Experimental fitting models of the SWCC.
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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\r\n\tOrganic synthesis has always been one of the central topics of research for the scientific community in the academic laboratories and industrial world. Many striking journal articles and remarkable reviews and books have been published in the past year describing the practicability and applications of the subject demonstrating the importance of organic synthesis. In the present book, we will be putting together the topics in organic synthesis which may include but not limited to, (1) the basic terms and concepts, (2) various organic reactions including reduction, oxidation, addition, elimination, rearrangements, and cycloadditions, (3) Total Synthesis of Natural products, (4) transition metal catalysts, organocatalysts, enzymes and biotransformations, (5) applications in medicinal chemistry and drug design and development, (6) purification methods and characterization techniques, etc. To set a limit and to increase the scope of the book, author(s) are encouraged to send the chapters that include selected examples with practical applications and good yielding reactions reported within the past decade. Older topics with significant findings or their essence to prepare the foundation may be included in the chapter are welcomed as well.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:null,priceUsd:null,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"f3bbbd989d0896f142d317ccb8abcc35",bookSignature:"Dr. Prashant S Deore",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8807.jpg",keywords:"Natural Product Synthesis, Organic Reaction Mechanism, Stereoselective synthesis, Chirality, C-H Functionalization, Cross-Coupling Reactions, Heterogeneous Catalysis, Homogeneous Catalysis, Green Synthesis, Green Solvents and Reagents, Bioorganic synthesis, Click Chemistry",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"December 10th 2018",dateEndSecondStepPublish:"January 14th 2019",dateEndThirdStepPublish:"March 15th 2019",dateEndFourthStepPublish:"May 20th 2019",dateEndFifthStepPublish:"July 19th 2019",remainingDaysToSecondStep:"2 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"251769",title:"Dr.",name:"Prashant",middleName:"S",surname:"Deore",slug:"prashant-deore",fullName:"Prashant Deore",profilePictureURL:"https://mts.intechopen.com/storage/users/251769/images/system/251769.png",biography:"Dr. Prashant S. Deore was born in India. He received a Master’s degree in organic chemistry from Pune University in 2007. In the same year, he qualified with the SET and CSIR-NET (JRF) and joined in the group of Prof. Narshinha P. Argade for the doctoral studies in National Chemical Laboratory, India. In 2014, he awarded with a Ph. D. in Chemistry and was a recipient of the 2nd prize in “2014 Eli Lilly and Company Asia Outstanding Thesis Awards”. In July 2014 he moved to Canada and joined as a postdoctoral researcher in the group of Prof. Richard Manderville at the University of Guelph, Canada. Presently, Dr. Deore is working on the collaborative project between the University of Guelph and Aterica health Inc., and providing consulting to the company. His research interest includes organic synthesis, fluorescent probes development, nucleic acid synthesis and modifications, and aptasensor development for proteins and food toxins.",institutionString:"University of Guelph",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"270935",firstName:"Rozmari",lastName:"Marijan",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/270935/images/7974_n.png",email:"rozmari@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"51278",title:"Study of Unsaturated Soils by Coupled Numerical Analyses of Water Flow-Slope Stability",doi:"10.5772/63903",slug:"study-of-unsaturated-soils-by-coupled-numerical-analyses-of-water-flow-slope-stability",body:'\nUnsaturated soils are characterized by negative pore-water pressure. In practical terms, partially saturated and unsaturated are synonymous: both terms indicate a degree of saturation lower than one; however, in specific terms, unsaturated implies the introduction of a third phase (gaseous) to the two-phase system already present in the saturated soils (liquid and solid phases only) [1].
\nCurrently, computer programs are helpful for solving problems of water flow and facilitate both the study of transient-state flow and the characterization of unsaturated soils, which, from an analytical standpoint, are complicated and laborious tasks [2].
\nTo demonstrate the application of the theoretical foundations presented in this chapter, an analysis of a tailings dam is presented as a case study. These structures are generally found in an unsaturated state. Thus, the primary goals of this analysis are to describe the applied methodology and to establish criteria and recommendations that can be followed to solve related problem types.
\nSeveral definitions exist that define soil suction and its significance [3–5]; however, for practical engineering applications, proposed definitions are either unsuitable or complex because they are largely based on thermodynamic concepts. In simpler terms, suction can be defined as a state of negative water pressure in the soil, which is influenced by several factors [6], including temperature, gravity, capillary effects, salt content, and electrical charge (van der Waals forces), among others.
\nTotal suction, or simply suction, is composed of two variables: (a) matric suction and (b) osmotic suction. Matric suction describes the difference between air pressure and water pressure [6], whereas osmotic suction is defined as the negative pressure resulting from the effect of the dissolved salts in the water of the soil matrix. Osmotic suction is commonly disregarded due to its lesser influence on total suction in addition to the difficulty of separating these two variables.
\nThe storage function, which is also defined by the soil-water characteristic curve (SWCC), describes the relationship between the water content of the soil (degree of saturation, gravimetric, or volumetric water content) and the soil suction. The nature of the SWCC is directly associated with grain-size distribution and soil structure. Therefore, the water content-suction ratio varies as a function of the material type (Figure 1).
\nSoil-water characteristic curve (SWCC) for different soil types [7].
The SWCC represents a fundamental relationship that can be used to describe the behaviour of unsaturated soils [8]. Similarly, the SWCC can be used to determine other properties, such as the permeability and shear strength of soil and the volumetric changes of soil [9].
\nSeveral methods and empirical relationships have been proposed to describe the SWCC. Several of these models use relationships that depend on the air entry value, the residual water content, or the slope of the curve [10, 11]. Other procedures are based on the grain-size distribution curve in addition to other soil properties (volume-mass properties) or the use of statistical correlations between soil data and soil water content [9, 12, 13]. The reliability of the models depends on the quality and quantity of data used for the statistical correlations [14]. Other methods consider the pore-size distribution within the soil, which, in certain cases, can be determined from the grain-size distribution curve of the material [15–17].
\nThe SWCC can be associated with three zones that describe the desaturation process of a soil (Figure 2). In addition, the SWCC allows for the saturated and residual water content to be determined, as well as their respective suction values, which are the main parameters that represent the SWCC as an input into one of the fitting methods mentioned in this chapter:
\nZones corresponding to the soil-water characteristic curve (SWCC).
Saturated capillary zone. The soil zone that is maintained in a saturated state, whose defining limit coincides with the air-entry value [18], which can be described as the value that the matric suction must exceed before air enters into the soil macropores.
Desaturation zone. The zone where water is displaced due to the air entry in the pores. The defining limit of this zone is determined by the residual water content or where water in the pores becomes discontinuous and permeability considerably decreases.
Residual zone. This section of the curve represents the zone where increases in suction do not produce significant changes in water content. As water is so scarce, it does not flow between pores, and its removal only occurs by evaporation [19]. This region is characterized by extremely high suction values.
Air-entry value. Represents the suction value at which air begins to displace water in pores, which begins with those of greatest size.
Residual value. Represents the suction value at which the liquid phase of the soil becomes discontinuous and surrounds soil particles as a thin film.
Residual water content. The content of water at which high suction values are required to remove any additional water from the soil mass.
Saturated water content. The water content in soil in a saturated state.
When laboratory data on the relationship between suction and water content are unavailable or insufficient, estimation models are one method used to determine the SWCC as a function of the index properties of soil (volume-mass and grain-size distribution relationships). Currently, there are several models that allow for the SWCC to be determined, including the following:\n
\nFitting methods are based on experimental or empirical equations that aim to define the SWCC according to data obtained from laboratory tests. Fitting methods are used when laboratory data are available, yet given the dispersion of the values, it is necessary to apply models to adjust or define the data trend to generate a representative curve for the material considered in the study.
\nSeveral models have been developed to define the SWCC [23], which consider fitting parameters that provide a range of flexibility to represent distinct materials. In Table 1, several of the most common fitting methods for SWCC are listed. These equations consider gravimetric water content as the primary variable; however, the equations can also use volumetric water content or the degree of soil saturation as inputs [24].
\nModel | \nEquation | \n
---|---|
Van Genuchten (1980) | \n|
Gardner (1958) | \n|
Brooks and Corey (1964) | \n|
Van Genuchten and Mualem (1976) | \n|
Van Genuchten (1980) | \n|
Fredlund and Xing (1994) | \n|
where | \n\n |
ws | \nsaturated gravimetric water content | \n
wr | \nresidual gravimetric water content | \n
soil suction | \n|
avb | \nadjustment parameter that depends on the air-entry value of the soil | \n
nvb | \nadjustment parameter that depends on the desaturation velocity of the soil once the air-entry value has been exceeded | \n
mvb | \nadjustment parameter related to the residual water content of soil, which is considered to be mvb=1-2/nvb | \n
ag | \nadjustment parameter derived from the air-entry value of the soil | \n
ng | \nadjustment parameter that depends on the desaturation velocity of the soil once the air-entry value has been exceeded | \n
ac | \nair pressure | \n
nc | \nsoil pore size index | \n
avm | \nadjustment parameter that depends on the air-entry value of the soil | \n
nvm | \nadjustment parameter that depends on the desaturation velocity of the soil once the air-entry value has been exceeded | \n
mvm | \nadjustment parameter related to the residual water content of soil, which is considered to be mvm=1-1/nvm\n | \n
avg | \nadjustment parameter that depends on the air-entry value of the soil | \n
nvg | \nadjustment parameter that depends on the desaturation velocity of the soil once the air-entry value has been exceeded | \n
mvb | \nadjustment parameter related to the residual water content of soil, is considered to be mvg=1-1/n o mvm=1-1/2n | \n
af | \nadjustment parameter that depends on the air-entry value of the soil | \n
nf | \nadjustment parameter that depends on the desaturation velocity of the soil once the air-entry value has been exceeded | \n
mf | \nadjustment parameter related to the residual water content of soil | \n
ψr | \nresidual suction | \n
e | \nirrational number | \n
Experimental fitting models of the SWCC.
The hydraulic conductivity function represents the relationship between hydraulic conductivity and soil suction and can be expressed as a function of the degree of saturation or volumetric water content of soil.
\nSeveral estimation methods are based on the SWCC and the saturated hydraulic conductivity at distinct suction intervals. These techniques can be classified into the following categories:\n
Empirical or experimental equations. These equations outline the relationship between the SWCC and a hydraulic conductivity function, including the models of Brooks and Corey [25] and Gardner [26].
Statistical equations. These equations consist of a physical model that represents the trajectories of water flow through soil pores of different sizes. Examples of these include the models of Van Genuchten and Burdine [27] and Van Genuchten and Mualem [28].
Correlation equations. These models are based on a proposed relationship between the SWCC and the hydraulic conductivity function, for example, the model of Leong and Rahardjo [29].
Regression equations. These models use values of hydraulic conductivity obtained from laboratory testing or other estimation method, for example, the model of Fredlund and Xing [30].
A summary of the main estimation methods expressed as a function of hydraulic conductivity is presented in Table 2.
\nModel | \nEquation | \n
---|---|
Van Genuchten and Burdine (1953) | \n|
Gardner (1958) | \n|
Brooks and Corey (1964) | \n|
Van Genuchten and Mualem (1976) | \n|
Fredlund and Xing (1994) | \n|
Leong and Rahardjo (1997) | \n|
where | \n|
hydraulic conductivity function | \n|
ks | \nsaturated hydraulic conductivity coefficient | \n
soil suction | \n|
ψaev | \nsoil suction at the air-entry value | \n
pore size distribution index | \n|
ρw | \nwater density | \n
acceleration of gravity | \n|
ag | \nadjustment parameter related to the air-entry value | \n
avb, avm | \nadjustment parameter related to the inverse of the air-entry value | \n
ng | \nsoil parameter that depends on the desaturation process once the air-entry value is exceeded | \n
nvb, nvm | \nadjustment parameter of the characteristic curve obtained from Van Genuchten’s model (1980) | \n
mvb | \nadjustment parameter (1-2/nvb); value oscillates between zero and one | \n
mvm | \nadjustment parameter (1-1/nvm); value oscillates between zero and one | \n
upper integration limit (1,000,000 kPa) | \n|
fictitious variable that describes soil suction (logarithm scale) | \n|
variable derived from the function of soil storage capacity (characteristic curve) | \n
Estimation models for determining hydraulic conductivity function.
In geotechnical engineering, water flow through soil can be categorized in several ways: laminar or turbulent flow (determined by the Reynolds number); one-dimensional (1D), two-dimensional (2D), or three-dimensional (3D) flows (depending on the number of planes); steady-state and transient seepage (constant and variable across time, respectively); and confined and unconfined flows (depending on the limits defining them).
\nOne- and two-dimensional water flow through an unsaturated element [24].
Considering that Figure 3(a) represents a soil sample subject to an upward flow and taking into consideration the law of continuity, the following can be proposed:
\nAfter applying Darcy’s law [31], the one-dimensional water flow through an unsaturated soil can be expressed as
\nwhere
\nFor the example of Figure 3(b), which demonstrates a two-directional water flow, the following expression can be deduced from the continuity equation:
\nAfter applying Darcy’s law [31], the following equation can be proposed to describe steady-state seepage in two directions for an unsaturated anisotropic soil:
\nUnder isotropic conditions, the previous equation can be expressed as follows:
\nThree-dimensional water flow through an unsaturated element [24].
For three-directional water flow, considering the unsaturated soil sample subjected to the water flow conditions indicated in Figure 4, where the hydraulic conductivities vary in all directions, the following expression can be deduced based on flow continuity:
\nOnce again, after applying Darcy’s law, the equation that describes the steady-state seepage in three directions in anisotropic conditions is detailed as follows:
\nFor isotropic soils, the previous equation can be simplified to
\nIn the transient seepage analysis and in contrast to steady state seepage, a variable hydraulic head exists over time. Variation occurs due to the changes in the boundaries of the system (due to variation in water levels over time).
\nFor practical applications, Darcy’s law [31] can be generalized to unsaturated water flow problems by considering hydraulic conductivity to be a function of the soil suction or suction head [32, 33]:
\nwhere
\nIf the osmotic pressure head is disregarded, then the total head of an unsaturated soil can be expressed as the sum of the matric suction head and the elevation head
where the additional term in the direction of the z-axis is due to the elevation head.
\nThe term on the right side of Eq. (10) can also be expressed as a function of the matric suction head:
\nwhere
If Eqs. (11) and (12) are substituted in Eq. 10, the expression that describes transient seepage in unsaturated soils can be expressed as follows:
\nEq. (13) is known as the Richards [33] equation, where given the boundary limits and initial conditions specific to a system, the equation provides the values for suction across space and time. It is highlighted that in using this equation, it is necessary to have data on the SWCC and the hydraulic conductivity function that are specific to the material being studied.
\nOne of the most common methods for evaluating slope stability is the general limit equilibrium (GLE) method. A series of equations has been proposed by several authors, who agree in dividing the slide zone into slices. The primary differences are related to the equations that these seek to satisfy and to the differential forces influencing each slice, including the existing relationship between shear and normal forces. The foundation of this method is based on two equations that determine the factor of safety and evaluate the relationship between normal and shear forces [34, 35]. Thus, one equation provides the factor of safety with respect to the equilibrium of moments (Fm) and the other with respect to horizontal forces (Ff).
\nFor the GLE, shear forces are determined according to the equation proposed by Morgenstern and Price [36]:
\nwhere
\nFor the GLE, the factor of safety is determined with respect to the method of moments and is determined by
\nHowever, the factor of safety with respect to the balance of forces is determined by
\nwhere
\nOne important factor that is relevant for the previous equations is the normal force
Mining waste (tailings) is disposed of in structures called tailings dams. The most important difference between a tailings dam and a typical water storage dam in the conventional water-retaining sense is that tailings dams do not contain an engineered water barrier and they are built and used simultaneously. For this reason, it is common for the originally conceived project to undergo constant modifications. Current technological advances allow for the numerical modelling of steady and transient state flow analyses for these structures, and along with adequate monitoring, their stability can be verified with coupled water flow-slope stability analyses before the occurrence of any potential errors. In the following sections, a cross section of a tailings dam is analysed (Figure 5), and the importance and benefits that result from the numerical model are highlighted; in addition, further recommendations are given for this type of analysis.
\nMaximum tailings dam cross section for two-dimensional model.
The properties of tailings dams are variable because they depend largely on the origin of the materials used for their construction. Several authors have performed tests with different materials and have specified typical values for these [37–40]. Based on these references, in Table 3, the properties of the materials from the case study considered in the numerical model of this section are provided.
\nMaterial | \nUSCS classification | \n||||
---|---|---|---|---|---|
\n | Name | \nSymbol | \n\n | \n | \n |
Fine material | \nSilt with sand | \nML | \n1.582 × 10−8 | \n0 | \n25 | \n
Coarse material | \nSilty sand | \nSM | \n1.000 × 10−6 | \n0 | \n35 | \n
Tailings properties for the tailings dam considered.
Assuming that the materials of the tailings dam are found in unsaturated state, for this analysis, the SWCC and hydraulic conductivity functions must be determined. If laboratory data are unavailable, it is possible to use estimates with the aid of material index properties, such as grain-size distribution curves, which are considered in the calculations performed here (Figure 6).
\nGrain-size distribution curves for tailings considered in the numerical model.
For the dam materials analysed in the present case study, the SWCC (that represent the relationship between water content and soil suction) of Figure 7 were determined by the following method:\n
For coarse material, based on data generated from a laboratory experiment with a pressure plate, the fitting Fredlund and Xing [30] SWCC equation was applied.
For fine material, the estimation method of Fredlund and Wilson [9] was initially used, and afterwards, the fitting Fredlund and Xing [30] SWCC equation was applied.
Soil-water characteristic curves of tailings dam materials.
In Figure 8, the hydraulic conductivity functions considered in the present dam case study are presented. A great similarity between the laboratory data and the estimated data can be observed. Thus, the use of estimation methods when laboratory data are unavailable represents a feasible solution and potential advantage; however, such models should be used with caution and rationality.
\nHydraulic conductivity functions of the tailings dam materials.
A steady-state seepage analysis was performed with Eq. (5), which can be solved numerically by the finite element method using the Seep/W algorithm [41]. For two-dimensional models, boundary conditions should be adequately defined in addition to discretizing the flow regions the best possible. Greater emphasis must be placed on areas that require greater detail in the expression of results, where numerical difficulties may be presented, or for areas with high contrast in the permeability of materials by orders of magnitude. In Figure 9, the boundary conditions and the discretization of the flow regions are detailed.
\nBoundary conditions and discretization model for the tailings dam with Seep/W [41].
Based on the steady-state seepage analysis, it is possible to estimate the position of the phreatic surface of the tailings dam and for the different pond levels (Figure 10).
\nVariation in the phreatic surface due to reduction of the freeboard with Seep/W [41].
Based on the previous results, the stability of the structures of the tailings dam can be evaluated by a GLE method, such as the Morgenstern-Price method, to define the slip surface for each level of the pond. In Figure 11, the slip surfaces are indicated, which were obtained from the Slope/W algorithm [42] and from considering the results of the steady-state groundwater flow analyses.
\nSlip surfaces due to phreatic surfaces for different pond levels with Slope/W [42].
A transient model (variable over time) was performed to evaluate the influence of rainfall on the tailings dam defined in Figure 5 by the numerical solution of Eq. 13. In addition, the behaviour of the pond levels is studied when the level varies 3.00 m with respect to the crest. In this case, the boundary conditions are modified to be a time-dependent function while the discretization of the model was maintained without modifications with respect to the mesh used for the steady-state analysis.
\nThe aforementioned model allows for the distinct stages of the analysis to be defined. The first set of calculations corresponds to the period of 0–48 h, after which, a storm would cause an immediate increase in water level of the pond (Figure 12). An evaluation of the infiltration due to rainfall during this period is also shown in Figure 13.
\nVariation in the water surface within the tailings structure due to rainfall and loss of freeboard for 48-h period with Seep/W [41].
Behaviour of the pore-water pressure near the ground surface due to rainfall and loss of freeboard.
Short analysis periods for materials of low permeability are often inadequate because they might not be able to clearly determine the influence of water. For example, in the previous analysis during the water filling of pond, the water surfaces variation was unable to be clearly distinguished. Similarly, rainfall was shown to have low significance because it was unable to infiltrate to a considerable enough depth to affect the slope stability.
\nTherefore, long-term analyses for these types of materials are more representative because they allow remark the water surfaces variation over a longer period of time. Thus, the results of these analyses are shown in Figure 14.
\nWater surfaces variation within the tailings structure for a transient analysis of 20 years with Seep/W algorithm [41].
Following the previous procedure and considering the pond levels indicated in Figure 12, the slip surfaces were defined by the Morgenstern-Price method with the Slope/W algorithm [42]. It is worth mentioning that a stability analysis for a period of 48 h did not provide significant results because during this time, the structure was not considerably influenced by the water. However, for long-term conditions, such stability analyses could play an important role in the study.
\nVariation in the factor of safety in the tailings dam over a period of 20 years.
In Figure 15, the variation of factor of safety over time is presented, wherein the variation in the position of water surface over time is considered (Figure 14). A decrease in stability over time is also observed. For this type of evaluations, numerical difficulties may be presented that are subsequently reflected in the result, which leads to erroneous behaviour. Therefore, it is recommended to manipulate the variables that may affect the model, such as the calculated time intervals (smaller time increments may lead to a more detailed response), the finite elements mesh, and the convergence parameters. An adequate manipulation of these variables can significantly improve the results of the numerical model [43].
\nIn current numerical modelling, it is common for 3D domains to be extruded, or in other words, two-dimensional sections are assigned a certain thickness. Then, the model is extended along a horizontal axis, resulting in a continuous, three-dimensional model.
\nExtrusions are recommended depending on the type of problem to be solved. For example, extrusions are suitable for analyses of protection levees or embankments with regular geometries that extend over long distances. In the case of structures with irregular geometries, such as dams, it is more suitable that calculations consider the specific topography of the site for these to be more representative. This latter method requires a greater amount and detail of information for the numerical model to be successfully resolved. However, it is convenient in this case to standardize certain surface areas of the model to avoid an excessive discretization of each region. In Figure 16, the geometries assumed for both cases performed here are shown.
\nGeometries: (a) 3D model extrusion and (b) 3D realistic model.
In assigning boundary conditions, sufficient regions must be created to allow the site-specific conditions to be adequately represented and well defined, which thus leads to optimum modelling results. In Figure 17, the conditions assigned in both scenarios of the case study analysis are shown.
\nBoundary conditions of the 3D models considered in the calculations with SVFlux algorithm [44].
The mesh generation for 3D models is perhaps the most complicated part of this process and even more so when considering site-specific topographic conditions. During these processes, the benefits of the extruded 2D models are evident because the generation of the mesh, as well as its distribution, is more regular. Moreover, 3D models of realistic topographies make mesh generation more difficult; in addition, 3D models require a greater number of elements to adapt to the model. In Figure 18, the distribution of the meshes obtained with the SVFlux algorithm is shown [44], and in Table 4, a comparison is made of the number of elements required for each model.
\nFinite element mesh used for calculation of the 3D models with SVFlux algorithm [44].
Model | \nNodes | \nElements | \n
---|---|---|
2D | \n220 | \n91 | \n
3D extruded | \n1342 | \n758 | \n
3D realistic topography | \n2889 | \n1580 | \n
Comparison of the number of finite elements for different analysis conditions.
Important differences are found when 3D model extrusions are compared to 3D models that consider site-specific topography. In Figure 19, it can be observed that the distribution of the hydraulic heads tends to vary in both cases. The 3D model extrusion shows a constant dissipation in the hydraulic head; however, this is not very representative of this type of structure. On the other hand, the 3D realistic model that considers site-specific topography shows a more variable behaviour in the distribution of the hydraulic head, which can be considered to be more representative of the analysed case study.
\nDistribution of hydraulic heads (m) with SVFlux algorithm [44].
The previous results can be verified by comparing the distributions of the hydraulic heads at the maximum cross section of the structure. Theoretically, the distributions of the 2D model, 3D model extrusion, and 3D realistic model with site-specific topography should be nearly identical or extremely similar considering the similar conditions and inputs for the analysis. In Figure 20, this comparison is shown.
\nVariation in the hydraulic heads (m) for different analysis criteria.
Several studies have demonstrated the importance of defining the relationship between the two-dimensional and three-dimensional models. The majority of studies agree in that the values for the factors of safety obtained from the 2D slope stability analyses are conservative, and these values tend to increase upon considering 3D models, which occurs because these calculations consider steady-state water conditions and disregard the filtration forces generated within the structure [45, 46]. This phenomenon is observed in Figure 21, where the results of a slope stability analysis during dry conditions are shown. In this case, the 3D model extrusion and 3D realistic model (considering site-specific topography) did not present significant differences.
\nOn the contrary, in Figure 22, the safety factors obtained for each scenario from a slope stability analysis with the linear phi-b model are shown, which consider water flow in the tailings structure. For these cases, the differences between each of the analyses and their criteria are distinguishable. According to the previous results, it is important to consider the water flow through the specific medium under study because it can significantly affect the stability of the earth structures. In this case, the 2D and 3D model extrusions show a high value for the factor of safety in comparison with the 3D realistic model. These differences can be attributed to the irregular topography, which causes the distribution of the hydraulic head to exhibit non-linear behaviour.
\nFactor of safety for distinct slope stability analyses in dry conditions (without water flow) with SVSlope algorithm [47].
Factor of safety for distinct slope stability analyses considering water flow through the tailings structure with SVSlope algorithm [47].
It is important to highlight that this type of analysis requires more exhaustive evaluations. In this case, only the importance of these calculations is reinforced, and methodological suggestions are proposed. However, additional numerical analyses and their respective validation in the field are imperative to adequately define the behaviour of these types of numerical models.
\nThe primary focus of this study was unsaturated soils. The most important specific concepts related to this subject were detailed with the goal of enabling their application with the aid of specialized computer programs based on the finite element method.
\nSeveral of the concluding comments and recommendations derived from the analysis of the case study in this chapter are detailed as follows:\n
When specialized laboratory results are unavailable (to describe variations in water content and permeability with respect to suction), the unsaturated soil property functions required for the analysis can be determined by estimation methods.
For the correct estimation of unsaturated soil property functions (soil-water characteristic curve and hydraulic conductivity function), a large amount of laboratory data can be required, specifically, results from different index properties, grain-size distribution curve, and soil permeability experiments.
To determine the appropriate unsaturated soil property functions (soil-water characteristic curve and hydraulic conductivity function) for the calculations in analyses performed here, the form and tendency of the soil curves were considered. However, it is possible to use statistical methods to define these functions. Certain programs will perform these calculations (such as SoilVision Database).
For numerical modelling that considers materials with high contrast in permeability by orders of magnitude, for example, it is common for numerical difficulties to be presented. To resolve this type of problems, highly permeable materials that do not contribute to the dissipation of the hydraulic head can be omitted; however, as a consequence, these will not have an effect in the final resolution of the model. If the material must be considered in calculations, then it can be substituted by gravel to facilitate the convergence of the model. To obtain satisfactory results, an adequate definition of the SWCC is necessary in addition to the hydraulic conductivity functions, which will be necessary to obtain representative solutions. Despite this, numerical complications may be present, which can only be reduced with convergence parameters, or in this case, by step-by-step analysis until an optimal solution is achieved.
Depending on the problem to be analysed and its complexity, more detailed discretizations may be required to decrease the numerical error of calculations. This approach should not be confused with the automatic generation of a dense finite element mesh because for many water flow models, the use of such discretizations is not justified and will only affect calculation times without leading to improvements in the solution of the problem.
Water infiltration plays an important role in the stability of deposits of mining wastes (tailing dams), and it is appropriate to consider water movement in these calculations to better understand its behaviour. Therefore, the benefits of numerical modelling are numerous because these methods allow for diverse situations, given relatively short periods of analysis, to be considered, thereby informing and enabling appropriate decision-making.
Currently, 3D models have wide advantages over 2D models because the latter do not consider all the variables that influence the behaviour of structures. Some of the main features that can be included in three-dimensional models are irregular geometry of the structure under study, topographic configuration of soil, unsaturated flow that represent more realistically the physical conditions of the problem, among others.
In 3D analysis, extrusions are recommended depending on the type of problem to be solved. For example, protection levees or embankments with regular geometries extending in great lengths are suitable extrusions. In the case of structures with irregular geometries, such as dams, it agrees that calculations are performed considering the topography of the site, to give greater representation to them.
Finally, for more representative numerical analyses, it is recommended to apply the theory of unsaturated soils in all those situations where the material is in this state. This chapter demonstrated that the considerations for modelling, estimating, and fitting methods of the soil properties functions provide the necessary elements to carry out these analyses in a simple way. Illustrated examples also evaluated the potential of numerical methods to increase the degree of realism in unsaturated soils analysis. Computer programs facilitate the study of transient flow and unsaturated soil conditions, cases that attempt to analytically solve are complicated and laborious. However, it should be recognized that the computer programs now replaces the judgement of an engineer.
\nType I interferonopathies are congenital genetic disorder of the interferon (IFN) system, characterized by certain clinical symptoms resulting from the overproduction of IFNα [1, 2, 3]. In our opinion, the term interferonopathy means a general pathology of the interferon system, congenital or acquired, which includes the following types of disorders of the IFN system: deficiency; paralysis of the IFN system; inadequate response on viruses, bacteria, and mutated tumor cells; and overproduction of type I IFN. Interferons are the cornerstone of immune defense against viral infections and are also involved in the regulation of immune responses. Currently there are isolated type I, II, and III interferons in accordance with their ability to interact with the three types of receptors. Type I interferons include IFNα/IFNβ; type II interferons, IFNγ; and type III interferons, interferon-like cytokines (IL-29, IL-28A, IL-28B) [4].
\nThe main role of type I interferons is to control viral infection. The synthesis and secretion of type I IFN is activated when our immune cells come in contact with viruses. Type I IFN is synthesized by epithelial cells, many cells of the immune system, including plasmacytoid dendritic cells (pDC) that recognize foreign or auto nucleic acids. Although both epithelial and pDC synthesize type I IFN simultaneously in different tissues, pDC-derived type I IFN actually exerts various immune responses through its cognate receptors on target cells. This results in modulation of diverse processes such as antigen presentation and activation of adaptive immunological process involving B and T cells [5]. For the synthesis of interferons in the body, cell activation is necessary. Toll-like receptors (TLRs); RIG-like receptors (RLRs), RIG-I; melanoma differentiation-associated protein 5 (MDA5); and cyclic GMP-AMP synthase (cGAS) participate in the recognition of foreign and host nucleic acid sites [6]. The main inducers of the synthesis of type I interferons are double-stranded and single-stranded RNA of viruses, as well as bacterial DNA [7]. RIG-like receptors recognize both single- and double-stranded viral RNAs, whereas cGAS (cyclic GMP-AMP synthase), in contrast, recognizes double-stranded DNA and RNA: DNA duplexes are formed during the replication of retroviruses and catalyze the synthesis of cGMP-AMP, which is the main agonist of the adapter protein—STING. After binding RNA, RIG-I and MDA5 bind the mitochondrial antiviral-signaling (MAVS) adapter protein. Both STING and MAVS stimulate downstream signaling cascades that include multiple kinases and finally lead to phosphorylation of IRF3 and induction of interferon synthesis [8]. Then type I IFN binds to the corresponding IFNAR receptors located on the cell membrane, which leads to the activation of Tyk2 and Jak1 kinases, which undergo phosphorylation and activate signal transduction and transcription activation proteins (STAT1 and STAT2). As a result, a heterotrimeric complex is formed, known as IFN-stimulating gene factor-3 (ISGF3), which includes IFN regulatory factor 9 (IRF9). Janus kinase (Jak) activation is negatively regulated by IFNα-inducible proteins SOCS1 and SOCS3. The binding of ISGF3 promotes interferon-stimulated genes (ISGs), which leads to their transcriptional activation and the collective actions of hundreds of ISGs, resulting in the production of a large number of induced IFN, which inhibits both viral replication and the spread of viruses. Rapid type I IFN secretion and then rapid synthesis induce activity of congenital and adaptive immunity cells by activation of pro-inflammatory cytokines that activate cellular and humoral antiviral immune response [9] (\nFigure 1\n).
\nMolecular mechanisms of the induction of type I and III interferon synthesis. PAMPs: dsRNA, double-stranded RNA; ssRNA, single-stranded RNA. Nucleic acid sensors: cGAS, cyclic GMP-AMP synthase; MDA5, melanoma differentiation-associated protein 5; RIG-I, RIG-I-like receptor dsRNA helicase enzyme. Adaptor proteins: TIRAP, toll-interleukin 1 receptor (TIR) domain-containing adaptor protein; MAVS, mitochondrial antiviral-signaling protein; STAT, signal transducer and activator of transcription. Nuclear factors: IRF, IFN regulatory factor; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; IFNAR, IFNα receptor; ISGs, interferon-stimulated genes; Tyk, tyrosine kinase; Jak, Janus kinase.
During acute viral infection, IFN level is significantly elevated, and more than 70% of cells acquire antiviral status, i.e., they are protected against virus penetration and are able to efficiently neutralize them. Type I IFN has several very important positive effects: direct and indirect antiviral effect, protective antiviral effect, antitumor effect, and immunomodulatory effect. At the same time, it was shown that increased production of IFN can lead to negative consequences similar to autoimmune reactions.
\nThe information presented by several authors about interferon system pathologies is vast and diverse but is not well-systematized. All known defects of IFN system, including type I and II IFN, whether congenital or acquired, including various disorders (deficiency; inadequate response to contact with viruses, bacteria, and mutated or tumor cells; IFN system paralysis; IFN overexpression), are pathologies of IFN system. All those defects of IFN system are collectively known as interferonopathies. There is an urgent need to create a classification of congenital and acquired disorders of the IFN system. We believe that the classification of IFN pathology would help in determining the correct approaches to the differentiated choice of adequate treatment tactics.
\nBased on our own and others’ experience, we have developed the interferonopathies classification as per the following table [1, 2, 3, 10, 11, 12, 13, 14, 15] (\nTable 1\n).
\nRecently several studies have presented genetic and molecular disorders accompanying rare Mendelian diseases that are associated with type I IFN overexpression resulting from defects in intracellular nucleic acid metabolism, DNAse deficiency, or defects in sensor nucleic acid recognition. Genetic disorders—Mendelian diseases (Aicardi-Goutières syndrome, familial chilblain lupus, spondyenchondromatosis, proteasome-associated autoinflammatory syndrome, Singleton-Merten syndrome)—resulting in inadequately high type I IFN overexpression accompanied by a certain range of clinical disorders are called type I interferonopathies. Interferonopathies have rare pathology; their occurrence varies from 1:10,000 to 1:1,000,000 people. According to the literature, the most common syndrome is Aicardi-Goutières [16]. The frequency of some recently described genetic disorders (e.g., PRAAS2) cannot be counted [17]. Such disorders cause a great number of own nucleic acids in cell cytoplasm to appear. It results in active DNA recognition and pathological overexpression of type I IFN which launch autoimmunity hyperactivation, thus leading to autoimmune inflammation affecting the central and peripheral nervous system. It also results to skin and vessel damage (vasculitis), lung damage, etc. Therefore rapid and efficient immune reaction to alien nucleic acids is positive when it causes type I IFN activation during pathogen invasion and antimicrobial protection. It becomes deleterious when it responds to own DNA which is due to the defect of own nucleic acid metabolism. Some neurological, vascular, and skin symptoms which are typical for type I interferonopathies are reviewed in such multifactorial diseases as exanthematous lupus erythematosus, widespread vasculitis, and autoimmune multiple myositis [6, 7, 18] (\nTable 2\n).
\nI. Congenital interferonopathies | \nII. Acquired—secondary interferonopathies | \n
---|---|
\n1. IFN deficiency\n 1.1 Interferon α deficiency (IFNα) 1.2 Interferon β deficiency (IFNβ) 1.3 Interferon γ deficiency (IFNγ) \n2. Interferon overexpression\n 2.1 IFNα overexpression 2.1.1 Autoinflammatory syndromes and autoimmune diseases (systemic lupus erythematosus (SLE), systemic angiitis, dermatomyositis), Down syndrome 2.1.2 Type I interferonopathies: Aicardi-Goutières syndrome (AGS), familial chilblain lupus (FCL), spondyenchondromatosis, proteasome-associated autoinflammatory syndrome (PRAAS), Singleton-Merten syndrome (SMS) | \n1. IFN deficiency\n 1.1 IFNα deficiency 1.2 IFNβ deficiency 1.3 IFNγ deficiency \n2. Interferon system paralysis\n 2.1 Blockage IFNα adequate response 2.2 Blockage IFNβ adequate response 2.3 Blockage IFNγ adequate response \n3. IFN overexpression\n 3.1 Cytokine storm | \n
Classification of interferonopathies.
Syndrome | \nResponsible gene | \nPhenotypes | \n
---|---|---|
Aicardi-Goutières syndrome | \nTREX1, RNASEH2B, RNASEH2C, RNASEH2A, SANHD, ADAR, IFIH1 | \nEncephalopathy, muscular dystonia, microcephaly, calcification of the basal ganglia in the substance of the brain, cramps, fever, increased acute phase blood markers, cytopenia, increased levels of interferon in the cerebrospinal fluid | \n
Singleton-Merten syndrome | \nIFIH1 DDX58 RIG-I | \nCardiovascular diseases with aortic calcification, osteoporotic manifestations, dental and skeletal abnormalities, psoriatic skin lesions | \n
Proteasome-associated autoinflammatory syndromes Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) | \nPSMB4 PSMB3 PSMB8 PSMB9 POMP | \nErythematous skin lesions, panniculitis, lipodystrophy, arthritis with the development of joint contractures, myalgia, hepatomegaly, splenomegaly, calcification of the basal ganglia in the brain, fever, increased acute phase blood markers Recurrent fevers in the first months of life, along with characteristic skin lesions, lipodystrophy, violaceous swollen eyelids, arthralgias, extremity contractures, and delayed physical development as well as systemic inflammation markers have been identified as CANDLE-related clinical manifestations | \n
STING-associated vasculopathy with onset in infancy (SAVI) | \nTMEM173 | \nVasculopathy with the formation of distal gangrene; necrosis; erythematous rash on the face, tip of the nose, and auricles; interstitial lung disease, arthralgia, fever | \n
Spondyloenchondrodysplasia (SPENCD) | \nACP5 | \nSpondylometaphyseal dysplasia, stunting, calcification of the basal ganglia in the substance of the brain, arthropathy, thrombocytopenia, deficiency of cellular and humoral immunity | \n
ISG15 deficiency | \nISG15 | \nCalcification of the basal ganglia in the substance of the brain, convulsions, mycobacterial infections | \n
USP18 deficiency (pseudo-TORCH syndrome) | \nUSP18 | \nCerebral hemorrhage and calcification, hepatomegaly, thrombocytopenia | \n
Trichohepatoenteric syndrome 2 | \nSKIV2L | \nWatery diarrhea, brittle and tangled hair, liver damage, mental retardation | \n
Retinal vasculopathy with cerebral leukodystrophy (RVCL) | \nTREX1 | \nThe main characteristics of RVCL include the middle-age onset, the progressive visual loss due to retinal vasculopathy (telangiectasias, microaneurysms, and retinal capillary obliteration around the macula), and variable neurological manifestations such as dementia or migraine | \n
Familial chilblain lupus | \nTREX1 | \nRare monogenic form of cutaneous lupus erythematosus; partly ulcerating acral lesions or painful bluish-red papules located in the fingers, toes, nose, and ears; arthralgias, affecting mainly large joints, without evidence of true arthritis; photosensitivity; or mouth ulcers | \n
X-linked reticulate pigmentary disorder (XLPDR) | \nPOLA1 | \nGeneralized hyperpigmentation intermingled with small hypomelanotic macules during early childhood, a distinctive face characterized by an upswept frontal hairline and arched eyebrows, as well as severe photophobia, recurrent respiratory infections, and severe gastrointestinal disorders | \n
Genetic disorders associated with immune dysregulations and clinical characteristics of interferonopathies associated with type I IFN overexpression.
Data available on genetic defects of intracellular nucleic acid metabolism greatly facilitate understanding of the mechanisms of insufficient immune activation, which can help in the development of new therapeutic approaches to the treatment of autoinflammatory and autoimmune diseases [1, 2, 3]. The progress in understanding immunopathogenesis mechanism makes it possible to set the exact targets for new therapeutic strategy development [1, 2]. The immune dysregulation syndrome is characterized by a high level of IFNα, a deficiency of regulatory T-lymphocytes, impaired functioning of B cells, and low content of low-density neutrophils. These neutrophils easily form neutrophilic extracellular traps (NET), and the resulting DNA complexes provoke an increase in IFNα synthesis, and then pDC recognizes autoDNA and produces IFNα [10, 11, 19]. These disorders are observed primarily in systemic lupus erythematosus. New approaches in treatment of SLE and other type I interferonopathies have been developed. Monoclonal antibody therapy in type I interferonopathies treatment with SLE is sifalimumab, rontalizumab against IFNα, and anifrolumab against IFNα receptor (IFNAR). Baricitinib (JAK1/JAK2 inhibitor) is currently at clinical studies (phases 2 and 3) in small cohort of patients with interferonopathies [20, 21, 22]. It is also known that treatment with baricitinib decreased disease signs and symptoms and allowed a significant reduction of corticosteroid treatment in patients with CANDLE and SAVI [23] (\nFigure 2\n).
\nTarget therapies by biologics in the treatment of type I IFN overproduction. IFNAR, IFNα receptor; ISGs, interferon-stimulated genes; Tyk, tyrosine kinase; Jak, Janus kinase; pDC, plasmacytoid dendritic cell; STAT, signal transducer and activator of transcription.
There are genetic defects in the synthesis of IFNα/IFNβ and IFNγ and defects in the receptors for IFNα and IFNγ (IFNAR and IFNGR) including genetic disorders associated with low IFN production according to recent studies. Those genetic defects of IFNs are accompanied by clinical signs of severe recurrent viral and/or mycobacterial infection.
\nCongenital defects of type I IFN are associated with mutation of genes participating in synthesis of IFNα/IFNβ resulting to deficiency of various molecules (STAT1, UNC93B1, MCM4, TLR3, TRAF3, TRIF, TBK1) and decline level of IFNα/IFNβ. Deficiency of IFNγ, its receptor IFNGR (IFNγR1), and IL-12 plays an important role in IFNγ regulation [12, 24, 25]. Congenital defects of type I IFN have been globally systematized in 2015 by Bousfiha et al. [24]. It has been proven that it causes severe viral and bacterial intracellular infections which are the cause of deaths. Such patients are needed in replacement therapy with recombinant IFNα2b in complex with antioxidants. Congenital defects of IFNγR1 receptor are associated with severe intracellular mycobacterial infections. Combined genetic defects leading to deficiency of IFNα and IFNγ are associated with an autosomal recessive mutation in the STAT1 gene, which causes severe viral and mycobacterial infections [12, 24, 25] (\nTable 3\n).
\nPredominant susceptibility to viral infection | \n||
---|---|---|
Syndrome | \nResponsible gene | \nPhenotypes | \n
Herpes simplex encephalitis (HSE) | \nAR (autosomal recessive inheritance): UNC 9381 TLR3 TRIF AD (autosomal dominant inheritance): TLR3 TRIF TRAF3 TBK1 | \nDominant clinical phenotype is HSE during primary infection with HSV1, usually between 3 months and 6 years of age Specific tests examining the TLR3 pathway marked decrease on the ability of patient’s fibroblasts to produce IFNβ/IFNλ in response to TLR3 agonists and HSV1 infection | \n
Warts, hypogammaglobulinemia, infection, myelokathexis (WHIM) syndrome | \nAD: CCXR4 | \nWarts/human papilloma virus infection Neutropenia, reduced B cell numbers | \n
Epidermodysplasia verruciformis | \nEVER1/TMC6, EVER2/TMC8 | \nHuman papilloma virus (group B1) infection and skin cancer | \n
STAT1 deficiency STAT2 deficiency | \n\n | Viral infections | \n
CD16 deficiency | \n\n | Severe viral infections | \n
IRF7 deficiency | \n\n | Severe influenza disease | \n
\nSusceptibility to mycobacteria\n | \n||
Syndrome | \nResponsible gene | \nPhenotypes | \n
IRF8 deficiency | \nAR: IRF8 | \nSusceptibility to mycobacteria, Candida, myeloproliferation | \n
RORc deficiency | \nRORc | \nSusceptibility to mycobacteria, Candida\n | \n
MSMD IL-12-IFNγ axis deficiency | \nAD: IFNGR1 Complete AR IFNGR1 and AR IFNGR2 Partial STAT1 LOF (AD), partial IFNGR1, partial IFNGR2, complete IL-12R1, complete IL-12B, complete ISG15, XL CYBB, IRF8, Tyk2, XL NEMO | \nMycobacterial osteomyelitis Serious disseminated BCG and environmental mycobacteria infections (soft tissue, bone marrow, lungs, skin, bones, and lymph nodes), Salmonella spp., Listeria monocytogenes, and viruses Usually less severe | \n
Genetic disorders and clinical characteristics of interferonopathies associated with type I IFN deficiency.
There are secondary acquired disorders in the IFN system, which cause a weakening of antiviral resistance in adults and children [12]. Different viruses can damage synthesis and production of IFN at various interferonogenesis stages. These secondary defects of the type I IFN lead to the occurrence of severe viral infections (herpesviral encephalitis), recurrent acute respiratory viral infections (recARVI), chronic recurrent HSV1 infection, atypical chronic EBV infections, and other atypical cases of virus infection. It was shown that viruses can avoid the effects of IFN and inhibit the action and synthesis of IFN using various molecular mechanisms. Numerous studies demonstrated that a lot of viruses (all herpesviruses, majority of respiratory viruses, hepatitis B and C viruses, etc.) produce proteins capable of inhibiting synthesis and production of IFNα/IFNβ and IFNγ. Viruses can damage each stage of the expression of ISGs [9] (\nFigure 3\n).
\nBlockage of signaling pathways for the induction of interferon by viruses (red hexagons indicate the points of application of all herpesviruses, majority of respiratory viruses, chronic hepatitis B and C viruses, etc.). dsRNA, double-stranded RNA; IRF, IFN regulatory factor; IFNAR, IFNα receptor; ISGs, interferon-stimulated genes; Tyk, tyrosine kinase; Jak, Janus kinase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; cGAS, cyclic GMP-AMP synthase; MAVS, mitochondrial antiviral-signaling protein; MDA5, melanoma differentiation-associated protein 5; STAT, signal transducer and activator of transcription; TRIF, TIR domain-containing adaptor inducing interferon-beta; Ku70, component of the nonhomologous end-joining pathway that repairs DNA double-stranded breaks.
Patients with recurrent acute respiratory viral infections and various chronic herpesvirus infections including recurrent herpes viral infections have secondary defects of IFN system. Immunocompromised children of various ages and adults may suffer from recARVI with the frequency of 10 to 16–24 and more times annually; almost in 100% of cases, it is associated with the presence of mono and mixed herpes viral infection. The frequency of recurrent chronic HSV1/HSV2 infection of facial and/or genital location in those patients may reach 16–24 times per year. Epstein-Barr virus may cause atypical virus infection associated with chronic fatigue syndrome [12].
\nThe problem of developing new approaches to the treatment of congenital and acquired defects of the IFN system is very acute [12, 26, 27, 28]. Acquired defects in the IFN system (93–96%) and impaired functioning of neutrophilic granulocytes (NG) are most often detected in patients with recurrent chronic herpes virus infections.
\nWe conducted experiment in vitro to study the effect of recombinant IFNα2b (rIFNα2b) on NG in viral (cells from patients with HSV1/HSV2 infection) and bacterial (model infection by fMLP) infections. The study showed positive regulation of the negatively charged IFNαβR1+IFNγR+TLR4+NG phenotype in patients with various chronic herpesvirus infections under the influence of rIFNα2b in vitro. It was noted that the number of NGs carrying IFNαβR1 and IFNγR and expression density of IFNαβR1 is increasing, wherein expression density of IFNγR and TLR4 is decreased [29]. rIFNα2b modulating effects on CD16+CD66b+CD33+CD11b+NG phenotype transformed by fMLP in experimental model of bacterial process in vitro, to promote remodeling of the pro-inflammatory NG phenotype into anti-inflammatory, have been shown [30]. Thus rIFNα2b has a protective effect on the NG phenotype according to experimental data.
\nIn clinical practice, the use of parenteral IFN to correct disorders in the IFN system is very difficult due to the presence of numerous side effects. One should also bear in mind the inefficiency of short courses of IFN therapy for restoration of the normal IFN system functioning in recARVI, recurrent chronic herpes viral infection of facial or genital location, and papilloma virus infection of the skin and mucosa characterized by recurrent episodes when the frequency of recARVI and/or recurrent attacks of HSV1/HSV2 infection may reach 14–24 and more per year. For over 20 years, we have been developing interferon therapy programs using drugs in Russian production—rectal suppositories and gel of recombinant human IFNα2b (rIFNα2b+aox) in combination with antioxidants (vitamins E and C) (Viferon) [12, 13, 14, 15, 26, 27]. During that period, we managed to demonstrate safety, antiviral, and immunomodulatory efficiency of this kind of IFN therapy, total absence of any side effects that are typical for parenteral IFN therapy, and total absence of antibodies against IFNα2b. Replacement therapy with rIFNα2b + aox is prescribed to patients with primary, genetically preconditioned, congenital or acquired IFN system disorders. In case of primary IFN system disorders, patients need a basic recovery therapy making it possible to eliminate viral antigens as much as possible; and then it is required to select dosage for permanent replacement therapy with rIFNα2b+aox. In case of acquired interferon deficiency, patients are prescribed with differentiated therapy with high, medium, and low doses of rIFNα2b+aox (\nFigure 4\n).
\nDynamics of changes in the system of IFN in immunocompromised children against the background of therapy with rIFNα2b+aox (Viferon).
At the same time, in case when we had treated the group of patients with combined immunodeficiency (defects of induced production of IFNα and IFNγ and dysfunctions of phagocytic and microbicidal activities of neutrophilic granulocytes) that was associated with recurrent acute respiratory viral infection and different chronic herpes viral coinfections, combined interferon and immunomodulatory therapy was used. The aim was to restore the levels of induced production of IFNα and IFNγ and to reconstruct dysfunctions of phagocytic and microbicidal activities of neutrophilic granulocytes and other deficient chains in antiviral immunity. One group of children, group 1, received an interferon therapy program (rIFNα2b+aox), and patients in group 2 received a program of combined interferon therapy (rIFNα2b+aox) and immunotherapy (glucosaminylmuramyldipeptide). The use of replacement and immunomodulatory mono-rIFNα2b+aox or in combination with immunotherapy (glucosaminylmuramyldipeptide) has helped us to receive very good clinical efficacies and has reached restoration of interferon status and normal functioning of neutrophilic granulocytes (p < 0.05) (\nFigure 5\n). At the same time, it is required to take into account both uneven viral infection syndrome manifestation and the rate of IFNα deficiency as well as peculiarities of immune system disorders in case of secondary immune deficiency [12, 13, 14, 15, 27].
\nThe state of the interferon system in immunocompromised children with recurrent respiratory infections on the background of differentiated programs interferon and immunotherapy. Note: group 1 received an interferon therapy program (rIFNα2b+aox); group 2 received a program of combined interferon therapy (rIFNα2b+aox) and immunotherapy (glucosaminylmuramyldipeptide); (*p < 0.05, reliability in relation to control).
Here is an example illustrating the change in clinical, immune, and interferon status in immunocompromised children with recurrent acute respiratory viral infections under the influence of interferonotherapy.
\nClinical case. Patient X, 3 years old. The child suffers from repeated acute respiratory viral infections 1–2 times per month (14–16 episodes per year); the duration of the acute period of respiratory viral infection is 7–10 days. The clinical symptoms of the disease were acute rhinitis, acute pharyngitis, acute laryngitis, acute tracheitis, febrile and subfebrile body temperature for 2–4 days, and severe symptoms of intoxication. The duration of the frequent incidence of acute respiratory viral infections is 2 years. The defects of the immune system are a decrease of CD3+CD4+ lymphocytes and CD3+CD8+ lymphocytes; a decrease of immunoregulatory index; neutropenia; a decrease of bacteria absorption and digestion processes by neutrophils; and a decrease of microbicidal activity of neutrophils. We tested spontaneous and Newcastle disease virus-induced IFN production during the incubation of peripheral blood (24 h, t 37°C in 5% CО2). The level of induced IFNα in the patient was 4 IU/ml versus 58 IU/ml in control. The patient was prescribed rIFNα2b+aox therapy with a total duration of 2.5 months.
\nTreatment program:
Local intranasal use of rIFNα2b+aox (Viferon gel, 36,000 IU/g), two to three times a day, 6 weeks.
Systemic rectal application of rIFNα2b+aox suppositories according to a “step-by-step” scheme:
300,000 IU per day, 10 days.
300,000 IU per day three times a week, 2 weeks.
300,000 IU per day two times a week, 2 weeks.
150,000 IU per day two times a week, 2 weeks.
150,000 IU per day once a week, 2 weeks.
Conducted local and systemic interferon therapy led to a reduction in the frequency of acute respiratory viral infections to three episodes per year lasting 5–7 days, proceeding in a milder form. Rehabilitation of immunity parameters occurred after 2.5 months of interferonotherapy, and the level of induced IFNα was normalized to 64 IU/ml.
\nSumming up the above information, we may conclude that new biological drugs based on mAb are effective and safe, and they are able to neutralize IFNα overexpression in type I interferonopathies, both in Mendelian’s diseases and in autoimmune disorders. At the same time, local and system use of rIFNα2b+aox (Viferon) in congenital and acquired IFN system defects associated with viral infection syndrome, where a differential dosage is selected individually taking into account the rate of deficiency and an adequate, extended course of therapy is optimal because it is associated with positive clinical and immunological effects without any negative and side effects. Our more than 20-year experience has shown that using recIFNα2b+aox in patients with congenital or acquired IFN system defects had demonstrated positive clinical effect and is safe [31]. IFN (rIFNα2b+aox) therapy can be used with very good clinical efficacy in cases of primary or secondary defects of induced production of IFNα and IFNγ. From the other side, it is very important that in patients with a genetic predisposition to the manifestation of autoimmune diseases, primarily vasculitis and systemic lupus erythematosus, we do not recommend to use IFN therapy.
\nIntechOpen implements a robust policy to minimize and deal with instances of fraud or misconduct. As part of our general commitment to transparency and openness, and in order to maintain high scientific standards, we have a well-defined editorial policy regarding Retractions and Corrections.
",metaTitle:"Retraction and Correction Policy",metaDescription:"Retraction and Correction Policy",metaKeywords:null,canonicalURL:"/page/retraction-and-correction-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\\n\\n1. RETRACTIONS
\\n\\nA Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
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\\n\\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\\n\\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\\n\\n3. CORRECTIONS
\\n\\nA Correction will be issued by the Academic Editor when:
\\n\\n3.1. ERRATUM
\\n\\nAn Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\\n\\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n3.2. CORRIGENDUM
\\n\\nA Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n4. FINAL REMARKS
\\n\\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\\n\\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
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\\n\\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
\\n\\nPolicy last updated: 2017-09-11
\\n"}]'},components:[{type:"htmlEditorComponent",content:'IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\n\n1. RETRACTIONS
\n\nA Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
\n\nA formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
\n\nPublishing of a Retraction Notice will adhere to the following guidelines:
\n\n1.2. REMOVALS AND CANCELLATIONS
\n\n2. STATEMENTS OF CONCERN
\n\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\n\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\n\n3. CORRECTIONS
\n\nA Correction will be issued by the Academic Editor when:
\n\n3.1. ERRATUM
\n\nAn Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\n\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n3.2. CORRIGENDUM
\n\nA Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n4. FINAL REMARKS
\n\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\n\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\n\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\n\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
\n\nPolicy last updated: 2017-09-11
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