co) are assumed to be spherical or pear-shaped and are either floating or supported on a substrate. The catalytic decomposition of the carbon precursor molecules (e.g. CO, CH4, C2H2, C2H4 and C2H6) is conjectured to occur on one half of the nano-particle surfaces (the lower curvature side for the pear shaped particles). The released carbon atoms diffuse into the catalyst nano-particles along the concentration gradients until carbon super-saturation at the particle temperature occurs (Moisala et al., 2003). Post super saturation of the catalyst particle, carbon atoms precipitate in solid carbon form on the opposite half of the catalyst particle around and below the bisecting diameter. This description is similar to the Vapor-Liquid-Solid (VLS) process suggested by (Tibbetts, 1984). As per this process, the solid carbon fibers grow from a super-saturated molten liquid catalyst droplet. Decomposition of the gas phase hydrocarbon molecules provides the carbon necessary for saturation of the molten catalyst. The possibility of gas phase and surface decomposition of the hydrocarbon molecules exists. Melting of metal catalyst particles at the normal synthesis temperature (900 – 1200 K) is plausible only as a result of non-equilibrium processes within the thin surface layer of the particle. Reduction in size of the particles also leads to increased carbon solubility within available process time.
The specific physical form (e.g. MWNT, SWNT, amorphous carbon and particle-encapsulated graphite cell) of the precipitated solid carbon depends on several factors; including catalyst particle size and precipitation rate (Moisala et al., 2003). When the precipitation rate is in equilibrium with or less than the carbon diffusion rate, graphitic layers are formed surrounding the catalytic nano-particles resulting in the thermodynamically most stable carbon forms. When the precipitation rate is larger than the carbon diffusion rate can CNT growth occur. Generally only catalytic nano-particles that are sufficiently small (<20nm) are active for CNT nucleation and growth, with the tube diameter corresponding to that of the catalytic nano-particle. For particles smaller than 20 nm, solid carbon atoms do not precipitate from the apex of the hemisphere but from a circular ring close to one of the diameters of the spherical particle. This accounts for the hollow core characteristic of CNTs with diameter approximately corresponding to that of the catalyst particles. For supported catalysts, formation occurs either by “extrusion” (also known as base growth as shown in Figure 3 (a)), in which CNTs grow upward from the nano-particles that remain attached to the substrate, or by lifting of the catalyst nano-particles by the growing CNT (tip growth as shown in Figure 3 (b)).
As summarized in Figure 3 (c) below, catalyst particle diameter plays an important role in defining the synthesized carbon nano-structure. Particles of the order of 1 nm diameter predominantly form SWNTs (Rao et al., 2001). MWNTs are formed with catalyst particle diameters in the range of 10~50 nm with the number of layers increasing with the particle diameter. Particles with diameters larger than 50 nm are covered with amorphous graphitic sheets often given another visually descriptive name “nano-onion.”
Figure 3.
Mechanisms for carbon nanotube growth (a) Base growth (b) tip growth (c) Structural dependence on catalyst particle size
Dai et al. provided a visually descriptive “yarmulke (Yiddish for skull cap) mechanism,” name to the observed growth of MWNTs (Dai et al., 1996). A key characteristic of this mechanism involves nucleation on the catalyst material (e.g. Fe, Ni, and Co) surface by decomposition of gaseous hydrocarbon molecules followed by diffusion of the hydrogen away from the surface. Once the nano-particle is supersaturated with the carbon atoms, the linking of the carbon atoms together in the form of a hexagonal sheet that conforms to the curvature of the particle is energetically favored (Tibbetts, 1984). For experiments in which the nano-particles are supported on a substrate the carbon "yarmulke” grows approximately half the particle diameter towards the substrate and then starts growing longitudinally with the particle remaining at the root. Newly arriving carbon atoms are integrated into the network and the tube grows longer. For experiments involving suspended catalytic nano-particles, the strain of the carbon sheet curving around the nano-particle is higher and conjectured to result in smaller diameter tube formation. A second yarmulke can form underneath the first with approximate spacing between the two equal to the interlayer spacing of graphite crystals (~0.34 nm). As additional yarmulkes grow, one beneath the other, older yarmulkes lift up to form the MWNT. The open ends of these structures remain chemisorbed to the catalytic particle. As the strain resulting from increasing curvature exceeds a certain value, nucleation of new inner walls ceases defining the diameter of the innermost tube. The pre-nucleation step involving saturation of the catalyst particle by dissolved carbon defines the maximum diameter of the catalyst nano-particles for CNT growth.
3. Flame synthesis of carbon nanotubes
3.1. Experimental investigation
The first experimental observation and conjecture of the formation of filamental carbon in flames (Singer & Grumer, 1959) came long before CNTs were discovered. Formation of CNTs by plasma arc discharge method was first reported in 1991 (Iijima, 1991). In the same year, formation of elongated carbonecous structures on the surface of a probe inserted in methane air diffusion flames (Saito et al., 1991) was reported and presence of C60 and C70 fullerens was detected in premixed flames (Howard et al., 1991). A year later, co-existence of MWNTs with soot like structures was detected in premixed flames (Howard et al., 1992). Prior to these reports, the highly ordered carbon cylindrical structures had been produced only by very energetic processes such plasma and laser vaporization but not in flames. These discoveries prompted scientist to investigate the potential of various types of hydrocarbon flames for synthesis of CNTs.
Flame is a unique synthesis medium that provides both energy and chemical species for the synthesis of CNTs and other carbon nano-forms. Schematics of various flame synthesis processes are shown in figure 4.
Figure 4.
Schematic for flame synthesis of carbon nanotubes (a) premixed flame (Gopinath & Gore, 2007; Height et al., 2004; Vander Wal et al., 2002) (b) counter-flow diffusion flame (Li et al., 2007; Merchan-Merchan et al., 2003; Saveliev, 2003; Xu et al., 2007)(c) co-flow diffusion flame (Unrau & Axelbaum, 2010; Vander Wal, 2000; Xu, 2007; Yuan et al., 2001; Yuan et al., 2001)(d) inverse diffusion flame(Lee et al., 2004; Unrau et al., 2007; Xu et al., 2006)
In a flame, fuel (generally hydrocarbons such as methane (CH4), ethylene (C2H4), and acetylene (C2H2) etc.) reacts with oxidizer (O2 from air) to produce gaseous mixture that includes carbon dioxide (CO2), water vapor (H2O), carbon monoxide (CO), hydrogen (H2), saturated and unsaturated hydrocarbons(C2H2, C2H4, C2H6 etc.) and radicals. Hydrocarbons and carbon monoxide constitute the gaseous precursor mixture that is the source of solid carbon deposited on catalyst particles to form carbon nanostructures. Metal catalysts, inserted in the flame either in the form of a substrate coating or as aerosol particles, provide the necessary reaction sites for deposition of solid carbon. Nanotubes are believed to form on the catalyst particle via the same carbon dissolution-diffusion-precipitation mechanism discussed in section 2 above. The structure of the formed carbon nanotube (MWNTs and/or SWNT) depends on the catalyst particle size and carbon deposition rate. Post flame gas phase chemistry, temperature at the surface of the catalyst particle and the structure and type of catalyst particle are the key controlling parameters for growth of nanotubes in the flame synthesis process.
In comparison with the other processes, flame synthesis is an auto-thermal process that is capable of providing temperature optimal for achieving desired synthesis conditions. Flame medium is characterized by a complex homogeneous gas phase kinetics that involves reactions between the fuel and the oxidizer with formation of water, carbon dioxide, and partial oxidation products and fuel pyrolysis with formation of secondary hydrocarbon species such as single and multi-chained hydrocarbons, polycyclic aromatic hydrocarbons, and soot precursors. In comparison with CVD, a flame medium is rich in intermediate radicals that are formed in high concentrations during intense homogeneous gas phase reactions. This homogeneous gas phase kinetics is closely coupled with the heterogeneous kinetics of gas-surface interactions leading to the formation of nano-structured solid carbon.
Post flame gas phase chemistry and temperature are a complex function of fluid dynamics, mass transfer and heat transfer phenomena at play inside a flame. Fuel and oxidizer primarily impact the gas phase composition and the maximum temperature in the flame. Hydrocarbon fuels such as CH4, C2H4 and C2H6 when used with oxygen/air as the oxidizer result in unique product gas phase compositions and maximum temperatures (~ 2000 K). The degree of mixing between fuel and the oxidizer that is identified by the parameter of equivalence ratio (ϕ), generally determines the extent to which the chemical oxidation reactions are complete to stable product gases such as CO2 and H2O. Intermediate product gases such as CO, C2H4, and C2H2 and in general CnHm provide compositions supportive of solid carbon formation. At steady state equivalence ratio is a spatially varying quantity within the diffusion flame structure. The zone of maximum temperature within the flame is also known as flame front is formed at the location where the local ϕ is equal to 1.
Configuration of the flame plays an important role in establishing the fluid dynamics, the mass and energy transfer and the chemistry in the flames. Flames are classified mainly as premixed, non-premixed (diffusion), and partially premixed. Diffusion flames are further characterized by the orientation of the reactant nozzles into co-flow diffusion, inverse diffusion, and counter flow diffusion. All of these flame configurations have been used for carbon nanotube growth. A premixed flame is defined as a flame where the oxidizer and fuel are completely mixed before burning (e.g. Bunsen flame). A co-flow jet burner establishes a diffusion flame with the fuel issued from an inner tube and the oxidizer is injected from an outer tube. When the fuel and the oxidizer are inverted in a co-flow jet burner, an inverse diffusion flame is formed. A counter-flow flame is established from two converging nozzles arranged in an opposed flow configuration with a fixed distance, where oxidizer issued from one nozzle impinges onto the fuel flow issued from the other. Independent of the flame type used, it must provide a source of carbon to form the graphite layers, utilize the catalytic metal nano-particles to form the solid graphitic layers from gas-phase carbon containing molecules, and provide a heat source for forming and activating the catalytic nano-particles. The flow structure of the flame can be laminar or turbulent based on the Reynolds number. However, only laminar flames have been used for synthesis of carbon nanotubes due to the uniform structure. In the further discussion only laminar flames have been addressed unless explicitly otherwise stated.
Use of inert diluents also affects the flame chemistry and temperature. Nitrogen (N2) and Argon (Ar) have been used as the diluents in many carbon nanotube flame synthesis experiments. The ambient conditions of pressure and temperature also impact the flame and hence the synthesis conditions for carbon nanotubes.
Metal catalysts in the form of both substrate and aerosol have been used for growing carbon nanotubes. Typical catalysts include transition metals such as Iron (Fe), Nickel (Ni), and Cobalt (Co). Alloys of transition with other metals like chromium (Cr), copper (Cu) and zinc (Zn) have been used. In the substrate method, a substrate coated with a catalyst layer is positioned at the appropriate location inside the flame. Catalyst nano-particles are formed on the substrate as a result of flame-substrate interactions. These particles further act as the nucleation site for nanotube growth. Stationary substrates have been typically used for synthesis of MWNTs because of the larger size of catalyst nano-particle (~20 nm). Catalyst can be injected inside a flame in the form of a vapor aerosol. Generally, nitrates of transition metals and metallocenes have been used in flame synthesis. Catalyst particles of the size of approximately ~5nm are formed due the condensation of the catalyst vapor, that are suitable for growth of SWNTs. Catalysts have been found to be very active towards a particular gas phase precursor of solid carbon, and hence structure and type of the catalyst play an important role in determining the growth rate as well as the structure of the CNTs.
3.2. Synthesis of MWNTs using flames
MWNTs and larger forms of nanotubes have been successfully synthesized using flames. Substrate type catalysts have been used in most of the experiments because of the inherently closer control over the catalyst formation processes. A variety of flame configurations mentioned above have been used with CH4, C2H4, C2H2, C3H8 and alcohols as the fuels and air or O2-N2 and O2-Ar mixtures as the oxidizer species.
3.2.1. Premixed flame synthesis
Premixed flames offer distinct advantages for CNT synthesis when compared to non-premixed flames. As the mixing of fuel and air occurs before ignition, equivalence ratios can be easily controlled by varying the mass flow rate of the fuel and/or the oxidizer. Premixed burners with a flat radial profile and variation only in the axial direction (e.g. McKenna burner) have been used for nanotube synthesis. The flame temperature can be reduced to an appropriate value by the use of chimneys. Uniform gas flow composition can be obtained by appropriate arrangements in the burner.
The first evidence for filamentous carbon growth in flames was established using premixed flames (Singer & Grumer, 1959). In the last two decades premixed flat flames have been extensively studied for synthesis of carbon nanotubes (Diener et al., 2000; Gopinath & Gore, 2007; Grieco et al., 2000; Howard et al., 1992; Howard et al., 1991; Vander Wal et al., 2002, 2002). Formation of C60 and C70 fullerenes was first observed in premixed flames by Howard et al. In their studies, sooty discharge from premixed laminar flames of benzene, oxygen and argon at low pressures (1.60 to 13.35 kPa) were analyzed using electron impact mass spectroscopy. The results showed presence of C60 and C70 fullerenes that were confirmed by FTIR (Fourier Transform Infrared Spectroscopy). The yields of C60, and C70 and the C70/C60 ratio were found to depend on temperature, pressure, carbon/oxygen ratio, and residence time in the flame. The amount of fullerenes formed in the flame was very low (0.009% to 0.03 % of the soot mass) as compared to that formed in graphite vaporization (1% to 14%). Nonetheless, this finding motivated combustion scientists to pursue the synthesis of CNTs using flames as the precursors (C60 and C70 fullerenes) were found in flames.
Vander Waal et al. carried out a comprehensive study of the MWNT synthesis in premixed flames. Premixed flat flame McKenna burner was used with SS chimney for cooling. Methane (CH4), Ethane (C2H6), Propane (C3H8), Ethylene (C2H4) and Acetylene (C2H2) were used as fuels with air as the oxidizer. At the top of the chimney, a circular molybdenum ring held the mesh (Stainless Steel) supported catalyst (cobalt) within the post-flame gases. The flame equivalence ratio was varied, adjusting the fuel flow rate to the burner while maintaining a constant air flow rate. The post-flame gas temperature was recorded to be (~1100 K). Meshes were retained in the flame gases for 12 minutes, measured from the time of insertion to extraction. Results of chemical equilibrium calculations were correlated with the experimental measurements to determine the optimal gas phase chemistry for the growth of CNTs. CO was identified as the main gas precursor. Both SEM and HRTEM imaging were used to correlate the nanotube morphology and internal structure to the reaction gas composition. The variations observed were understood in light of the gas composition and the interaction of the reactive components with both the deposited Co catalyst particles and supporting metal substrate. Coated and uncoated (with Co catalyst) meshes were subjected to post flame gases. The uncoated SS meshes resulted in a dense random CNT growth because of formation of catalysts through surface break up. However coated meshes showed a uniform and dense growth confirming the dominance of catalyzed CNT formation. With C2H2 flames high deposition was found even on uncoated meshes. Most significantly, catalyst particles are observed at many tips using the uncoated SS mesh, characteristic of surface breakup processes.
Gopinath and Gore further investigated the carbon containing gas phase species responsible for deposition of carbon during the synthesis of MWNTs. Premixed flames of ethylene and air were established in a flat flame McKenna burner. Due to the flat flame profile, radial gradients were ignored. This assumption significantly simplified the computational analysis of the flame and post flame chemistry. The yellowish high carbon region just above the flame was found to be best suited for the gas phase chemistry required to encourage CNT growth. In order to enable the required gas phase chemistry and temperature to exist around the catalyst substrate, a chimney was placed just above the flame. The chimney served two functions, (a) it prevented the optimal gas phase chemistry of the near flame zone from dissipating and (b) it provided the necessary wall losses to quench the post flame environment to attain the ideal temperature for rapid CNT growth. A cooling chimney was used to cool the flame products and obtain appropriate post flame temperatures for CNT synthesis. A N2 co-flow stream was employed to stabilize the flat flame. The air flow rate was held constant at 11.5 lpm and the equivalence ratio (ϕ) was varied by changing the fuel flow rate. A 2 nm thin layer of cobalt catalyst was deposited commercially, using a physical vapor deposition technique, on SS304 200 mesh standard TEM grids. The experimental arrangement is shown in figure 5 (a). The gas phase temperature and substrate temperature were measured using a thermocouple and found to be within 10 K of each other at 1100 K under steady state conditions confirming the observations by Vander Wal.
Figure 5.
Experimental synthesis of carbon nanotubes using premixed flames (a) Experimental arrangement, (b) & (c) TEM images of nanotube growth on cobalt catalyst at ϕ = 1.55 (d) HRTEM image of MWNTs at ϕ = 1.55 (e) HRTEM image of closed MWNT (Gopinath & Gore, 2007)
Figure 5 shows the TEM images of the carbon nanotubes synthesized during the experiment at the equivalence ratio of 1.55. Figure 5 (b) and (c) show the low magnification images of the CNTs. Optimum yield of nanotubes was produced at this particular value of equivalence ratio. As shown in figure 5 (d) and (e), the magnified images reveal the multi-walled structure of nanotubes. The well-graphitized structure is evident from this image. These observations were found to be consistent with the experiments performed by Vander Wal.
3.2.2. Diffusion flame synthesis
Formation of fibrous carbon in diffusion flames was first observed by Saito et al. (Saito et al., 1991; Saito et al., 1986) while conducting soot characterization studies on methane air diffusion flames. The growth was observed beyond a certain height above the burner with associated color change from brown to black. Later, Yuan et al. completed detailed characterization studies using methane- air (Yuan et al., 2001), ethylene-air and N2 diluted ethylene-air flame synthesis (Yuan et al., 2001) of CNTs. The catalytic supports (Ni-Cr) used were in the form of wires and grids undergoing an oxidation process, and grids pre-loaded with Co nano-particles.
In the experiment done with methane by Yuan and co-workers, SEM images suggested that most nanotubes have a particle attached at the base near the substrate. Since the particles were not seeded in the flame and the images indicated their presence it is apparent that the particles are lifted from the surface. The base location of most of the particles supports the base growth model for the CNTs. Nevertheless, some particles were found at the tip of the nanotube indicating catalyst surface breakup. This phenomenon has been reported by Vander Waal et al. in their reports on premixed flame synthesis especially with an uncoated stainless steel mesh. Soot was formed when only Ni-Cr wire was held in the flame without any support mesh. This indicated that the stainless steel mesh may be essential for the formation of CNTs. Soot was found to grow over a broad range of conditions in the flame whereas CNTs grow in a narrower region in the presence of a catalyst. The optimum harvest conditions were observed within non-dimensional physical locations between h/H = 0.2 to 0.3 and r/R = 0.6 to 0.9. The temperature of nanotube formation was found to be around 1520 K. The CNTs were collected on Ni-Cr wire whereas brown deposits were formed on the stainless steel mesh later identified as iron oxide. CNT formation was observed even at low catalyst concentration indicating that soot formation and CNT growth may be competing phenomenon in the flame. Optimum region for CNT growth was found to be in the region of minimum oxygen concentration. However, the rate of catalyst particle formation was found to be low. Thus, it was suggested that oxygen might play an important role in the formation of metal catalysts. However, high concentrations of oxygen might lead to oxidation of the CNT precursors and incipient CNTs. The zone of temperature was also determined to be a critical parameter for the synthesis of CNTs.
With the ethylene flames Yuan and coworkers tried to study growth mechanism for the carbon nanotubes inside the flame. The effect of N2 addition to the flame on the growth of nanotubes was assessed. Soot instead of CNT formation occurred when a bare stainless steel mesh was used as the substrate. However, when pre-oxidized substrate was used CNT growth was visible indicating the criticality of formation of metal oxides for CNT growth. When Ni-Cr wire similar to methane experiment was placed in the ethylene flame amorphous carbon growth was visible that signified the difference between formation mechanism of CNTs in methane and ethylene flames. The deposition rate for gray material was found to be more than 3 mg/min. With increase in sampling time the production rate of amorphous carbon increased leading to eventual solidification of the tube due to deposition of carbon on the nanotube walls. The increase in the thickness was attributed to deposition of pyrolytic carbon on to the carbon nanotube walls. Addition of N2 to the flame resulted in decreased synthesis temperature (from 1820 K to 1517 K) and carbon gas concentration that led to fewer nanotubes. However, more uniform nanotubes resulted in the presence of N2. Cobalt coated grids resulted in well aligned and uniform CNTs with diameters well correlated to the catalyst particle. Similar observations related to the optimum temperature for nanotube synthesis were made by Lee et al. (Lee et al., 2004) for an ethylene air inverse diffusion flame. It was observed that when the gas temperature was varied from 1400 to 900 K, well-aligned MWNTs with diameters ranging from 20 to 60 nm were formed on the probe’s surface. Ni was used as catalyst in the form of Ni(NO)3 particles pre-loaded on the substrate. Reduction up to 60% in melting temperature of the transition metal due to small particle size of the bulk value has been reported (Moisala et al., 2003; Petroski et al., 1998). This fact was used to explain the formation of active catalyst particles in the temperature well below the bulk melting temperature of Ni (~1726 K).
Xu et al. (Xu et al., 2006)examined the effect of different types of catalysts on growth of carbon nanotubes in a methane air inverse diffusion flame. They tried to correlate composition of the catalyst with the observed morphology of the carbon nanotube. A methane air inverse diffusion flame of total height of 15 mm was established. Temperatures and concentrations were determined, at various radial locations at particular heights from the burner, using spontaneous Raman spectroscopy. Optimum range for nanotube growth was found to be at a height of Z = 12 mm and radius r between 2 – 4 mm. Peak concentrations of CO and H2 were found in the optimum synthesis range. Ideal temperature range for CNT growth was reported to be in between 1200 – 1400 K.
Counter flow diffusion flames are been increasingly used for synthesis of MWNTs due to their 1-D geometry and convenience in positioning the catalyst substrate in the flame (Hou et al., 2009; Li et al., 2007; Merchan-Merchan et al., 2003; Merchan-Merchan et al., 2004; Merchan-Merchan et al., 2002; Merchan-Merchan et al., 2009; Saveliev, 2003; Xu et al., 2007). Merchan-Merchan et al. (Merchan-Merchan et al., 2002) recorded the formation of CNTs in a methane oxygen counter diffusion flame without any catalysts. They employed an atmospheric, opposed flow burner with N2 co-flow in which the oxidizer was enhanced to 50% oxygen or greater. High resolution SEM and TEM images revealed soot like structure with presence of carbon nano-particles and nanotubes however, no catalyst particles were found embedded in the soot like structure. The tube diameter and length were approximately 20 and 320 nm, respectively. The distribution of the sizes of nano-particles and nanotubes was found to be bimodal, indicating that both structures originated in similar sized solid carbon precursor seed. Presence of nano-particles and nanotubes inside soot like structure pointed towards a similar mechanism responsible for formation of all three structural forms. Currently, oxy-flames are being pursued for CNT synthesis (Hou et al., 2009; Merchan-Merchan et al., 2009) due to the high temperature and radical concentration obtained at the flame location.
3.3. Flame synthesis of SWNTs
Similar to the synthesis of MWNTs, a combustion system tailored with an ideal source of carbon, heat source, and appropriate catalytic material, can result in the production of single-walled carbon nanotubes. In the flame method, the catalytic precursors are generally introduced into the flame system in the gas-phase and nucleate and condense to solidify into spherical metallic nanoparticles. Flame parameters can be used to obtain an appropriate flame environment that would allow the formation of ideal sizes of catalytic particles for carbon nanotube inception and growth. The available literature on the flame synthesis of SWNTs is scarce, in contrast to flame synthesis of MWNTs, consisting of only a handful of experiments that have been conducted on the synthesis of SWNTs.
To some extent all products obtained in the SWNT synthesis experiment have common morphological trends; even though they are synthesized in flames formed using different burner configurations and conditions. These morphological trends include (Merchan-Merchan et al., 2010): (i) SWNTs always coexist with metallic and/or soot particles, (ii) particles often appear to be poisoned; even when ultra small catalytic particles, ideal for SWNT inception, can be achieved, they can be heavily encapsulated with amorphous carbon becoming inactive as catalysts for nanotubes, (iii) the presence of larger metallic particles with very short SWNTs.
Vander Wal studied the effect of catalysts in aerosol form on the growth of CNTs (Vander Wal, 2002). Primarily SWNTs were grown on aerosol catalyst particles using an acetylene air flame. Same flame configuration was used except the catalyst in form of Fe(III) nitrate (Fe(NO)3) vapor dissolved in a solvent was introduced through a nebulizer. Absolute ethanol was found to be the optimum solvent for the catalyst. The experiment was directed towards identifying the correct precursor for the SWNT growth by introduction of pyrolysis gas mixtures (CO/H2/He and C2H2/H2/He) and studying the effect of catalyst particle size on the growth of SWNT. Higher CO concentrations led to metal particles becoming encapsulated within amorphous carbon. There appears to be a minimum limit for presence of CO and H2 and maximum limit for presence of H2O for the production of SWNT synthesis. Increase in catalyst vapor concentration led to increased particle size, making them ineffective for fullerenic growth. Therefore, a need for appropriate gas phase precursor and catalyst particle size was identified for SWNT growth. C2H2 was found responsible for poisoning of catalysts and presence of H2 was deemed essential for etching of the catalyst particle.
Height et al. (Height et al., 2004) studied the transitional conditions between soot formation and CNT formation and the effect of operating conditions on structure of nanotubes. Optimum zone for equivalence ratio was identified that was required for formation of SWNTs. A premixed C2H2/O2 flame with argon dilution of 15 molar percent, cold gas feed velocity of 30 cm/s, and burner pressure of 6.7 kPa formed the basis of the experiments. Iron penta-carbonyl (Fe(CO)5) vapor was used as the catalyst. Carbon nanotubes were formed as the distance above the burner surface is increased. A nanotube formation window for equivalence ratio was anticipated with upper and lower limits determined by sooting and carbon availability factors. Flames with equivalence ratios between 1.4 and 2.0 were examined, with samples extracted at 70 mm HAB (approx. 53 ms). Multistep mechanism for nanotube formation in flames was recognized. Post flame gas chemistry and formation of appropriate size catalyst particles were identified as the most critical steps. An order of magnitude growth-rate for the nanotubes in this interval is between 10 and 100 µm per second. Optimal condition for SWNT growth is around ϕ of 1.6 and appropriate size of catalyst particles.
The growth mechanism for SWNTs has been found to be very similar to the mechanism for other forms of solid carbon like soot. It has been well known that the precursors for soot are Polyaromatic Hydrocarbons (PAH) that are formed through the breakdown of C2H2. However, presence of high concentration of C2H2 causes the catalyst particle to be coated with amorphous carbon inhibiting the growth of SWNT. An earlier abundance of carbon species might poison the particle and prevent CNT inception earlier on in the flame volume. Therefore, following occurrences can affect the formation of SWNTs in a flame (Diener et al., 2000): (i) soot formation begins at a time where the metal particles have not yet grown large enough to act as a SWNT catalyst; (ii) catalytic particles with suitable size are synthesized but the large amount of acetylenic species poison the catalytic particles preventing their activation and inception of SWNTs.
Even though all the above mentioned experiments were conducted with fixed flame parameters and single catalyst material, the synthesized forms of carbon nano-materials is found to change dramatically. It is observed that change of flame position induces variation in macro-morphology and in the microstructure of the formed carbon nano-materials. The modification of growth conditions is directly related to variation of the flame environment pertinent to the specific flame location. Temperature, radical and hydrocarbon concentrations are strong functions of axial position in the flame. Availability of specific hydrocarbons at given flame location alters the growth mechanism leading to the selective production of various nanoforms. Hence, there is a need for more fundamental study related to the establishment of optimum growth region and the associated structure of carbon nanotubes inside a flame environment.
4. Growth controlling parameters
As mentioned previously, gas phase composition, temperature and the catalyst are the three major factors that determine the optimum region for carbon nanotube growth inside a flame. Careful control of these variables can result in a high yield rate of pure carbon nanotubes when compared to other synthesis methods. In this section, effect of each of these variables on the carbon nanotube growth is outlined.
4.1. Gas phase composition inside a flame
Carbon nanotubes are formed when carbon in gaseous form is deposited in form of the structured solid on to a catalyst particle. The concentration of gaseous precursors and the resulting deposition rate play an important role in determining the structure of the nanotube that is dependent on the concentration of gaseous precursor. These gaseous precursors are formed through the complex phenomena that occur inside a flame.
4.1.1. Fuel type and equivalence ratio
At steady state, the concentration of gaseous precursors in a flame is a function of the type of fuel, configuration of the flame and the local equivalence ratio (ϕ). Fuel rich flames (ϕ > 1) are utilized for nanotube growth. In a premixed flat flame the equivalence ratio is uniform. Therefore, premixed flames have been studied to understand the effect of equivalence ratio on nanotube growth (Gopinath & Gore, 2007; Height et al., 2004; Vander Wal, 2000; Vander Wal et al., 2002).
Vander Waal et al. characterized the equivalence ratio range that may be ideal for CNT growth for different fuels. They found that methane did not produce any significant CNT growth. Ethane produced various nanostructures for equivalence range of 1.52 < ϕ < 1.9. For ethylene the growth started at ϕ = 1.50 and best results are obtained at equivalence ratio of 1.62. Acetylene provided high growth of CNTs at all equivalence ratios. However, the growth was non-uniform and MWNTs with large diameter were obtained.
Gopinath and Gore observed that CNTs with maximum yield and best morphology were produced with ethylene flame for the equivalence ratio range of 1.5 < ϕ < 1.6. For a richer equivalence ratio (1.62 < ϕ < 1.75), the yield of CNTs fell substantially. For a leaner equivalence ratio (1.47 < ϕ < 1.49), the yield of CNTs was less than the maximum yield range, even for longer residence times. For ϕ < 1.45, no CNTs were observed to grow and for ϕ > 1.75, non- CNT structures of low yield were found to be predominant.
In the experiments carried out by Height et al. with C2H2/O2/Ar flames for growth of SWNTs, they examined the flame for equivalence ratio range of 1.4 < ϕ < 2.0. Nanotubes were observed to form between 1.5 < ϕ < 1.9. For low ϕ (1.4 < ϕ < 1.5) the condensed material (particles and nanotubes) in the flame was dominated by discrete particles. For ϕ of 1.9 and higher, soot-like structures were found to dominate with clustered networks of primary particles ranging in size from 5 to 20 nm.
From these observations it is seen that for ethylene and acetylene there is a general agreement on the range of equivalence ratio (1.5 < ϕ < 1.8) optimal for CNT growth. However for other fuels like (methane) there is no consensus. This suggests that the growth of CNTs is a function of gas phase concentrations of carbon containing gases which is in turn a combined function of equivalence ratio and type of fuel used.
In case of diffusion flames the mixing and hence the equivalence ratio is determined by the mass transfer due to diffusion between fuel and oxidizer streams. Hence the equivalence ratio is a function of spatial location and is difficult to measure experimentally. Thus the CNT growth region cannot be directly related to the equivalence ratio. However, when similar conditions were used by Yuan et al. (Yuan et al., 2001; Yuan et al., 2001) for CNT growth with ethylene and methane, ethylene deposited amorphous carbon whereas methane deposited CNTs. This observation suggests that, also in case of diffusion flames CNT growth gas composition in the flame.
Vander Wal et al. (Vander Wal et al., 2000) also noted that dilution of fuel with an inert like N2 or Ar might be critical to the nanotube synthesis. Absence of diluent resulted in soot formation and encapsulation of the catalyst nano-particle with amorphous carbon. Yuan et al. (Yuan et al., 2001)observed that addition of diluent (N2) reduced the temperature in the synthesis region that further resulted in reduced but more uniform yield of CNTs. Addition of diluents leads to altered flame structure which in turn can affect the gas phase composition.
From the discussion above, it is clear that, there remains a need for characterizing different flames for similar gas phase composition that is favorable for CNT growth.
4.2.2. Gas phase precursors: CO and C2H2
In a flame environment, various carbon containing gas phase species are formed that are responsible for deposition of solid carbon. The two main contributors are hydrocarbons (CnHm) and carbon monoxide (CO).
Hydrocarbons decompose at high temperature to form solid carbon. With increase in number of carbon atoms (CH4, C2H6, C3H8) these compounds become unstable. Methane is the most stable hydrocarbon that begins to decompose at 1200 K. Un-saturated hydrocarbons such as C2H2 and C2H4 are very susceptible to decomposition due to presence of disruptive π bonds. C2H2 is found to be unstable even at room temperature. In fact, C2H2 is one of the main precursors for soot formation inside flame. It also contributes primarily to the formation of carbon nanotubes if sooting conditions are avoided. Very fast decomposition of acetylene is the main cause of catalyst deactivation due to encapsulation by amorphous carbon.
Carbon monoxide (CO) participates in deposition of solid carbon via the Boudard (CO disproportionation) reaction and the hydrogenation reaction that are shown in equation (1) and (2) respectively.
2CO(g)↔C(s)+CO2(g)ΔH=−171kJ/molE1
CO+H2↔C(s)+H2OΔH=−131kJ/molE2
The decomposition rate of CO disproportionation reaction is found to be low when compared with the acetylene decomposition, making it the ideal precursor for SWNT formation. Based on thermodynamic equilibrium, temperature range of 800 - 1100 K has been found to be ideal for CO disproportionation at normal pressure (Moisala et al., 2003). However, this range may not be ideal for catalyst particle formation, carbon dissolution and carbon precipitation. CNT yield is found to increase with increase in the CO pressure.
C2H2 and CO exhibit preferential activity towards certain catalysts. Comparative studies between these two gaseous precursors (Vander Wal, 2002; Vander Wal & Hall, 2001) in pyrolysis flames indicated that CO reacts with Fe based catalyst through carbide formation whereas C2H2 is active towards Ni based catalysts. Particle size plays a critical role towards determining the catalytic activity. Fe nano-particles of all sizes are generally inactive (toward nanotube synthesis) within C2H2 mixtures.
To assess the effect of carbon precursor on nanotube growth, gas phase chemistry in a premixed flame was studied by Vander Wal et al. (Vander Wal et al., 2002). Concentrations of various gases in the post flame environment were determined using gas phase equilibrium calculations. Water gas shift reaction was assumed to be at equilibrium. Based on the experimental results and calculations a strong relation emerged between the optimum CNT synthesis conditions and the concentration of CO and H2. An optimum window for nanotube synthesis based on CO and H2 concentrations was deduced as shown in figure 6 (a). The concentration of C2 species was found to be negligible in comparison to CO based on detailed chemistry calculations. Hence, CO was considered to be the main carbon source. However, the study lacked a comparison between the amount of solid carbon deposited and the gas phase carbon present in various species, making the above assumption speculative. The post flame temperatures were found to be constant irrespective of variation in the adiabatic flame temperature. With an identical H2 concentration, there was a dramatic increase in the CNT yield with increases in CO concentration. At very high CO concentrations (in case of C2H2 flames) PAH and soot formation may result in the encapsulation of the catalyst material and reduction in CNT yields. At very high CO concentrations, surface carbon builds up to form an inactive layer on the catalyst surface (coking layer) without a carbon removal mechanism. Once formed, such a layer prevents further contact with carbon gas-phase species and thus stops the carbon atom supply.
Detailed chemistry calculations instead of equilibrium were performed by Gopinath and Gore (Gopinath & Gore, 2007) for a similar premixed flame arrangement. The hypothesis of water gas equilibrium at the CNT synthesis conditions was assessed. The effect of variation in equivalence ratio on the substrate temperature was found to be negligible confirming the observations by Vander Wal. The effect of changing equivalence ratios on CNT yield was interpreted, based on gas phase chemistry, using chemical kinetics computations. A one-dimensional premixed flame code with a post flame heat loss model, including detailed chemistry, was used to estimate the gas phase chemical compositions in the region of interest. The CNTs formed were in a very small amount even at the highest yield location. Hence it was difficult to quantitatively relate the change in the gas phase chemistry to CNT synthesis. Comparison of variation of concentration with equivalence ratio for different gas phase species was done to assess the effect of gas phase chemistry. Significant rise of up to 10 orders of magnitude was found to occur for C2 hydrocarbons and up to 6 orders of magnitude of CH4 relative to hydrogen mole fraction near the maximum yield equivalence ratio. On the other hand, the trends for CO and H2 concentration showed monotonic variation with equivalence ratio. Rapid departures from the partial equilibrium of the water gas shift reaction and rapid changes in mole fraction ratios of C2 unburned hydrocarbon to H2 were observed in the range of equivalence ratios suitable for CNT growth. Based on this observation, it was argued that C2 species might play an important role in carbon deposition as compared to CO. The slow kinetics of the CO disproportionation reaction at the experimental conditions was found to be in favor of the argument. Based on chemical kinetics calculations the optimum window was found to shift slightly to the lower side (as shown in Figure 6 (b) with maximum CO concentration ~10 %). Water gas shift reaction was found to diverge from the equilibrium at the CNT synthesis conditions. Hence the need of detailed chemistry calculations was established to correctly assess the effect of gas phase chemistry on the synthesis of CNTs in flames.
From the discussion it is evident that CO and C2H2 both contribute to the nanotube synthesis. However, further experimental and computational studies are required to examine the competing effects of C2H2 and CO on solid carbon formation in a flame.
Figure 6.
Optimal CO and H2 conditions for CNT synthesis based on partial equilibrium calculations (Vander Wal et al., 2002) and detailed chemistry calculations (Gopinath & Gore, 2007)4.2.3 Effect of other gas phase constituents: H2, CO2 and H2O
Other gas phase constituents of the flame chemistry also have significant effect on CNT growth. H2 acts as the primary etching agent to remove surface-adsorbed carbon. Higher H2 concentrations greatly facilitate the catalysis of uniform and graphitic CNTs. However, very high concentrations of H2 could compete for adsorption sites on the catalyst surface, thereby slowing the rate of CO adsorption and subsequent carbon supply to the CNT. H2O and CO2 participate indirectly in the CNT synthesis by altering the water-gas shift equilibrium. CO2 is not known to contribute to the surface reactions nor can to interfere with adsorption of H2 or CO. H2O interacts with the adsorbed carbon on the particle surface. Gasification of surface carbon by H2O at elevated temperatures can also hinder CNT growth. Thus CNT synthesis is hindered at lean conditions due to higher concentrations of H2O, CO2.
4.3. Temperature
Temperature is one of the important parameter that governs the growth of carbon nanotubes inside a flame. Evolution of temperature field and gas phase chemistry occurs simultaneously inside a flame, because of the coupled energy and mass transfer phenomena. The gas-solid interactions responsible for deposition of carbon are endothermic and thus are favored by high temperature (~ 1000 K). Flame environment provides an inherent source of heat and thus high temperature which makes it one of the ideal candidates for CNT growth. However, the temperature field inside the flame shows a large variation ranging from ~ 2000 K near the flame front to the cooler regions of ~ 800 K. Thus, appropriate regions of the flame need to be probed for the growth of carbon nanotubes. Li et al. (Li et al., 2009) tried to characterize the effect of temperature on the CNT growth in counter-flow flames. According to their study the ideal range for CNT growth was found to be 1000-1200 K which is also comparable to the temperature range of CVD synthesis method. At this location in the flame the concentration of various carbon precursors is also found to be high. Similar observations have been reported by Vander Wal et al. (Vander Wal et al., 2002) and Gopinath and Gore (Gopinath & Gore, 2007) in case of premixed flames. Xu et al. also reported similar temperature range around ~1200 K for synthesis of MWNTs in an inverse diffusion flame.
The gas phase composition and temperature range discussed above are typically measured at scales much larger than those corresponding to that of the C60 molecule inception, growth and organization. Therefore, the ranges defined above can be deceptively broad and yet support a narrower range at the micro scale. In situ measurements of carbon growth species such as C2H2 and abstraction and addition processes involving H and C atoms are needed to develop nano scale and micro scale models.
4.4. Catalyst
Mainly, transition metals such as Iron (Fe), Nickel (Ni), Cobalt (Co) have been employed for CNT synthesis in a flame. Alloys of these metals with metals like Copper (Cu) and Zinc (Zn) have also been used. Properties of these catalyst materials can be found in literature (Moisala et al., 2003). Fe has the highest melting point (~1800 K) amongst the transition metal catalysts and is found to be reactive towards CO as compared to C2H2 (Baker et al., 1972; Baker et al., 1973; Vander Wal, 2002, 2002). It is found to be active even at smaller particle diameters (~1 nm) and hence has been successfully used for synthesis of SWNTs. It supports formation of MWNTs at sufficiently high temperature and CO concentration (Xu et al., 2006). MWNT formation has been extensively reported on stainless steel (Baker et al., 1973; Soneda & Makino, 2000; Vander Wal et al., 2002). Nickel has the lowest melting point amongst the transition metals (~1725 K) and is active towards C2H2 as compared to CO. It has a diametrical size threshold of ~5 nm above which it becomes active towards solid carbon deposition. Ni has been used for growth of MWNTs in flames with other carbon forms. Nickel when used as a substrate inside a flame undergoes surface break-up similar to Fe. Usually, with nickel the catalyst particles are found on the tip of the nanotubes indicating tip growth through surface growth. The MWNTs produced by nickel are well aligned as compared to Fe, however when subjected to high concentration of C2H2 nickel particles are poisoned due amorphous carbon deposition.
In case of substrate catalyst, the required catalytic nano-particles responsible for CNT growth are formed inside the flame primarily through the probe surface breakup induced by surface carbonization. The surface breakup occurs due lattice stress mismatch which a result of oversaturation of metal surface with solid carbon. This formation mechanism of catalyst nano-particles generally creates a wide variety of sizes and geometries (Baird et al., 1974; Moisala et al., 2003; Soneda et al., 2002; Soneda & Makino, 2000) which are determined by various factors, such as temperature, chemical species, and carbon solubility of the metal. Two other possible mechanisms for the direct formation of nano-particles on a metal probe surface in flames are OH oxidation-hydrogen reduction and evaporation–condensation. The inherent presence of oxygen-bearing species (e.g. OH) near the flame front on the fuel side can lead to local oxidization of the metal probe. However, these two mechanisms contribute little to nano-particle formation due to limited oxygen content and lower temperature. Furthermore, carbon-bearing species are overwhelmingly dominant in the local flame structure such that the surface breakup mechanism dominates for nano-particle formation.
In case of aerosol form, vapor molecule containing catalyst particle (nitrates, carbonyls or metallocenes of transition metals) undergoes rapid decomposition inside the flame to form the atoms of transition metal catalyst. These atoms coagulate further downstream in the flame giving rise to metal catalyst particle distribution that form the active sites for nanotube growth. The particle sizes generated in this case are of the order of ~ 5nm that are suitable for SWNT growth. In fact, simultaneous growth of SWNT and the catalyst particle has been reported (Vander Wal, 2002). Ferrocene and nickelocene were used as the catalyst precursors for formation of catalyst particles. It was observed that it was difficult to form catalyst particle sizes above 5nm by the aerosol method due to large number of particles needed for coagulation (5 nm particle corresponds to ~104 atoms). It has been observed that Nickel becomes active towards nanotube synthesis for particle sizes above 5 nm. Thus it has been difficult to synthesize SWNTs using Ni.
5. Mathematical models for growth of CNTs in flames
Growth of carbon nanotubes in a flame environment is a multistep multi-scale phenomenon. Mathematical modeling of the various processes occurring during the synthesis is essential for gaining predictive capability and minimizing the number of experiments. As shown in figure 7 various processes occur either simultaneously or consecutively at different length scales. The two main spatial scales can be identified as (i) the bulk scale that includes the entire flame ~ 10 cm (as shown in figure 7 (a)) and (ii) the catalyst particle scale where the deposition of solid carbon occurs at small-scale ~ 100 nm (as shown in figure 7 (c)). The growth process can be broken down into following steps, (a) establishment of the flame that acts as the source for gaseous precursors and heat (b) simultaneous formation of catalyst particles and growth of carbon nanotube occurring at nano-scale. Each of the above mentioned process requires mathematical modeling along with a model to couple the models at various length scales.
Figure 7.
Formation of carbon nanotubes in a flame environment
Accurate mathematical description of advection, diffusion and chemical processes is necessary in order to predict the gas phase composition and temperature in the flame environment. The fluid dynamics of the flame is captured through the solution of Navier-Stokes (NS) equations. Energy and species equation need to be solved simultaneously with the NS equations to completely capture the mass and energy transfer. Most of the reported experiments have used laminar flames for nanotube growth. Thus, a 2-D axisymmetric CFD calculation may be sufficient for capturing the flow in most of the cases. As described in section 3, in case of premixed flames, or counter flow diffusion flames, flat flame profiles have been employed in CNT synthesis. For these flames, even a 1-D formulation can provide acceptable solutions, where in which 1-D continuity and momentum equation are solved along with energy and species equations. The equation of state provides the required relation between density, pressure and temperature. CHEMKIN packages based on this philosophy (e.g., premix and oppdiff) and other similar ones have been extensively used to model premixed and counter diffusion flames. The chemistry is modeled via detailed chemical kinetics mechanisms. However, in some of the growth experiments these flame environments have been modified by use of cooling chimneys (Gopinath & Gore, 2007; Vander Wal et al., 2002) in case of premixed flames and by the insertion catalyst substrates in case of counter flow flames (Li et al., 2007; Merchan-Merchan et al., 2003; Xu et al., 2007). In these situations, 2-D simulation that accurately captures the development of boundary layer along the walls needs to be used for better prediction of quantities inside the flame and post flame environment. In case of co-flow and inverse flow diffusion flames 2-D computations coupled with mixture fraction formulation comprise a good solution strategy. As the flow is inherently 2-D in these flames, one dimensional solution does not fare well. Axisymmetric combustion codes like UNICORN have been successfully used to model axisymmetric diffusion flames (Katta et al., 2005; Unrau et al., 2010). Complete mathematical description of the flame environment provides the required information of the gas phase composition and temperature at the bulk reactor scale. This information is further used to calculate various parameters related to the growth of carbon nanotubes.
Growth of carbon nanotubes at the catalyst particle surface through the deposition of solid carbon constitutes the next length scale i.e. the particle scale. The literature related to the flame synthesis of CNTs/CNFs is overwhelmingly experimental and provides observations rather than fundamental explanations and models (Naha et al., 2007). However, there have been few good attempts of describing the growth process of carbon nanotubes inside a flame (Celnik et al., 2008; Naha & Puri, 2008; Naha et al., 2007; Unrau et al., 2010; Wen et al., 2008; Zhang & Smith, 2005).
Development of gas phase chemistry and formation of catalyst particles occur simultaneously in a flame environment as shown in figure 7 (b). Catalyst particle coagulation in the aerosol form needs to be mathematically described along with the gas phase chemistry (Celnik et al., 2008; Kuwana & Saito, 2005; Wen et al., 2008). Kuwana and Saito (Kuwana & Saito, 2005) have described nano-particle growth from ferrocene in which they provided a two-step catalytic reaction model for the formation of Fe nano-particles. Wen et al. (Wen et al., 2008; Wen et al., 2007) employed a sectional method developed on simultaneous particle and molecule modeling (SPAMM) approach developed by Pope and Howard (Pope & Howard, 1997). In this approach, catalyst particle formation is modeled as reactions, that can be incorporated into a gas-phase reaction mechanism and allow for the simultaneous modeling of the gas-phase chemistry and the nano-particle formation processes.
Growth of carbon nanotube at the catalyst particle can be visualized as a collection of following process, (a) diffusion of carbon precursor gas species and their conversion to solid carbon (b) diffusion of the solid carbon over the surface of the catalyst particle and through the bulk, (c) encapsulation of the catalyst particle by the solid carbon and (d) nucleation and growth of the carbon nanotube. A schematic of these processes occurring together is shown in figure 7 (c).Diffusion of gaseous carbon species to the catalyst particle followed by the deposition of carbon is usually assumed to occur at the leading face of the particle. In most of the studies, this combined process has been modeled in terms of impingement rate based on the kinetic theory (Naha & Puri, 2008; Naha et al., 2007; Wen et al., 2008). It can also be modeled in terms of reaction kinetics for the dissociation reaction of the individual gas species as mentioned in section 4.1. The deposited carbon is also desorbed, which can be described in an Arrhenius type equation. The solid carbon remaining at the leading face of the particle can now diffuse either along the surface of the catalyst nano-particle or through the particle. Surface diffusion leads to coating of the particle by the solid carbon. This process can be captured through a rate equation (Naha et al., 2007; Zhang & Smith, 2005). On the other hand the diffusion of solid carbon through the bulk of the particle establishes a concentration gradient across the particle. The concentration of solid carbon inside the catalyst particle can be obtained by solving the unsteady mass diffusion equation over the volume of the particle. At the trailing face of the catalyst particle, CNT nucleation can be considered to occur due to precipitation of the bulk diffused solid carbon. The nucleation and growth of the CNTs can be modeled based on a critical threshold cluster density number similar to the soot growth mechanism.
In conclusion, the mathematical description of the CNT growth process, involves large temperature and species variation occurring at the scale of flame environment, whereas the processes at the nano-scale are determined by the mass and energy transfer across the boundary layer. Thus, a careful multi-scale modeling approach is necessary to capture the essence of the nanotube growth.
6. Conclusions and future trends
From this review it is evident that flames have emerged as a viable method for bulk synthesis of CNTs and related nanostructures. The synthesis of CNTs and related nanostructures is affected by the flame environment’s temperature and chemical species, geometry, burner configuration, and catalyst composition. Flames provide the chemical species and the thermal energy necessary for driving the synthesis process. Flame synthesis processes are scalable and large scale production of SWNTs has been reported (Richter et al., 2008). However, control over the complex processes occurring in a flame is deemed critical for generation of appropriate condition for CNT growth. A large variety of hydrocarbons have been used as fuels for flames. Thus identification of the optimum ingredients, fuel and oxidizer, for the development of industrial processes is essential. Measurements of carbon nanotube growth rates under well defined micro-scale gas phase environment are scarce. Development of boundary layer around the catalyst particle or substrate inside a flame environment needs to be carefully examined. More sophisticated models are required for capturing mass and energy transfer across the boundary layer. Multi-scale modeling approach is essential for these computations. Spectroscopic diagnostic techniques at the micro-scale need to be applied in the boundary layer region to obtain insitu measurement of species concentration and temperature near the catalyst surface. These measurements can provide the missing link of data between the large scale and the nano-scale processes occurring simultaneously during the flame synthesis of CNTs. It has been observed that careful control of the synthesis process is essential to preserve the properties of the CNTs and to avoid any impurities. However, flame environment is characterized by presence of large number of chemical species and varying temperature field. Thus control techniques are necessary for pure and uniform yield of CNTs in the flame environment. Electric biasing of the catalyst substrate has been found helpful in alignment of CNTs in flames. Better control over the flame temperature with use of chimneys has led to uniform growth of CNTs. Addition of diluents to the flame has resulted in temperature reduction and more uniform growth of CNTs. Injection of pyrolysis gases in a non-hydrocarbon flame (H2-O2) flame has also been attempted for improved control.
In summary, future work in flame synthesis of CNTs is needed for the definition of a standard set of reactants based on nano-scale and micro-scale measurements and computations of the optimum growth environment. Macro-scale reactor geometries and bulk material composition that lead to desirable product quality and yield need to be defined. Finally, cost versus quality tradeoffs depending on the specific needs of an application will decide the method for synthesis of carbon nanotubes.
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/16801.pdf",chapterXML:"https://mts.intechopen.com/source/xml/16801.xml",downloadPdfUrl:"/chapter/pdf-download/16801",previewPdfUrl:"/chapter/pdf-preview/16801",totalDownloads:6059,totalViews:1095,totalCrossrefCites:13,totalDimensionsCites:32,totalAltmetricsMentions:0,impactScore:11,impactScorePercentile:98,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"November 11th 2010",dateReviewed:"April 10th 2011",datePrePublished:null,datePublished:"July 20th 2011",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/16801",risUrl:"/chapter/ris/16801",book:{id:"466",slug:"carbon-nanotubes-synthesis-characterization-applications"},signatures:"Jay P. Gore and Anup Sane",authors:[{id:"41428",title:"Dr.",name:"Jay",middleName:null,surname:"Gore",fullName:"Jay Gore",slug:"jay-gore",email:"gore@purdue.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"87553",title:"Mr.",name:"Anup",middleName:null,surname:"Sane",fullName:"Anup Sane",slug:"anup-sane",email:"asane@purdue.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Purdue University West Lafayette",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Mechanism of carbon nanotube formation in a catalytic synthesis process ",level:"1"},{id:"sec_3",title:"3. Flame synthesis of carbon nanotubes",level:"1"},{id:"sec_3_2",title:"3.1. Experimental investigation",level:"2"},{id:"sec_4_2",title:"3.2. Synthesis of MWNTs using flames",level:"2"},{id:"sec_4_3",title:"3.2.1. Premixed flame synthesis",level:"3"},{id:"sec_5_3",title:"3.2.2. Diffusion flame synthesis",level:"3"},{id:"sec_7_2",title:"3.3. Flame synthesis of SWNTs",level:"2"},{id:"sec_9",title:"4. Growth controlling parameters",level:"1"},{id:"sec_9_2",title:"4.1. Gas phase composition inside a flame",level:"2"},{id:"sec_9_3",title:"4.1.1. Fuel type and equivalence ratio",level:"3"},{id:"sec_10_3",title:"4.2.2. Gas phase precursors: CO and C2H2",level:"3"},{id:"sec_12_2",title:"4.3. Temperature",level:"2"},{id:"sec_13_2",title:"4.4. Catalyst ",level:"2"},{id:"sec_15",title:"5. Mathematical models for growth of CNTs in flames ",level:"1"},{id:"sec_16",title:"6. Conclusions and future trends",level:"1"}],chapterReferences:[{id:"B1",body:'BairdT.FryerJ. R.GrantB.\n\t\t\t\t\t1974 Carbon formation on iron and nickel foils by hydrocarbon pyrolysis- reactions at 700 C. Carbon,\n\t\t\t\t\t12\n\t\t\t\t\t5\n\t\t\t\t\t591602 , 0008-6223'},{id:"B2",body:'BakerR. T. K.BarberM. A.WaiteR. J.HarrisP. 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C.ChenZ.\n\t\t\t\t\t2001 Ethylene flame synthesis of well-aligned multi-walled carbon nanotubes. Chemical Physics Letters,\n\t\t\t\t\t346\n\t\t\t\t\t1-2 , 2328 , 0009-2614'},{id:"B60",body:'YuanL. M.SaitoK.PanC. X.WilliamsF. A.GordonA. S.\n\t\t\t\t\t2001 Nanotubes from methane flames. Chemical Physics Letters,\n\t\t\t\t\t340\n\t\t\t\t\t3-4 , 237241 , 0009-2614'},{id:"B61",body:'ZhangY.SmithK.\n\t\t\t\t\t2005 A kinetic model of CH4 decomposition and filamentous carbon formation on supported Co catalysts. Journal of Catalysis,\n\t\t\t\t\t231\n\t\t\t\t\t2\n\t\t\t\t\t354364 , 0021-9517'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Jay P. Gore",address:"",affiliation:'
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1. Introduction
Following a meal, pancreatic β-cells produce insulin in response to increasing blood glucose and other metabolite levels for regulating systemic glucose homeostasis. Tissue insulin sensitivity, which characterizes the ability of a given concentration of insulin to correct blood glucose levels, is the driving force behind this homeostasis. Multiple processes in several organs are involved in this typically well-regulated homeostatic mechanism, including decreased glucose output from the liver (hepatic glucose output), increased glucose uptake into skeletal muscle and adipose tissue (where glucose is stored as glycogen), suppression of free fatty acid (FFA) release from adipocytes (suppression of lipolysis), and increased lipid accumulation in the liver and adipocytes. A sophisticated insulin-dependent signal transduction cascade controls these metabolic processes. Insulin resistance (IR) is defined as decreased insulin-stimulated glucose uptake into muscle and adipocytes and faulty insulin regulation of hepatic glucose production in patients with type 2 diabetes (T2D) and in many subjects affected by other conditions characterized by insulin resistance, such as obesity and polycystic ovary syndrome. The term insulin resistance was first coined to explain the considerable variability in the insulin dose necessary to lower high glucose levels in people with T2D, and then to characterize the magnitude of change in blood glucose level when a given amount of insulin and glucose was administered. The “defined quantity of insulin” is crucial because people with insulin resistance often have hyperinsulinemia, a condition in which insulin levels in the blood are higher than normal relative to the amount of blood glucose concentration under both fasting and fed conditions; this hyperinsulinemia compensates for IR in peripheral tissues to bring blood glucose levels back to normal [1].
When pancreas fails to supply excess insulin in humans with insulin resistance, a major defect in whole-body glucose homeostasis occurs, resulting in hyperglycemia and glucose intolerance (the latter including impaired fasting glucose and impaired glucose tolerance), which are the defining features of T2D. It is worth noting that, somewhat counterintuitively, patients with T2D frequently maintain “relative hyperinsulinemia” until the condition is at an advanced stage. IR is defined by insulin’s inability to induce glucose uptake into muscle and adipose cells due to a failure of the glucose transport mechanism mediated, at the molecular level, by glucose transporter type 4 (GLUT4) in those tissues. Furthermore, one of the hallmarks of IR is the inability to decrease hepatic glucose production, which is mostly due to a persistent increase in hepatic gluconeogenesis. IR has been linked to a variety of diseases. Indeed, IR represents a risk factor for various conditions, such as metabolic disorders (including T2D and obesity), heart disease, liver diseases (e.g., non-alcoholic fatty liver disease and non-alcoholic steatohepatitis), cancer, neurodegenerative diseases and frailty [2, 3, 4]. Despite the fact that IR is inextricably linked to T2D, an important factor involved in T2D pathophysiology is represented by the pancreas’ incapacity to function properly to compensate for the significant rise in blood glucose levels by secreting enough insulin to meet the increasing demand and help get blood glucose levels back to normal. IR is a key risk factor for T2D, yet it is not commonly recognized or treated in people without diabetes. The main reason for this phenomenon is that many people with insulin resistance do not have abnormal blood glucose levels. Therefore, diagnosis of IR is based on measuring insulin levels, which is not commonly done in clinical practice. Furthermore, only a small fraction of subjects with IR develop T2D, which is likely due to a propensity to β-cell failure in these subjects. There are no procedures to identify this susceptible subpopulation at this time. Individuals with IR are predisposed to significant disorders linked to T2D, including retinopathy, neuropathy and kidney disease, even if they do not have T2D [5]. In this chapter, the association between the early possible causes of IR is first discussed. Obesity is common in people with IR, but it is unclear whether concomitant hyperinsulinemia contributes to obesity development or whether it is a consequence of obesity-associated IR. We then look at how different metabolic tissues, such as muscle, adipose tissue, and the liver, communicate with one another. The mechanisms of impaired insulin signaling and the role of abnormal GLUT4 trafficking in the development of IR are also discussed. Extracellular factors that may contribute to IR are postulated. This discussion is then followed by a discussion of various intracellular molecular factors that contribute to IR. These factors have been considered as involved in processes that lead to IR. There are several ways for determining insulin action. Many laboratories have lately resorted to employing surrogate markers of insulin sensitivity and IR [6]. The “traditional” definition of IR is a condition in which blood glucose levels are abnormally high and insulin concentration needed to maintain glucose homeostasis is greater than predicted [7, 8].
2. Pathway to insulin resistance
Despite years of research, there is still a lot of uncertainty about the causative and temporal link between obesity, hyperinsulinemia, and IR. The proximal and distal parts of the insulin signaling system, which governs metabolism, can be arbitrarily partitioned. The classical components—which comprise the insulin receptor, insulin receptor substrate (IRS) proteins, phosphoinositide 3-kinase (PI3K) and AKT-constitute the proximal segment of the insulin signaling system. A common trait of the proximal components is their sparseness, which means that just a little part of each element is necessary to elicit a physiological signal. This guarantees signal amplification across the network. The proximal portion is also susceptible to very complex feedforward and feedback control, and is incorporated into a broader network that is dynamically regulated by combinatorial signaling inputs. The AKT substrates that are intimately related to the many physiological activities of insulin and are typically specialized to a particular cell type are referred to as the “distal segment” of the insulin signaling pathway. The distal elements are generally phosphorylated, which is a common trait. Insulin signaling begins with the hormone binding to its surface receptor, followed by activation of the receptor tyrosine kinase and tyrosine phosphorylation. IRS proteins are phosphorylated, causing them to create a signaling complex, which contains proteins with Src homology domains such as PI3K. As a result, phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3 or PIP3] is produced. Serine/threonine (Ser/Thr) protein kinases like PDK1 and AKT, for example, are recruited to the inner leaflet of the plasma membrane. AKT is phosphorylated by PDK1 at one of its phosphorylation sites. Partially phosphorylated AKT activates mTORC2, while phosphorylation of AKT specifically at Ser473 results in complete AKT activation. Thus, AKT is a critical node in the insulin signaling pathway. AKT performs a variety of biological roles and is involved in the majority, if not all, of physiological metabolic processes. The Rab GTPase-Activating Protein (GAP) is an AKT substrate, which activates TBC1D4 (TBC1 Domain Family Member 4), a protein that regulates GLUT4 trafficking within the plasma membrane. The activation of glucose transport by insulin is the key mechanism that is disrupted in insulin-resistant muscle and fat cells. The GLUT4 is a facilitative glucose transporter, which is found in skeletal muscle, heart, adipocytes, and insulin-responsive neurons; it regulates muscle/fat glucose transfer. Unlike other transporters (like GLUT1), GLUT4 has a set of specific trafficking cues that let it migrate from endosomes and the trans-Golgi network (TGN) to a special intracellular population of vesicles known as “GLUT4 storage vesicles” (GSVs) [9, 10, 11]. GSVs act as a distinct controlled exocytic compartment that distributes GLUT4 to the cell surface in response to insulin and serves as a storage depot assuring low rates of glucose absorption in the fasting state. Although exercise increases GLUT4 translocation in muscle cells, it does so through a different mechanism than that regulated by insulin. AKT plays a critical role in the insulin-regulated GLUT4 translocation [12, 13]. These characteristics typically coexist, and there is strong evidence that each can cause the other two branches of the triad to emerge: obesity, hyperinsulinemia, and IR are caused by overnutrition in humans and animals; in humans, IR and obesity may also be caused by continuous insulin administration or by genetic factors; in addition, IR in humans may be caused by pharmacological interventions resulting in hyperinsulinemia [14, 15].
3. The trio-axis of obesity-hyperinsulinemia-insulin resistance
Obesity and IR are two topics that come up frequently. The long period during which obesity, IR and hyperinsulinemia develop, makes the determination of causative links between these conditions (which usually coexist in most persons with T2D at the time of diagnosis) particularly difficult. Obesity is common in people with IR, although it is unclear whether simultaneous hyperinsulinemia plays a role in obesity development or it is predominantly a result of obesity-dependent IR [16]. The study of first-degree relatives of people with T2D who only show some of these traits has shown to be one of the most effective strategies for addressing some unanswered questions in humans. As a result, a trait seen in relatives is more likely to appear early in the course of the disease. It has been found that these subjects can have considerable IR in skeletal muscle and liver (and possibly fat), along with modest hyperinsulinemia, even if they are not obese or glucose-intolerant [15, 17, 18]. Individuals who are lean and glucose-tolerant but exhibit IR have been identified in larger cross-sectional studies [19]. In these instances, obesity is unlikely to be the primary cause of tissue IR. However, the term “obesity” is defined differently depending on race and genetic background, and it should therefore used with caution. Body mass index may be more important in determining the risk of IR. Body weight, in general, and visceral fat (but not subcutaneous fat), in particular, should be considered for evaluation [20].
First-degree relatives of people with T2D had greater levels of circulating FFAs and intramuscular lipids than healthy control subjects [21], suggesting that intramyocellular lipid content represents an early abnormality in the pathogenesis of insulin resistance and that it may contribute to the impaired glucose uptake in skeletal muscle of insulin-resistant subjects to a greater extent than overall adiposity. This is in line with severe IR observed in patients with lipodystrophy syndromes, which are a heterogeneous group of diseases characterized by selective absence of adipose tissue, loss of functional adipocytes, ectopic steatosis, and severe dyslipidemia and IR [22, 23]. On the other hand, individuals with moderate or severe obesity can be “metabolically healthy” [24]. While it appears acceptable, based on this research, to conclude that obesity is not a risk factor essential for the development of IR, it is vital to highlight that the majority of subjects with IR are obese. As we will discuss later in the text, the amount and location of adiposity required to create IR varies greatly between subjects.
4. Insulin resistance and hyperinsulinemia
Defining the temporal link between hyperinsulinemia and IR is difficult since, as far as we know, IR does not exist in the absence of hyperinsulinemia in humans, and vice versa. Hyperinsulinemia can produce obesity and IR in humans, as evidenced by trials in which insulin is administered to induce hyperinsulinemia in otherwise healthy individuals or as it occurs naturally in people with insulinomas [25, 26]. Transgenic expression of multiple copies of the normal insulin gene causes hyperinsulinemia in mice, resulting in IR and glucose intolerance [27]. Inhibition of insulin secretion has also been shown to improve insulin sensitivity and to decrease body weight in rodents [28, 29, 30]. In mice, deletion of one copy of the insulin gene resulted in a reduction of the Western diet-induced hyperinsulinemia and in an improvement of insulin sensitivity [31]. Overall, the hypotheses that hyperinsulinemia causes IR and promotes obesity, or that IR associated with obesity causes hyperinsulinemia, both remain acceptable for the initial events involved in T2D pathophysiology. In actuality, IR and hyperinsulinemia coexist and lead to T2D in almost all cases [32]. Several data suggest a concept in which hyperinsulinemia is responsible for, or at least partly contributes to, many of the negative effects of IR; this implies that IR is a state in which many of the insulin actions are preserved, a condition known as “selective IR” [33, 34, 35]. This was first observed in the liver, where increased insulin levels are unable to decrease hepatic glucose output in people with T2D, although lipogenesis (a canonical insulin action in the liver) remains elevated [36, 37]. One explanation for this selectivity is that insulin signaling pathway in the liver splits into two arms, with IR affecting only the arm regulating hepatic gluconeogenesis but not the arm regulating lipid metabolism. Hepatic de novo lipogenesis is essentially a cell-autonomous phenomenon, whereas cell-nonautonomous suppression of hepatic glucose production by insulin depends upon the insulin-mediated decrease of adipocyte lipolysis and circulating FFAs [38]. There has also been evidence of selective IR in muscle and adipose tissue. Those insulin-regulated activities which are not affected by IR—such as lipogenesis, protein synthesis, or transcriptional control mediated by FOXO proteins—are hyperactivated in the context of hyperinsulinemia and are likely to worsen IR or its consequences [33, 34, 39, 40].
5. Heterogeneity in the development of insulin resistance and progression of metabolic disease and T2D
T2D patients are divided into different phenotypic clusters based on their symptoms and clinical features. Individuals in one of these groups share phenotypic traits. As a result, performing a comprehensive analysis of these groups will be of great importance in clinical settings. Phenotype data analysis and combination of phenotype data with genetic data are essential to gain a better understanding of the variability in the development and presentation of IR in humans [10, 11, 41].
6. Tissue-specific progression to insulin resistance
The appearance of IR occurs in various tissues in a specific order. The development of IR in several tissues—including skeletal muscle, liver, and adipose tissue—is a hallmark of fully developed T2D in humans [18, 19, 39, 40, 42]. Evidence shows a hierarchical progression of IR in skeletal muscle, liver and adipose tissue, whereby IR develops in one tissue and then spreads to other tissues via systemic circulating components. For example, IR in the liver and adipose tissue appears to occur prior to IR in muscle in C57Bl/6 mice fed a high-fat diet [43, 44, 45, 46]. An equivalent pattern in humans is unlikely, since first-degree relatives of persons with T2D who are in the early stages of the disease already have IR in both muscle and liver (and possibly fat) [47]. Since insulin sensitivity in humans is often measured as whole-body glucose consumption (to which adipose tissue contributes only to a small extent), the temporal development of IR in adipose tissue in humans is less obvious. Interestingly, multiple investigations show that insulin modulates hepatic glucose production via reducing adipocyte lipolysis in a non-cell-autonomous manner [45]. Given these findings, it is reasonable to believe that adipose tissue IR is a precursor to metabolic disease and T2D. However, there is a clear distinction between insulin action on the liver and insulin action on muscle: even in people with T2D, the defect in insulin sensitivity in the liver can be almost completely overcome by sufficiently high levels of insulin, whereas muscle (and fat) insulin sensitivity defects persist at higher insulin concentrations [40, 48, 49]. This indicates that the processes that cause IR in muscle and liver are distinct.
Tissue-specific insulin receptor gene knockouts in mice have provided persuasive evidence that IR in a particular tissue can at least spread to other organs. Experimenting with a specific deficiency in insulin action in muscle, fat, or liver has resulted in the spread of IR to other tissues in a number of cases [50]. However, depending on the tissue that is first targeted and/or in which a specific gene deletion occurs, the mechanism of inter-tissue communication varies. The deletion of GLUT4, which is essential for glucose uptake in adipose tissue and skeletal muscle, is one of the best examples of this inter-tissue communication. In mice, deletion of GLUT4 resulted in IR not only in the tissue from which the transporter was removed, but also in all metabolic tissues, including the liver. Surprisingly, normalization of blood glucose levels reverses IR in the liver and adipose tissue in muscle-specific Glut4 gene-knockout mice. This shows that glucotoxicity generated IR in this animal model, which is not the case in many other IR models, including the Western diet-fed C57BL/6J mice, which do not show considerable hyperglycemia [48, 49, 50, 51]. As a result, while these animal studies have been useful in uncovering mechanisms of IR in specific tissues, their clinical applicability is less evident because complete deletion of a gene preferentially in one tissue does not occur in humans. Nonetheless, these experiments have provided persuasive evidence that metabolic or signaling changes in one tissue can have systemic effects by influencing insulin activity in other organs, a phenomenon that has been well-validated by clinical findings [50, 51].
7. Impaired insulin signaling in insulin resistance
Over the past 40 years, much research has resulted in a precise understanding of the insulin signaling system, which mediates the insulin’s physiological activities. One popular theory is that IR is caused by a defect in one or more of these signaling components. Another viewpoint is that IR is only caused by a shift in metabolic flux. For example, since the 1960s fatty acids have been proven to impede cells’ ability to utilize carbohydrate by allosterically modifying crucial rate-limiting steps in carbohydrate metabolic pathways. Several pieces of evidence, however, refute this claim. IR can be seen in cells or tissues long after the animal tissues have been removed, implying that changes that contribute to IR are long-lasting and cannot be explained by the acute action of a systemic factor. Fatty acids decrease the insulin-dependent translocation of GLUT4 to the plasma membrane and limit glucose uptake, there is no indication that this inhibition is caused by an allosteric change of GLUT4. Finally, IR can persist even after significant changes in dietary intake and after changes in metabolic state induced by pharmacological interventions. Thus, based on this information, it is reasonable to believe that IR is caused by an alteration in insulin signaling, although the exact location of the defect in the insulin signaling pathway remains unknown. Many essential components of the insulin signaling system have been identified. These components are divided into two parts: (i) the proximal part, which represents the core canonical signaling pathway, which includes the insulin receptor, IRS, PI3K and AKT; and (ii) the distal part, which includes TBC1D4, GSK3 (glycogen synthase kinase-3) and PDE3B (phosphodiesterase 3B). IR has been linked to defects in proximal insulin signaling system, that are associated with cellular stress. Many of the intracellular stressors discussed in the next sections activate a variety of intracellular Ser/Thr kinases, including novel PKCs (protein kinase C), JNK (c-Jun amino-terminal kinase), mTOR (mammalian target of rapamycin)and S6 kinase, which phosphorylate either the insulin receptor or the insulin receptor-related protein (INSRR). This could be a negative-feedback route that inhibits insulin signaling, according to the theory. However, as it will be discussed later, mounting evidence suggests that proximal insulin signaling system is unaffected in IR, implying that IR is caused by abnormalities in distal components of the insulin signaling network [52, 53, 54].
8. Insulin resistance and insulin signaling at the proximal level
The current focus on proximal insulin signaling abnormalities as a cause of IR stems from research into rare, monogenic severe types of IR that were discovered to be caused by mutations in the insulin receptor gene or by the development of insulin receptor blocking antibodies. Because of the superficial parallels between these rare conditions and T2D, it is reasonable to conclude that both diseases are caused by abnormalities in insulin receptor function, with the degree of receptor failure varying only slightly. Despite early enthusiasm for this theory, subsequent research found that IR in most forms of T2D was caused by neither impaired insulin receptor activity nor changes in the expression or quantity of insulin receptors. Insulin-binding experiments in rat adipocytes found that only 2.4% of total insulin receptors are required for a full biological response, implying that metabolic cells like muscle, fat and liver cells have an abundance of insulin receptors; this finding became known as the “spare insulin receptor” hypothesis. Insulin-mediated glucose uptake is reduced in insulin-resistant skeletal muscle cells and adipocytes. Since a slight decrease in the number of insulin receptors could only diminish insulin sensitivity and not the maximal insulin response [54, 55, 56, 57, 58]. While some studies contradict the “spare insulin receptor” hypothesis, recent genetic studies in mice support the idea that insulin signaling is preserved when the number of insulin receptors is reduced: mice with heterozygous loss of the insulin receptor had normal glucose and insulin tolerance and no impairment in AKT signaling in muscle or adipose tissue [59, 60, 61, 62].
The concept of spare insulin receptors shifted focus to a “postreceptor defect”, which is represented by defects in signaling downstream intermediates of the insulin receptor as the cause of IR [57, 58, 63]. Loss-of-function mutations in a number of signaling genes—including TBC1D4, AKT2, and IRS1 in humans—have been linked to severe forms of IR and T2D; moreover, cancer treatments that block PI3K or AKT have been linked to IR and T2D in humans. IR is caused in mice by targeted deletion of these genes. In addition, IR results in reduction of skeletal muscle AKT phosphorylation in response to insulin stimulation [34, 64, 65].
Given evidence of “spareness” for IRS, PI3K and AKT, the possibility that abnormalities in proximal insulin signaling might be responsible for IR has to be questioned, in the same way that the “spare receptor” theory has to be questioned. Homozygous deletion of AKT2, the most prevalent AKT gene isoform, resulted in a 90% reduction in insulin-stimulated AKT phosphorylation, but with no discernible defect in phosphorylation of the AKT substrate, or protein synthesis in response to insulin. In this situation, there was a tiny quantity of AKT1 expression that was not influenced by the gene deletion and was enough to deliver a completely functional message as response to insulin [66, 67]. Similarly, whereas AKT2 accounts for 85% of total AKT in the liver, its ablation does not result in significant glucose intolerance because the remaining AKT1 compensates for this defect [68]. The insulin dose-response curve in adipocytes, where the curve for AKT phosphorylation is “shifted to the right” compared to that for AKT substrate phosphorylation or insulin action, indicates that partial phosphorylation of AKT is sufficient for maximal biological responses, providing additional evidence for “spareness” in proximal insulin signaling network. At “normal” insulin concentrations, phosphorylation of AKT substrates requires only 1% of the entire AKT pool to be activated [69, 70, 71]. Furthermore, AKT phosphorylation is reduced in muscle from T2D patients, while downstream substrate phosphorylation is unaffected. Importantly, studies in animals fed a Western diet have indicated that IR begins before any detectable insulin signaling defect. Only 42 days of Western diet feeding resulted in reduced insulin-stimulated AKT phosphorylation, but TBC1D4 phosphorylation remained normal. As a result, minor changes in phosphorylation of proximal insulin signaling components may result in insulin sensitivity, but they are unlikely to result in a reduction in the maximal physiologic response [53].
Thus, how can the predominance of abnormalities in proximal insulin signaling components observed in diverse IR models, such as lower AKT phosphorylation, be reconciled? It is possible that these defects are a result of defective glucose metabolism rather than the cause. This could be a direct effect secondary to compensatory hyperinsulinemia, a typical hallmark of IR (since persistent hyperinsulinemia can lead to degradation of proximal insulin signaling components); alternatively, it may be a cell-autonomous effect due to a reduction in AKT phosphorylation as a result of defective glycolysis. Many studies used insulin-stimulated AKT phosphorylation in mice (sometimes in response to a maximal, pharmacological dosage of insulin) as an indicator of insulin sensitivity [72, 73, 74, 75].
However, under physiological settings such as the response to a meal (with minimal insulin release), AKT phosphorylation is barely detectable, due to the non-linearity between AKT phosphorylation and phosphorylation of its substrates. As a result, when evaluating the physiological importance of insulin signaling, it is critical to look at the phosphorylation of a variety of AKT substrates to determine if there is a major deficiency in “AKT activity” in vivo. These findings suggest that a minor impairment in proximal insulin signaling network is unlikely to account for the significant reduction in insulin-stimulated glucose uptake observed in patients with T2D. Furthermore, these findings underline that lower AKT2 phosphorylation should not be used as a direct marker or even as a proxy measure of IR [71].
Negative feedback loops originating from Ser/Thr kinases that phosphorylate and limit the action of IRS proteins have also been proposed as a cause of IR. This theory is refuted by a number of studies. Since Platelet-derived growth factor (PDGF) by-passes these proteins to activate glucose uptake, mice bred to overexpress PDGF receptor (PDGFR) in muscle presented an ideal model to explore whether deficiencies in insulin receptor or IRS were implicated in experimental IR. In these mice, PDGF treatment resulted in increased glucose uptake in muscle [76]. Notably, when PDGFR transgenic rats were fed a Western diet, muscle glucose uptake in response to PDGF was decreased to the same degree as insulin-mediated uptake. This refutes a role for inhibitory Ser/Thr phosphorylation of the insulin receptor or IRS as a cause of IR, indicating that the deficiency in glucose uptake or IR does not involve the insulin receptor or IRS [8, 53, 54, 77, 78].
Furthermore, in mice, targeted mutation of one of the major putative inhibitory sites in IRS1 (Ser307), deletion of potential mediators of IR, such as PKC (which is reported to phosphorylate insulin receptor), and pharmacological blockade of key negative feedback pathways, such as mTOR (which is activated by insulin signaling and inhibits signaling by phosphorylating IRS through a negative feedback mechanism) [78, 79, 80, 81].
Finally, investigations in humans with IR or T2D revealed that insulin-stimulated muscle glucose uptake is reduced by 50–100% even at maximum insulin dosages [82, 83, 84, 85], with no change or reduction in AKT phosphorylation [86, 87, 88]. Only a few of these studies addressed the mechanism of AKT substrate phosphorylation in depth, and those that did found no deficiency or poorly linked with IR. These findings support the theory that the proximal insulin signaling network in human tissues has enough “spareness” to overcome even a moderate deficiency in AKT phosphorylation [87, 88, 89], and that lowered AKT phosphorylation is adequate to ensure a normal signal transduction. As previously stated, faulty proximal insulin signaling is most likely a result of IR rather than a cause of IR [90].
9. GLUT4 and insulin resistance
Insulin stimulates the transfer of intracellular GLUT4 storage vesicles to the cell surface, resulting in glucose uptake in skeletal muscle cells and adipocytes (Figure 1) [91, 92, 93, 94]. Insulin-dependent GLUT4 translocation has been linked to IR in both skeletal muscle and adipose tissue. This decrease in GLUT4 availability at the plasma membrane causes a reduced glucose uptake, which can lead to other IR-related consequences like reduced AKT phosphorylation, protein synthesis defects, and increased lipolysis [72, 95, 96]. GLUT4 does not show spareness, unlike proximal insulin signaling components such as IRS1 and AKT. The fact that heterozygous GLUT4 gene-knockout mice acquire metabolic disease exemplifies this concept [97].
Figure 1.
Translocation of glucose transporter type 4 (GLUT4) from GLUT4 storage vesicles (GSVs) to the plasma membrane of normal adipocytes and skeletal muscle cells (a). This process is altered in conditions characterized by insulin resistance (b).
However, while GLUT4 levels are lowered by 50% in human adipose tissue from patients with T2D, such levels remain unaltered in skeletal muscle, implying that GLUT4 levels cannot explain IR development in skeletal muscle [98]. Despite normal GLUT4 levels, insulin-stimulated GLUT4 translocation to the cell surface in skeletal muscle is faulty in both individuals with T2D [92] and in several rodent models of IR [99, 100]. Importantly, while exercise-modulated GLUT4 translocation to the cell surface is unaffected [101], the impairment in muscle GLUT4 trafficking in T2D is insulin signaling-specific. Insulin and exercise both cause GLUT4 translocation to the cell surface from discrete intracellular compartments [102].
The ultimate defect that defines IR is the impaired GLUT4 translocation to the plasma membrane. However, it is unknown how the numerous potential intracellular IR mediators mentioned later affect GLUT4 trafficking. Three options are discussed here. First, GLUT4 translocation requires that GLUT4 is localized in the appropriate intracellular compartment, the so-called GLUT4 storage vesicles (GSVs); GLUT4 targeting to GLUT4 GSVs has been hypothesized to be altered in IR [91, 100]. However, whereas this would likely result in GLUT4 degradation, GLUT4 levels in skeletal muscle from patients with IR remain unaffected. Second, given the importance of protein phosphorylation in insulin action [101, 102, 103, 104], it is possible that the defect is caused by a distal component of the insulin-regulated phosphorylation network such as TBC1D4, which regulates GLUT4 trafficking, although there is no convincing evidence for defective TBC1D4 phosphorylation in IR [105]. TBC1D4 is unlikely to be the only AKT target causing GLUT4 translocation, as cells lacking TBC1D4 still have some insulin-sensitive glucose transport [106]. Recent phosphoproteomics studies have revealed the existence of a wide range of insulin-responsive phosphoproteins in metabolic cells, allowing for the identification of insulin signaling targets in the distal part of the insulin signaling pathway that may be involved in the development of IR [104]. Indeed, IR is associated with massive alterations in the architecture of the entire insulin signaling pathway, according to examination of muscle cells from T2D patients [107]. Finally, a direct alteration of GLUT4 or a defect in a yet undiscovered protein that interacts with GLUT4 could cause the abnormalities in GLUT4 trafficking. This could include carbonylation and oxidation-induced inactivation of GLUT4, which have been observed in humans as a response to short-term overnutrition [108]. Protein carbonylation is linked to H2O2 production, lipid peroxidation and IR, suggesting a link between such molecular processes and the development of IR [109].
10. Adipose tissue and insulin resistance
While IR is regularly seen in lean first-degree relatives of patients with T2D, it is also found in many lean “healthy” individuals, suggesting that IR is more common than previously thought. In this regard, dietary habits, physical activity level and genetics are important factors that can significantly contribute to IR. Adipose tissue makes a significant contribution to the development of IR. Limitations in peripheral adipose tissue storage capacity and expansion in response to over nutrition (as it occurs in overweight and obesity) lead to increased circulating lipids, subsequent lipid accumulation in non-adipose tissues (ectopic lipid in liver, skeletal muscle, heart, and pancreas) and development of lipid-induced IR and metabolic derangements [110, 111]. Because of this, and since there is a clear link between IR and increased adipose tissue mass, we will discuss the role of adipose tissue mass and lipotoxicity as significant drivers of IR, as well as the emerging mechanisms by which adipocytes contribute to systemic IR.
10.1 Adipose tissue dysfunction
IR in adipocytes could be the first step in the progression of adipose tissue dysfunction, similar to IR in muscle and liver. In adipocytes from first-degree relatives of patients with T2D, there is a low expression of markers of insulin sensitivity such as GLUT4 and adiponectin (a crucial systemic insulin-sensitizing adipokine produced by adipose tissue), supporting this theory [112]. Furthermore, adipocyte hypertrophy (increase in adipocyte size) appears to precede T2D onset in Pima Indians, a group of Native Americans with a high incidence of IR and T2D [113]. Additionally, mouse models with adipose-specific IR also have IR in their muscle and liver. Notably, IR in the muscle of adipose-specific Glut4 gene-knockout mice was only present in vivo but not when muscles were isolated and assessed in vitro, implying a role for systemic factors (which did not include circulating FFAs or inflammatory cytokines) in the progression of IR from adipose tissue-specific pathology [114, 115].
Human genetic research has also suggested that adipose tissue plays a significant role in IR. Studies in identical twins or first-degree relatives of T2D patients have shown that inheritance has a substantial influence in IR and T2D [116]. More than 250 genetic loci have been linked to T2D so far, however they only account for 25% of T2D heritability [117]. While these investigations have generally discovered genes linked to beta-cell function and insulin secretion, deeper analysis of phenotypes more closely aligned with IR have begun to uncover genetic drivers of IR in other organs. Surprisingly, several of these drivers are involved in the function of adipose tissue [118]. Although subclinical lipodystrophy is a rare cause of severe IR, it has been suggested that milder forms of lipodystrophy are responsible for IR in general, supporting a model in which excessive lipid spillover into circulation is a proximal, mechanistic cause of altered insulin action. Specifically, when the individual’s capacity to store lipids in adipose tissue has been exceeded, lipid spillover into circulation leads to elevated plasma FFAs and triglyceride levels, which result in increased ectopic storage of these molecules in non-adipose tissues—such as liver and skeletal muscle—and subsequent metabolic derangements via lipotoxicity (lipid-induced toxicity). Surprisingly, genes in the insulin signaling system linked to IR (IRS1 and GRB14) are also linked to familial partial lipodystrophy [119].
PPARG (Peroxisome Proliferator-Activated Receptor Gamma, a master positive regulator of adipogenesis) and CCDC92, DNAH10, and L3MBTL3 (regulators of adipocyte differentiation) were among the 53 loci discovered in a study employing an integrated genomic approach to find genes related to IR. Thiazolidinediones are insulin-sensitizing peroxisome proliferator-activated receptor gamma agonists that are used in the treatment of T2D and act by promoting adipogenesis and adipose tissue growth (through cell size and cell number increase or adipocyte hypertrophy and hyperplasia) [119]. The availability of additional lipid storage induced by thiazolidinediones may therefore promote insulin sensitivity by alleviating lipotoxicity [120]. These drugs also improve insulin sensitivity in first-degree relatives of T2D patients, implying that adipose tissue hypertrophy and “unhealthy” lipid storage are critical regulators of insulin action and contributors to IR [121].
Adipose tissue’s primary function is to store fat and release it into circulation when needed, and it has the unique capacity to expand in response to nutrient overload. Lipids can be released into the bloodstream when the adipocyte capacity to store lipids has been exceeded [39]. There is compelling evidence that the accumulation of excess lipids in non-adipose tissues (e.g., skeletal muscle and liver), known as lipotoxicity (a.k.a. lipid-induced toxicity), plays a role in the development of muscle and liver IR [122]. As a result, studies aimed at understanding the cause and magnitude of increased circulating lipid levels in IR are now being pursued. Furthermore, intracellular lipid accumulation in cells and tissues—including pancreatic beta cells and liver—has been linked to the onset of cellular dysfunctions, such as secretory abnormalities and inflammation (Figure 2). Elevated circulating FFA levels have been linked to IR, and this has been proposed as a possible cause of lipotoxicity [123].
Figure 2.
Excessive adipocyte lipid storage in response to overnutrition, resulting in adipocyte hypertrophy, inflammation and increased release of free fatty acids (FFAs) into circulation, leading to ectopic fat accumulation, lipotoxicity and development of insulin resistance in non-adipose tissues, such as liver and skeletal muscle.
In humans and animals, lipid infusion causes muscle IR and enhanced hepatic gluconeogenesis, the latter attributable to changes in metabolic fluxes rather than to fat accumulation [123, 124, 125]. Furthermore, animals with increased circulating FFA levels due to increased lipolysis develop muscle and hepatic IR, whereas obese mice with reduced fat cell lipolysis are protected from glucose intolerance [126]. It is worth noting that, as discussed elsewhere [127], circulating FFA levels in patients with IR or T2D usually are not elevated. However, there are several confounders in this measurement, including the wide range of FFA levels in healthy adults and the fact that fasting FFAs are typically assessed rather than the more relevant postprandial FFAs. Nonetheless, there is strong evidence that serum FFA levels are elevated in first-degree relatives of patients with T2D [127, 128], implying that this elevation represents an early stage of the disease. It is unclear if the rise in circulating FFA levels is related to defects in insulin-mediated regulation of lipolysis, to alterations in fat storage capacity, or to an increase in adipose tissue mass without defects in lipolysis. Lipolysis per gram of adipose tissue mass is considerably lower in obese subjects, suggesting that enlargement of adipose tissue mass is the principal driver of abnormal FFA homeostasis [129].
Adipose tissue can grow in size by either hypertrophy, which involves the enlargement of existing adipocytes, or hyperplasia, which involves the generation of new fat cells from preadipocytes via adipogenesis, resulting in an increase in the number of tiny adipocytes [130]. Subcutaneous adipose tissue is more expandable than visceral adipose tissue in humans, whereas the opposite is true in C57BL/6J male mice [131]. Female mice, interestingly, show expandability of both adipose tissue depots in response to Western diet feeding, suggesting that sex hormones and other sex-dependent elements play a role in this process [131, 132]. Pathological adipose tissue expandability under situations of overnutrition, particularly adipose tissue hypertrophy, has got a lot of attention as a likely cause of IR. Indeed, first-degree relatives of patients with T2D have greater amounts of hypertrophic adipose tissue, implying that changes in cell size—presumably due to defective adipogenesis—represent an early event in the pathophysiology of T2D. Hypertrophic large adipocytes are linked to poor metabolic outcomes when compared to hyperplastic adipocytes [39, 133], which have been shown to confer metabolic health in obesity [134, 135, 136]. More importantly, hypertrophic adipocytes may contribute to an increase in circulating FFA levels due to their reduced FFA storage capacity. Reduced preadipocyte differentiation, diminished de novo lipogenesis or FFA uptake in hypertrophic adipocytes, and/or reduced adipose tissue expandability due to physical limits on expanding cell size may all contribute to decreased lipid storage capacity by the hypertrophic adipose tissue. Furthermore, adipogenesis abnormalities may result in decreased generation of beige adipocytes, thereby contributing to higher circulating FFA levels; indeed, beige adipocytes differentiate from a subpopulation of progenitors resident in white adipose tissue and have the ability to promote FFA oxidation through thermogenesis [137, 138].
10.2 Circulatory factors released from adipocytes
Adipose tissue secretes a number of factors (termed “adipokines”) into the bloodstream that regulate energy metabolism. These factors include cytokines, hormones, extracellular matrix proteins, as well as growth and vasoactive factors. The type of adipose tissue expansion has been demonstrated to impact the secretion of certain of these factors under IR conditions. Since the discovery of leptin as the first adipokine [139], a growing list of adipose tissue-secreted factors implicated in IR has been discovered, with roles in IR that are either protective or causative [20, 140].
Leptin, for example, regulates whole-body energy metabolism by acting on feeding centers in the brain to suppress food intake and increase energy expenditure; leptin deficiency causes obesity, hyperinsulinemia, IR and impaired glucose homeostasis [141]. Adiponectin, another well-known adipokine secreted from adipocytes, has been linked to regulation of cell insulin sensitivity. In humans, circulating adiponectin levels are favorably linked with whole-body insulin sensitivity; additionally, physical training increases circulating adiponectin levels and the expression of its receptors in muscle, which may mediate the improvement of IR in response to exercise [142]. Surprisingly, small and subcutaneous adipocytes release more adiponectin than visceral or large adipocytes [143]. Anti-atherogenic, anti-inflammatory, and insulin-sensitizing effects of adiponectin have also been discovered [144]. It is worth mentioning, however, that while adiponectin’s positive benefits in rats are outstanding, the role of this adipokine in humans is less obvious, and Mendelian randomization studies on adiponectin’s relationship with metabolic disease in humans have generated inconsistent results [145, 146].
Adipocytes release a variety of substances, including metabolites like lipids and extracellular vesicles that contain proteins and microRNAs. Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are a unique class of lipids synthesized in adipocytes that have been shown to increase insulin sensitivity and reduce inflammation; accordingly, individuals with IR have lower circulating FAHFA levels [147]. As a result, further research into this metabolite class is necessary. Adipocytes, for example, release tiny lipid-encapsulated extracellular vesicles into the bloodstream. These vesicles may alter metabolic processes in other target tissues, such as the liver, according to increasing evidence based on mouse studies. MicroRNAs represent one of the components found in extracellular vesicles that have been linked to this mechanism. While investigations on microRNAs are intriguing, many fundamental aspects about the mechanism of their controlled secretion and their tissue targeting and entry into target cells remain unknown [148, 149].
Many circulating factors are also produced by other adipose tissue-resident cells, such as immune or vascular cells, rather than by adipocytes themselves (the so-called “stromal vascular fraction” of adipose tissue). Some of these adipokines, such as tumor necrosis factor (TNF), resistin or vascular endothelial growth factor (VEGF), are important regulators of tissue homeostasis and may be secreted as a result of adipose tissue enlargement during the development of obesity [150]. Nonetheless, inflammatory cytokines have been widely suggested as possible IR-inducing adipokines, and several of these factors have significant proinflammatory activities [151, 152, 153].
11. Inflammation and insulin resistance
It is now well recognized that cells of both innate and adaptive immunity, notably macrophages, infiltrate hypertrophic adipose tissue in most obesity models, and that this is accompanied by a loss of immunosuppressive regulatory T cells in visceral fat depots [154]. When macrophages in adipose tissue are activated in response to overnutrition, they polarize towards a proinflammatory phenotype and release cytokines that may trigger IR in all metabolic tissues [155]. Diet-induced obesity in mice and humans is unmistakably linked to elevated levels of systemic inflammatory markers, including C-reactive protein (CRP) and enhanced immune cell infiltration of adipose tissue and other organs [156]. In addition, inflammatory cytokines, such as TNF, can elicit IR in metabolic tissues when infused in humans [157]. Although macrophage infiltration into hypertrophic adipose tissue is well documented, the role of inflammation in IR is convoluted and controversial; for example, inflammatory markers are not elevated in first-degree relatives of T2D patients [158]. Furthermore, in Western diet-fed mice, tissue IR occurs before the adipose tissue infiltration by a considerable number of immune cells, and genetic or pharmacological anti-inflammatory methods do not prevent the development of Western diet-induced IR [159, 160]. The administration of a neutralizing antibody against interleukin-1 (IL-1), a proinflammatory cytokine implicated in IR, to approximately 4000 patients with T2D and almost 5000 subjects with prediabetes resulted in a significant decrease in CRP levels, as well as in a modest positive effect on cardiovascular outcomes, but without reducing the frequency of new-onset T2D or increasing fasting glucose levels [161, 162, 163].
Overall, evidence suggests that adipose tissue infiltration by macrophages is unlikely to be the major cause of IR. Macrophage infiltration into the growing adipose tissue may affect its function in addition to systemic inflammation, but the exact impact of this infiltration is unknown [164]. Anti-inflammatory macrophages (M2), on the other hand, have been shown to promote angiogenesis and preadipocyte differentiation, which aids adipose tissue expansion [165, 166]. The diversity of cytokines, their concentrations, and the timing of their release into the tissue are likely to have a considerable impact on the final biological response, contributing to the observed inconsistent results. The ability of genetically induced adipocyte IR to elicit adipose tissue inflammation adds to the growing body of evidence that inflammation may be a consequence rather than a cause of IR. Hyperinsulinemia has been shown to induce adipose tissue inflammation, implying that the latter is a late event in the IR pathophysiology [30].
12. Intracellular mediators and insulin resistance
Many extrinsic stimuli and genetic alterations can antagonize insulin action in vitro and in vivo, and their investigation has led to the identification of a series of molecules as putative intracellular mediators of IR. In the sections that follow, we will look at the role of a few intracellular components that have got a lot of attention as drivers of IR. It is worth noting that mechanisms of action of these components are not well-established yet, and further research is needed to better understand their role in IR development.
12.1 Accumulation of ceramides
Ceramides have been implicated as IR mediators by a large body of research. Ceramides are essential precursors of most of the complex sphingolipids localized in lipid bilayers, including sphingosine, sphingomyelins, and glucosylceramides. Ceramides accumulate in muscle, liver and adipose tissue of subjects with IR, according to human and animal studies [167, 168, 169, 170]. In insulin-resistant tissues, the levels of 16- or 18-carbon chain-length ceramides are raised, whereas the levels of other chain-length ceramides are not consistently changed [171, 172]. Indeed, in adipose tissue from obese subjects, the level of ceramide synthase isoform 6 (CERS6), which synthesizes C16 ceramide, is raised [171]. Surprisingly, the presence of a double bond in the ceramide backbone promotes IR, as ablation of the enzyme responsible for its formation (dihydroceramide desaturase 1) abrogates IR [173]. While it is unclear how specific extrinsic mediators of IR cause increased intracellular ceramide levels, it is possible that excess FFAs serve as a crucial substrates for ceramide biosynthesis [174, 175, 176].
Another theory connects intracellular ceramide to levels of circulating adiponectin. Ceramidase activity is found on adiponectin receptors, and lower adiponectin levels in IR may lead to decreased ceramidase activity and, consequently, to higher ceramide levels [177, 178]. AMP-activated protein kinase (AMPK), a major metabolic sensor that regulates mitochondrial biogenesis and metabolism, is activated by adiponectin, potentially regulating ceramide via increased mitochondrial lipid oxidation [179]. By using small-molecule inhibitors or genetic deletion of ceramide-producing enzymes to neutralize ceramide accumulation in metabolic organs, researchers were able to reverse or prevent IR induced by the Western diet in C57BL/6 mice with diet-induced obesity [122]. The relationship between ceramide and decreased insulin action is not univocal, as it is for many possible intracellular mediators of IR. In fact, ceramide suppresses AKT activity, although IR is unlikely to be caused by defects in AKT, which is a proximal arm of insulin signaling (as it has previously been mentioned). Ceramide could be part of a wider, IR-related stress mechanism that leads to mitochondrial dysfunction and to the production of reactive oxygen species (ROS). Ceramide has also been connected to the release of pro-inflammatory cytokines, which have been involved in IR, as it has previously been described [180, 181].
12.2 Accumulation of diacylglycerol (DAG)
Another popular theory for the cause of IR is the accumulation of diacylglycerols (DAGs) in muscle, adipocytes and liver, as a result of elevated serum FFA levels [182, 183]. Protein kinase C (PKC) is recruited to the plasma membrane by DAGs, where it phosphorylates and inhibits insulin receptor kinase activity. While it is quite plausible that DAG levels are elevated in insulin-resistant tissues, a scenario in which DAG-dependent phosphorylation of the insulin receptor is the major cause of IR raises a number of questions. Given the “spareness” of the insulin receptor and proximal signaling intermediates, it is doubtful that IR is caused solely by abnormalities in these components, at least in muscle. In contrast to other insulin-responsive proteins, the stoichiometry of insulin receptor phosphorylation at the region implicated in DAG-mediated IR is low and not detectable by conventional phosphopeptide analysis [79, 104, 184]. PKC deletion in the liver had little effect on whole-body insulin sensitivity in mice, indicating against PKC being a key target of DAG-induced IR in that tissue [79, 104], although this has since been challenged by studies in rats showing that acute knockdown of PKC in the liver protected animals from IR. However, antisense oligonucleotides were delivered systemically, which could target PKC expression in other organs. While technical differences between these studies and others have been suggested as a reason for the discrepancies observed [183], there appears to be enough disagreement about the role of the DAG-PKC-insulin receptor pathway in IR to warrant further investigation and, in particular, validation by multiple independent laboratories [185].
12.3 Mitochondrial dysfunction and reactive oxygen species (ROS)
IR has been linked to a decrease in mitochondrial function. Mitochondrial dysfunction is a term that has been used to describe a variety of mitochondrial phenotypes, including decreased respiratory capacity and ATP production, decreased number of mitochondria, accumulated mitochondrial damage due to defects in mitophagy, and altered mitochondrial morphology caused by changes in mitochondrial fission-fusion dynamics. Many of these alterations are also linked to an increase in mitochondrial ROS generation, which has long been linked to IR [186, 187, 188].
It is not unexpected that IR is linked to higher levels of reactive oxygen species (ROS). This is due to the fact that IR is frequently accompanied by a positive energy balance, which leads to an excess of reducing equivalents (NADH and FADH2). This determines a reductive stress on the mitochondrial respiratory electron transport chain, which invariably results in the formation of free electrons and, as a result, in an increased production of various forms of ROS [189]. Furthermore, enhanced ROS production has been found in response to a variety of extracellular stressors linked to IR, including inflammation [190]. Superoxide, H2O2, reactive nitrogen andoxidized lipids accumulate in insulin-resistant cells or tissues, and a mitochondria-targeted small molecule transiently produced mitochondrial ROS in muscle and adipocytes, causing IR. As a result, attempts to reduce ROS levels have been proven to reverse or prevent IR in mice [191, 192, 193, 194].
Reduced levels of coenzyme Q (CoQ) have recently been linked to IR in humans [44]. In mitochondria, CoQ is a key component of the electron transport chain, transferring electrons from complex I or II to complex III. Furthermore, unlike complex I, CoQ receives electrons directly from the electron-transferring flavoprotein, and this is unrelated to proton pumping or mitochondrial membrane potential, relying only on the availability of oxidized CoQ. Reduced CoQ accumulates, causing reductive stress in complex I, complex II and other dehydrogenases that feed electrons into the CoQ pool, resulting in increased ROS production [195]. As a result, lowering the total CoQ pool [44] will most likely lower the ROS production threshold at a given energy demand-supply ratio. It is also worth noting that FFA oxidation produces far more ROS than carbohydrate oxidation [195]. This is because the electron-transferring flavoprotein feeds a higher proportion of reducing equivalents straight into the CoQ pool during FFA oxidation. Therefore, as lipid metabolism increases, the supply of reducing equivalents outnumbers the demand, lowering the ratio of oxidized to reduced CoQ. This is likely worsened when total CoQ levels are low, as seen in IR [44], resulting in reductive stress and increased ROS production. The mechanism that regulates CoQ levels in IR is unknown. Intriguingly, statins, which are commonly used as cholesterol-lowering drugs, have been linked to IR in humans [196], with the possibility that this relationship is related to the statin-induced reductions in CoQ biosynthesis [44]. Unfortunately, given the low bioavailability of CoQ , oral supplements, which are frequently recommended as an antioxidant strategy, are unlikely to be successful in replenishing the mitochondrial CoQ pool in patients with IR or even in individuals who take statins. Other hazardous intermediates can be generated, in addition to ROS, as a result of mitochondrial respiration abnormalities. Acylcarnitine is an example of incompletely oxidized lipids produced by lipid overload. Acylcarnitine has been reported to accumulate in IR, indicating a deficiency in or an overabundance of the mitochondrial oxidative ability. In this regard, it has been postulated that lipid-induced mitochondrial stress mediates IR, although the exact mechanisms remain elusive [197].
12.4 Insulin resistance associated with stress pathway
Many of the pathways involved in IR pathophysiology, such as those involving ceramides, DAGs or ROS, are now being linked as part of what we call an “intracellular IR stress pathway”, according to new evidence. Ceramide, for example, promotes mitochondrial fission and ROS production [198, 199]. In subjects with IR, the quantity of mitochondrial ceramide is higher, and enzymes involved in ceramide biosynthesis have been found in mitochondria [185, 200, 201, 202, 203]. Ceramide is involved in apoptosis triggered by mitochondria in some cells, including insulin-producing pancreatic beta cells, but not in other metabolic tissues [204, 205, 206]. Ceramide also contributes to endoplasmic reticulum stress, which frequently co-occurs with mitochondrial stress and has been proposed as a driver of IR, where endoplasmic reticulum stress causes JNK activation, which, as previously described, affects the insulin signaling pathway via inhibitory IRS1 Ser/Thr phosphorylation [204, 205, 206]. Ceramide also induces PKC, a DAG-regulated kinase, to translocate to mitochondria, activating it and causing mitochondrial damage through an unknown mechanism [207]. Ceramides and DAGs are also biochemically connected; sphingomyelin synthase, for example, converts ceramide to DAG. Finally, in rats, reducing mitochondrial ROS levels with mitochondria-targeted catalase improved insulin sensitivity while lowering muscle DAG levels [208]. The potential connection of many of these suspected IR-causing elements into a dynamic network should help to resolve some of the current debates on this topic.
12.5 Signals from the mitochondria
Despite the interest in mitochondrial dysfunction in IR, it is unclear how intramitochondrial signals, like ceramide or ROS, may cause changes in insulin action, such as impaired GLUT4 translocation, which occurs mostly in the cytosol. The mitochondrial permeability transition pore (mPTP), a multiprotein complex located in the inner mitochondrial membrane, is a promising candidate for “inside-out” mitochondrial signaling because it opens under conditions of mitochondrial stress—most notably involving mitochondrial ROS—to allow molecules to be transported from mitochondria to the cytoplasm [209]. In L6 myotubes, inhibiting mPTP prevented ceramide- or palmitate-induced IR, and mice with defective mPTP opening were protected from diet-induced IR in skeletal muscle [210]. Although at least a part of the impact is attributable to its anti-obesogenic effect, deletion of mPTP in the liver has been shown to protect mice from liver steatosis and IR [211].
13. Conclusions and perspectives
The rising frequency of IR, as well as its crucial involvement in a variety of diseases, demands a greater understanding of the processes behind IR pathogenesis and how they interact with genetics and various surroundings, notably dietary factors. We have attempted to offer an overview of the main mechanisms hypothesized to contribute to IR in this chapter, highlighting both supportive and non-confirmatory evidence when appropriate. Many of the molecules and processes studied as causative in IR, in our opinion, function in series as a connected pathway or a loop rather than acting independently. Unfortunately, there has been a recent trend to describe IR as a dysfunction of insulin signaling, regardless of whether a simultaneous examination of insulin action on glucose metabolism has identified a defect in the latter process. We feel that this method has produced significant problems in the field, and we wish to send a message that simple, unitary errors in proximal insulin signaling are unlikely to be a major cause of IR. Rather, IR develops as a result of a variety of challenges that disrupt cellular homeostasis, resulting in cellular stress that can have a variety of deleterious consequences on insulin signal sensing and transmission.
The difficulty in translating findings from model organisms to humans, particularly in terms of differentiating IR causation from the multiplicity of effects, is a key roadblock in investigating the underpinnings of IR. By discovering causal genetic variants, human genetics holds a lot of promise for tackling this problem. However, genetics can only explain a portion of the pathophysiology of IR. Environmental variables play a crucial role in determining susceptibility to IR development and interact with genetics. Furthermore, the heterogeneity of metabolic diseases like T2D demands detailed phenotyping. Focusing on phenotypes that has better track with IR has proven difficult to achieve in the large cohorts. It is required to identify genetic polymorphisms that only explain a small proportion of disease in the human population. Despite these limitations, a number of genetic loci linked to human IR have been discovered, leading to a renewed focus on adipose tissue enlargement as a critical aspect of IR. However, since IR is a systemic condition, we expect future investigations to discover variations in genes governing multiple cellular processes throughout organs as linked to IR pathophysiology.
A more systematic approach involving large-scale omics to analyze the molecular landscape rather than relying on individual components as causal would be required to gain a better understanding of IR. Moreover, while knockout mice have been critical in characterizing the biochemistry of insulin action, they have also sparked numerous debates. One reason for this is that gene deletions typically result in adaptive processes that are difficult to define and may have limited physiological value, as indicated in a recent study with muscle-specific Akt gene-knockout mice [58]. In animals with both insulin and insulin-like growth factor 1 (IGF-1) receptors removed in muscle, similar adaptation mechanisms have been reported [212].
The ultimate goal of understanding mechanisms behind IR is to develop new, effective anti-IR therapeutic strategies. One key point to consider in this endeavor is whether such therapies would be beneficial if the initial insult—nutritional overload—persists. While IR is typically considered abnormal, as it is linked to a variety of disease outcomes, it is also a prevalent component of many normal physiological states, such as starvation, pregnancy, and hibernation. IR is believed to play a protective or adaptive role in such conditions, supporting survival by saving glucose for the brain and other vital tissues and organs or for the fetus during pregnancy. It is possible that IR has a similar function in metabolic disease. Since the primary metabolic tissues are frequently exposed to potentially harmful quantities of nutrients, IR could be a protective mechanism that helps to prevent tissue nutrition overload [190]. However, this comes at a price, namely concomitant hyperinsulinemia, which is the most serious pathophysiological consequence of IR. Insulin-sensitizing drugs may thus act as a “circuit breaker”, reducing hunger, inflammation and IR by suppressing hyperinsulinemia. As a result, we believe there is still a strong need to describe the molecular characteristics that drive IR in order to identify appropriate targets that can break the IR vicious cycle.
Acknowledgments
The authors are also thankful to Guru Nanak Dev University (Amritsar, Punjab, India) for providing various facilities to carry out the present work.
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"insulin, insulin receptor, insulin resistance, glucose uptake, glucose metabolism",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/82197.pdf",chapterXML:"https://mts.intechopen.com/source/xml/82197.xml",downloadPdfUrl:"/chapter/pdf-download/82197",previewPdfUrl:"/chapter/pdf-preview/82197",totalDownloads:7,totalViews:0,totalCrossrefCites:0,dateSubmitted:"December 13th 2021",dateReviewed:"April 4th 2022",datePrePublished:"June 11th 2022",datePublished:null,dateFinished:"June 11th 2022",readingETA:"0",abstract:"Insulin resistance (IR) is a condition in which insulin-mediated regulation of glucose metabolism in body tissues (primarily liver, adipose tissue and skeletal muscle) becomes disrupted. IR is a characteristic marker of type 2 diabetes and cardiovascular diseases. IR is generally associated with metabolic abnormalities, including hyperinsulinemia, impaired glucose homeostasis, hyperlipidemia and obesity. IR can arise from pathological, genetic and environmental factors or from a combination of these factors. Studies conducted in recent decades showcase the important role of adipose tissue in the development of IR via release of lipids and different circulating factors. These extracellular factors influence the intracellular levels of intermediates including ceramide and various lipids that influence the cell responsiveness to insulin. These intermediates are suggested to promote IR via inhibition of one or more components of insulin signaling pathway (e.g., insulin receptor, insulin receptor substrate proteins). This chapter will shed light on various molecular mechanisms and factors contributing to IR, which will help the researchers to design potential therapeutic strategies and interventions for efficiently managing IR and its related disorders.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/82197",risUrl:"/chapter/ris/82197",signatures:"Atamjit Singh, Nikhita Ghai and PreetMohinder Singh Bedi",book:{id:"11261",type:"book",title:"Insulin Resistance - Evolving Concepts and Treatment Strategies",subtitle:null,fullTitle:"Insulin Resistance - Evolving Concepts and Treatment Strategies",slug:null,publishedDate:null,bookSignature:"Dr. Marco Infante",coverURL:"https://cdn.intechopen.com/books/images_new/11261.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-502-7",printIsbn:"978-1-80355-501-0",pdfIsbn:"978-1-80355-503-4",isAvailableForWebshopOrdering:!0,editors:[{id:"409412",title:"Dr.",name:"Marco",middleName:null,surname:"Infante",slug:"marco-infante",fullName:"Marco Infante"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Pathway to insulin resistance",level:"1"},{id:"sec_3",title:"3. The trio-axis of obesity-hyperinsulinemia-insulin resistance",level:"1"},{id:"sec_4",title:"4. Insulin resistance and hyperinsulinemia",level:"1"},{id:"sec_5",title:"5. Heterogeneity in the development of insulin resistance and progression of metabolic disease and T2D",level:"1"},{id:"sec_6",title:"6. Tissue-specific progression to insulin resistance",level:"1"},{id:"sec_7",title:"7. Impaired insulin signaling in insulin resistance",level:"1"},{id:"sec_8",title:"8. Insulin resistance and insulin signaling at the proximal level",level:"1"},{id:"sec_9",title:"9. GLUT4 and insulin resistance",level:"1"},{id:"sec_10",title:"10. Adipose tissue and insulin resistance",level:"1"},{id:"sec_10_2",title:"10.1 Adipose tissue dysfunction",level:"2"},{id:"sec_11_2",title:"10.2 Circulatory factors released from adipocytes",level:"2"},{id:"sec_13",title:"11. Inflammation and insulin resistance",level:"1"},{id:"sec_14",title:"12. Intracellular mediators and insulin resistance",level:"1"},{id:"sec_14_2",title:"12.1 Accumulation of ceramides",level:"2"},{id:"sec_15_2",title:"12.2 Accumulation of diacylglycerol (DAG)",level:"2"},{id:"sec_16_2",title:"12.3 Mitochondrial dysfunction and reactive oxygen species (ROS)",level:"2"},{id:"sec_17_2",title:"12.4 Insulin resistance associated with stress pathway",level:"2"},{id:"sec_18_2",title:"12.5 Signals from the mitochondria",level:"2"},{id:"sec_20",title:"13. Conclusions and perspectives",level:"1"},{id:"sec_21",title:"Acknowledgments",level:"1"},{id:"sec_24",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Himsworth HP. Diabetes mellitus: Its differentiation into insulin-sensitive and insulin-insensitive types. 1936. International Journal of Epidemiology. 2013;42:1594-1598'},{id:"B2",body:'Jee SH, Kim HJ, Lee J. Obesity, insulin resistance and cancer risk. 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Examination of ‘lipotoxicity’ in skeletal muscle of high-fat fed 0. The Journal of Physiology. 2009;587:1593-1605'},{id:"B204",body:'Kim Y-R et al. Hepatic triglyceride accumulation via endoplasmic reticulum stress-induced SREBP-1 activation is regulated by ceramide synthases. Experimental & Molecular Medicine. 2019;51:1-16'},{id:"B205",body:'Boslem E et al. A lipidomic screen of palmitate-treated MIN6 β-cells links sphingolipid metabolites with endoplasmic reticulum (ER) stress and impaired protein trafficking. The Biochemical Journal. 2011;435:267-276'},{id:"B206",body:'Flamment M, Hajduch E, Ferré P, Foufelle F. New insights into ER stress-induced insulin resistance. Trends in Endocrinology and Metabolism. 2012;23:381-390'},{id:"B207",body:'Sumitomo M et al. Protein kinase Cdelta amplifies ceramide formation via mitochondrial signaling in prostate cancer cells. The Journal of Clinical Investigation. 2002;109:827-836'},{id:"B208",body:'Lee H-Y et al. Mitochondrial-targeted catalase protects against high-fat diet-induced muscle insulin resistance by decreasing intramuscular lipid accumulation. Diabetes. 2017;66:2072-2081'},{id:"B209",body:'Riojas-Hernández A et al. Enhanced oxidative stress sensitizes the mitochondrial permeability transition pore to opening in heart from Zucker fa/fa rats with type 2 diabetes. Life Sciences. 2015;141:32-43'},{id:"B210",body:'Taddeo EP et al. Opening of the mitochondrial permeability transition pore links mitochondrial dysfunction to insulin resistance in skeletal muscle. Molecular Metabolism. 2014;3:124-134'},{id:"B211",body:'Cho J et al. Mitochondrial ATP transporter depletion protects mice against liver steatosis and insulin resistance. Nature Communications. 2017;8:14477'},{id:"B212",body:'O’Neill BT et al. Differential role of insulin/IGF-1 receptor signaling in muscle growth and glucose homeostasis. Cell Reports. 2015;11:1220-1235'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Atamjit Singh",address:null,affiliation:'
Department of Pharmaceutical Sciences, Guru Nanak Dev University, India
Department of Pharmaceutical Sciences, Guru Nanak Dev University, India
Drug and Pollution Testing Lab, Guru Nanak Dev University, India
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The model parameters deciphered here are the amplitude coefficient (k), horizontal location (x0), depth of the body (z), and shape (q). Inversion of the model parameter suggests that constraining the horizontal location and the shape factor offers the most reliable results. Investigation of convergence rate, histogram, and cross-plot examination suggest that the interpretation method developed for the self-potential anomalies is stable and the model parameters are within the estimated ambiguity. Inversion of synthetic noise-free and noise-corrupted data for single structures and multiple structures in addition to real field information exhibits the viability of the method. The model parameters estimated by the present technique were in good agreement with the real parameters. The method has been used to invert two field examples (Sulleymonkoy anomaly, Ergani, Turkey, Senneterre area of Quebec, Canada) with application of subsurface mineralized bodies. This technique can be very much helpful for mineral or ore bodies investigation of idealized geobodies buried within the shallow and deeper subsurface.",book:{id:"7315",slug:"minerals",title:"Minerals",fullTitle:"Minerals"},signatures:"Arkoprovo Biswas",authors:[{id:"250390",title:"Dr.",name:"Arkoprovo",middleName:null,surname:"Biswas",slug:"arkoprovo-biswas",fullName:"Arkoprovo Biswas"}]},{id:"71052",doi:"10.5772/intechopen.90880",title:"Enhanced Humidity Sensing Response in Eu3+-Doped Iron-Rich CuFe2O4: A Detailed Study of Structural, Microstructural, Sensing, and Dielectric Properties",slug:"enhanced-humidity-sensing-response-in-eu-sup-3-sup-doped-iron-rich-cufe-sub-2-sub-o-sub-4-sub-a-deta",totalDownloads:596,totalCrossrefCites:7,totalDimensionsCites:7,abstract:"The CuFe(2−x)EuxO4 (where x = 0.00, 0.01, 0.02, 0.03) nanoparticles are synthesized by solution combustion method. The influence of Eu3+ on the structural, morphological, dielectrical, and humidity sensing study is recorded. The XRD pattern peaks of the as-prepared CuFe(2−x)EuxO4 (where x = 0.00, 0.01, 0.02, 0.03) nanoparticle confirm the polycrystalline spinel cubic structure with a small amount of CuO impurity phase at 38.87° and 48.96°. Surface morphology of the samples was studied by scanning electron microscope (SEM) images of the nanoparticles, and their respective average grain size was estimated using Image software. Chemical composition of all prepared samples was analyzed by EDS spectra. The dielectric parameters of AC conductivity, electric modulus, and impedance of the samples were measured over a range of frequencies from 0.1 KHz to 1 MHz at room temperature. Europium-doped copper ferrite samples showed good humidity sensing response, response and recover times, and stability over a %RH range of 11–91%. These types of samples are very useful for sensor application, battery applications, electronic applications, and automotive applications.",book:{id:"9247",slug:"mineralogy-significance-and-applications",title:"Mineralogy",fullTitle:"Mineralogy - Significance and Applications"},signatures:"I.C. Sathisha, K. Manjunatha, V. Jagadeesha Angadi, B. Chethan, Y.T. Ravikiran, Vinayaka K. Pattar, S.O. Manjunatha and Shidaling Matteppanavar",authors:[{id:"266255",title:"Dr.",name:"Veerabhadrappa",middleName:null,surname:"Jagadeesha Angadi",slug:"veerabhadrappa-jagadeesha-angadi",fullName:"Veerabhadrappa Jagadeesha Angadi"},{id:"321561",title:"Dr.",name:"I.C.",middleName:null,surname:"Sathisha",slug:"i.c.-sathisha",fullName:"I.C. Sathisha"},{id:"321562",title:"Dr.",name:"K.",middleName:null,surname:"Manjunatha",slug:"k.-manjunatha",fullName:"K. Manjunatha"},{id:"321564",title:"Dr.",name:"B.",middleName:null,surname:"Chethan",slug:"b.-chethan",fullName:"B. Chethan"},{id:"321565",title:"Dr.",name:"Y.T.",middleName:null,surname:"Ravikiran",slug:"y.t.-ravikiran",fullName:"Y.T. Ravikiran"},{id:"321566",title:"Dr.",name:"Vinayaka K.",middleName:null,surname:"Pattar",slug:"vinayaka-k.-pattar",fullName:"Vinayaka K. Pattar"},{id:"321567",title:"Dr.",name:"S.O.",middleName:null,surname:"Manjunatha",slug:"s.o.-manjunatha",fullName:"S.O. Manjunatha"},{id:"321568",title:"Dr.",name:"Shidaling",middleName:null,surname:"Matteppanavar",slug:"shidaling-matteppanavar",fullName:"Shidaling Matteppanavar"}]},{id:"27435",doi:"10.5772/34861",title:"A Review of Pathological Biomineral Analysis Techniques and Classification Schemes",slug:"a-review-of-pathological-biomineral-analysis-techniques-and-classification-schemes",totalDownloads:4303,totalCrossrefCites:1,totalDimensionsCites:6,abstract:null,book:{id:"1600",slug:"an-introduction-to-the-study-of-mineralogy",title:"An Introduction to the Study of Mineralogy",fullTitle:"An Introduction to the Study of Mineralogy"},signatures:"Maria Luigia Giannossi and Vito Summa",authors:[{id:"101919",title:"PhD.",name:"Maria Luigia",middleName:null,surname:"Giannossi",slug:"maria-luigia-giannossi",fullName:"Maria Luigia Giannossi"},{id:"108348",title:"Dr.",name:"Vito",middleName:null,surname:"Summa",slug:"vito-summa",fullName:"Vito Summa"}]},{id:"68162",doi:"10.5772/intechopen.87260",title:"A Review of the Role of Natural Clay Minerals as Effective Adsorbents and an Alternative Source of Minerals",slug:"a-review-of-the-role-of-natural-clay-minerals-as-effective-adsorbents-and-an-alternative-source-of-m",totalDownloads:992,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"The minerals with unique properties such as natural clay minerals (NCMs) have promising approach in environmental and industrial sphere. In fact, under some specific conditions the NCMs could be used either as effective adsorbent material or alternative source of minerals. This chapter presents an outline of a general review of factors that affect the application ability of NCMs and a descriptive analysis of NH4+ and REE adsorption behavior and extraction of rare earth elements (REE) by an ion-exchange with NH4+ ions onto NCMs. Clays and NCMs both effectively remove various contaminants from aqueous solution and serve as alternative sources of minerals, as extensively discussed in this chapter. This review compiles thorough literature of current research and highlights the key findings of adsorption (NH4+ and REE) that use different NCMs as adsorbents or alternative sources of minerals (i.e., REE). The review confirmed that NCMs excellently remove different cations pollutants and have significant potential as alternative source of REE. However, modification and further development of NCMs applications for getting the best adsorption and the best extraction of REE onto NCMs, which would enhance pollution control and leaching system is still needed.",book:{id:"7315",slug:"minerals",title:"Minerals",fullTitle:"Minerals"},signatures:"Aref Alshameri, Xinghu Wei, Hailong Wang, Yang Fuguo, Xin Chen, Hongping He, Chunjie Yan and Feng Xu",authors:[{id:"172947",title:"Prof.",name:"Xin",middleName:null,surname:"Chen",slug:"xin-chen",fullName:"Xin Chen"},{id:"250327",title:"Dr.",name:"Aref",middleName:null,surname:"Alshameri",slug:"aref-alshameri",fullName:"Aref Alshameri"},{id:"306625",title:"Dr.",name:"Aref",middleName:null,surname:"Alshameri",slug:"aref-alshameri",fullName:"Aref Alshameri"},{id:"306656",title:"Prof.",name:"Fuguo",middleName:null,surname:"Yang",slug:"fuguo-yang",fullName:"Fuguo Yang"},{id:"306658",title:"Dr.",name:"Wei",middleName:null,surname:"Xinghu",slug:"wei-xinghu",fullName:"Wei Xinghu"},{id:"306660",title:"Prof.",name:"Wang",middleName:null,surname:"Hailong",slug:"wang-hailong",fullName:"Wang Hailong"},{id:"306664",title:"Prof.",name:"Yan",middleName:null,surname:"Chunjie",slug:"yan-chunjie",fullName:"Yan Chunjie"},{id:"306665",title:"Dr.",name:"Xu",middleName:null,surname:"Feng",slug:"xu-feng",fullName:"Xu Feng"},{id:"306671",title:"Prof.",name:"He",middleName:null,surname:"Hongping",slug:"he-hongping",fullName:"He Hongping"}]}],mostDownloadedChaptersLast30Days:[{id:"71052",title:"Enhanced Humidity Sensing Response in Eu3+-Doped Iron-Rich CuFe2O4: A Detailed Study of Structural, Microstructural, Sensing, and Dielectric Properties",slug:"enhanced-humidity-sensing-response-in-eu-sup-3-sup-doped-iron-rich-cufe-sub-2-sub-o-sub-4-sub-a-deta",totalDownloads:596,totalCrossrefCites:7,totalDimensionsCites:7,abstract:"The CuFe(2−x)EuxO4 (where x = 0.00, 0.01, 0.02, 0.03) nanoparticles are synthesized by solution combustion method. The influence of Eu3+ on the structural, morphological, dielectrical, and humidity sensing study is recorded. The XRD pattern peaks of the as-prepared CuFe(2−x)EuxO4 (where x = 0.00, 0.01, 0.02, 0.03) nanoparticle confirm the polycrystalline spinel cubic structure with a small amount of CuO impurity phase at 38.87° and 48.96°. Surface morphology of the samples was studied by scanning electron microscope (SEM) images of the nanoparticles, and their respective average grain size was estimated using Image software. Chemical composition of all prepared samples was analyzed by EDS spectra. The dielectric parameters of AC conductivity, electric modulus, and impedance of the samples were measured over a range of frequencies from 0.1 KHz to 1 MHz at room temperature. Europium-doped copper ferrite samples showed good humidity sensing response, response and recover times, and stability over a %RH range of 11–91%. These types of samples are very useful for sensor application, battery applications, electronic applications, and automotive applications.",book:{id:"9247",slug:"mineralogy-significance-and-applications",title:"Mineralogy",fullTitle:"Mineralogy - Significance and Applications"},signatures:"I.C. Sathisha, K. Manjunatha, V. Jagadeesha Angadi, B. Chethan, Y.T. Ravikiran, Vinayaka K. Pattar, S.O. Manjunatha and Shidaling Matteppanavar",authors:[{id:"266255",title:"Dr.",name:"Veerabhadrappa",middleName:null,surname:"Jagadeesha Angadi",slug:"veerabhadrappa-jagadeesha-angadi",fullName:"Veerabhadrappa Jagadeesha Angadi"},{id:"321561",title:"Dr.",name:"I.C.",middleName:null,surname:"Sathisha",slug:"i.c.-sathisha",fullName:"I.C. Sathisha"},{id:"321562",title:"Dr.",name:"K.",middleName:null,surname:"Manjunatha",slug:"k.-manjunatha",fullName:"K. Manjunatha"},{id:"321564",title:"Dr.",name:"B.",middleName:null,surname:"Chethan",slug:"b.-chethan",fullName:"B. Chethan"},{id:"321565",title:"Dr.",name:"Y.T.",middleName:null,surname:"Ravikiran",slug:"y.t.-ravikiran",fullName:"Y.T. Ravikiran"},{id:"321566",title:"Dr.",name:"Vinayaka K.",middleName:null,surname:"Pattar",slug:"vinayaka-k.-pattar",fullName:"Vinayaka K. Pattar"},{id:"321567",title:"Dr.",name:"S.O.",middleName:null,surname:"Manjunatha",slug:"s.o.-manjunatha",fullName:"S.O. Manjunatha"},{id:"321568",title:"Dr.",name:"Shidaling",middleName:null,surname:"Matteppanavar",slug:"shidaling-matteppanavar",fullName:"Shidaling Matteppanavar"}]},{id:"65826",title:"Introductory Chapter: Mineral Exploration from the Point of View of Geophysicists",slug:"introductory-chapter-mineral-exploration-from-the-point-of-view-of-geophysicists",totalDownloads:1635,totalCrossrefCites:3,totalDimensionsCites:3,abstract:null,book:{id:"7315",slug:"minerals",title:"Minerals",fullTitle:"Minerals"},signatures:"Khalid S. Essa and Marc Munschy",authors:[{id:"102766",title:"Prof.",name:"Khalid S.",middleName:null,surname:"Essa",slug:"khalid-s.-essa",fullName:"Khalid S. Essa"},{id:"292929",title:"Prof.",name:"Marc",middleName:null,surname:"Munschy",slug:"marc-munschy",fullName:"Marc Munschy"}]},{id:"69811",title:"Chemical Synthesis and Characterization of Luminescent Iron Oxide Nanoparticles and Their Biomedical Applications",slug:"chemical-synthesis-and-characterization-of-luminescent-iron-oxide-nanoparticles-and-their-biomedical",totalDownloads:564,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The syntheses and characterizations of biocompatible luminescent magnetic iron oxide nanoparticles has drawn particular attention as diagnostic and drug delivery tools for treatment of cancer and many other diseases. This chapter focuses on the chemical synthetic methods, magnetic and luminescent properties, including the biomedical applications of iron oxide nanomaterials and luminescent magnetic iron oxide-based nanocomposite materials. The influences of functionalizing with short ligands such as dopamine and L-cysteine on the magnetic properties of synthesized nanoparticles are described. The chapter contains some data on necessary reagents and protocols for bioconjugation aimed at cell culture and step by step the MTT assays used to evaluate cytotoxicity are also presented. In the final section of the chapter, we focus on the biomedical applications specifically for diagnosis and treatment of breast cancer treatment. This chapter also investigates the application of various characterization techniques for analysis of the structural, optical and magnetic properties of the iron oxide nanoparticles and as their nanocomposites.",book:{id:"9247",slug:"mineralogy-significance-and-applications",title:"Mineralogy",fullTitle:"Mineralogy - Significance and Applications"},signatures:"Martin Onani, Leandre Brandt and Zuraan Paulsen",authors:[{id:"258023",title:"Dr.",name:"Martin",middleName:null,surname:"Onani",slug:"martin-onani",fullName:"Martin Onani"},{id:"302723",title:"Dr.",name:"Leandré Bianca",middleName:null,surname:"Brandt",slug:"leandre-bianca-brandt",fullName:"Leandré Bianca Brandt"},{id:"302725",title:"MSc.",name:"Zuraan",middleName:null,surname:"Paulsen",slug:"zuraan-paulsen",fullName:"Zuraan Paulsen"}]},{id:"27429",title:"An Introduction to Mineralogy",slug:"an-introduction-to-mineralogy",totalDownloads:6621,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"1600",slug:"an-introduction-to-the-study-of-mineralogy",title:"An Introduction to the Study of Mineralogy",fullTitle:"An Introduction to the Study of Mineralogy"},signatures:"Cumhur Aydinalp",authors:[{id:"98959",title:"Prof.",name:"Cumhur",middleName:"---",surname:"Aydinalp",slug:"cumhur-aydinalp",fullName:"Cumhur Aydinalp"}]},{id:"27435",title:"A Review of Pathological Biomineral Analysis Techniques and Classification Schemes",slug:"a-review-of-pathological-biomineral-analysis-techniques-and-classification-schemes",totalDownloads:4303,totalCrossrefCites:1,totalDimensionsCites:6,abstract:null,book:{id:"1600",slug:"an-introduction-to-the-study-of-mineralogy",title:"An Introduction to the Study of Mineralogy",fullTitle:"An Introduction to the Study of Mineralogy"},signatures:"Maria Luigia Giannossi and Vito Summa",authors:[{id:"101919",title:"PhD.",name:"Maria Luigia",middleName:null,surname:"Giannossi",slug:"maria-luigia-giannossi",fullName:"Maria Luigia Giannossi"},{id:"108348",title:"Dr.",name:"Vito",middleName:null,surname:"Summa",slug:"vito-summa",fullName:"Vito Summa"}]}],onlineFirstChaptersFilter:{topicId:"651",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81626",title:"Use of Natural Safiot Clay for the Removal of Chemical Substances from Aqueous Solutions by Adsorption: A Combined Experimental and Theoretical Study",slug:"use-of-natural-safiot-clay-for-the-removal-of-chemical-substances-from-aqueous-solutions-by-adsorpti",totalDownloads:24,totalDimensionsCites:0,doi:"10.5772/intechopen.101605",abstract:"The main objective of this work was to investigate the potential of Natural Safiot Clay (NSC), as an adsorbent for the removal of two cationic dyes such as Basic Blue 9 (BB9) and Basic Yellow 28 (BY28) from single and binary systems in aqueous solutions. For this, the effects of three factors controlling the adsorption process, such as initial dye concentration, adsorbent dose, and initial pH on the adsorption extent, were investigated and examined. The natural safiot clay was characterized using the following technique: energy-dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM), DRX, and Fourier transform infrared (FT-IR) and pH of the point of zero charge (pHZPC). Energy-dispersive X-ray spectroscopy results indicate high percentages of Silica and Alumina. FT-IR spectrum identified kaolinite as the major mineral phase in the presence of quartz, calcite, and dolomite. The quantum theoretical study confirms the experimental results, through the study of the global and local reactivity and the electrophilicity power of the dyes. The electrophilicity power of dyes affects the removal efficiency. The theoretical study proves that BB9 (ω = 6.178) is more electrophilic than BY28 (ω = 2.480) and more interactions with surface sites. The results of the molecular dynamics simulation indicate that the dyes are adsorbed parallel to the surface of natural Safi clay (kaolinite), implying the strong interaction with the kaolinite atoms. All the results of quantum chemistry calculations and simulations of molecular dynamics are in perfect agreement with the results of the experimental study.",book:{id:"11137",title:"Mineralogy",coverURL:"https://cdn.intechopen.com/books/images_new/11137.jpg"},signatures:"Aziz El Kassimi, Mohammadine El Haddad, Rachid Laamari, Mamoune El Himri, Youness Achour and Hicham Yazid"},{id:"80866",title:"Normative Mineralogy Especially for Shales, Slates, and Phyllites",slug:"normative-mineralogy-especially-for-shales-slates-and-phyllites",totalDownloads:44,totalDimensionsCites:0,doi:"10.5772/intechopen.102346",abstract:"First, an insight into normative mineralogy and the most important methods for calculating the standard or norm minerals, such as the CIPW norm, is given. This is followed by a more detailed explanation of “slatenorm” and “slatecalculation” for low and very low metamorphic rocks, such as phyllites, slates, and shales. They are particularly suitable for fine-grained rocks where the mineral content is difficult to determine. They enable the determination of a virtual mineral inventory from full chemical analysis, including the values of carbon dioxide (CO2), carbon (C), and sulfur (S). The determined norm or standard minerals include the minerals—feldspars, carbonates, micas, hydro-micas, chlorites, ore minerals, and quartz. The advantages of slatenorm and slatecalculation compared to other methods for calculating normal minerals of sedimentary rocks are discussed.",book:{id:"11137",title:"Mineralogy",coverURL:"https://cdn.intechopen.com/books/images_new/11137.jpg"},signatures:"Hans Wolfgang Wagner"},{id:"80770",title:"Mg-Ilmenite from Kimberlites, Its Origin",slug:"mg-ilmenite-from-kimberlites-its-origin",totalDownloads:57,totalDimensionsCites:0,doi:"10.5772/intechopen.102676",abstract:"The main regularities of the saturation of kimberlite rocks with the accessory mineral Mg-ilmenite (Ilm), the peculiarities of the distribution of Ilm compositions in individual pipes, in different clusters of pipes, in diamondiferous kimberlite fields, are considered as the example of studies carried out within the Yakutian kimberlite province (Siberian Craton). Interpretation of different crystallization trends in MgO-Cr2O3 coordinates (conventionally named “Haggerty’s parabola”, “Steplike”, “Hockey stick”, as well as the peculiarities of heterogeneity of individual zonal and polygranular Ilm macrocrysts made it possible to propose a three-stage model of crystallization Ilm: (1) Mg-Cr poor ilmenite crystallizing from a primitive asthenospheric melt; (2) Continuing crystallization in the lithospheric contaminated melt by MgO and Cr2O3; (3) Ilmenite subsequently underwent sub-solidus recrystallization in the presence of an evolved kimberlite melt under increasing oxygen fugacity (ƒO2) conditions.",book:{id:"11137",title:"Mineralogy",coverURL:"https://cdn.intechopen.com/books/images_new/11137.jpg"},signatures:"Sergey I. Kostrovitsky"},{id:"80553",title:"Investigation of Accessory Minerals from the Blatná Granodiorite Suite, Bohemian Massif, Czech Republic",slug:"investigation-of-accessory-minerals-from-the-blatn-granodiorite-suite-bohemian-massif-czech-republic",totalDownloads:48,totalDimensionsCites:0,doi:"10.5772/intechopen.102628",abstract:"The Central Bohemian magmatic complex belongs to the Central European Variscan belt. The granitic rocks of this plutonic complex are formed by several suites of granites, granodiorites, and tonalites, together with small bodies of gabbros, gabbro diorites, and diorites. The granodiorites of the Blatná suite are high-K, calc-alkaline to shoshonitic, and metaluminous to slightly peraluminous granitic rocks. Compared to the common I-type granites, granodiorites of the Blatná suite are enriched in Mg (1.0–3.4 wt.% MgO), Ba (838–2560 ppm), Sr. (257–506 ppm), and Zr (81–236 ppm). For granodiorites of the Blatná suite is assemblage of apatite, zircon, titanite, and allanite significant. Zircon contains low Hf concentrations (1.1–1.7 wt.% HfO2). The composition of titanite ranges from 83 to 92 mol.% titanite end-member. Allanite is relatively Al-poor and displays Feox. ratio 0.2–0.5.",book:{id:"11137",title:"Mineralogy",coverURL:"https://cdn.intechopen.com/books/images_new/11137.jpg"},signatures:"Miloš René"},{id:"80423",title:"Minerals as Prebiotic Catalysts for Chemical Evolution towards the Origin of Life",slug:"minerals-as-prebiotic-catalysts-for-chemical-evolution-towards-the-origin-of-life",totalDownloads:106,totalDimensionsCites:0,doi:"10.5772/intechopen.102389",abstract:"A transition from geochemistry to biochemistry has been considered as a necessary step towards the emergence of primordial life. Nevertheless, how did this transition occur is still elusive. The chemistry underlying this transition is likely not a single event, but involves many levels of creation and reconstruction, finally reaching the molecular, structural, and functional buildup of complexity. Among them, one apparent question is: how the biochemical catalytic system emerged from the mineral-based geochemical system? Inspired by the metal–ligand structures in metalloenzymes, many researchers have proposed that transition metal sulfide minerals could have served as structural analogs of metalloenzymes for catalyzing prebiotic redox conversions. This assumption has been tested and verified to some extent by several studies, which focused on using Earth-abundant transition metal sulfides as catalysts for multi-electron C and N conversions. The progress in this field will be introduced, with a focus on the CO2 fixation and ammonia synthesis from nitrate/nitrite reduction and N2 reduction. Recently developed methods for screening effective mineral catalysts were also reviewed.",book:{id:"11137",title:"Mineralogy",coverURL:"https://cdn.intechopen.com/books/images_new/11137.jpg"},signatures:"Yamei Li"},{id:"80338",title:"Ionic Conductivity of Strontium Fluoroapatites Co-doped with Lanthanides",slug:"ionic-conductivity-of-strontium-fluoroapatites-co-doped-with-lanthanides",totalDownloads:54,totalDimensionsCites:0,doi:"10.5772/intechopen.102410",abstract:"Britholites derivatives of apatite’s that contain lanthanium and neodymium in the serial compounds Sr8La2−xNdx(PO4)4(SiO4)2F2 with 0 ≤ x ≤ 2 were subject of the present investigation. The solid state reaction was the route of preparing these materials. Several techniques were employed for the analysis and characterization of the synthesized powders. The chemical analysis results indicated that molar ratio Sr+La+NdP+Si was of about 1.67 value of a stoichiometric powder. The X-ray diffraction data showed single-phase apatites crystallizing in hexagonal structure with P63/m space group were successively obtained. Moreover, the substitution of lanthanium by neodymium in strontium phosphosilicated fluorapatite was total. This was confirmed by the a and c lattice parameters contraction when (x) varies coherently to the sizes of the two cations. The infrared spectroscopy and the 31P NMR (MAS) exhibited the characteristic bands of phosphosilicated fluorapatite. The pressureless sintering of the material achieved a maximum of 89% relative density. The sintered specimens indicated that the Nd content as well as the heating temperature affected the ionic conduction of the materials and the maximum was 1.73 × 10−6 S cm−1 obtained at 1052 K for x = 2.",book:{id:"11137",title:"Mineralogy",coverURL:"https://cdn.intechopen.com/books/images_new/11137.jpg"},signatures:"Khouloud Kthiri, Mohammed Mehnaoui, Samira Jebahi, Khaled Boughzala and Mustapha Hidouri"}],onlineFirstChaptersTotal:10},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 29th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:32,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:36,paginationItems:[{id:"82195",title:"Endoplasmic Reticulum: A Hub in Lipid Homeostasis",doi:"10.5772/intechopen.105450",signatures:"Raúl Ventura and María Isabel Hernández-Alvarez",slug:"endoplasmic-reticulum-a-hub-in-lipid-homeostasis",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"82409",title:"Purinergic Signaling in Covid-19 Disease",doi:"10.5772/intechopen.105008",signatures:"Hailian Shen",slug:"purinergic-signaling-in-covid-19-disease",totalDownloads:5,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82374",title:"The Potential of the Purinergic System as a Therapeutic Target of Natural Compounds in Cutaneous Melanoma",doi:"10.5772/intechopen.105457",signatures:"Gilnei Bruno da Silva, Daiane Manica, Marcelo Moreno and Margarete Dulce Bagatini",slug:"the-potential-of-the-purinergic-system-as-a-therapeutic-target-of-natural-compounds-in-cutaneous-mel",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82103",title:"The Role of Endoplasmic Reticulum Stress and Its Regulation in the Progression of Neurological and Infectious Diseases",doi:"10.5772/intechopen.105543",signatures:"Mary Dover, Michael Kishek, Miranda Eddins, Naneeta Desar, Ketema Paul and Milan Fiala",slug:"the-role-of-endoplasmic-reticulum-stress-and-its-regulation-in-the-progression-of-neurological-and-i",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}}]},overviewPagePublishedBooks:{paginationCount:32,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI)",institutionString:"Australian College of Business & Technology",institution:null}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. 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The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}},{id:"441116",title:"Dr.",name:"Jovanka M.",middleName:null,surname:"Voyich",slug:"jovanka-m.-voyich",fullName:"Jovanka M. 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Animals need to receive a properly balanced diet. One of the new challenges we are now faced with is sustainable animal diets (STAND) that involve the 3 P’s (People, Planet, and Profitability). We must develop animal feed that does not compete with human food, use antibiotics, and explore new growth promoters options, such as plant extracts or compounds that promote feed efficiency (e.g., monensin, oils, enzymes, probiotics). These new feed options must also be environmentally friendly, reducing the Carbon footprint, CH4, N, and P emissions to the environment, with an adequate formulation of nutrients.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/20.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11416,editor:{id:"175967",title:"Dr.",name:"Manuel",middleName:null,surname:"Gonzalez Ronquillo",slug:"manuel-gonzalez-ronquillo",fullName:"Manuel Gonzalez Ronquillo",profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",biography:"Dr. Manuel González Ronquillo obtained his doctorate degree from the University of Zaragoza, Spain, in 2001. He is a research professor at the Faculty of Veterinary Medicine and Animal Husbandry, Autonomous University of the State of Mexico. He is also a level-2 researcher. He received a Fulbright-Garcia Robles fellowship for a postdoctoral stay at the US Dairy Forage Research Center, Madison, Wisconsin, USA in 2008–2009. He received grants from Alianza del Pacifico for a stay at the University of Magallanes, Chile, in 2014, and from Consejo Nacional de Ciencia y Tecnología (CONACyT) to work in the Food and Agriculture Organization’s Animal Production and Health Division (AGA), Rome, Italy, in 2014–2015. He has collaborated with researchers from different countries and published ninety-eight journal articles. He teaches various degree courses in zootechnics, sheep production, and agricultural sciences and natural resources.\n\nDr. Ronquillo’s research focuses on the evaluation of sustainable animal diets (StAnD), using native resources of the region, decreasing carbon footprint, and applying meta-analysis and mathematical models for a better understanding of animal production.",institutionString:null,institution:{name:"Universidad Autónoma del Estado de México",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,series:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517"},editorialBoard:[{id:"175762",title:"Dr.",name:"Alfredo J.",middleName:null,surname:"Escribano",slug:"alfredo-j.-escribano",fullName:"Alfredo J. 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