Affinities (
\r\n\tThe properties of metamaterials are designed not from the properties of their base materials, but rather from the metamaterial's newly designed structures. The precise shapes, geometries, sizes, orientations, and arrangements of metamaterial composing elements render metamaterials versatile ‘smart’ properties related to manipulating electromagnetic waves, by blocking, absorbing, enhancing, or bending waves of specific wavelengths. This allows achieving benefits extending far beyond what could be achieved by employing conventional materials.
\r\n\tMetamaterials have broad and diverse potential applications including optical filters, medical devices, remote aerospace devices and materials, sensors, infrastructure monitoring, highly effective management of solar power, high-frequency battlefield communication, lenses for high-gain antennas, shielding structures to prevent earthquake damage, acoustic materials, etc. Metamaterial research area is highly interdisciplinary: it involves electrical engineering, electromagnetics, classical optics, studies in the solid-state physics field, antenna engineering, optoelectronics, material science, nanoscience and nanotechnology, semiconductor design, and even can involve computational chemistry.
Biosensors measure the real-time reversible interactions between biologically-relevant molecules independent of labels. Typically, they harness an optical phenomenon to detect the binding of a solution molecule (analyte) to its immobilized partner (ligand) on a sensor and record the output as a “sensorgram”, which tracks the binding signal in arbitrary units proportional to mass sensed at the surface of the biosensor as a function of time. These cutting-edge biophysical tools are revolutionizing our understanding of molecular-level processes because they reveal an entire binding profile between unlabeled reactants and dissect it into kinetic components from which an affinity can be deduced. By definition, the affinity or equilibrium dissociation constant (
\n\t\t\t\t\tFigure 1 depicts the way in which three different biosensor platforms address samples. The Octet is a fairly new technology that uses bio-layer interferometry by employing fiber-optic sensors incorporated on disposable tips. Another emerging technology, the ProteOn, uses surface plasmon resonance (SPR) and gold sensor chips, as does the Biacore. For more information about the principles upon which these detectors are based, the reader is referred to the manufacturers’ websites; www.fortebio.com, www.bio-rad.com, and www.biacore.com. By reversing the configuration where now the sensors move to the samples, the Octet renders the microfluidics that delivers samples to a stationary sensor chip in the ProteOn and Biacore systems, unnecessary. The Octet adopts a well-based dip-and-read format in which a column of up to eight sensor tips immerses into samples held in an open shaking microplate (Fig. 1A). Binding steps are defined by moving these sensors along the rows in the plate and the tips are discarded at the end of the assay. Dipping into samples rather than injecting them allows the Octet to measure longer association times and re-use samples within an assay or recover them for other uses. The ProteOn also processes samples in parallel, delivering them via six injections that flow perpendicularly to create a unique six-by-six interaction array (Fig. 1B). This generates 36 “reaction spots” (shown by the red squares in Fig. 1B) where flowpaths intersect and 42 “interspots” (in each direction), which provide a local-referencing option as an alternative to traditional whole-channel referencing. In contrast, the Biacore 3000 injects one sample at a time over up to four serially-addressed flow cells, one of which typically serves as a reference channel (Fig. 1C).
\n\t\t\t\tSample addressing in (A) Octet QK, (B) ProteOn XPR36, and (C) Biacore 3000 biosensors. The sample plate used in A is black.
The above-named SPR platforms support a limited number of immobilized ligands per experiment and rely upon being able to regenerate them. In contrast, the Octet can analyze up to 96 ligands per experiment on inexpensive single-use sensors that can be regenerated to make an assay more cost-effective. The throughput offered by the ProteOn may make regeneration unnecessary if the 36 interactions that can be addressed in a single binding cycle cover all the desired permutations. An unique advantage of the Octet’s configuration is that ligands can be loaded
It is important to assess the performances of emerging technologies relative to well-establish ones since biosensors are now routinely multiplexed to meet the demands of drug discovery for higher throughput. Determining whether there is consensus across different biosensor platforms operated by independent users has been a theme of several benchmark studies (Rich et al., 2009; Navratilova et al., 2007; Katsamba et al., 2006; Papalia et al., 2006; Cannon et al., 2004; Myszka et al., 2003). The largest and most recent of these engaged 150 participants from 20 countries who used instruments from ten different manufacturers. These collaborations enhance the biosensor community’s ability to design experiments and provide insights into the variability of biosensor data where it can become difficult to discriminate between sub-optimal instrument quality and an unskilled user. Inspired by these studies and the continuing evolution of biosensors, we compared the performances of two parallel-processing platforms, namely the Octet QK and the ProteOn XPR36 interaction array, head-to-head with the serial flow Biacore 3000 unit that represents the current “workhorse” of the biosensor research community as judged from it being the most frequently cited platform in the literature (Rich & Myszka, 2008). First, we addressed binding kinetics which is perceived as the signature role of biosensors based upon the abundance of literature on the topic. Then we explored competitive binding which, despite its relevance to drug discovery, is scarcely reported on in the literature.
\n\t\t\tFor the purpose of comparing instruments side by side and to enable other investigators to reproduce our work, we adopted a commercially available antigen/antibody pair as a model system. The murine monoclonal antibody 4901 (Wong et al., 1993) was chosen because it binds various forms of calcitonin gene-related peptide (CGRP) with affinities that fall within a measurable range (high picomolar to mid-nanomolar) and allows for facile regeneration in all assay orientations. CGRP is implicated in migraine and other types of pain and thus interfering with its biological activity is relevant to drug discovery (Geppetti et al., 2005). We studied wild-type (1-37) rat-CGRP-alpha (rCGRPα) and 1-37, 26-37, and 32-37 forms of human-CGRPα (hCGRPα), which spanned molecular masses of 609Da to 3806Da and bound antibody 4901 with affinities ranging from 0.5nM to about 500nM. We oriented the assay in three different ways. First, we presented naked peptides to antibody-coupled sensors. Secondly we presented Fab fragments to N-biotinylated peptides that were captured via streptavidin sensors. Lastly, we deduced an affinity of the CGRP/4901 interactions indirectly via solution competition. The following sections describe each assay orientation as published elsewhere (Abdiche et al., 2008).
\n\t\t\tWhen the goal is to generate binding kinetics, it is prudent to present a monomeric partner in solution so that its binding can be modeled easily without interference of avidity (Myszka, 1999). Therefore, one way to study the CGRP/4901 interaction was to allow the solution peptides to bind amine-coupled antibody. None of the peptides could be detected directly on the Octet due to their binding signals being within instrument noise, but all were clearly visible on the SPR platforms; small molecule analysis is routine on the Biacore 3000 (Navratilova et al., 2007; Papalia et al., 2006; Cannon et al., 2004; Myszka et al., 2003) and was first described on the ProteOn by Bravman et al., 2006. These authors introduced a method called “one-shot kinetics” that exploits the parallel injection mode of the ProteOn to deliver in a single step a six-membered dilution series of the analyte over six surfaces of immobilized ligand with varying binding capacities. This generates a robust data set because a large number of binding curves are fit simultaneously to converge upon an unique pair of kinetic rate constants, whose ratio gives a global affinity for the interaction. Using this method, we analyzed four peptides binding to multiple levels of coupled 4901 by regenerating the immobilized antibody after each “one-shot” series and duplicating every injection. The kinetic analysis of one of these peptides, namely hCGRPα 32-37, is shown in Fig. 2A. This interaction was also amenable to an equilibrium analysis (Frostell-Karlsson et al., 2000) as a non-kinetic route to the affinity owing to all the binding responses reaching plateau values within the association phase (Fig. 2B).
\n\t\t\t\tOne-shot kinetics on the ProteOn. (A) Primary data (noisy lines) for hCGRPα 32-37 binding five levels of coupled antibody 4901 (where 1-5 depict the high to low surface capacities) and their simultaneous fit to a simple kinetic model (solid lines) that gave a
Kinetic rate constants determined in two assay orientations. Not all permutations of biosensor, peptide, and assay orientation were investigated (see
The ProteOn and Biacore platforms returned remarkably similar kinetic rate constants for an array of CGRPs binding coupled 4901 IgG (Figure 3, solid symbols) and the affinity ranking was consistent with 4901’s known species-selectivity and its epitope that incorporates the ten most C-terminal residues of CGRP.
\n\t\t\tAnother assay orientation that we explored was the direct binding of Fab to N-biotinylated full-length peptides on streptavidin or neutravidin sensors. This method was less convenient than the one described above because the reagents had to be modified. While the Fab was easily detectable on the Octet, it rebound the CGRP-saturated tips, to different extents depending upon the CGRP used, as evidenced by the deviation of the dissociation phase from a single exponential decay (black lines in Fig. 4A and 4B). While rebinding is a drawback of the Octet’s well-based format, it was rectified by spiking the dissociation buffer with high concentrations of a tight-binding competing antigen (100μM rCGRPα) (red lines in Fig. 4A and 4B).
\n\t\t\t\tPrimary Octet data for “one-shot” kinetics of 4901 Fab binding streptavidin tips coated with (A) rCGRPα or (B) hCGRPα, dissociating them into buffer (black) or a sink (red). (C) and (D) show the kinetic fits (in black) of the “sinked” data (in color) in panels A and B, respectively. The global fit in D is for quadruplicate analyses on one column of tips.
Not only did the fitted kinetic rate constants and affinities (Table 1) describe the Octet data very well (Fig. 4C and 4D), but they agreed closely with those obtained for similar analyses on ProteOn and Biacore platforms (Figure 5) and previously published values (Zeller et al., 2008). The Octet and ProteOn data were performed in a parallel “one-shot” kinetic mode whereas the Biacore data were collected in a serial multi-cycle mode by regenerating the surfaces after each injection.
\n\t\t\tDirect comparison of 4901 Fab interacting with hCGRPα surfaces on different biosensors. The measured data and their global fits are overlaid. The timing of the binding steps varied according to the biosensor used.
While the Octet cannot detect small molecules directly, it can access affinities indirectly via solution competition. An advantage of deducing a solution affinity is that it is unbiased by the assay orientation and unaffected by the immobilization process. In this type of experiment, two binding partners are mixed in solution at various concentrations and the free concentration of one of them is probed by an immobilized molecule whose affinity is not being measured. An appealing feature of our model system was that the sensors could be coated with the tight-binding rCGRPα to probe the weaker affinities of the other peptides (Figure 6).
\n\t\t\t\tSolution competition on the Octet using rCGRPα-saturated tips to probe for free antibody binding sites in (A) standard curve (twofold serial dilution of 4901) and (B) inhibition curve (fivefold serial dilution of hCGRPα 26-37 into a fixed concentration of 4901). (C) Overlay plot of the inhibition by rCGRPα (red) and 1-37 (blue), 26-37 (green), and 32-37 (grey) hCGRPα with fits in black.
Similar results were obtained on all three biosensors (Table 1), but only the Biacore was sensitive enough to work at the sub-nanomolar concentrations of fixed antibody binding sites needed to estimate the tight affinity of the rat peptide. Ideally, the concentration of the partner being detected at the sensor (in this case, the antibody) should be fixed (at or) far below the anticipated affinity of the solution interaction being measured in order for binding to be driven by affinity. If it is fixed far above the anticipated affinity of the solution interaction, then binding will be driven mainly by concentration and thus will instead determine the antibody’s “active concentration” by titrating out CGRP in a stoichiometric manner.
\n\t\t\tThe ProteOn and Biacore returned virtually identical kinetics (Figure 3) regardless of the assay orientation used, while those determined on the Octet were typically within twofold of them with direct binding of small molecules beyond its detection limit (Table 1). The affinity of the rCGRPα/4901 interaction was consistently around 0.5nM by SPR by all three methods, suggesting that neither binding partner had been adversely affected upon immobilization or modification. In contrast, the wild-type hCGRPα discriminated between the Fab and intact
\n\t\t\t\tCGRPα | \n\t\t\t\t\t\t\tCGRP binding coupled 4901 | \n\t\t\t\t\t\t\t4901 Fab binding CGRP on sensor | \n\t\t\t\t\t\t\tSolution competition with IgG (or Fab) | \n\t\t\t\t\t\t||||||
\n\t\t\t\t\t\t\t | Octet | \n\t\t\t\t\t\t\tProteOn | \n\t\t\t\t\t\t\tBiacore | \n\t\t\t\t\t\t\tOctet | \n\t\t\t\t\t\t\tProteOn | \n\t\t\t\t\t\t\tBiacore | \n\t\t\t\t\t\t\tOctet | \n\t\t\t\t\t\t\tProteOn | \n\t\t\t\t\t\t\tBiacore | \n\t\t\t\t\t\t
Rat 1-37 | \n\t\t\t\t\t\t\tND | \n\t\t\t\t\t\t\t0.565 | \n\t\t\t\t\t\t\t0.569 | \n\t\t\t\t\t\t\t2 | \n\t\t\t\t\t\t\t0.612 | \n\t\t\t\t\t\t\t0.432 | \n\t\t\t\t\t\t\tND | \n\t\t\t\t\t\t\tND | \n\t\t\t\t\t\t\t0.54 (0.45) | \n\t\t\t\t\t\t
Hu 1-37 | \n\t\t\t\t\t\t\tND | \n\t\t\t\t\t\t\t5.78 | \n\t\t\t\t\t\t\t4 | \n\t\t\t\t\t\t\t36 | \n\t\t\t\t\t\t\t16.2 | \n\t\t\t\t\t\t\t17.3 | \n\t\t\t\t\t\t\t28 (22) | \n\t\t\t\t\t\t\t7 (20.3) | \n\t\t\t\t\t\t\t5.8 (18.2) | \n\t\t\t\t\t\t
Hu 26-37 | \n\t\t\t\t\t\t\tND | \n\t\t\t\t\t\t\t8.13 | \n\t\t\t\t\t\t\t9.55 | \n\t\t\t\t\t\t\tNT | \n\t\t\t\t\t\t\tNT | \n\t\t\t\t\t\t\tNT | \n\t\t\t\t\t\t\t38 (27) | \n\t\t\t\t\t\t\t34 (23.6) | \n\t\t\t\t\t\t\t44 (23.1) | \n\t\t\t\t\t\t
Hu 32-37 | \n\t\t\t\t\t\t\tND | \n\t\t\t\t\t\t\t147 | \n\t\t\t\t\t\t\t202 | \n\t\t\t\t\t\t\tNT | \n\t\t\t\t\t\t\tNT | \n\t\t\t\t\t\t\tNT | \n\t\t\t\t\t\t\t500 (280) | \n\t\t\t\t\t\t\t370 (224) | \n\t\t\t\t\t\t\t460 (239) | \n\t\t\t\t\t\t
Affinities (
IgG; the Fab bound hCGRPα on chip with a threefold weaker affinity than its IgG counterpart with the trend being corroborated by solution competition measurements. In a separate experiment, we confirmed that the naked and N-biotinylated peptides bound with identical kinetics when flowed over coupled IgG. Our results demonstrate that the assay orientation can affect the results as much or more than the biosensor used.
\n\t\t\tThe next application we explored was competitive binding because of its relevance to drug discovery. Most drugs functioning as antagonists are aimed at blocking a natural interaction such as that between a ligand and its receptor. Monoclonal antibodies (Abs) are becoming increasingly utilized as therapeutic entities in blocking these ligand-receptor interactions. An epitope is defined as the three-dimensional region on an antigen (Ag) where an antibody binds. Discriminating Abs based on their epitope rather than their apparent affinity for the target Ag is often more important because of established protocols for affinity maturation by protein engineering, while changing an epitope to a desired one is not typically possible. We decided to illustrate the use of biosensor blocking assays in the context of epitope binning (Abdiche et al., 2009).
\n\t\t\tBiosensors are essentially mass-based detectors. Therefore, determining whether an Ab blocks another’s ability to bind Ag is simply a yes/no read-out, regardless of the assay orientation used. Under conditions that favor complete blocking, i.e. overlapping epitopes, no binding response will be detected at the sensor for any of the arrowed interactions in Figure 7. In contrast, a binding signal at each of these interactions identifies a pair of Abs that can coexist on the Ag at distinct, non-overlapping epitopes and thus form a sandwich complex. Using this yes/no detection of the arrowed interactions, we assign Abs to epitope bins according to their blocking profiles relative to one another.
\n\t\t\t\tThree assay orientations that can be used in epitope binning. In each case, the antigen binds the black Ab before the red Ab.
In order for two Abs to belong to the same bin, they must block one another and exhibit similar blocking profiles when each is paired with the other Abs in the test panel. Thus, the observation that two Abs block one another is necessary but not sufficient to conclude that they belong to the same bin. Once two Abs have been assigned to the same bin it is possible that another Ab will be discovered in the future that blocks one and not the other, thus resolving them into different bins. We used six Abs (1-6) against a dimeric Ag to illustrate “in tandem” and “premix” methods and six different Abs (A-F) against an unrelated monomeric Ag to illustrate the “classical sandwich” method. We performed each assay on the three above-mentioned biosensors and since all biosensors gave similar results we only show data from the ProteOn because its two-dimensional interaction array makes it particularly well-suited to pairwise and combinatorial approaches to binning. The following sections describe each assay orientation in turn.
\n\t\t\tIn tandem blocking is probably the simplest conceptually. It involves coating the sensors with Ag and presenting two Abs one after another, namely a “saturating Ab” followed by a “competing Ab” (Fig. 7A). Figure 8 shows how we performed an in tandem binning on the ProteOn and addressed 36 pairs of Abs in a single binding cycle with a complete set of six “self-blocking” controls along the diagonal of the interaction array. Consolidating the results into a matrix that can be read horizontally or vertically (Table 2) revealed three blocking patterns or “bins”, namely Ab1 and 3; Ab2 and 4; and Ab5 and 6. Thus, Ab1 and 3 each sandwiched with Ab5 and 6, whereas Ab2 and 4 blocked all six.
\n\t\t\tIn tandem binning. (A) Immobilizing Ag on all vertical channels. (B) Saturating with six Abs (1-6) on separate vertical channels. (C) Competing with the same Abs (1-green, 2-pink, 3-blue, 4-cyan, 5-black, and 6-orange) in the horizontal direction, where the plots are grouped and named (in red) by the “saturating” Ab that was prebound to the immobilized Ag.
We used the same set of reagents, namely Abs1-6 raised against a dimeric Ag, to illustrate the premix approach, which involved premixing the Ag separately with a large molar excess of each Ab, and then presenting these preformed complexes to an array of Abs coupled to
\n\t\t\t\tSaturating Ab | \n\t\t\t\t\t\t\tCompeting Ab | \n\t\t\t\t\t\t|||||
\n\t\t\t\t\t\t\t | 1 | \n\t\t\t\t\t\t\t2 | \n\t\t\t\t\t\t\t3 | \n\t\t\t\t\t\t\t4 | \n\t\t\t\t\t\t\t5 | \n\t\t\t\t\t\t\t6 | \n\t\t\t\t\t\t
1 | \n\t\t\t\t\t\t\tSB | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t\tNB | \n\t\t\t\t\t\t\tNB | \n\t\t\t\t\t\t
2 | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t\tSB | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t
3 | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t\tSB | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t\tNB | \n\t\t\t\t\t\t\tNB | \n\t\t\t\t\t\t
4 | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t\tSB | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t
5 | \n\t\t\t\t\t\t\tNB | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t\tNB | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t\tSB | \n\t\t\t\t\t\t\tB | \n\t\t\t\t\t\t
6 | \n\t\t\t\t\t\t\tNB | \n\t\t\t\t\t\t\t? | \n\t\t\t\t\t\t\tNB | \n\t\t\t\t\t\t\t? | \n\t\t\t\t\t\t\t? | \n\t\t\t\t\t\t\tSB (?) | \n\t\t\t\t\t\t
the chip (Figure 7B). Three controls are needed to validate the assay. First, the premixed Abs themselves in the absence of Ag should be presented to the naked coupled Abs to confirm that they do not bind one another non-specifically; indeed, one should confirm empirically that all three assay orientations depicted in Figure 7 are free of non-specific Ab/Ab interactions. Second, the Ag is premixed with buffer to establish the Ag-binding response expected to each of the coupled Abs. Third, the Ag should be premixed with a solution counterpart of each coupled Ab on the chip to demonstrate that the premixed Abs are at high enough concentrations to self-block.
\n\t\t\t\tOn the ProteOn, a premix binning experiment involves coupling an array of Abs along the vertical channels and then injecting Ag premixed with an array of Abs along the horizontal channels. Ag premixed with buffer is used as the sixth sample. Thus, in a single binding cycle, we addressed 36 interactions that incorporated six Ag-only controls, five self-blocking controls, and 25 sandwiching pairs. Relative to the Ag-only response, a premixed Ab either abolished or augmented binding, consistent with it respectively blocking or sandwiching with the coupled Ab (Figure 9). Of the six Abs tested, only Ab6 (orange curve) did not fully block Ag binding at the concentration tested, even against itself when coupled on chip, consistent with this Ab’s weak affinity for the Ag. The premix binnings agreed with those determined by tandem binning.
\n\t\t\tPremix binning. One example of each blocking pattern is shown, grouped by coupled Ab. Premixed Abs are distinguished by color (2-pink, 3-green, 4-blue, 5-black, 6-orange, and none-red). The different response values of the three panels reflect the different coupled levels of Abs 2, 3, and 5.
The classical sandwich assay involves coupling an Ab onto the sensor, binding Ag, and then binding another Ab (Fig. 7C). Only monomeric Ags can be binned in this way because multivalent Ags could potentially bind the coupled Ab with one subunit and the solution Ab with another subunit, even if the two Abs in question bound overlapping epitopes. On the ProteOn, this assay involves coupling six Abs in the vertical direction and then rotating to the horizontal direction to inject Ag followed by an array of Abs. By matching the sandwiching Abs to the coupled ones, a complete set of “self-sandwich” controls are generated along the diagonal of the interaction array. Based on the patterns of blocking activity shown for the six Abs in Figure 10 when paired against one another, B and F binned together, D and E binned together, and A and C were unique because they each sandwiched with the other five Abs.
\n\t\t\tClassical sandwich binning. Panels are grouped and labeled by the coupled Ab (A-F) and colored by the sandwiching Ab (A-black, B-blue, C-red, D-green, E-orange, and F-pink).
Although it is obvious in most of our examples when Abs did and did not bind, some Abs bound with intermediate responses that introduced uncertainty into whether they blocked or sandwiched. For example, the panel marked Ag/Ab6 in Fig. 8C shows an in tandem binning result where the competing array was exposed to “free” and “Ab-bound” Ag because Ab6 dissociated rapidly from the Ag (arrowed in Fig. 8B) rather than “saturating” it, as desired. However, when Ab6 was used in the “competing” step (orange curves in Fig. 8C) it clearly binned with Ab5 (black curves). Similarly, premixing Ab6 gave an intermediate binding response (orange curves, Figure 9) because it was at a concentration below its affinity for the Ag (which was unknown at that time). In general, weak binders like Ab6 should be assigned the role of “competing” Ab when studied in tandem or “on chip” in the premix or classical sandwich methods. However, Abs that dissociate rapidly from their Ag may be inappropriate candidates for coupling in classical sandwich assays because there may be insufficient Ag bound when a sandwiching Ab is presented subsequently. Since weak binders can often give ambiguous results when studied in some assay orientations, it is prudent to switch the roles of the two Abs in question and/or explore other orientations to verify a result.
\n\t\t\t\tAg heterogeneity is another possible source of ambiguity in interpreting biosensor blocking data because consensus across all three assay orientations assumes that the Ag is a uniform population. If it is not, the assay orientations may give conflicting outcomes.
\n\t\t\tRecently, a number of next-generation Octet units have been released that provide solutions to some of the shortcomings of the QK platform. One improvement is a better signal-to-noise that may now make the direct detection of small molecules possible and allow for lower surface capacities that may be preferred for kinetic runs. Moreover, their 384-well plate formats enable higher throughputs by addressing 16 interactions at once and trays of sensor tips can be re-racked to extend their lifetime.
\n\t\tAssay orientation can affect the results as much or more than the biosensor used. While the ProteOn XPR36 and Biacore 3000 platforms returned virtually identical affinities within each assay orientation tested, the Octet QK’s lower sensitivity made it amenable to fewer uses and required a sink to abolish rebinding artifacts. Despite these limitations, the Octet’s affinities were within twofold of those determined by SPR. Binning results were comparable across the three biosensors, but differed in throughput due to each platform’s unique configuration that could be exploited in creative assay design. Biosensors are versatile and reliable tools that continue to evolve and provide valuable information on diverse molecules in a research, diagnostic, and drug discovery setting above and beyond binding kinetics.
\n\t\tI gratefully acknowledge Arvind Rajpal and Pavel Strop for their useful comments.
\n\t\tRestoration of calcium levels is essential for the human body, which leads to proper function such as enzyme activity, hormone secretion, neurological stimulation, and/or muscle function. Calcium homeostasis is in relationship with different tissues and structures such as bone, parathyroid gland, and kidney. Regulation of calcium-homeostasis-related events begins with rapid changes in the parathormone (PTH) release from parathyroid gland cells. Hypocalcemic or hypercalcemic responses are controlled by a specific receptor that senses the changes in serum calcium levels [1]. If calcium levels decrease, the mechanism provides a rapid increase in the PTH level to maintain proper calcium levels. Once calcium is balanced to the normal values, continual calcium release suppresses the PTH through a negative-feedback mechanism. Major and pulsatile events occur during the process itself through calcium-sensing receptors (CaSRs) [2]. This G-protein-coupled receptor is a unique part of the parathyroid gland function to monitor changes in serum calcium levels. This process is carried out by two main mechanisms which are, respectively, stimulation of the kidneys and intestine to increase the absorption of calcium and stimulation of the bones to release calcium into the blood [3, 4].
PTH mRNA expression levels are suppressed by the 1-25OH2D modulation, despite CaSR expression with its effect on the modulation of the PTH release. Ritter et al. report that PTH release decreased by 1–25(OH)2D, 1 hydroxy-vitamin D, and 25(OH)D in mice parathyroid cells in culture [5, 6, 7, 8, 9, 10, 11]. Earlier in this study, Kim et al. showed a lack of upregulation of PTH transcription in the Vitamin D Receptor (VDR) knockout mice, and lack of suppression of PTH transcription by 1,25(OH)2D administration [12]. Consistent with both researcher and current literature, the 1–25(OH)2D reduces the PTH mRNA expression and has an antiproliferative effect on parathyroid cells from uremic rats, subsequently enhancing the VDR expressions. Acute changes in the calcium levels of sHPT patients enhance the CaSR and Klotho expressions by Vitamin D [5, 13].
The location of the parathyroid glands is on the posterior side of the thyroid gland. Mostly there are four glands and rarely supernumerary glands [14]. Starting from the early phases of embryogenesis, the pharyngeal pouches give rise to parathyroid glands along with many organs [15, 16]. The third and the fourth pharyngeal pouches particularly emerge as parathyroid glands [17]. Inferior and superior parathyroid glands develop with thymus and a portion of the thyroid respectively [15]. Different cell adhesion after separation from the pharyngeal pouch modulates the formation of parathyroids, while the thymus continues to migrate above the heart [16]. Separation of the superior parathyroid glands is carried out during the seventh week of the development and after detaching the pharyngeal wall, the parathyroid fuses with the posterior surface of the thyroid [14].
The parathyroid glands are derived from the endoderm during embryogenesis. Endoderm consists of a high amount of actin fibers that provide formation and expansion to the ectoderm. Numerous signaling molecules and proteins maintain the progression of morphogenesis. Particularly, Glial cell missing 2 (
In order to understand the development of the parathyroid gland, extensive research on murine models is performed. To identify the involving molecules and signaling processes, researchers have proven most of the downstream and upstream mediators. The remaining unknown factors remain to be elucidated. In current practice, the known factors involving the development and maturation of the parathyroid glands are evaluated in murine models and related parathyroid disorders. This chapter summarizes the molecular findings based on the cell type distribution of parathyroid and pathophysiology up to the present.
The vascular structure of the parathyroid glands is separated from the outside by a fibrous thin capsule. Such capsules contain thin fibrous bands that disperse toward the inner parts by fibrous structures. This provides access to the blood vessels, lymphatics, and nerves to provide nutrients to the tissue [20, 21]. Macroscopic appearances may vary depending on cell type, cell/organelle amount, blood supply status, and the amount of fat content of the tissue [1, 22].
In literature, cell-type distribution in the parathyroid tissue has been reported based on either two or three different cell types. In some reports, it has been stated as two: oxyphil and chief cells [14], while another group of researchers has elucidated histological evidence that there are water-clear cells besides oxyphil and chief cells [23]. Besides, there is another group of cell types that are observed with disease and/or age-related changes, which are not yet classified as a specific cell type. Although this type is not yet classified, the transitional chief cells are present and particularly reported as
Water-clear cells contain many glycogen granules in their cytoplasm and are rarely seen. These cells are clinically encountered in the tissues of patients with secondary hyperparathyroidism (sHPT) and primary hyperparathyroidism (pHPT) [25]. In 1992, Emura’s study on rabbit parathyroid tissue stated that water-clear cells contained a large number of vacuoles in the parathyroid tissue sections, which were observed with electron microscopy and were found scattered around the chief cells. Water-clear cells reside in between the perivascular space and the basal lamina that have been observed to have a desmosomal connection with chief cells [26]. In 2013, Ezzat et al. showed that these cells were not associated with PTH secretion and serum calcium levels. In addition, they reported that only 0.3% of pHPT cases had “water-clear cell hyperplasia” or “water-clear cell adenomatosis” [27]. A recent report presented that the water-clear cell hyperplasia ratio is less than 1% of all pHPT cases [28]. Distinct features or changes in the water-clear cell accumulation in parathyroid tissue or relation with disorders remain to be elucidated.
The chief cells constitute the cellularly dominant cell type of parathyroid tissue, and it was described by Baker in 1942 [29]. Baker describes these cells as the dark “primary cells” with distinctive cytoplasmic structures. Their rod-shaped mitochondria are homogeneously distributed throughout the cytoplasm [20]. In addition, Trier reported that he did not observe the dark and pale stained oxyphil cells, neither with light nor with electron microscopy, which Baker mentioned in his notes in 1942.
The chief cells are usually rich in intracellular fat content. Cells are supported by a thin connective tissue and accordingly are located more closely to the capillaries [30]. Although the chief cells may contain more than one nuclei (multinucleic cells), the nuclear matrix structures are densely arranged [31]. Chief cells are considered the main cell type, and cells are mostly spherical or oval-shaped with long nuclei and narrow cytoplasm [32]. The knowledge about the cell shapes of the chief cells is mostly obtained from histological examinations. Besides, observations by using live imaging or confocal microscopy are either absent or limited. Since it has been reported that single chief cell diameters are 0.2 μm wide according to electron microscope images [33, 34] and 6–8 μm histologically [23]. The agranular membrane structure of the Golgi body of the chief cells was first visualized in 1957 [35]. Due to the eosinophilic cytoplasm, they may appear dark or light in color at the time of staining.
To date, the parameters such as age, disease history, and drug use, which are the definitive features of parathyroid function, may affect cytoplasm amount or changes in the cytoplasm content or nucleus size for all processes [32, 36, 37]. In brief, functional activity and cytoplasm content are the two related main chief cell behaviors of the parathyroid. The most distinctive feature of the chief cells is that they contain a large number of secretory vesicles. These membrane-covered vesicles mostly contain PTH [38].
As is known, the main function depends on the chief cells, which are responsible cell type for PTH release. These cells play an important role in calcium homeostasis, thanks to the CaSR expression on its surface. The receptor detects the low amount of extracellular calcium changes and releases the appropriate amount of PTH to balance the calcium in the blood [23, 39].
Oxyphil cells are the cells with well-circumscribed eosinophilic cytoplasm and pycnotic nuclei [1, 20, 39]. Between 1952 and 1953, Parade compared monkey, equine, and human parathyroid tissues and reported that the size and number of mitochondria in oxyphil cells varied between species. In addition, the variability in the number of mitochondria in human oxyphilic cells is also associated with age [23, 33, 34]. As of note, rat parathyroid tissue does not contain oxyphil, oxyphil-like, or mitochondria-rich cell groups [32]. In 1958, Trier observed that some of the oxyphilic cells were stained “dark” and some were “pale.” He described pale-stained oxyphilic cells as having “low” mitochondrial content, and dark-staining oxyphil cells as having “excessive” mitochondrial content [20]. Both studies have confirmed the outcome of oxyphil cells.
In 1981, Allen and Thorburn examined the activity of oxyphil cells in abnormal parathyroid tissue of 114 patients with sHPT due to chronic kidney disease. The absence and presence of oxyphil cells in human parathyroid tissues were evaluated in this retrospective study, in which histological evaluation was associated with clinical practice. They reported that hyperparathyroidism was seen in more than one parathyroid tissue in 55% of the cases, and adenoma was found in one of the four parathyroid glands in 69% of the cases. They also reported that oxyphil cells were found in 91% of the cases, and the number of oxyphilic cells was positively correlated with serum calcium level [40].
In 1990, Suzuki et al. reported oxyphil cell function in 148 parathyroid tissues from patients who are taking hemodialysis. They calculated for each tissue by proportioning the area occupied by oxyphilic cells by morphometric measurements concerning the total parathyroid cross-sectional area (oxyphil cell area/total area). Additionally, it has been reported that serum PTH levels do not have a statistically significant relationship with age and the dialysis duration; however, the total tissue size is positively correlated with PTH release. Based on the results, they concluded that the oxyphil cell/total tissue area was not effective in PTH release in patients with chronic renal failure [41].
In 1996, Tanaka et al. used 22 sHPT tissues to understand oxyphil cell function. The study reported that 10 of these tissues had oxyphil cells and the mRNA expression of PTH was found to increase. Then, performed heterotransplantation in mice to determine oxyphilic cell function by evaluating serum PTH levels. As a result, the change in PTH levels was positively correlated with transplanted tissue size, not the cell number or type [42].
Despite the reported studies, there is no definite information about the exact function of oxyphil cells, but this question was clarified in many ways by Ritter and Brown et al. [5, 6, 23, 39]. Histologically, increased eosinophilic content from the chief cell through oxyphil cell, suggesting that oxyphil cells are formed by “transition.” As evidence, the oxyphil cells have been shown to express PTH [42] and
On the one hand, the CaSR expression levels of oxyphil cells are statistically found higher than other parathyroid cells. On the second hand, there was no significant difference in Vitamin D Receptor (VDR) expression [5, 39]. The higher mitochondrial content of oxyphil cells indicates that energy requirements are much higher than in chief cells. Mitochondria are also responsible for VDR function. One study by Ritter et al. elucidated that 25-hydroxyvitamin D-1α-hydroxylase (1αOHase) is highly expressed and this is the inactive form of Vitamin D [5]. In addition, the amount of 1αOHase in human parathyroid tissue was directly proportional to calcium levels. The study reported that calcimimetic therapy in patients with chronic renal failure causes a significant increase in the amount of 1αOHase in oxyphil cells [5, 6].
A recent commentary also highlighted Ritter’s findings after 5 years. Metabolic changes of parathyroid tissue are significantly affected by changes in tissue volume and/or cell type, cell count rate due to drug use, or changes in serum calcium level. Concomitant CaSR induction and its persistence are also known to affect the expression profile [47]. Thus, in terms of PTH expression, it has been clarified that oxyphil cells contain more PTH than chief cells. Some of these data also confirm the findings of Allen and Thorburn in 1981 [40].
Calcium or di-/trivalent cations induce the activation of CaSR, which triggers the PTH release [48]. Definitive research studies have demonstrated the outcomes from direct or indirect approaches so far. The comparisons and the evaluations were mainly performed with the diseased tissues, not the healthy parathyroids due to the difficulties in retrieval processes. There is only a limited number of papers that compare/evaluate healthy parathyroid tissue expression profiles of cellular content. Particularly, the location and the size of the parathyroid gland make it difficult to obtain from healthy individuals. Researchers, surgeons, and physicians reported different approaches to finding and/or distinguishing the parathyroid tissue during thyroid operation [49, 50, 51]. This challenge still exists, and suggested techniques such as near-infrared autofluorescence [52] are not readily available for the use of numerous surgeons. Essentially, it is a fact that even if healthy tissue is donated, it will take a long time to reach the appropriate sample size required to conduct various studies. Therefore, a limited number of healthy parathyroid tissues either used or to be used in studies for comparisons.
The further part of this chapter continues with parathyroid tissue from the primary and secondary hyperparathyroidism patients (adenoma and hyperplasia tissues respectively) were compared according to their cellular content. The changes in their expression profiles were evaluated with different stages of the related diseases.
Starting 25 years ago, most of the papers evaluated the CaSR, PTH, proliferation markers, and transcription factors expression changes by mRNA and/or protein levels (mostly immunohistochemistry, western blot, ELISA methods). The clinical characteristics and the cell content of the parathyroid tissue were compared by Yamaguchi et al. in 1997. Samples are retrieved from patients who have secondary hyperparathyroidism and cell proliferation specific marker PCNA (proliferating cell nuclear antigen) expression was compared between normal, adenoma, and hyperplasia parathyroid tissues. This study divided the cell content in each tissue group including dark-stained chief cells, clear chief cells, vacuolated chief cells, transitional oxyphil cells, and oxyphil cells [53]. This divided cell type classification was very similar to the report by Trier in 1958 [20]. Among 27 out of 40 normal parathyroid tissues were found positive for PCNA, and no correlation between age and expression levels is observed. Cell content was reported as clear-chief>dark-chief>oxyphil cells, respectively. However, the normal parathyroid tissue was obtained from thyroid cancer patients, and a definite interpretation should not be made without ignoring this situation. Adenoma tissue showed remarkably higher PCNA expression levels, and the cell content included mostly clear chief cells and less commonly transitional oxyphil cells. In 129 parathyroid hyperplasia tissue samples, all of the divided cell types of this study were found distinguishable. The PCNA expression was found significantly higher in the nodular type from the glandular structure of the parathyroid. The authors concluded that clear chief cells are the most proliferative cell group in all samples, and the dark chief cell group was found the lowest proliferative group [53]. Yamaguchi’s study alone is one of the rare studies that evaluate the highest number of parathyroid tissues in its related field.
In 2000, Corbetta et al. demonstrated that 27 parathyroid adenoma tissues contain only chief cells. Cell isolation, cultivation under different calcium concentrations, PTH levels, and CaSR expression levels were evaluated. Additionally, it is stated that there was no correlation between different calcium sensitivity and pathology. Furthermore, PTH and CaSR mRNA and protein levels were significantly reduced when compared with normal tissue, and the authors concluded that defective calcium sensing occurs in abnormal parathyroid tissue [54]. This study may be considered as a starting point for understanding the defects in the sensing mechanism of the CaSR. Failure to obtain the expected changes in the PTH level under different calcium concentrations should not be interpreted as a resistance mechanism.
In 2006, Brown et al. stated that three different Vitamin D prodrugs, which are lacking side-chain hydroxyl groups, were treated with bovine parathyroid cells and showed that PTH levels decreased based on the related concentrations. The prodrugs have different affinities to the VDR; however, utilization of the VDR decreases PTH synthesis for treatment of secondary hyperparathyroidism [7]. The inhibition of PTH synthesis was performed in vitro using prodrugs at that time of the work, and this indicates a new aspect of parathyroid research. Continued with Ritter et al. in 2006, by the same research group, competitive VDR binding of the vitamin D analogs was examined. In this report, two main conclusions were included. One is the 25(OH)D3 has the highest affinity to the VDR among other analogs, and direct action mechanisms through VDR suppress PTH [8]. The PTH regulation versus VDR activation may be explained by a compensatory mechanism model. Although the authors did not exclude other regulatory systems such as the negative feedback mechanism of the PTH [10]. Studies conducted between 2005 and 2011 mostly did not focus on cell-type-specific changes. Instead, the relationships between VDR and PTH were investigated in terms of regulation mechanism, especially in bovine, rat, and other knockout-animal models.
In 2012, Ritter et al. defined the differential mRNA expression of parathyroid glands by cell types. In this paper, histological examination was provided and the size of the chief, oxyphil, and transdifferentiated oxyphil cells was reported. Consistent with previous reports, the high oxyphil cell amount was reported in chronic kidney diseased patients, accordingly higher PTH and CaSR expression was elucidated as well. In addition, oxyphil cells showed
In 2014, Shi et al. demonstrated a flow cytometric cell sorting of 20 parathyroid adenoma tissues from primary hyperparathyroidism patients. They divided the cells into three distinct populations including the chief, oxyphil, and lymphocytes. The cutting-edge research from Shi et al. provided electron microscopy images of each population and also demonstrated the immunofluorescence staining of CaSR and mRNA expressions of
In 2015, Howson et al. investigated the oxyphil-cell-rich adenoma tissues from primary hyperparathyroidism patients. During the 10-year follow-up period, among obtained 2739 tissues, 91 of the parathyroid adenoma were found oxyphil cell adenoma type. About 80% of these patients were symptomatic and most commonly had higher serum calcium and PTH levels than the classical type of adenoma. On the contrary, the frequency of oxyphilic adenomas was not rare, and patients trend toward a higher rate of morbidity and potential mortality if left untreated [56].
In 2017, two different groups presented water-clear cell-type adenoma and hyperplasia cases. The clinical symptoms of the adenoma patient were unintentionally led and treated for hyperparathyroidism due to the clinical features. However, after surgical removal of the two adenoma tissues from the same patient, the histopathological evaluation showed water-clear cell double parathyroid adenomas [57]. This is followed by another case report that presents primary hyperparathyroidism clinically. Contrary to the clinic, the histopathological results showed enormous unilateral water-clear cell hyperplasia in parathyroid [28]. Both of the cases concluded that despite ultrasonography, biochemical, and clinical follow-up, these extremely rare cases unintentionally misled the physicians [28, 57]. In the same year, another study by Ritter et al. was reported. In that study, parathyroid hyperplasia tissues were retrieved from chronic kidney patients and grouped according to their calcimimetic treatment (cinacalcet versus paricalcitol versus cinacalcet+paricalcitol). The effects of treatment processes on the cell type of the parathyroid tissue were compared with four healthy parathyroid tissues. According to the histopathological evaluation, parathyroid oxyphil cell content was found to increase significantly for the cinacalcet-treated patients [58]. The role of the CaSR activation possibly led to a new comprehension to understand the outcome of conventional treatment with vitamin D analogs or calcimimetics on the cellular composition of the parathyroid.
In 2020, Ding et al. provided a comparison of clinical characteristics and oxyphil cell proportion through 78 patients. In total, 295 parathyroid tissue samples were retrieved from 78 patients who did not have cinacalcet treatment. Clinical characteristics included serum calcium, phosphorus, alkaline phosphatase, age, dialysis duration, and preoperative PTH levels. The samples were divided based on the mean oxyphil cell ratio (high oxyphil cell content and low oxyphil cell content, respectively). Subsequently, etiopathogenesis and histological examinations were evaluated. They reported that preoperative PTH levels of the patients were found lower than the oxyphil cell-rich group [37]. This finding contradicts the previous study by Howson [56]. Furthermore, Ding et al. reported that if parathyroid tissue contains more oxyphil cells, it became lighter than the tissue with fewer oxyphil cells. As of note, weight comparison was performed between parathyroid hyperplasia tissues [37].
At the beginning of 2021, Altinay et al. demonstrated the cellular composition of the hyperplasia and adenoma tissues while comparing normal parathyroid glands. Furthermore, PTH, GATA3, and PAX8 levels were evaluated histologically. As a result, expression of GATA3 and PTH was found more prominent in pathologic parathyroid tissues when compared with normal. Particularly the GATA3 staining has shown positive only for parathyroid, not thyroid tissue. Chief cell amount was high in adenoma and hyperplasia tissues; however, PTH staining was found low when compared with normal tissue. In addition, adenoma displayed less PTH and GATA3 expression histologically [59].
Another study from Rodriguez et al. reported the clinicopathological outcome of the oxyphil cell clusters, which were detected in parathyroid adenoma tissue. The main idea is to define the particular effect of the oxyphil cell content-rich/poor tissue composition and localization. Despite clinic versus histopathological comparisons so far, this study has a similar manner with distinct oxyphil cell subgroups [60]. Rodriguez’s team investigated histopathological function with symptomatology, and this could depend on the changes in the percentage of the oxyphil cells. Clinically, observations included age, sex, body mass index, and symptomatic reasons for surgical initiation such as nephrocalcinosis, osteoarticular and/or neuropsychiatric and/or cardiovascular symptoms. Biochemical parameters were as follows: ionic calcium, corrected serum calcium, albumin, PTH, 25-OH Vitamin D, alkaline phosphatase, creatinine, glomerular filtration rate (GFR), and urinary calcium excretion. Additionally, oxhyphil cell percentages were divided into the following four categories: 0–24, 25–49, 50–74, and 75–100% [60]. In terms of variables, this is the most comprehensive evaluation to date associated with clinical (including both biochemical and symptomatic) and parathyroid cell groups. In total 261 parathyroid tissues obtained from 238 patients were used. Eventually, 77% of tissues have less than 25% in the percentage of oxyphil cells and 8% of tissues are greater than 75% in terms of percentage of oxyphil cells. No significant difference was found in terms of biochemical parameters such as calcium, phosphorus, alkaline phosphatase, PTH, and 25-OH vitamin D. In addition, the localization of the adenoma tissues did not show significant changes when compared between inferior and superior glands. Different distributions of the oxyphil cell clusters among varied cell percentages showed no significant changes. Although, increased thyroid nodularity and higher prevalence in cardiovascular symptoms are shown within the less oxyphil cell groups (<25%). Imaging tests also justified a correlation between better localization with increased oxyphil cell group (>75%). Nevertheless, preoperative GFR and urinary calcium excretion significantly worsen the patients’ symptoms that were altered in parathyroid tissues containing high oxyphil cells. Findings in the non-pathological tissue samples from normocalcemic patients showed an absence/low level in the oxyphil cells [60]. These conditions are still controversial.
Parathyroid carcinomas influence the laboratory values, which are similar to those with hyperparathyroidism (primary or secondary). For instance, increased serum PTH levels are around thousands, and a palpable mass may be detected in the neck region. Currently, carcinoma can be observed in any (upper or lower) of the glands and is not considered to have any priority within the four existing glands while the invasion of the adjacent thyroid gland is observed [61]. The histological resemblance of parathyroid adenoma causes a challenge for diagnosis. Observations in parathyroid carcinoma tissue include increased mitotic potential, necrosis, formation of encapsulated structures, and spread from the capsule through adjacent tissues [62].
Studies on parathyroid cancer are gaining attention. A recent study evaluated whether tumor volume and tumor size were associated with disease severity [63]. Another study determined circulating miRNA expression levels as a potential diagnostic biomarker in parathyroid carcinomas [64, 65].
Despite all these findings, in terms of cell type, water-clear, oxyphil, and chief cells do not provide a differential diagnosis. The prime reasons are a rarity, and it is not possible to impose a limitation in terms of cell composition.
To further understand the parathyroid gland function and development, studies were carried out by numerous researchers. Indicated contributions already shaped the required future studies for this composite tissue. The parathyroid gland is a relatively small tissue while the behavior and changes in its composition provide a fine balance in terms of its function. Thus, this has enabled us to come a little closer to elucidating the actual mechanisms. Foremost, the mechanisms that maintain certainty in all research results can be listed as the following:
Parathyroid cells mostly contain three types of cells; chief, oxyphil, and water-clear cells.
Depending on the circumstances such aging and diseases may affect and increase the oxyphil cell amount.
The cells that switch between chief through oxyphil cells can affect different mechanisms, which are still uncategorized.
Categorization of the differentiating cells may explain the influence of autocrine/paracrine effect on tissue behavior.
So-called “transdifferentiated cells” can be classified as another cell type that will provide a separate diagnosis criterion such as prognosis, degree, or etiology of parathyroid-related-diseases.
Expression patterns of the same transcription factors such as GCM2, MAFB, and RXR are the most difficult part of distinguishing the cell-type-specific features. Even with all the findings in the literature, one question still remains; where does the border of differential cellular diagnosis end? The answer to this question is still unknown.
The role of autocrine and paracrine effects in parathyroid cell differentiation cannot be ignored. Each person’s metabolism balances this process individually; therefore, studies should include larger cohorts. More collaborative studies are required between researchers. The lack of oxyphil cells in some murine models is another challenge. This indicates that understanding the cellular composition/regulation of parathyroid tissue behavior is mandatory, particularly for primary human parathyroid tissue cell studies.
The emergence of oxyphilic cells is perhaps a defense mechanism that is developed from the parathyroid tissue against external signalings, which was first reported by Christi in 1955 [31]. However, this is yet to be confirmed. Another remark can be made from the state of immunogenicity, which is considered as a defense mechanism or after pathological disturbances leads to adverse circumstances, and as a result, the oxyphil cells differentiate from chief cells. Nevertheless, several studies have focused on the presence of other immunological markers for parathyroid tissue. Verified studies to date have limited definitions for the expression of immunological markers such as human leukocyte antigens (HLAs) [66, 67, 68, 69]. Revealing the possible relationship of immunological and/or defense mechanisms in parathyroid cell composition requires more studies such as different co-culture models. This can be a starting point for future studies.
A few important subjects that have not been finalized yet in terms of parathyroid tissue are:
Histological studies are contributing to the field; however, more biomarker research is required for the specific differential prognosis of related diseases.
The inverse relationship between the increased oxyphilic cell and the lighter tissue structure is still not understood, whereas the studies that determine weight through cell composition of the parathyroid tissue could provide paramount importance.
In conclusion, the approaches that have been proposed in the literature paved the way for future research objectives. Differentiating points obtained by comparing the outcomes and the data of different researchers raise new questions. The exact mechanism for basic parathyroid biology requires new
The author would like to thank Prof. Emrah Yucesan for his valuable feedbacks. This chapter is dedicated to all patients undergoing treatment for parathyroid-related diseases who agreed to participate in the studies from many researchers highlighted in this section. This chapter was supported by the Research Fund Unit of the Bezmialem Vakif University.
The authors declare no conflict of interest.
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There is growing evidence that telomere stability can be affected by occupational and environmental exposure, as some of these factors have been correlated with increase in inflammation, oxidative stress, DNA damage, chromosome aberration, and epigenetic alterations. Both extremely short and long telomeres have been associated with neurodegenerative, cardiovascular diseases (CVD) and cancer risk. Occupational and environmental exposure to several synthetic and natural chemicals has been found to be associated with changes in telomere length, although the molecular mechanism is not fully understood. Telomeric DNA is relatively less capable of repair, resulting in accelerated shortening during the cell cycle and replicative senescence. It is recognized that diet plays an important role in telomere maintenance. Prevention of exposure to environmental and occupational hazards as well as psychological stressors can reduce the risk of telomere instability. 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Kahl and Juliana da Silva",authors:[{id:"170193",title:"Dr.",name:"Juliana",middleName:null,surname:"Da Silva",slug:"juliana-da-silva",fullName:"Juliana Da Silva"},{id:"187307",title:"MSc.",name:"Vivian Francilia",middleName:null,surname:"Silva Kahl",slug:"vivian-francilia-silva-kahl",fullName:"Vivian Francilia Silva Kahl"}]}],mostDownloadedChaptersLast30Days:[{id:"49878",title:"Immunophenotyping of Acute Leukemias – From Biology to Clinical Application",slug:"immunophenotyping-of-acute-leukemias-from-biology-to-clinical-application",totalDownloads:3341,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Immunophenotyping is an essential part of the modern diagnostic workup of acute leukemias and thus for an appropriate treatment of these complex and heterogeneous diseases. It provides a lot of useful information in this setting that transfers directly from laboratory to clinical management of patients. Lineage definition is the first goal leading to proper initial therapy. Some phenotypic patterns define specific subsets correlating with poor (mixed phenotype, dendritic cell neoplasm) or favorable (cortical T-lymphoblastic leukemia) outcome, thus guiding the application of treatment modalities. An advanced analysis of phenotypic data can address specific issues, such as the still debated role of multilineage dysplasia. The quality of response to chemotherapy is monitored by the detection of minimal residual disease and peripheral blast clearance during chemotherapy delivering. That allows a sharp discrimination of prognosis and again can drive the intensity of therapies proportionally to the disease chemosensitivity.",book:{id:"4720",slug:"flow-cytometry-select-topics",title:"Flow Cytometry",fullTitle:"Flow Cytometry - Select Topics"},signatures:"Francesco Mannelli",authors:[{id:"178848",title:"M.D.",name:"Francesco",middleName:null,surname:"Mannelli",slug:"francesco-mannelli",fullName:"Francesco Mannelli"}]},{id:"50878",title:"Detection of Anti-HLA Antibodies by Flow Cytometer",slug:"detection-of-anti-hla-antibodies-by-flow-cytometer",totalDownloads:3172,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Lives of patients with solid organ failure depend physically, emotionally, and economically on others. Improvement in organ transplantation is one of the most important medical breakthroughs of the twenty-first century. Being healthy upon organ transplantation is the second chance to live the life. This is frequently observed in heart-, lung-, and liver-transplanted patients. For instance, upon kidney transplantation, dialysis dependence terminates and life quality of the patients increases. The major difficulty in organ transplantation is the low number of organ donation. Thus, the number of patients in the waiting list for the cadaveric transplantation increases day by day. Under these limited circumstances, required conditions should be further provided for the long survival rates of recipients with allogeneic graft without any problem. Human leukocyte antigen (HLA) tissue typing and anti-HLA antibodies produced before and after the transplantation adversely affect the graft survival and thus the survival of an individual. Investigation of pretransplantation immune status of recipients is significant. Particularly, donor-specific anti-HLA antibodies determine early and long-term graft survival. Flow cytometer is one of the most important devices used in anti-HLA antibody detection and also for other clinical and scientific purposes. Compared to conventional methods, it supports transplantation clinics due to its high sensitivity and specificity. The use of flow cytometer dependent methods in transplantation field increases progressively.",book:{id:"4720",slug:"flow-cytometry-select-topics",title:"Flow Cytometry",fullTitle:"Flow Cytometry - Select Topics"},signatures:"Tülay Kılıçaslan Ayna and Aslı Özkızılcık Koçyiğit",authors:[{id:"178265",title:"Dr.",name:"Tulay",middleName:null,surname:"Kilicaslan Ayna",slug:"tulay-kilicaslan-ayna",fullName:"Tulay Kilicaslan Ayna"}]},{id:"44225",title:"Role of Enhancer of Zeste Homolog 2 Polycomb Protein and Its Significance in Tumor Progression and Cell Differentiation",slug:"role-of-enhancer-of-zeste-homolog-2-polycomb-protein-and-its-significance-in-tumor-progression-and-c",totalDownloads:3949,totalCrossrefCites:6,totalDimensionsCites:9,abstract:null,book:{id:"3536",slug:"chromatin-remodelling",title:"Chromatin Remodelling",fullTitle:"Chromatin Remodelling"},signatures:"Irene Marchesi and Luigi Bagella",authors:[{id:"91878",title:"Prof.",name:"Luigi",middleName:null,surname:"Bagella",slug:"luigi-bagella",fullName:"Luigi Bagella"},{id:"164852",title:"Dr.",name:"Irene",middleName:null,surname:"Marchesi",slug:"irene-marchesi",fullName:"Irene Marchesi"}]},{id:"48399",title:"The Multiplexing of Assays for the Measurement of Early Stages of Apoptosis by Polychromatic Flow Cytometry",slug:"the-multiplexing-of-assays-for-the-measurement-of-early-stages-of-apoptosis-by-polychromatic-flow-cy",totalDownloads:1781,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"The detection of apoptosis has been a stalwart application for flow cytometric analysis for decades and this review of flow cytometric methods to detect early stages of apoptosis includes the use of the pivotal assay to detect early and late apoptosis, the Annexin V assay which when multiplexed with biologically functional fluorescent dyes to measure mitochondrial function and Reactive Oxygen Species (ROS) generation allows further identification of functionally different subsets within apoptotic populations. Here we show how this polychromatic approach can be used to demonstrate which subset of cells show changes in mitochondrial function and when ROS is generated in a time dependent manner. This polychromatic approach to flow cytometry leads to the identification of over ten sub-populations of cells during classic apoptosis or programmed cell death (PCD).",book:{id:"4720",slug:"flow-cytometry-select-topics",title:"Flow Cytometry",fullTitle:"Flow Cytometry - Select Topics"},signatures:"G. Warnes",authors:[{id:"108846",title:"Dr.",name:"Gary",middleName:null,surname:"Warnes",slug:"gary-warnes",fullName:"Gary Warnes"}]},{id:"49834",title:"The Role of Telomeres and Telomere-associated Proteins as Components of Interactome in Cell-signaling Pathways",slug:"the-role-of-telomeres-and-telomere-associated-proteins-as-components-of-interactome-in-cell-signalin",totalDownloads:1777,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Telomeres represent ends of all eukaryotic chromosomes and serve specialized biological role in maintaining genomic integrity by preventing end fusions and degradation. Various protein complexes associate with telomeres to either protect them from DNA damage machinery or maintain telomere length homeostasis. These protein complex subunits cross talk with a variety of cell-signaling components to either maintain telomere integrity or perform other functions, which are either dependent or independent of telomeres and/or their telomeric role. Mutations in these protein components lead to the development of various human diseases, such as age-related disorders, which occur mainly due to telomere dysfunction or cancer development due to telomerase reactivation. This chapter focuses on the structural and functional aspects of telomeric proteins and their importance in human diseases.",book:{id:"5085",slug:"telomere-a-complex-end-of-a-chromosome",title:"Telomere",fullTitle:"Telomere - A Complex End of a Chromosome"},signatures:"Ekta Khattar and Vinay Tergaonkar",authors:[{id:"118589",title:"Prof.",name:"Vinay",middleName:null,surname:"Tergaonkar",slug:"vinay-tergaonkar",fullName:"Vinay Tergaonkar"},{id:"176764",title:"Dr.",name:"Ekta",middleName:null,surname:"Khattar",slug:"ekta-khattar",fullName:"Ekta Khattar"}]}],onlineFirstChaptersFilter:{topicId:"403",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. 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Her research interest is in antibiotic resistance, host-pathogen interaction, and therapeutics development for staphylococcal pathogens, mainly Staphylococcus aureus, which causes hospital-acquired infections. Currently, her research is mostly focused on the study of oral pathogens, particularly Staphylococcus spp.",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorThree:null},{id:"4",title:"Fungal Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",isOpenForSubmission:!0,editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",slug:"yuping-ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",biography:"Dr. Yuping Ran, Professor, Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China. Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. 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He is currently a rated researcher by the National Research Foundation of South Africa at category C2. He has published widely in the field of infectious diseases and has overseen several MSc’s and PhDs. His research activities mostly cover topics on infectious diseases from epidemiology to control. His particular interest lies in the study of intestinal protozoan parasites and opportunistic infections among HIV patients as well as the potential impact of childhood diarrhoea on growth and child development. He also conducts research on water-borne diseases and water quality and is involved in the evaluation of point-of-use water treatment technologies using silver and copper nanoparticles in collaboration with the University of Virginia, USA. 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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. 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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",institutionURL:null,country:{name:"India"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:19,paginationItems:[{id:"82804",title:"Psychiatric Problems in HIV Care",doi:"10.5772/intechopen.106077",signatures:"Seggane Musisi and Noeline Nakasujja",slug:"psychiatric-problems-in-hiv-care",totalDownloads:1,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Future Opportunities and Tools for Emerging Challenges for HIV/AIDS Control",coverURL:"https://cdn.intechopen.com/books/images_new/11575.jpg",subseries:{id:"6",title:"Viral Infectious Diseases"}}},{id:"82827",title:"Epidemiology and Control of Schistosomiasis",doi:"10.5772/intechopen.105170",signatures:"Célestin Kyambikwa Bisangamo",slug:"epidemiology-and-control-of-schistosomiasis",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"New Horizons for Schistosomiasis Research",coverURL:"https://cdn.intechopen.com/books/images_new/10829.jpg",subseries:{id:"5",title:"Parasitic Infectious Diseases"}}},{id:"82817",title:"Perspective Chapter: Microfluidic Technologies for On-Site Detection and Quantification of Infectious Diseases - The Experience with SARS-CoV-2/COVID-19",doi:"10.5772/intechopen.105950",signatures:"Andres Escobar and Chang-qing Xu",slug:"perspective-chapter-microfluidic-technologies-for-on-site-detection-and-quantification-of-infectious",totalDownloads:2,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"SARS-CoV-2 Variants - Two Years After",coverURL:"https://cdn.intechopen.com/books/images_new/11573.jpg",subseries:{id:"6",title:"Viral Infectious Diseases"}}},{id:"82667",title:"Perspective Chapter: Analysis of SARS-CoV-2 Indirect Spreading Routes and Possible Countermeasures",doi:"10.5772/intechopen.105914",signatures:"Cesare Saccani, Marco Pellegrini and Alessandro Guzzini",slug:"perspective-chapter-analysis-of-sars-cov-2-indirect-spreading-routes-and-possible-countermeasures",totalDownloads:8,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"SARS-CoV-2 Variants - Two Years After",coverURL:"https://cdn.intechopen.com/books/images_new/11573.jpg",subseries:{id:"6",title:"Viral Infectious Diseases"}}}]},overviewPagePublishedBooks:{paginationCount:13,paginationItems:[{type:"book",id:"6667",title:"Influenza",subtitle:"Therapeutics and Challenges",coverURL:"https://cdn.intechopen.com/books/images_new/6667.jpg",slug:"influenza-therapeutics-and-challenges",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Shailendra K. 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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",institutionURL:null,country:{name:"India"}}}]},{type:"book",id:"7064",title:"Current Perspectives in Human Papillomavirus",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7064.jpg",slug:"current-perspectives-in-human-papillomavirus",publishedDate:"May 2nd 2019",editedByType:"Edited by",bookSignature:"Shailendra K. Saxena",hash:"d92a4085627bab25ddc7942fbf44cf05",volumeInSeries:2,fullTitle:"Current Perspectives in Human Papillomavirus",editors:[{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",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. 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In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{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:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"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:"322007",title:"Dr.",name:"Maria Elizbeth",middleName:null,surname:"Alvarez-Sánchez",slug:"maria-elizbeth-alvarez-sanchez",fullName:"Maria Elizbeth Alvarez-Sánchez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",country:{name:"Mexico"}}},{id:"337443",title:"Dr.",name:"Juan",middleName:null,surname:"A. 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Gonzalez-Sanchez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico System",country:{name:"United States of America"}}},{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"}}}]}},subseries:{item:{id:"28",type:"subseries",title:"Animal Reproductive Biology and Technology",keywords:"Animal Reproduction, Artificial Insemination, Embryos, Cryopreservation, Conservation, Breeding, Epigenetics",scope:"The advances of knowledge on animal reproductive biology and technologies revolutionized livestock production. Artificial insemination, for example, was the first technology applied on a large scale, initially in dairy cattle and afterward applied to other species. Nowadays, embryo production and transfer are used commercially along with other technologies to modulate epigenetic regulation. Gene editing is also emerging as an innovative tool. This topic will discuss the potential use of these techniques, novel strategies, and lines of research in progress in the fields mentioned above.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/28.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11417,editor:{id:"177225",title:"Prof.",name:"Rosa Maria Lino Neto",middleName:null,surname:"Pereira",slug:"rosa-maria-lino-neto-pereira",fullName:"Rosa Maria Lino Neto Pereira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9wkQAC/Profile_Picture_1624519982291",biography:"Rosa Maria Lino Neto Pereira (DVM, MsC, PhD and) is currently a researcher at the Genetic Resources and Biotechnology Unit of the National Institute of Agrarian and Veterinarian Research (INIAV, Portugal). She is the head of the Reproduction and Embryology Laboratories and was lecturer of Reproduction and Reproductive Biotechnologies at Veterinary Medicine Faculty. She has over 25 years of experience working in reproductive biology and biotechnology areas with a special emphasis on embryo and gamete cryopreservation, for research and animal genetic resources conservation, leading research projects with several peer-reviewed papers. Rosa Pereira is member of the ERFP-FAO Ex situ Working Group and of the Management Commission of the Portuguese Animal Germplasm Bank.",institutionString:"The National Institute for Agricultural and Veterinary Research. Portugal",institution:null},editorTwo:null,editorThree:null,series:{id:"13",title:"Veterinary Medicine and Science",doi:"10.5772/intechopen.73681",issn:"2632-0517"},editorialBoard:[{id:"90066",title:"Dr.",name:"Alexandre",middleName:"Rodrigues",surname:"Silva",slug:"alexandre-silva",fullName:"Alexandre Silva",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRt8pQAC/Profile_Picture_1622531020756",institutionString:null,institution:{name:"Universidade Federal Rural do Semi-Árido",institutionURL:null,country:{name:"Brazil"}}},{id:"176987",title:"Ph.D.",name:"María-José",middleName:"Carrascosa",surname:"Argente",slug:"maria-jose-argente",fullName:"María-José Argente",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9vOQAS/Profile_Picture_1630330499537",institutionString:null,institution:{name:"Miguel Hernandez University",institutionURL:null,country:{name:"Spain"}}},{id:"321396",title:"Prof.",name:"Muhammad Subhan",middleName:null,surname:"Qureshi",slug:"muhammad-subhan-qureshi",fullName:"Muhammad Subhan Qureshi",profilePictureURL:"https://mts.intechopen.com/storage/users/321396/images/system/321396.jpg",institutionString:null,institution:{name:"University of Agriculture",institutionURL:null,country:{name:"Pakistan"}}},{id:"183723",title:"Dr.",name:"Xiaojun",middleName:null,surname:"Liu",slug:"xiaojun-liu",fullName:"Xiaojun Liu",profilePictureURL:"https://mts.intechopen.com/storage/users/183723/images/system/183723.jpg",institutionString:null,institution:null}]},onlineFirstChapters:{paginationCount:0,paginationItems:[]},publishedBooks:{paginationCount:4,paginationItems:[{type:"book",id:"10664",title:"Animal Reproduction",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/10664.jpg",slug:"animal-reproduction",publishedDate:"May 25th 2022",editedByType:"Edited by",bookSignature:"Yusuf Bozkurt and Mustafa Numan 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