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This Special Issue is dedicated to the 80th anniversary of Nikolay Yanev, a renowned Bulgarian mathematician and an eminent member of the international branching processes community. We present a brief description of his academic career path and his role as a founder of the Bulgarian school of branching processes and their applications. [ABSTRACT FROM AUTHOR]

Simple Summary: Several procedures have been developed to infer cell-cycle time and the duration of the cycle phases, including tritiated thymidine autoradiography and the immunodetection of thymidine analogues after their incorporation into replicating DNA. These methods have supplied important insights to reveal, on fixed tissue sections and using light or electron microscopy, the proliferative behavior of different cell types under different experimental contexts. Thymidine analogous labeling has provided knowledge about cell growth kinetics that would never have been obtained by histological methods alone. Tritiated thymidine autoradiography, 5-bromo-2′-deoxyuridine (BrdU) 5-chloro-2′-deoxyuridine (CldU), 5-iodo-2′-deoxyuridine (IdU), and 5-ethynyl-2′-deoxyiridine (EdU) labeling have been used for identifying the fraction of cells undergoing the S-phase of the cell cycle and to follow the fate of these cells during the embryonic, perinatal, and adult life in several species of vertebrate. In this current review, I will discuss the dosage and times of exposition to the aforementioned thymidine analogues to label most of the cells undergoing the S-phase of the cell cycle. I will also show how to infer, in an asynchronous cell population, the duration of the G1, S, and G2 phases, as well as the growth fraction and the span of the whole cell cycle on the base of some labeling schemes involving a single administration, continuous nucleotide analogue delivery, and double labeling with two thymidine analogues. In this context, the choice of the optimal dose of BrdU, CldU, IdU, and EdU to label S-phase cells is a pivotal aspect to produce neither cytotoxic effects nor alter cell cycle progression. I hope that the information presented in this review can be of use as a reference for researchers involved in the genesis of tissues and organs. [ABSTRACT FROM AUTHOR]

In recent years, interest in the possible molecular regulators of cell proliferation and differentiation in a wide range of regeneration models has grown significantly, but the cell kinetics of this process remain largely a mystery. Here we try to elucidate the cellular aspects of regeneration by EdU incorporation in intact and posteriorly amputated annelid Alitta virens using quantitative analysis. We found that the main mechanism of blastema formation in A. virens is local dedifferentiation; mitotically active cells of intact segments do not significantly contribute to the blastemal cellular sources. Amputation-induced proliferation occurred predominantly within the epidermal and intestinal epithelium, as well as wound-adjacent muscle fibers, where clusters of cells at the same stage of the cell cycle were found. The resulting regenerative bud had zones of high proliferative activity and consisted of a heterogeneous population of cells that differed in their anterior–posterior positions and in their cell cycle parameters. The data presented allowed for the quantification of cell proliferation in the context of annelid regeneration for the first time. Regenerative cells showed an unprecedentedly high cycle rate and an exceptionally large growth fraction, making this regeneration model especially valuable for studying coordinated cell cycle entry in vivo in response to injury. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cell (MSC) products are promising therapeutic candidates to treat a wide range of pathologies. The successful commercialization of these cell therapies will, however, depend on the development of reproducible cell production processes. For this, using microcarriers as growth supports within controlled conditions may be a viable process option. Although increasing microcarrier concentration may be associated with greater productivity due to the increased available culture surface, additional friction or shocks between microcarriers are likely to lead to undesired cell death. However, data detailing the impact of microcarrier collisions on MSC growth remains scarce. The following work demonstrates that MSC growth on microcarriers is greatly influenced by particle concentration even when little impact is observed on the apparent growth rate. It is suggested that the apparent growth rate may result in an equilibrium between growth and death kinetics which are independently affected by particle concentration and that certain MSC quality attributes may be progressively degraded in parallel. In addition, the theoretical reduction of the MSC growth rate was modeled according to the ratio between the average interparticle distance and the Kolmogorov scale. This study is an original contribution toward understanding the hydrodynamic effects in microcarrier‐based stem cell cultures. [ABSTRACT FROM AUTHOR]

Tritiated thymidine autoradiography, 5-bromo-2′-deoxyuridine (BrdU) 5-chloro-2′-deoxyuridine (CldU), 5-iodo-2′-deoxyuridine (IdU), and 5-ethynyl-2′-deoxyiridine (EdU) labeling have been used for identifying the fraction of cells undergoing the S-phase of the cell cycle and to follow the fate of these cells during the embryonic, perinatal, and adult life in several species of vertebrate. In this current review, I will discuss the dosage and times of exposition to the aforementioned thymidine analogues to label most of the cells undergoing the S-phase of the cell cycle. I will also show how to infer, in an asynchronous cell population, the duration of the G1, S, and G2 phases, as well as the growth fraction and the span of the whole cell cycle on the base of some labeling schemes involving a single administration, continuous nucleotide analogue delivery, and double labeling with two thymidine analogues. In this context, the choice of the optimal dose of BrdU, CldU, IdU, and EdU to label S-phase cells is a pivotal aspect to produce neither cytotoxic effects nor alter cell cycle progression. I hope that the information presented in this review can be of use as a reference for researchers involved in the genesis of tissues and organs.

In recent years, interest in the possible molecular regulators of cell proliferation and differentiation in a wide range of regeneration models has grown significantly, but the cell kinetics of this process remain largely a mystery. Here we try to elucidate the cellular aspects of regeneration by EdU incorporation in intact and posteriorly amputated annelid Alitta virens using quantitative analysis. We found that the main mechanism of blastema formation in A. virens is local dedifferentiation; mitotically active cells of intact segments do not significantly contribute to the blastemal cellular sources. Amputation-induced proliferation occurred predominantly within the epidermal and intestinal epithelium, as well as wound-adjacent muscle fibers, where clusters of cells at the same stage of the cell cycle were found. The resulting regenerative bud had zones of high proliferative activity and consisted of a heterogeneous population of cells that differed in their anterior–posterior positions and in their cell cycle parameters. The data presented allowed for the quantification of cell proliferation in the context of annelid regeneration for the first time. Regenerative cells showed an unprecedentedly high cycle rate and an exceptionally large growth fraction, making this regeneration model especially valuable for studying coordinated cell cycle entry in vivo in response to injury.

Background: The olfactory cleft (OC) comprising the olfactory epithelium (OE) is the most important anatomical location for olfactory function. Endoscopic sinus surgery (ESS) is used to treat diseases related to the OC and improve olfactory dysfunction. However, iatrogenic OE injury occasionally occurs. Comprehensive knowledge of the olfactory region is required to avoid damage to the OE during endoscopic procedures. Methods: Immunohistochemistry was performed on olfactory mucosa obtained from the unaffected side of olfactory neuroblastoma surgical specimens. The OE was defined as the epithelium containing mature olfactory sensory neurons (OSNs). The distribution and cell kinetics of the OE were examined. Results: The OE was selectively localized to the anterior two‐thirds of the superior turbinate (ST) and in the nasal septum (NS) just opposite to the ST; the OE was not detected within the mucosa of the superior meatus. The density of mature OSNs was high at the ethmoid tegmen but gradually decreased with distance from the ethmoid tegmen. The extent of cell death and proliferation was relatively even across the OE. Analysis of airflow profiles revealed that resection of inferior ST does not decrease airflow to the OC. Conclusion: The results indicate that the distribution and degree of differentiation of mature OSNs are heterogenous throughout the OE. Epithelial resection of the anterior or superior ST has the potential to damage olfactory function. Resection of the inferior or posterior ST or widening of the superior meatus is a safer alternative that does not damage mature OSNs or alter airflow to the OC. [ABSTRACT FROM AUTHOR]

Abstract In this current study, antiproliferative effect of Hec1/Nek2 Mitotic Pathway inhibitor INH1 was investigated in adenocarcinomic human alveolar basal epithelial cells A549 and human cervix carcinoma HeLa cell lines in vitro. To this end cell index values by xCELLigence Real‐Time Cell Analysis DP instrument, mitotic index, BrdU proliferation assay and apoptotic index analysis were used. The results of the current study showed that INH1 had cytostatic and cytoskeletal effects on A549 and cytostatic effect on HeLa cells. The IC50 concentration was determined as 56 µM with the xCelligence device for both cell lines. IC50 concentration was used for all other parameters. While this concentration decreased the mitotic index BrdU proliferation values, it increased the apoptotic index values of both of cell lines. There were significant differences between the control and the experimental groups (p

The paper deals with applying mathematical modeling to study tumor growth process and optimizing cancer treatment. A structured review of the studies devoted to this problem is given. The role of the cell life cycle in understanding the tumor growth and the mechanisms of cancer treatment is discussed. It is important that modern cancer treatment methods, in particular, chemotherapy and radiation therapy, affect both normal and tumor cells in certain stages of the life cycle and do not influence on cells in other stages. Cell life cycle description is given as well as the mechanisms that maintain and restore normal density of the cell population. A graph of cell life cycle stages and transitions is demonstrated. Dynamic mathematical model of proliferative homeostasis in the cell population is proposed, which takes into account the heterogeneity of cell populations by life cycle stages. The model is a system of differential equations with delays. The stationary state of the model is investigated, which allows to determine the parameters values for the normal cell population. The results of a numeric experiment is obtained, which is focused on the process of cell population density recovery after mass death of cells. As the experiment shows, after cell death, the densities of cells in different life cycle stages are restored to normal values, which corresponds to the concepts of proliferative homeostasis in cell populations.

Cerebellar neurons are generated from the rhombic lip and the neuroepithelium. In this study, we analyze the histogenesis of the cerebellar neuroepithelium in terms of cellular kinetics. The experimental animals are the offspring of pregnant dams injected with 5-bromo-2ʹ-deoxyuridine (BrdU) on embryonic day 13. We infer the fraction of S-phase cells by examining a range of survival times after a single BrdU-exposure and a cumulative BrdU-labeling sequence, which allow for the derivation of cell-cycle parameters and phase durations. The current results indicate that the dose of BrdU employed (35 mg/kg) provides saturation S-phase labeling from at least 1 h after marker delivery. The duration of G2, mitotic phase, and G1 are 1.2, 0.5, and 6.9 h, respectively. The duration for the S-phase, growth fraction, and the whole cycle are obtained on the basis of two proliferative models, steady-state and exponential growth. Both models provided similar results. In conclusion, our results indicate that the steady-state and the cumulative S-phase labeling paradigms can be adopted to analyze cell cycle parameters in the cerebellar neuroepithelium. Current results can help in understanding the regulatory mechanisms of cerebellar histogenesis and the cell biological mechanisms of the proliferative cycle of the neuroepithelium. [ABSTRACT FROM AUTHOR]

The Berg-Purcell expression for the diffusion-controlled binding rate to N sites uniformly distributed on the surface of a sphere is generalized to clusters of receptors located at the poles of a cell. By replacing a partially reactive surface with one that is covered with N circular sites that act independently, one can derive analytic expressions for the diffusion-controlled rate constant for clusters of binding sites. This has application to systems where the reactive sites are located in a specific region or regions on the surface of the protein or cell. These include peptide hormones reacting with target receptors, protein-ligand reactions and bacterial chemotaxis. Multiple sensory receptors both at one and two poles of a sphere are studied.

Neurogenesis in the adult brain, a powerful mechanism for neuronal plasticity and brain repair, is altered by aging and pathological conditions, including metabolic disorders. The search for mechanisms and therapeutic solutions to alter neurogenesis requires understanding of cell kinetics within neurogenic niches using a high-throughput quantitative approach. The challenge is in the dynamic nature of the process and multiple cell types involved, each having several potential modes of division or cell fate. Here we show that cell kinetics can be revealed through a combination of the BrdU/EdU pulse-chase, based on the circadian pattern of DNA replication, and a differential equations model that describes time-dependent cell densities. The model is validated through the analysis of cell kinetics in the cerebellar neurogenic niche of normal young adult male zebrafish, with cells quantified in 2D (sections), and with neuronal fate and reactivation of stem cells confirmed in 3D whole-brain images (CLARITY). We then reveal complex alterations in cell kinetics associated with accelerated aging due to chronic high caloric intake. Low activity of neuronal stem cells in this condition persists 2 months after reverting to normal diet, and is accompanied by overproduction of transient amplifying cells, their accelerated cell death, and slow migration of postmitotic progeny. This combined experimental and mathematical approach should allow for relatively high-throughput analysis of early signs of pathological and age-related changes in neurogenesis, evaluation of specific therapeutic targets, and drug efficacy. [ABSTRACT FROM AUTHOR]

Vitamin D is widely known to regulate bone health, but there is increasing evidence that it may also ameliorate colitis through inflammation, cell proliferation and apoptosis, and the microbiota. The purpose of this review is to systematically examine the mechanisms by which vitamin D reduces colitis. PubMed and Web of Science were searched for articles published between 2008 and 2019 using key words such as “vitamin D,” “colitis,” “inflammatory bowel disease,” “inflammation,” “apoptosis,” “cell proliferation,” and “gut bacteria”. Retrieved articles were further narrowed and it was determined whether their title and abstracts contained terminology pertaining to vitamin D in relation to colitis in human clinical trials, animal studies, and cell culture/biopsy studies, as well as selecting the best match sorting option in relation to the research question. In total, 30 studies met the established criteria. Studies consistently reported results showing that vitamin D supplementation can downregulate inflammatory pathways of COX-2, TNF-α, NF-κB, and MAPK, modify cell kinetics, and alter gut microbiome, all of which contribute to an improved state of colitis. Although vitamin D and vitamin D analogs have demonstrated positive effects against colitis, more randomized, controlled human clinical trials are needed to determine the value of vitamin D as a therapeutic agent in the treatment of colitis.

Abstract: The secondary hair germ (SHG)—a transitory structure in the lower portion of the mouse telogen hair follicle (HF)—is directly involved in anagen induction and eventual HF regrowth. Some crucial aspects of SHG functioning and ontogenetic relations with other HF parts, however, remain undefined. According to recent evidence (in contrast to previous bulge‐centric views), the SHG is the primary target of anagen‐inducing signalling and a source of both the outer root sheath (ORS) and ascending HF layers during the initial (morphogenetic) anagen subphase. The SHG is comprised of two functionally distinct cell populations. Its lower portion (originating from lower HF cells that survived catagen) forms all ascending HF layers, while the upper SHG (formed by bulge‐derived cells) builds up the ORS. The predetermination of SHG cells to a specific morphogenetic fate contradicts their attribution to the “stem cell” category and supports SHG designation as a “germinative” or a “founder” cell population. The mechanisms of this predetermination driving transition of the SHG from “refractory” to the “competent” state during the telogen remain unknown. Functionally, the SHG serves as a barrier, protecting the quiescent bulge stem cell niche from the extensive follicular papilla/SHG signalling milieu. The formation of the SHG is a prerequisite for efficient “precommitment” of these cells and provides for easier sensing and a faster response to anagen‐inducing signals. In general, the formation of the SHG is an evolutionary adaptation, which allowed the ancestors of modern Muridae to acquire a specific, highly synchronized pattern of hair cycling. [ABSTRACT FROM AUTHOR]

The classic Luria-Delbrück model for fluctuation analysis is extended to the case where the split instant distributions of cells are not i.i.d.: the lifetime of each cell is assumed to depend on its birth date. This model takes also into account cell deaths and non-exponentially distributed lifetimes. In particular, it is possible to consider subprobability distributions and to model non-exponential growth. The extended model leads to a family of probability distributions which depend on the expected number of mutations, the death probability of mutant cells, and the split instant distributions of normal and mutant cells. This is deduced from the Bellman-Harris integral equation, written for the birth date inhomogeneous case. A new theorem of convergence for the final mutant counts is proved, using an analytic method. Particular examples like the Haldane model or the case where hazard functions of the split-instant distributions are proportional are studied. The Luria-Delbrück distribution with cell deaths is recovered. A computation algorithm for the probabilities is provided. [ABSTRACT FROM AUTHOR]

Aim: Though odontogenic lesions have in common origin from the primitive odontogenic epithelium , there is a diversity in their initiation behavior and growth. The aggressive nature of odontogenic keratocyst similar to ameloblastoma in comparision with the other common odontogenic (dentigerous and radicular) cyst could be due to possible differences in their epithelial linings. PCNA (Proliferating cell nuclear antigen) is a cell cycle related antigen, used in the study of cell kinetics of these epithelial linings, to corelate the biological behaviour among these common odontogenic lesions. Objectives: This paper has intended to study the cell kinetics of 4 selected odontogenic lesions (dentigerous cyst, radicular cyst,odontogenic keratocyst and ameloblastoma) to demonstrate differences in their epithelial linings. Material and Methods: Sixty samples of paraffin embedded tissue specimens (archival tissues) were included (15 radicularcysts, 15 odontogenic keratocysts; 15 dentigerous cysts and15 Ameloblastoma. Results: Among cyst OKC had higher values than DC and RC. When staining results of all the cyst were compared individually with ameloblastoma ,the staining results of OKC was similar to ameloblastoma ,and ameloblastoma presented higher values than OKC (p=0.000). Conclusion: The results of this study show 1) Though OKC and DC are developmental in origin and radicular cyst is inflammatory, OKC has intrinsic growth potential among these cyst 2). Ameloblastoma has similar proliferative potential as OKC and hence it has been reinforced as KCOT(Keratocystic odontogenic tumour) in the recent classification.

Sponges have a remarkable capacity to rapidly regenerate in response to wound infliction. In addition, sponges rapidly renew their filter systems (choanocytes) to maintain a healthy population of cells. This study describes the cell kinetics of choanocytes in the encrusting reef sponge Halisarca caerulea during early regeneration (0–8 h) following experimental wound infliction. Subsequently, we investigated the spatial relationship between regeneration and cell proliferation over a six-day period directly adjacent to the wound, 1 cm, and 3 cm from the wound. Cell proliferation was determined by the incorporation of 5-bromo-2′-deoxyuridine (BrdU). We demonstrate that during early regeneration, the growth fraction of the choanocytes (i.e., the percentage of proliferative cells) adjacent to the wound is reduced (7.0 ± 2.5%) compared to steady-state, undamaged tissue (46.6 ± 2.6%), while the length of the cell cycle remained short (5.6 ± 3.4 h). The percentage of proliferative choanocytes increased over time in all areas and after six days of regeneration choanocyte proliferation rates were comparable to steady-state tissue. Tissue areas farther from the wound had higher rates of choanocyte proliferation than areas closer to the wound, indicating that more resources are demanded from tissue in the immediate vicinity of the wound. There was no difference in the number of proliferative mesohyl cells in regenerative sponges compared to steady-state sponges. Our data suggest that the production of collagen-rich wound tissue is a key process in tissue regeneration for H. caerulea, and helps to rapidly occupy the bare substratum exposed by the wound. Regeneration and choanocyte renewal are competing and negatively correlated life-history traits, both essential to the survival of sponges. The efficient allocation of limited resources to these life-history traits has enabled the ecological success and diversification of sponges.

In this paper, we present a strategy for tuning the parameters of a multiscale model of structured cell populations in which physiological mechanisms are embedded into the cell scale. This strategy allows one to cope with the technical difficulties raised by such models that arise from their anchorage in cell biology concepts: localized mitosis, progression within and out of the cell cycle driven by time- and possibly unknown-dependent and nonsmooth velocity coefficients. We compute different mesoscopic and macroscopic quantities from the microscopic unknowns (cell densities) and relate them to experimental cell kinetic indexes. We study the expression of reaching times corresponding to characteristic cellular transitions in a particle-like reduction of the original model. We make use of this framework to obtain an appropriate initial guess for the parameters and then perform a sequence of optimization steps subject to quantitative specifications. We finally illustrate realistic simulations of the cell populations in cohorts of interacting ovarian follicles. [ABSTRACT FROM AUTHOR]

Although the fields of systems and integrative biology are in full expansion, few teams are involved worldwide into the study of reproductive function from the mathematical modeling viewpoint. This may be due to the fact that the reproductive function is not compulsory for individual organism survival, even if it is for species survival. Alternatively, the complexity of reproductive physiology may be discouraging. Indeed, the hypothalamo-pituitary-gonadal (HPG) axis involves not only several organs and tissues but also intricate time (from the neuronal millisecond timescale to circannual rhythmicity) and space (from molecules to organs) scales. Yet, mathematical modeling, and especially multiscale modeling, can renew our approaches of the molecular, cellular, and physiological processes underlying the control of reproductive functions. In turn, the remarkable dynamic features exhibited by the HPG axis raise intriguing and challenging questions to modelers and applied mathematicians. In this article, we draw a panoramic review of some mathematical models designed in the framework of the female HPG, with a special focus on the gonadal and central control of follicular development. On the gonadal side, the modeling of follicular development calls to the generic formalism of structured cell populations, that allows one to make mechanistic links between the control of cell fate (proliferation, differentiation, or apoptosis) and that of the follicle fate (ovulation or degeneration) or to investigate how the functional interactions between the oocyte and its surrounding cells shape the follicle morphogenesis. On the central, mainly hypothalamic side, models based on dynamical systems with multiple timescales allow one to represent within a single framework both the pulsatile and surge patterns of the neurohormone GnRH. Beyond their interest in basic research investigations, mathematical models can also be at the source of useful tools to study the encoding and decoding of the (neuro-) hormonal signals at play within the HPG axis and detect complex, possibly hidden rhythms, in experimental time series. [ABSTRACT FROM AUTHOR]

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We recently reported the synthesis of NOSH-aspirin, a novel hybrid compound capable of releasing both nitric oxide (NO) and hydrogen sulfide (H 2 S). In NOSH-aspirin, the two moieties that release NO and H 2 S are covalently linked at the 1, 2 positions of acetyl salicylic acid, i.e., ortho -NOSH-aspirin. Here we report on the synthesis of meta - and para -NOSH-aspirins. We also made a head-to-head evaluation of the effects of these three positional isomers of NOSH-aspirin on colon cancer cell kinetics and induction of reactive oxygen species, which in recent years has emerged as a key event in causing cancer cell regression. Electron donating/withdrawing groups incorporated about the benzoate moiety significantly affected the potency of these compounds with respect to colon cancer cell growth inhibition. [ABSTRACT FROM AUTHOR]

The erythroid lineage is a particularly sensitive target of radiation injury. We model the dynamics of immature (BFU-E) and mature (CFU-E) erythroid progenitors, which have markedly different kinetics of recovery, following sublethal total body irradiation using a two-type reducible age-dependent branching process with immigration. Properties of the expectation and variance of the frequencies of both types of progenitors are presented. Their explicit expressions are derived when the process is Markovian, and their asymptotic behavior is identified in the age-dependent (non-Markovian) case. Analysis of experimental data on the kinetics of BFU-E and CFU-E reveals that the probability of self-renewal increases transiently for both cell types following sublethal irradiation. In addition, the probability of self-renewal increased more for CFU-E than for BFU-E. The strategy adopted by the erythroid lineage ensures replenishment of the BFU-E compartment while optimizing the rate of CFU-E recovery. Finally, our analysis also indicates that radiation exposure causes a delay in BFU-E recovery consistent with injury to the hematopoietic stem/progenitor cell compartment that give rise to BFU-E. Erythroid progenitor self-renewal is thus an integral component of the recovery of the erythron in response to stress. [ABSTRACT FROM AUTHOR]

Branching processes are classical growth models in cell kinetics. In their construction, it is usually assumed that cell lifetimes are independent random variables, which has been proved false in experiments. Models of dependent lifetimes are considered here, in particular bifurcating Markov chains. Under the hypotheses of stationarity and multiplicative ergodicity, the corresponding branching process is proved to have the same type of asymptotics as its classic counterpart in the independent and identically distributed supercritical case: the cell population grows exponentially, the growth rate being related to the exponent of multiplicative ergodicity, in a similar way as to the Laplace transform of lifetimes in the i.i.d. case. An identifiable model for which the multiplicative ergodicity coefficients and the growth rate can be explicitly computed is proposed. [ABSTRACT FROM AUTHOR]

Mathematical modeling allows relating molecular events to single-cell characteristics assessed by multiparameter cytometry. In the present study we labeled newly synthesized DNA in A549 human lung carcinoma cells with 15-120 min pulses of EdU. All DNA was stained with DAPI and cellular fluorescence was measured by laser scanning cytometry. The frequency of cells in the ascending (left) side of the 'horseshoe'-shaped EdU/DAPI bivariate distributions reports the rate of DNA replication at the time of entrance to S phase while their frequency in the descending (right) side is a marker of DNA replication rate at the time of transition from S to G2 phase. To understand the connection between molecular-scale events and scatterplot asymmetry, we developed a multiscale stochastic model, which simulates DNA replication and cell cycle progression of individual cells and produces in silico EdU/DAPI scatterplots. For each S-phase cell the time points at which replication origins are fired are modeled by a non-homogeneous Poisson Process (NHPP). Shifted gamma distributions are assumed for durations of cell cycle phases (G1, S and G2M), Depending on the rate of DNA synthesis being an increasing or decreasing function, simulated EdU/DAPI bivariate graphs show predominance of cells in left (early-S) or right (late-S) side of the horseshoe distribution. Assuming NHPP rate estimated from independent experiments, simulated EdU/DAPI graphs are nearly indistinguishable from those experimentally observed. This finding proves consistency between the S-phase DNA-replication rate based on molecular-scale analyses, and cell population kinetics ascertained from EdU/DAPI scatterplots and demonstrates that DNA replication rate at entrance to S is relatively slow compared with its rather abrupt termination during S to G2 transition. Our approach opens a possibility of similar modeling to study the effect of anticancer drugs on DNA replication/cell cycle progression and also to quantify other kinetic events that can be measured during S-phase. © 2014 International Society for Advancement of Cytometry [ABSTRACT FROM AUTHOR]

Abstract: In mammals, the number of ovulations at each ovarian cycle is determined during the terminal phase of follicular development by a tightly controlled follicle selection process. The mechanisms underlying follicle selection take place on different scales and different levels of the gonadotropic axis. These include the endocrine loops between the ovary and the hypothalamic-pituitary complex, the dynamics of follicle populations within the ovary and the dynamics of cell populations within ovarian follicles. A compartmental modelling approach was first designed to describe the cell dynamics in the selected follicle. It laid the basis for a multiscale model formulated with partial differential equations of conservation law type, resulting in the structuring of the follicular cell populations according to cell age and cell maturity. In this model, the selection occurs as a FSH (follicle stimulating hormone)-driven competition between simultaneously developing follicles. The selection output (mono-ovulation, poly-ovulation or anovulation) results from a subtle interplay between the hypothalamus, the pituitary gland and the ovaries, combined with slight differences in the initial conditions or ageing and maturation velocities of the competing follicles. This modelling approach is proposed as a useful complement to experimental studies of follicular development and in turn, the mechanisms of follicle selection raise challenging questions on the mathematical ground. [Copyright &y& Elsevier]

Aim: Though odontogenic lesions have in common origin from the primitive odontogenic epithelium , there is a diversity in their initiation behavior and growth. The aggressive nature of odontogenic keratocyst similar to ameloblastoma in comparision with the other common odontogenic (dentigerous and radicular) cyst could be due to possible differences in their epithelial linings. PCNA (Proliferating cell nuclear antigen) is a cell cycle related antigen, used in the study of cell kinetics of these epithelial linings, to corelate the biological behaviour among these common odontogenic lesions. Objectives: This paper has intended to study the cell kinetics of 4 selected odontogenic lesions (dentigerous cyst, radicular cyst,odontogenic keratocyst and ameloblastoma) to demonstrate differences in their epithelial linings. Material and Methods: Sixty samples of paraffin embedded tissue specimens (archival tissues) were included (15 radicularcysts, 15 odontogenic keratocysts; 15 dentigerous cysts and15 Ameloblastoma. Results: Among cyst OKC had higher values than DC and RC. When staining results of all the cyst were compared individually with ameloblastoma ,the staining results of OKC was similar to ameloblastoma ,and ameloblastoma presented higher values than OKC (p=0.000). Conclusion: The results of this study show 1) Though OKC and DC are developmental in origin and radicular cyst is inflammatory, OKC has intrinsic growth potential among these cyst 2). Ameloblastoma has similar proliferative potential as OKC and hence it has been reinforced as KCOT(Keratocystic odontogenic tumour) in the recent classification. [ABSTRACT FROM AUTHOR]

The use of computational methods to improve the understanding of biological responses to various types of radiation is an approach where multiple parameters can be modelled and a variety of data is generated. This study compares cellular effects modelled for low absorbed doses against high absorbed doses. The authors hypothesized that low and high absorbed doses would contribute to cell killing via different mechanisms, potentially impacting on targeted tumour radiotherapy outcomes. Cellular kinetics following irradiation with selective low- and high-linear energy transfer (LET) particles were investigated using the Virtual Cell (VC) radiobiology algorithm. Two different cell types were assessed using the VC radiobiology algorithm: human fibroblasts and human crypt cells. The results showed that at lower doses (0.01 to 0.2 Gy), all radiation sources used were equally able to induce cell death (p>0.05, ANOVA). On the other hand, at higher doses (1.0 to 8.0 Gy), the radiation response was LET and dose dependent (p<0.05, ANOVA). The data obtained suggests that the computational methods used might provide some insight into the cellular effects following irradiation. The results also suggest that it may be necessary to re-evaluate cellular radiation-induced effects, particularly at low doses that could affect therapeutic effectiveness. [ABSTRACT FROM AUTHOR]

Stem and precursor cells play a critical role in tissue development, maintenance, and repair throughout the life. Often, experimental limitations prevent direct observation of the stem cell compartment, thereby posing substantial challenges to the analysis of such cellular systems. Two-type age-dependent branching processes with immigration are proposed to model populations of progenitor cells and their differentiated progenies. Immigration of cells into the pool of progenitor cells is formulated as a non-homogeneous Poisson process. The asymptotic behavior of the process is governed by the largest of two Malthusian parameters associated with embedded Bellman-Harris processes. Asymptotic approximations to the expectations of the total cell counts are improved by Markov compensators. [ABSTRACT FROM AUTHOR]

We introduce a methodology based on the Luria-Delbruck fluctuation model for estimating the cell kinetics of clonally expanding populations. In particular, this approach allows estimation of the net cell proliferation rate, the extinction coefficient and the initial (viable) population size. We present a systematic approach based on spatial partitioning, which captures the local fluctuations of the number and sizes of individual clones. However, partitioning introduces measurement error by inflating the number of clones, which is dependent on time and the degree of cell migration. We perform various in silico experiments to explore the properties of the estimators and we show that there exists a direct relationship between precision and observation time. We also explore the trade-off between the measurement error and the estimation accuracy. By exploring different scales of cellular fluctuations, from the entire population down to those of individual clones, we show that this methodology is useful for inferring important parameters in neoplastic progression. [ABSTRACT FROM AUTHOR]

This article proposes saddlepoint approximations to the expectation and variance–covariance function of multitype age-dependent branching processes. The proposed approximations are found accurate, easy to implement, and much faster to compute than by simulating the process. Multiple applications are presented, including the analyses of clonal data on the generation of oligodendrocytes from their immediate progenitor cells, and on the proliferation of Hela cells. New estimators are also constructed to analyze clonal data. The proposed methods are finally used to approximate the distribution of the generation, which has recently found several applications in cell biology. [ABSTRACT FROM AUTHOR]

Abstract: In this short work, by combining the total cell evolution curve and the two-compartment model, the evolution of one of the subpopulations is simulated while the system interacts with a proliferating regulatory factor. [Copyright &y& Elsevier]

Stem cells are undifferentiated cells that are defined by their ability to both self-renew and to differentiate in order to produce mature progeny cells, including both non-renewing progenitors and terminally differentiated effector cells. Human mesenchymal stem cells can potentially be used in therapy in a variety of conditions on the basis of their demonstrated efficiency in animal models of human diseases, varying from Parkinson's disease to neoplasia. Given that ionizing radiation is a crucial and widespread diagnostic and therapeutic tool in oncology, it is important to investigate further the factors and mechanisms that underlie stem cell radiosensitivity. The study uses human mesenchymal stem cells, characterized using monoclonal antibodies and cultured in complex osteogenic medium after being irradiated at 0.5 Gy, 1 Gy, 2 Gy and 4 Gy using a 60Co source. Genetic alterations and DNA repair were evaluated using the Alkaline comet assay. Osteogenic differentiation was confirmed by histology stainings (Alizarin Red S, Alcian Blue and von Kossa) and cell proliferation assesed using the MTT based proliferation assay. Our research team challenges current knowledge by investigating the effects of ionizing radiation on stem cells in culture, focusing on the importance of DNA damage and stem cell kinetics in oncology and radiotherapy. [ABSTRACT FROM AUTHOR]