Vaccines against COVID-19 approved for emergency use authorization.
\r\n\tThorough research and analyses of most upfront neuroimaging techniques and various in vivo applications of specific mapping of normal function and under diseases are the purpose of this book. This book would hopefully capture the interests of colleagues interested in neuroimaging principles and applications, research and developments, as well as disease diagnosis and treatment, and could help convey the methodological and developmental perspectives of brain function in the medical application and research field.
\r\n\t
The investigations of dielectrics, ferroelectrics, sensor, dipolar glasses and composite materials have attracted great attention in solid-state physics and material science in recent years. These studies reveal inter-and intra-molecular interactions and encourage increasing applications of these materials in modern technology. Dielectric substances are insulators or poor conductor of electricity. In these materials, the electrostatic field persists for a long time. These materials do not have free electrons, but the application of the electric field changes their behaviour. They have the ability to be polarized under the action of the electric field [1]. Dielectric materials are classified into two main categories (i) Non-ferroelectric (called normal dielectric or paraelectric) materials and (ii) Ferroelectric materials. The non-ferroelectric materials are divided into three categories according to the prevailing polarization mechanism as (i) non-polar dielectrics, (ii) polar dielectrics and (iii) dipolar dielectrics [1]. The non-polar dielectric materials consist of one type of atoms. These types of dielectric materials become polarized in an external electric field due to the relative displacement of electric charge with respect to the nucleus. The polar dielectric materials are made up of molecules without a permanent dipole moment, and dipolar dielectrics include materials whose molecules possess a permanent dipole moment.
Ferroelectric materials are unusual dielectrics that possess reversible spontaneous electric polarization, which can be reversed by applying stress or electric field. This property of showing spontaneous polarization persists over a certain temperature interval [2]. Above the critical temperature, called Curie temperature or transition temperature, the substance loses its property of spontaneous polarization and becomes paraelectric. This change of phase property, i.e., ferroelectric phase to paraelectric phase, is associated with anomalous behaviour of many physical properties along with a change of crystal structure from low to a high symmetry. The alignment of the electric dipoles may extend only over a region of the crystal, while in another region, the direction of spontaneous polarization may be reversed. Such regions of uniform polarization are called domains, a term acquired from ferromagnetism. If we first applied a small uniform electric field (E), directed, (say) in the positive direction, we will induce uniform polarization P (a linear relationship between P and E) because the field is not larger enough to switch any of the domains with the unfavorable direction of polarization and the crystal will behave like the normal dielectric [2, 3].
A material can be either piezoelectric, pyroelectric or ferroelectric, only if its crystalline symmetry is inherent (i.e., it lacks an inversion centre). A basic principle due to Neumann is that any physical property exhibited by a crystal must have at least the symmetry of the point group of the crystal. Thus, the above properties, which are inherently asymmetric, can only arise in asymmetric crystals. All crystal structures can be divided into 32 crystal classes. Of the 32 crystallographic point groups, 11 exhibit centre symmetry, leaving 21 non-centrosymmetric point groups. One of the 21 groups, however, have an inversion centre, causing it to lose its non-centrosymmetric nature, leaving 20 non-centrosymmetric point groups which have asymmetric properties. All the crystals in these 20 classes are piezoelectric [3, 4]. When such a non-centrosymmetric crystal is subjected to mechanical stress, the ions are displaced from each other in an asymmetric manner, and the crystal becomes electrically polarized. This is called the piezoelectric effect. The inverse effect of it, i.e., an applied electric field produces strain (causes the material to either expand or contract, depending on the field direction) has also been observed. The piezoelectric effect is often used to convert electrical energy into mechanical energy and vice-versa. Quartz is the best example of piezoelectric material and the one most frequently used in transducers. Out of the 20 piezoelectric point groups, only 10 have a unique polar-axis responsible for the appearance of a spontaneous electric polarization even in the absence of an applied electric field [3, 4]. If a piezoelectric material also shows the change in spontaneous polarization (
Classification of piezoelectric and pyroelectric materials [
The relationship between the piezoelectric, pyroelectric and ferroelectric materials is shown schematically in Figure 2. A dielectric material is an electrical insulator that can be polarized under an external applied electric field. Dielectric materials are often characterized by their dielectric permittivity, which describes the material’s resistance against polarization by an external electric field [7, 8]. A group of dielectrics that show a change of strain or stress due to an applied external electric field or conversely to the change of the polarization due to a mechanical excitation are called piezoelectrics. Pyroelectrics are a group of piezoelectrics that show a change of polarization due to a change in temperature. Ferroelectric materials have both pyroelectric and piezoelectric properties.
Venn diagram showing the relationship between various types of dielectric materials [
Ferroelectricity is the phenomenon that refers to the state of spontaneous polarization, usually vanishes above a certain temperature called Curie or transition temperature (
where
A phase transition is the transformation of the thermodynamic system from one phase or state of matter to another. It is a collective phenomenon in which critical behaviour depends on a small number of parameters and is universal for many systems. During a phase transition of a given medium, certain properties of the medium change, often discontinuously, as a result of some external condition, such as temperature, pressure, etc. Phase transition involves some change of symmetry. According to Paul Ehrenfest, phase transitions can be divided into two groups known as first- and second-order phase transitions, depending on whether the transition is discontinuous or continuous, respectively. Paul Ehrenfest classified phase transitions based on the behaviour of the thermodynamic Gibbs free energy as a function of other thermodynamic variables. Under this scheme, phase transitions were labeled by the lowest derivative of the Gibbs free energy that is discontinuous at the transition. First-order phase transitions exhibit a discontinuity in the first derivative of the Gibbs free energy with respect to the thermodynamic variable [10]. Second-order phase transitions are continuous in the first derivative but exhibit discontinuity in a second derivative of the Gibbs free energy with respect to a thermodynamic variable [10]. In the first-order phase transition, volume, entropy and polarization of the crystal change discontinuously at the transition point. In the second-order phase transition, the specific heat changes discontinuously, ‘whereas volume, entropy and polarization change continuously at the phase transition point. In the first-order phase transition, the energy appearing as latent heat in an infinitely narrow temperature range interval, while in the second-order phase transition, there is no release of the latent heat but the expansion of the coefficient exhibits anomalous behaviour over a finite range of temperature [11, 12].
In ferroelectrics, two common types of phase transition are identified. These are named depending on how the order parameter (polarization) changes during the transition. It is common to observe that as the temperature is raised, the bulk polarization decreases and vanishes abruptly at a Curie temperature (
Schematic potential well [
The detailed microscopic theory of how this happens will be different from material to material, but the macroscopic properties of the phase transition will be similar across many different classes of materials. A first-order phase transition is one that has a discontinuity in the order parameter itself, while a second-order phase transition is one that has a discontinuity in the first derivative of the order-parameter. In a first-order transition, the polarization varies continuously until the Curie temperature, at which there is a discontinuity shown in Figure 4a. In a second-order transition, the order parameter itself is a continuous function of temperature, but there is a discontinuity in its first derivative at Curie temperature shown in Figure 4b [13].
Plots of spontaneous polarization versus temperature: (a) first-order transition (b) second order transition [
The intensity of polarization (
Ferroelectric (P-E) hysteresis loop [
At this stage, the whole specimen represents a single domain. This is usually accompanied by a distortion in the crystal along the polarization direction. The extrapolation of the saturation value to zero field gives the magnitude of the spontaneous polarization (
The electric field acting at the site of atom or molecule is, in general, significantly different from the macroscopic filed
where
Generally, at ordinary electric fields, the magnitude of polarization (
where
where
Eq. (5) gives the dielectric constant of an isotropic medium or cubic medium. This is represented by a scalar quantity. The dielectric susceptibility (
Thus, like susceptibility, the dielectric constant (
The polarizability
where
where the summation is over all the atoms or atomic sites.
On rearranging the terms and making use of Eq. (5) gives
Using Eq. (6), we get
Solving for
This is known as the Clausius-Mossotti relation. It relates the dielectric constant to the atomic polarizability, but only for crystal structures for which the Lorentz field Eq. (2) obtains. The total polarization (
Atomic contributions to electric polarization [
where
Electronic polarizability (
where
Ionic polarizability (
If the relative displacement of the positive and negative ions is
where
Dipolar polarizability (
where
Frequency dependence of the various contributions to the polarizability [
We find that in the optical frequency range, the dielectric constant (
Ferroelectric crystals have been classified into the following types [1, 2, 3, 4, 5, 6].
According to the chemical composition of the crystal.
Hydrogen bonded and its isomorphs such as KH2PO4 (KDP), triglycine sulphate (TGS), Rochelle salt (RS) and lead hydrogen phosphate (LHP) etc.
Double oxides such as BaTiO3, potassium niobite (KNbO3) and lithium niobate (LiNbO3) etc.
Based on the number of directions allowed to the spontaneous polarization are of two types.
Single-axis of polarization such as Rochelle salt, KDP etc.
Several-axes of polarization such as BaTiO3 etc.
According to the existence or lack of centre of symmetry in non-polar phase.
Non-centre of symmetrical non-polar phase such as KDP and Rochelle salt.
Centre of symmetrical non-polar phase such as BaTiO3 and TGS crystals, etc.
According to the nature of the phase change.
Order–disorder type such as KDP, RS, TGS, LHP and CsH2PO4 (CDP) etc.
Displacive type such as BaTiO3, LiNbO3 and KNbO3 etc.
In the order–disorder group of ferroelectrics, the ferroelectric phase transition is associated with an individual ordering of ions. These are the crystals that contain H-bonds and in which the motion of protons is related to the ferroelectric properties. The examples are KH2PO4, RS, TGS, CsH2PO4, PbHPO4 and RbH2PO4, etc. The displacive group of ferroelectrics is the one in which the ferroelectric phase transition is associated with the displacement of a whole sublattice of ions of one type relative to a sublattice of another type. The displacive type ferroelectrics possess perovskite ABO3 type structures. Examples are BaTiO3, LiNbO3 and KNbO3, etc. Consider the case of BaTiO3 crystal, as shown in Figure 8. The unit cell is cubic with
Structures of BaTiO3:
This situation leads to net dipole moment and hence produces the spontaneous polarization
Single cell potential for (a) displacive (b) order–disorder ferroelectrics [
Many of the experimental results on the macroscopic properties of ferroelectrics such as polarization and dielectric constant as well as their temperature, electric field and pressure dependence, etc. In 1920, Valasek [20] was discovered ferroelectricity in Rochelle salt. Thereafter, for about twenty years, the mechanism of ferroelectricity remained a mystery. In the period between 1935 and 1938, ferroelectricity in KDP crystal and its isostructural crystals was observed [21]. In order to explain ferroelectricity in KDP, a microscopic model Hamiltonian of disordered proton compositions was proposed, based on which a pseudospin model was developed by Slater [22] and Takagi [23] later independently. Ferroelectricity in Barium titanate (BaTiO3) was reported in 1945–1946 [24, 25], and a microscopic model of
where
where
where
We consider a ferroelectric crystal having an intrinsic spontaneous polarization (
where
Using Eq. (22) into (23), we obtained the equation of state for the ferroelectric system of the form
Eq. (24) has two roots: (i) the first root
Suppose spontaneous polarization
It is obvious that the value of
By combining Eqs. (26) and (27) we get
where
Consider first case
One of the two roots of
When the temperature is below
The term of
We plot the reciprocal of the susceptibility as a function of temperature in Figure 10a. This theoretical plot agrees well with the experimental data; the slope of the
Functional relations of (a)
For
Using the value of
We get (
When
The function
As explained above the condition for the occurrence of spontaneous polarization (
Functional relations of (a)
Combing the Eq. (30) with Eq. (34) and keeping in the mind that
At the transition temperature
Various physicists have developed model theories of ferroelectricity. An introductory idea of model theories that have been developed to explain the phenomenon of ferroelectricity is given below. Many experimental and theoretical attempts were made to explain the phenomenon of ferroelectricity in single and polycrystals and proposed a number of theories. The first theoretical explanation of the ferroelectric properties of Rochelle salt was proposed by Kurchatov [41]. Slater [22] put forward the first molecular theory of ferroelectricity and suggested that the ferroelectric behaviour in KDP and Rochelle salt is principally due to the ordering of H-bonds. A general theory of ferroelectricity established at that time by Cochran’s lattice dynamic theory [33] and Lines statistical theory [42] have provided for major understanding of the ferroelectric phenomena of ferroelectricity.
A simple order–disorder model Hamiltonian was proposed by Mason [43]. In this model, a proton motion along an H-bond. A proton may transfer from one-well to another, and vice versa, stochastically over a potential barrier, and this model does not explain the isotope effect. Blinc [44] introduced the concept of proton tunneling motion between the two equilibrium sites in the double-well minimum O-H--O bond potential. The Blinc’s [44] concept was quickly put into the simple formalism of the pseudospin-model by De Gennes [45] and independently by Matsubara [46]. De Gennes [45] showed that the proton in a double minimum type potential has described by a one-half pseudospin. The pseudospin model Hamiltonian developed to explain the proton system and the triggering of phase transition can be ascribed to the ordering of the proton in the double-well potential. The dipoles formed by the proton ordering make a small contribution to the spontaneous polarization
Later on, Arefev et al. [48] and Brout et al. [49] suggested that essentially the same concept could also be applied such that KDP etc. In this case, where the permanent electric dipoles move-in a potential with more than one equilibrium position and the soft mode collective excitations are not phonons but rather the unstable pseudospin phonon coupled-wave. Kaminow [50] experimentally confirmed the existence of soft mode in KDP crystal, and the other investigators also confirmed the soft mode in other ferroelectric crystals. It is now well recognized that the several interesting properties of ferroelectrics are associated with the high-temperature dependence of the soft mode. Cowely [51] has given a microscopic theory of ferroelectricity in which the temperature dependence of the normal mode (soft mode) arises from anharmonic interactions between normal modes. These anharmonic interactions in a crystal are quite small, at least at low temperatures, so that an anharmonic crystal provides an example of the many-body system in which interactions between the elementary excitations are both small and non-singular. In the harmonic approximation, the equations of motion of the shell model can be obtained from a quadratic function of the displacements of the ions and of the electronic dipoles produced on the ions during the lattice vibrations. The anharmonic interactions arise from the cubic and higher terms in potential function, and in general, there will be anharmonic interactions between all the displacements and all the dipoles. In the ferroelectrics, the root at wave vector
A very successful attempt has been made to give a microscopic theory of ferroelectric crystals given by Cochran [33, 52]. This lattice dynamical theory is based on the hypothesis that the ferroelectric transitions are the results of the instability of the crystal lattice with respect to one of the homogeneous (wave number
When
This Eq. (36) produces one essential anomaly needed to explain a ferroelectric transition. In order to complete understanding the ferroelectric behaviour, it is necessary to investigate the temperature of
Ferroelectric materials have been extensive applications [3, 54] in a large number of areas due to their peculiar and interesting properties such as high permittivity capacitors (BaTiO3), ferroelectric non-volatile FeRAM memories (due to bi-stable polarization in modulation and deflector), pyroelectric sensors, piezoelectric and electrostrictive transducers (TGS crystal), electrooptic and optoelectronic devices (due to their non-linear polarizability), thermistors, storage and laser devices, sensors, resonators and actuators which have revolutionized consumer electronics, automobile industry, biomedical diagnosis, underwater acoustic technology, defense-related sectors, gas sensing devices and surface acoustic wave technology, etc. The major areas of applications [3, 54] of ferroelectrics have received a great deal of attention amongst all the above capacitors, ferroelectric memories, pyroelectric sensors, piezoelectric, electrostrictive transducers, electrooptic devices and thermistors. The basic specifications required for capacitors are small size, large capacitance (materials with a large dielectric constant are desired). High frequency characteristics (ferroelectrics with a high dielectric constant are sometimes associated with dielectric dispersions, which must be taken into account for practical applications). Ferroelectric relaxors such as Pb(Mg1/3Nb2/3)O3 and Pb(Zn1/3Nb2/3)O3 are some examples of these applications.
The bi-stable polarization of ferroelectrics makes them useful for binary memory systems. There are volatile and non-volatile memory devices in erasable semiconductor memories. Non-volatile memory does not require a holding voltage. Dynamic random-access memory (DRAM), which is widely used because of its high integration capability, is an example of volatile memory. Data stored in these memories are lost when the electric power is shut off. To record information of polarization may be reversed or reoriented by application of an electric field greater than the coercive field. For erasure, the polarization can be returned to its original state with an applied field of opposite polarity. To read the stored information, it is retrieved by electrical or optical means. Optical memory is an electrically addressed light valve. For example, BaTiO3, (Pb,La)(Zr,Ti)O3 and Pb5Ge3O11 single crystals are extensively used as light values. When a ferroelectric thin film with a large polarization-electric field hysteresis is used as the memory capacitor, non-volatile memory is realized. When a voltage is applied to the gate and the field-effect transistor (FET) assumes the “on” state, a pulse voltage to the drain generates a drain current dependent on the remanent polarization state. A large electric field is applied to a ferroelectric film in every process in the ferroelectric RAM (FeRAM), the polarization hysteresis characteristic degrades with increasing cycles. This problem of ferroelectric films needs to be overcome for non-volatile memory applications. The development of the ferroelectric memory started with DRAMs is composed of a FET and memory capacitor, then moved into FeRAMs and is now focused on metal ferroelectric semiconductor field-effect transistors (MFSFETs). BaTiO3, LiNbO3 and KH2PO4 crystals, etc., are some examples of these applications.
The pyroelectric properties of polar materials were studied a long time ago, and such materials were belonged as electric stones, measuring the current or voltage response of a crystal to a temperature change, either by continuous heating or by the absorption of sinusoidally modulated radiation. This is basically due to the temperature dependence of the spontaneous polarization of a polar material. The pyroelectric sensors are widely used for monitoring temperature or infrared radiation (IR). Practical applications of the pyroelectric material in temperature sensors and infrared (IR) light detectors lead to some commercial making of ferroelectric ceramics. Pyroelectric detectors can be used to record infrared images. The converse effect is called the electrocaloric effect, which may be a future cooling system. Materials such as TGS, LiTaO3, Sr1/2Ba1/2Nb2O6 etc. are some examples. Another important application of piezoelectric devices. Certain materials produce electric charges on their surfaces when mechanical stress is applied. The induced charges are proportional to the mechanical stress. This is called the piezoelectric effect, which was discovered in Quartz by Pierre and Jacques Curie in 1880. Materials showing this phenomenon also conversely have a geometric strain proportional to an applied electric field showing the converse piezoelectric effect, discovered by Gabriel Lippmann in 1881. The root of the word “piezo” means “pressure” in Greek. Hence the original meaning of the word piezoelectricity implied “pressure electricity”. The phenomenon of Piezoelectricity is widely utilized in the fabrication of various devices such as sensors, transducers, actuators, surface acoustic wave (SAW) devices, frequency control devices etc. Quartz, BaTiO3, (Pb, Sm)TiO3, LiNbO3, and LiTaO3 etc., are some materials that can be used for these applications.
Authors are thankful to Prof. S.C. Bhatt, Prof. P.D. Semalty for valuable suggestions and discussions.
The challenge of the epidemic outbreak has reached alarming levels, shocking national healthcare systems to unpreparedness and causing international deployment. No drug therapy has been found to be effective in the treatment of the virus, despite COVID-19 being declared a global pandemic by the World Health Organization (WHO). In contrast, several randomized controlled trials conducted towards treatment have not yet provided practical guidance on therapeutic choices and pharmacologic therapy. Several successful research tests for therapy are currently underway. Other emerging, non-conventional drug discovery approaches include alternative ways to discover potent anti-SARS-CoV2 drugs that are quicker and less expensive. In addition, while drugs for COVID-19 are being repurposed and discovered, new drug delivery systems will play a major role in developing effective delivery systems that have the potential to attack viruses, enhance physicochemical characteristics, and avoid possible drug resistance that contributes to superior therapies. The best way to produce pharmaceutical drugs that cure SARS-CoV-2 is to find potential molecules from the medicines available for sale [1].
Coronavirus disease 19 (COVID-19) is a remarkably highly contagious and pathogenic infectious disease caused by severe acute respiratory syndrome- coronavirus-2 (SARS-CoV-2), which originated in Wuhan, China in December 2019 and spread worldwide. The infectibility of these viruses could only be in the wild before the outbreak of extreme acute respiratory syndrome (SARS) in 2002 and middle-eastern respiratory syndrome (MERS) in 2012 as spotted by the world. While the disease dissipated across the globe throughout the natural environment, the mode of transmission to humans from the wild was insignificant and still unknown. Analysis of the whole genome sequence of the bats, however, was shown to be 96% similar with a severe acute respiratory syndrome-like (SARS-like) bat virus and 79.5% comparable with SARS-CoV, indicating that it is the possible route of transmission to humans [2]. There are four genera of CoVs: Alphacoronavirus, Betacoronavirus (βCoV), Gammacoronavirus, and Deltacoronavirus. Two new βCoVs, extreme acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV), have appeared over the past 12 years, and these viruses can cause significant human illnesses. The absence of adequate drug treatment and related elevated morbidity and death rates of these two CoVs, as well as their ability to cause epidemics, illustrate the need for innovative drug development for the prevention of diseases of CoV [3].
The size of the genome of the coronavirus ranges from 26 to 32 kb and contains 6 to 11 open reading frames (ORFs) encoding polyproteins with 9680 amino acids [4]. About 80 percent of the SARS-CoV-2 genome has been studied to be similar to the previous human coronavirus (SARS-like bat CoV) while, notable differences in SARS-CoV and SARS-CoV-2 genome have been reported in various studies, such as the lack of 8a protein and perturbations in the number of amino acids in 8b and 3c protein in SARS-CoV-2 [5]. The SARS-CoV2 genome is a polycistronic single-stranded RNA (+ssRNA) with a 5′-cap structure and 3′-poly-A tail (~30 kb), utilized as a template for translating polyproteins (pp1a/pp1ab) into the replication/transcription machinery (RTM) of a double membrane vesicle (Figure 1) (
Genomic organization of SARS-CoV-2. Schematic genomic structure of SARS-CoV-2 based on the SARS-CoV-2 Wuhan-Hu-1. The genome is categorized into two domains: Non-structural proteins and structural and accessory proteins. The S protein contains an S1 and S2 subunit, which are divided by the S cleavage site. Abbreviations: ORF, open reading frame; S, spike; E, envelope; M, membrane; N, nucleocapsid; NTD, N-terminal domain; RBD, receptor-binding domain; FP, fusion peptide; HR1 & 2, heptad repeat 1 and heptad repeat 2, containing the core binding motif in the external subdomain; TA, transmembrane anchor; IT, intracellular tail.
For the ORFs from the 5′ end, a region of about 20 kb corresponds to the two ORFs; ORF1a and ORF1b encoding 11 and 5 non-structural proteins: nsp1 to nsp11 and nsp12 to 16, respectively. The largest SARS CoV2 ORF1 gene (about two-thirds of the total length of the gene) contains −1 frameshift between ORF1a and ORF1b, resulting in the formation of two conserved polypeptide domains: pp1a and pp1ab. The ribosomal frameshift is involved in the translation of ORF1a directly from the RNA genome, near to the bottom of ORF1, which contains one ORF1ab polypeptide. There are ORFs encoding a few to more than ten structural/non-structural proteins downstream from the ORF1ab [8]. In ORF1ab as well as in other ORFs, CoVs often code different non-structural proteins, particularly near the 3′ end, although the specifics of the exact genes in the SARS-CoV-2 genome are still unclear primarily due to overlapping genes encoded in a different coding frame [9]. Two viral proteases, papain-like protease (PLpro) and 3C-like protease (3CLpro), are cleaved by the large replicase polyprotein 1a (pp1a) and pp1ab encoded by the 5 terminal open reading frame 1a/b (ORF1a/b) to produce non-structural proteins (NSPs) [10]. The NSPs contain two viral cysteine proteases (nsp3), chymotrypsin like, 3C like, or main protease (nsp5), RNA-dependent RNA polymerase (nsp12), helicase (nsp13) and others that may be involved in SARS-CoV-2 transcription and replication. [4]. In addition, four major structural proteins are coded by ORFs on a third of the genome near the 3′ terminus: spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins (Figure 2). Different CoVs encode unique structural and accessory proteins, such as HE protein, 3a/b protein, and 4a/b protein, in addition to these four major structural proteins. The sgRNAs of CoVs is translated back from both these structural and accessory proteins [11, 12, 13].
The virion structure of SARS-CoV-2. The spike (S), envelope (E), membrane (M) proteins form the envelope of the CoV, and the nucleocapsid (N) proteins form the capsid to pack the genomic RNA.
The structural research was initiated by studying in silico modeling Wuhan-Hu1 market seafood pneumonia virus genome [14, 15]. Focused on reported studies on SARS-CoV-2, we highlighted the number of nsp structures of this virus available: the papain-like protease (PLpro, nsp3; PDB code: 7D47), the main protease (3CLpro, nsp5; PDB code: 6LZE), the RNA-dependent RNA polymerase (RdRp, nsp12) in complex with cofactors nsp7 and nsp8 (PDB code: 6M71), the helicase (nsp 13; PDB code: 6ZSL), the Spike glycoprotein (S)(PDB code: 6XR8) and the RNA binding domain of nucleocapsid (N) phosphoprotein (PDB code: 6VYO).
For SARS-CoV2, the papain-like proteinase (PLpro) domain is included in nsp3 (1945 amino acids; located in the polyprotein, from 818 to 2819 aa), a 217.28 kDa membrane-associated replicase product [16]. Nsp3 consists of two transmembrane regions and approximately 10–16 recognizable domains, nine of which are conserved, responsible for cleavages at the polyprotein replicate’s N-terminus and assembly of viral-induced double-membrane cytoplasmic vesicles and viral replication, with nsp4 (Figure 3). It prevents the holding of NF-kappa-B signals. The inhibition of IRF3 host phosphorylation and dimerization and subsequent nuclear translocation was antagonized with type 1 interferon innate immune stimulation [17]. Additionally, PLpro has a deubiquitinating/deISGyling activity and processes cellular substrates from both ‘Lys-48’-and’ Lys-63′-linked polyubiquitin chains [18]. The role of Nsp3 is important to CoV replication and its domains include several predicted or demonstrated RNA replication accessories, such as ssRNA binding and unwinding domains, as well as those for which no separate function has yet been determined [19], cleaves ISG15 in vitro preferentially from substrates and utilizes host ADP-ribosylation to bind ADP-ribose [20].
Overview of the SARS-CoV2 nsp3 structural and genomic organization along with crystal structure of SARS-CoV-2 papain-like protease (PLpro). (PDB ID: 7D47). Abbreviations: DUF3655, protein of unknown function; macro, macro domain; SUD-N, SARS-unique domain binding G-quadruplexes; SUD-M, single-stranded poly(a) binding domain; PL2pro, coronavirus polyprotein cleavage domain; viral protease, papain like viral protease; NBD, nucleic-acid binding domain; 7tm GPCRs, seven-transmembrane G protein-coupled receptor superfamily; TM helix 5&6, transmembrane helix 5&6.
The SARS-CoV-2 nsp5 contains 306 amino acids (located in the replicase polyprotein pp1ab, 3264 to 3569 aa), a 33.8-kDa main protease (Mpro), which is also referred to as 3C-like protease (3CLpro) [21, 22]. The active site in SARS-CoV2 Mpro organized in between Domain I (8–99 aa) and Domain II (100–183 aa) was shown to be structurally similar to SARS-CoV Mpro. Both domains contribute one residue to the catalytic dyad (His41 and Cys145), linked to the helical domain IIII (200–306 aa) by a long loop region (184–199 aa) (Figure 4) [6]. Several co-crystalized SARS-Mpro structures bound with inhibitors, 11a and 11b (6LZE), I2 (2D2D), N1 (1WOF), N3 (2AMQ), and N9 (2AMD), revealed the position of S1, S2, and S4 subsites, especially in the active site close to His41 and Cys145, which is crucial for substrate recognition containing the core sequence [ILMVF]-Q-|-[SGACN] along with Tyr161 and His163 in the substrate-binding pocket [23]. Studies have estimated that the Mpro pp1ab protein has at least 11 conserved restriction sites, beginning with its autolytic cleavage site and even able to bind ADP-ribose-1′ [24, 25].
Structural representation of SARS-CoV-2 Mpro monomer (PDB ID: 6LZE) (ribbon representation) composed of: N-terminal domain I (cornflower blue), domain II (green), and C-terminal domain III (pink). Substrate recognition site in (green and red) and catalytic dyad residues, His41 and Cys145 are highlighted and labeled.
The SARS-CoV-2 nsp12 is a key component of the replication/transcription machinery sharing a strong structural homology with nsp12 of SARS-CoV, indicating that its function and mode of action may be well conserved [26]. SARS-CoV-2 nsp12, is a 106.7 kDa molecular weight protein with a chain length of 932 amino acids (located on the replicase polyprotein 1ab, 4393 to 5324 aa.), also referred to as RNA dependent RNA polymerase (RdRp) [27], has the capacity to synthesize the entire (−) RNA chains as a positive sense RNAs, as templates for additional genomic RNA (gNR) and subgenomic RNAs generation (sgRNAs) of the virus [21]. RNA-dependent RNA polymerases (RdRps) are a multi-domain protein that catalyzes polymerization of RNA-template (phosphodiesters formation between ribonucleotides), in the presence of divalent metal ions and thus play a major role in the viral replication and transcription of the SARS-CoV2 [28, 29]. The SARS-CoV-2 nsp12 (S1 to Q932) exists in complex with cofactors nsp7 (S1 to Q83) and nsp8 (A1 to Q198) heteromer with the second nsp8 attached to the distinct binding site. nsp12 contains the right-hand RdRp domain (S367 to F920) and the nidovirus-specific N-terminal β hairpin (D29 to K50) and extension domain (D60 to R249) which adopts the nidovirus RdRp-associated nucleotidyltransferase (NiRAN) architecture (Figure 5). The RdRp domain is divided into 3 sub-domains; the finger subdomain (L366–A581 and K621–G679), the palm subdomain (T582–P620 and T680–Q815), and the thumb subdomain (H816–E920) [30]. The nsp7-nsp8 heterodimer binding site is well conserved in the palm domain and overlaps with the functional domains of the preserved polymerase regions (fingers and thumb domains). In addition, seven preserved motifs (A-G) arranged in the polymerase active site domain, involved in template and nucleotide binding and catalysis, were also revealed by SARS-CoV-2 nsp12 structure [31]. Motif A contains the residue of classical divalent ion-binding glutamate (D) in position (618) & (623) of the conserved sequence 611-TPHLMGW
Domain organization of COVID-19 virus nsp12 and structural ribbon representation of the SARS-Cov-2 RNA-dependent RNA polymerase in complex with cofactors nsp7-nsp8 (PDB ID: 6M71) displaying domains, conserved motifs (A-G), and protein regions in the structure. A broad N-terminal extension (red) consisting of the NiRAN domain (violet) and the interface domain (cornflower blue) adjacent to the polymerase domain comprises SARS-CoV nsp12-nsp7(orange)-nsp8 (light pink) complex. The interdomain borders are labeled with residue numbers.
SARS-CoV-2 nsp13 is a 66.85 KDa protein, with a chain length of 601 aa. (located replicase polyprotein pp1ab, from 5325 to 5925 aa), also referred to as the Helicase [33]. SARS-CoV Nsp13 is a key enzyme in the disassembly of double stranded oligonucleotides into single strand using hydrolyzed energy of NTPs [34], having a N-terminal zinc-binding domain (ZBD) containing 3 zinc-finger motifs consisting of 2 tandem C-terminal RecA-like helicase domains (RecA1 and RecA2) and bridging stalk and 1B domains (Figure 6). The RecA-like domains catalyze the unwinding of the double stranded RNA and the NTP hydrolysis translocation of the complex. The stalk domain acts as a connection between the domain RecA-like/1B and the ZBD, which acts as an interface with other replicative machinery components [35, 36]. Nsp13 is strongly conserved among nidoviruses (percentage similarity of 99.8% with SARS-CoV, the only 1 amino acid substitution I570 V) consists of five domains that fold in a triangular pyramid shape [37]. These domains hold incredibly high conservation of protein sequences along with its essential role in viral replication, thus making it a vital target for a wide variety of therapeutics to target this viral family [38]. Helicase exhibits various enzymatic roles, including not only hydrolysis of NTPs required by the capping process, but also removal of 50–30 directionally RNA duplexes and 50-triphosphatase RNA activity. In addition, the association of Helicase nsp13 with RdRp Nsp12 promotes RNA unwinding activity and is a crucial viral replication enzyme, in all coronaviruses [39].
Domain representation of SARS-CoV2 nsp13 and the structural ribbon representation of the SARS-CoV-2 helicase (PDB ID: 6ZSL). The interdomain borders are labeled with residue numbers. The colors of the protein domains are indicated in panel a (ZBD-red, stalk-cyan blue, 1B-green, 1A-orange and 2A-pink). Three zinc atoms are shown as black spheres. The NTPase active site (violet) consists of six residues-Lys288, Ser289, Asp374, Glu375, Gln404 and Arg567.
The newly discovered SARS-CoV2 S-glycoprotein is a glycosylated trimer, each protomer with a chain length of 1260 amino acids (residues 14–1273), with a molecular weight of 141.1 kDa, consisting of two subunits, the surface subunit S1 and the transmembrane unit S2 [40, 41]. The surface subunit S1 is composed of 672 amino acids (residues 14–685) and differentiated into four divisions: N-terminal domain (NTD), a C-terminal domain (CTD, also known as the receptor-binding domain, RBD), and two subdomains (SD1 and SD2). The transmembrane S2 subunit is composed of 588 amino acids (residues 686–1273) and contains an N-terminal hydrophobic fusion peptide (FP), two heptad repeats (HR1 and HR2), a transmembrane anchor (TA), and an intracellular tail (IT), arranged as FP-HR1-HR2-TA-IT (Figure 7). A polybasic amino acid bridge (−QTQT-
Crystal structure of SARS-CoV 2 spike protein (S) PDB ID: 6XR8. Different domains of the spike protein that includes; signal sequence (SS), the N-terminal domain (NTD), receptor-binding domain (RBD), subdomain 1 and 2 (SD1&2), protease cleavage sites (S1/S2/S2′), fusion peptide (FP), heptad repeat 1 and 2 (HR1&2), central helix (CH), connector domain (CD), transmembrane anchor (TA), and intracellular tail (IT).
SARS-CoV-2’s N (Nucleocapsid) protein is a putative RNA-binding protein responsible for gathering the viral RNA genome for encapsulation in the viral membrane into compact ribonucleoprotein (RNP) complexes [45]. N is the structural unit present in the nucleocapsid of the SARS-CoV-2 genome, 46 kDa protein and comprises of 419 amino acids (aa) containing three distinctly diverse domains: The N-terminal domain (NTD)/RNA-binding domain (46–174 aa), the serine/arginine-rich (SR-rich; 184–197 aa) linker region (LKR; 175–254 aa) and the C-terminal domain (CTD; 255–364 aa) (Figure 8) [46]. Both domains (NTD & CTD) are flanked by an inherently disordered region IDR, which is the central linker region (LKR) with a Ser/Arg (SR)-rich area containing alleged phosphorylation sites [47, 48]. An asymmetric unit crystal configuration of the N-terminal RNA nuclear protein binding field showed the sandwiched fold shared by the CoV N-NTD with the same right hand (loop) - (β-sheet core) - (loop), with the order β1-η1- β2- β3- β4- β5- β6- β7. The core β-sheet consists of five β-strands with just 3₁₀ helix ahead of strand β2 and a β-strand between the strands β2 and β 5. The β-hairpin is functionally important in mutational analysis of amino acid residues at the RNA binding N-terminal domain of SARS-CoV2 [49]. The structures of the N-CTD RNA binding domain highlight the reserved architecture of 3₁₀ helix acidic coil containing a β-sheet core of 5 antiparallel β-sheets, and an expanded β3–4 hairpin with the order η1-α1-α2-η2-α3-α4-β1-β2-α5-η3. Generally, the RNA binding domain of the N protein is essentially simple and sometimes defined as a right hand-like shape with a protruding fundamental finger, basic palm and acidic wrist [50].
Schematic representation of SARS-CoV-2 Nucleocapsid (N) protein domains. Three intrinsically disordered regions, i.e., N-arm, linker region (LKR) and C-tail, and the N-terminal domain (NTD) and C-terminal domain (CTD) are illustrated. The charged Ser/Arg (SR)-rich motif (colored light yellow) is shown. Cartoon view of the N protein NTD domain (PDB ID: 6M3M), a monomer, colored by the number variants at different positions, and CTD (PDB ID: 7C22), a heterodimer with one monomer colored gray and the other colored blue indicating various regions within the structure as observed in SARS-CoV-2 genomes.
Therapeutics facilities aid physicians and scientist to help patients with the better cure for the disease and develop a vaccine. The production of novel therapeutics and vaccination is now at the earliest possible time to curb the epidemic. In addition, continuous attempts are being made at regional, national, and person levels to recognize the host, genomics, epidemiological interactions, and propagation modes of SARS-CoV-2 in order to control the epidemic. Scientists worldwide are actively working to establish an optimal antiviral agent and vaccine against SARS-CoV-2 [51]. One way of preventing this issue is to test two or three drugs with minimal prolixity that operate on various cellular signals with viral replication. A further approach that helps researchers to curb the variety of individual antimicrobials for emerging and re-emerging infectious diseases is the high-performance screening of host-virus interaction level composite libraries for synergistic combinations [52, 53]. Nevertheless, the screening of experimental small molecule drugs in combinations and other potent anti-SARS-CoV-22 agents with new and improved key characteristics can be effective which can be helpful in COVID-19 therapy. Potential medicines include previously used or tested medicines for diagnosing diseases and medicines recently discovered or developed. In most cases, the benefits of drug repurposing are safety evaluation, preclinical monitoring, and in some cases the development processes would not take much time and thus reduce the time needed for drug development. The chances of failure with repurposed drugs would be smaller as the early steps of medication efficacy and safety testing have already been completed and the treatment has already been shown to be sufficiently effective in a preclinical and human model [54]. Antiviral therapies are being investigated towards treatment of COVID-19 because the SARS-CoV-2 replication of leads to wide variation of the clinical manifestations. As significant functional proteins of SARS-CoV-2, Nsps and other structural and accessory proteins are involved in transcription of RNA, synthesis of protein, post-translational modification, viral duplication and contagion of the host. Among them, PLpro (nsp3), 3CLpro (nsp5), RdRp (nsp12), Helicase (nsp13), Spike glycoprotein (S) and Nucleocapsid (N) are the most important targets for the development of small-molecule inhibitors due to the enzyme active site and clear biological functions [55].
Protease inhibitors are drugs that inhibit the activity of protease enzyme responsible for viral development, infection, and replication by cleaving it into smaller fragments. They bind to the active site of the enzyme, mediate and block the maturation of freshly formed virions [51]. Two major targets: PLpro and 3-CLpro in the replicase 1a and 1ab domain are essential component for virus reproduction and regulation of host cell response thus being the important target for the SARS-CoV-2 inhibitors (Figure 9). Ribavirin (SCH-18908) [NCT00578825], an antiviral drug acts on the replicase protein, preventing binding of the nucleotides, resulting in reduced viral replication or the formation of defective virions. Lopinavir [NCT04321174] and Ritonavir [NCT04330690], are protease inhibitors used to treat HIV infections by inhibiting the HIV protease enzyme to form an inhibitor-enzyme complex and proteolytic cleavage of the viral polyprotein precursors [3]. Darunavir [NCT01448707], another (HIV-1) nonpeptidic protease inhibitor with the inhibition activity of the dimerization and catalytic activity of HIV-1 protease. Saquinavir [DB01232] inhibiting HIV1/2 protease-mediated lysis of HIV gag and pol polyproteins was found cytotoxically active at conc. Above 50 μM [56]. Rupintrivir (DB05102) a broad-spectrum antiviral agent is a potent 3C-Like protease inhibitor against norovirus, picornavirus, and coronavirus proteases in development against human rhinoviral (HRV) infections that has been recently co-crystallized with its target [57]. Larazotide acetate (AT1001) (NCT03569007) a paracellular permeability peptide inhibitor has been studied for the treatment of autoimmune diseases such as type I diabetes mellitus, gastrointestinal diseases and disorders. Studies have revealed that AT1001 potentially binds to the Mpro catalytic domain showing up intermolecular interactions [58]. Teicoplanin (DB06149), a glycopeptide antibiotic widely used to treat bacterial infections, has been reported to be active against SARS-CoV-2 in
Repurposed protease inhibitors for COVID-19 treatment.
RdRp is a critical non-structural protein component of the SARS-CoV-2 genome that uses a metal-ion-dependent mechanism to catalyze viral RNA synthesis. However, due to its comprehensive knowledge about the different domains and its functions, strong preservation among evolutionary RNA viruses and the lack of homologous sequences in mammalian cells; the ease progress and consequent access to biochemical assays to quickly detect large collections of compounds [63]. Remdesivir (GS-5734) [NCT04252664], a nucleoside analogue acts on the replicase polyprotein 1ab of SARS-CoV-2 genome preventing RNA polymerase function resulting in ending the transcription of RNA and reduces the production of viral RNA. Penciclovir [NCT00820534], another nucleoside analogue, synthetic acyclic guanine derivative with antiviral activity targets the RdRp inhibiting the DNA synthesis of virus-infected cells and terminating viral replication (Figure 10). β-D-N4-hydroxycytidine, an orally bioavailable, broad-spectrum antiviral ribonucleoside analogous to multiple RNA viruses like influenza, CoV, equine encephalitis and Ebola viruses have been found in
Repurposed replicase inhibitors for COVID-19 treatment.
SARS-CoV-2 replication enzyme, helicase has the properties of unwinding and splitting DNA and RNA into two single-stranded nucleic acids and these characteristic of the enzyme marks it as a potential target to be studied [68]. Bananins have been shown to inhibit SARS-CoV ATPase activity leading to inhibition of viral replication
For the entry of coronavirus into a host cell, transmembrane Spike (S) glycoprotein is essential. Fusion of the membrane and activation of the virus entry require cleavage at the S1–S2 junction and because of their vital role in the interaction between the virus and the cell receptor, spike protein can be an important potential target for antiviral agents [76]. The receptors that mediate the fusion of the S protein of SARS-CoV2 into the host cell are angiotensin converting enzyme-2 (ACE-2) and type 2 transmembrane protease serine (TMPRSS2). Cleavage via TMPRSS2 the fusion of the S protein to the ACE-2 receptor is achieved and thus are the potential drug targets in the SARS-CoV-2 therapeutics [51]. Umifenovir (Arbidol) [NCT04350684], an antiviral drug has been found to block and effectively prevent the trimerization and cell adherence and entry of SARS-CoV-2 spike glycoprotein interacting with the key residues in the target domain indicating as the potential target [77]. Griffithsin, a lectin protein has demonstrated antiviral properties and can potently inhibit viral entry and prevent binding to the S glycoprotein both in vitro and in vivo SARS-CoV infection with limited cytotoxic effects. Previous studies have shown griffithsin to inhibit MERS-CoV infectivity in
SARS-CoV-2 nucleocapsid (N) protein is a multifunctional protein that plays a key role in the assembly of the virus and its transcription of the RNA. During the packing of the RNA genome, the N protein is critical in the creation of helical ribonucleoproteins, controlling viral RNA synthesis during replication and transcription. Infected host cells and their cellular functions are also regulated by the N protein [82]. Previous studies identified a special ribonucleotide-binding pocket composed of strongly conserved residues in the NTD by solving the complex structure of CoV NP-NTD bound with ribonucleotide monophosphate. Compounds that bind to this RNA-binding pocket may inhibit normal NP function and may be used to regulate CoV diseases. 6-chloro-7-(2-morpholin-4-yl-ethylamino) quinoxaline-5,8-dione (H3) (Figure 11) revealed inhibitory activity on the RNA-binding of NP [83]. Mefuparib hydrochloride, CVL218, a Poly [ADP-ribose] polymerase 1 (PARP1) inhibitor have shown to exhibit effective inhibitory activity against SARS-CoV-2 replication without apparent cytopathic effect in
Repurposed structural and accessory protein inhibitors for COVID-19 treatment.
Various vaccines across the globe are in the progress of development against COVID-19, while the efficacy, productive and stability of most of them is still unclear. The latest report from the World Health Organization states about 69 vaccine candidates in the progress of clinical trial and about 181 candidates in pre-clinical development [87]. About 7% of vaccinations in the state of preclinical trials performed are based on practice. Hereby, we list the current status of several vaccines across the globe approved by Food and Drug Administration (FDA), European Medicine Agency (EMA), World Health Organization (WHO), Indian Council of Medical Research (ICMR) and other countries medical advisory boards under progress of development for the emergency use authorization (EUA) in order to curb the pandemic (Table 1).
S.No. | Candidate | Developer | Type | Approval Status (EUA) |
---|---|---|---|---|
1 | BNT162b2 | Pfizer–BioNTech | mRNA | FDA Approved |
2 | mRNA-1273 | ModernaTX, Inc. | mRNA | FDA Approved |
3 | Sputnik-V | Gamaleya | Ad26, Ad5 | EMA Approved |
4 | ChAdOx1 nCoV19 | Oxford-AstraZeneca | Non-Replicating Viral Vector | WHO Approved |
5 | Covaxin (BBV152 A, B, C) | Serum Institute, Bharat Biotech | Inactivated | ICMR Approved (India) |
6 | CoronaVac | Sinovac | Inactivated | Approval limited (China, Indonesia) |
7 | Convidicea (Ad5-nCoV) | CanSino Biologics | Viral vector | Approval limited (China) |
8 | EpiVacCorona | Vector Institute | Protein vaccine | Approved for Early use (Russia) |
9 | Sinopharm | Sinopharm | Inactivated | Approval limited |
10 | BBIBP-CorV | Beijing Institute of Biological Products-Sinopharm | Inactivated | Approval limited |
Vaccines against COVID-19 approved for emergency use authorization.
The principle of drug repurposing is very beneficial and may have proven success, although this may differ with the severity as well as the subjects in whom therapy is performed. In the case of vaccinations, several vaccines have shown promising effects throughout the globe and the proceeding steps will soon provide hope for the early commercial launch of COVID-19 vaccines. Since the structural organization and genomic constitution of the SARS-CoV-2 is similar to that of SARS-CoV, antiviral drugs and other therapeutic measures employed to control the disease at the time can be utilized in order to control this epidemic condition. However, the rate and amount of research and clinical COVID-19/SARS-CoV-2 studies to improve potential treatments and therapies for this disorder will surely help us in order to curb the disease soon. Consequently, the design and production of SARS-CoV-2 vaccines is similarly critical in comparison to the development of new medicines and clinical trials of old drugs. Experience from SARS-CoV and MERS-CoV suggests that there is a major focus on creating animal models that can summarize different forms of human disease and assess the safety and efficacy of vaccines.
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nOAI-PMH
\\n\\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\\n\\nPeer Review Policies
\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\\n\\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\\n\\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. 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He obtained a Master’s degree in Public Health and PhD in Public Health and Epidemiology. He has a background in Clinical Medicine and has taken courses at higher diploma levels in public health from University of Transkei, Republic of South Africa, and African Medical and Research Foundation (AMREF) in Nairobi, Kenya. Dr. Kasenga worked in different places in and outside Malawi, and has held various positions, such as Licensed Medical Officer, HIV/AIDS Programme Officer, HIV/AIDS resource person in the International Department of Diakonhjemet College, Oslo, Norway. He also managed an Integrated HIV/AIDS Prevention programme for over 5 years. He is currently working as a Director for the Health Ministries Department of Malawi Union of the Seventh Day Adventist Church. Dr. Kasenga has published over 5 articles on HIV/AIDS issues focusing on Prevention of Mother to Child Transmission of HIV (PMTCT), including a book chapter on HIV testing counseling (currently in press). 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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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A dynamic career research platform which is based on the thematic areas of comparative vertebrate physiology, stress endocrinology, reproductive endocrinology, animal health and welfare, and conservation biology. \nEdward has supervised 40 research students and published over 60 peer reviewed research.",institutionString:null,institution:{name:"University of Queensland",institutionURL:null,country:{name:"Australia"}}},editorTwo:null,editorThree:null,series:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517"},editorialBoard:[{id:"258334",title:"Dr.",name:"Carlos Eduardo",middleName:null,surname:"Fonseca-Alves",slug:"carlos-eduardo-fonseca-alves",fullName:"Carlos Eduardo Fonseca-Alves",profilePictureURL:"https://mts.intechopen.com/storage/users/258334/images/system/258334.jpg",institutionString:null,institution:{name:"Universidade Paulista",institutionURL:null,country:{name:"Brazil"}}},{id:"191123",title:"Dr.",name:"Juan José",middleName:null,surname:"Valdez-Alarcón",slug:"juan-jose-valdez-alarcon",fullName:"Juan José Valdez-Alarcón",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBfcQAG/Profile_Picture_1631354558068",institutionString:"Universidad Michoacana de San Nicolás de Hidalgo",institution:{name:"Universidad Michoacana de San Nicolás de Hidalgo",institutionURL:null,country:{name:"Mexico"}}},{id:"161556",title:"Dr.",name:"Maria Dos Anjos",middleName:null,surname:"Pires",slug:"maria-dos-anjos-pires",fullName:"Maria Dos Anjos Pires",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS8q2QAC/Profile_Picture_1633432838418",institutionString:null,institution:{name:"University of Trás-os-Montes and Alto Douro",institutionURL:null,country:{name:"Portugal"}}},{id:"209839",title:"Dr.",name:"Marina",middleName:null,surname:"Spinu",slug:"marina-spinu",fullName:"Marina Spinu",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLXpQAO/Profile_Picture_1630044895475",institutionString:null,institution:{name:"University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca",institutionURL:null,country:{name:"Romania"}}},{id:"92185",title:"Dr.",name:"Sara",middleName:null,surname:"Savic",slug:"sara-savic",fullName:"Sara Savic",profilePictureURL:"https://mts.intechopen.com/storage/users/92185/images/system/92185.jfif",institutionString:'Scientific Veterinary Institute "Novi Sad"',institution:{name:'Scientific Veterinary Institute "Novi Sad"',institutionURL:null,country:{name:"Serbia"}}}]},onlineFirstChapters:{paginationCount:13,paginationItems:[{id:"81566",title:"New and Emerging Technologies for Integrative Ambulatory Autonomic Assessment and Intervention as a Catalyst in the Synergy of Remote Geocoded Biosensing, Algorithmic Networked Cloud Computing, Deep Learning, and Regenerative/Biomic Medicine: Further Real",doi:"10.5772/intechopen.104092",signatures:"Robert L. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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