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Sample records for cell cycling models

  1. A hybrid mammalian cell cycle model

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    Vincent Noël

    2013-08-01

    Full Text Available Hybrid modeling provides an effective solution to cope with multiple time scales dynamics in systems biology. Among the applications of this method, one of the most important is the cell cycle regulation. The machinery of the cell cycle, leading to cell division and proliferation, combines slow growth, spatio-temporal re-organisation of the cell, and rapid changes of regulatory proteins concentrations induced by post-translational modifications. The advancement through the cell cycle comprises a well defined sequence of stages, separated by checkpoint transitions. The combination of continuous and discrete changes justifies hybrid modelling approaches to cell cycle dynamics. We present a piecewise-smooth version of a mammalian cell cycle model, obtained by hybridization from a smooth biochemical model. The approximate hybridization scheme, leading to simplified reaction rates and binary event location functions, is based on learning from a training set of trajectories of the smooth model. We discuss several learning strategies for the parameters of the hybrid model.

  2. Modeling of SONOS Memory Cell Erase Cycle

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    Phillips, Thomas A.; MacLeod, Todd C.; Ho, Fat H.

    2011-01-01

    Utilization of Silicon-Oxide-Nitride-Oxide-Silicon (SONOS) nonvolatile semiconductor memories as a flash memory has many advantages. These electrically erasable programmable read-only memories (EEPROMs) utilize low programming voltages, have a high erase/write cycle lifetime, are radiation hardened, and are compatible with high-density scaled CMOS for low power, portable electronics. In this paper, the SONOS memory cell erase cycle was investigated using a nonquasi-static (NQS) MOSFET model. Comparisons were made between the model predictions and experimental data.

  3. Modelling cell cycle synchronisation in networks of coupled radial glial cells.

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    Barrack, Duncan S; Thul, Rüdiger; Owen, Markus R

    2015-07-21

    Radial glial cells play a crucial role in the embryonic mammalian brain. Their proliferation is thought to be controlled, in part, by ATP mediated calcium signals. It has been hypothesised that these signals act to locally synchronise cell cycles, so that clusters of cells proliferate together, shedding daughter cells in uniform sheets. In this paper we investigate this cell cycle synchronisation by taking an ordinary differential equation model that couples the dynamics of intracellular calcium and the cell cycle and extend it to populations of cells coupled via extracellular ATP signals. Through bifurcation analysis we show that although ATP mediated calcium release can lead to cell cycle synchronisation, a number of other asynchronous oscillatory solutions including torus solutions dominate the parameter space and cell cycle synchronisation is far from guaranteed. Despite this, numerical results indicate that the transient and not the asymptotic behaviour of the system is important in accounting for cell cycle synchronisation. In particular, quiescent cells can be entrained on to the cell cycle via ATP mediated calcium signals initiated by a driving cell and crucially will cycle in near synchrony with the driving cell for the duration of neurogenesis. This behaviour is highly sensitive to the timing of ATP release, with release at the G1/S phase transition of the cell cycle far more likely to lead to near synchrony than release during mid G1 phase. This result, which suggests that ATP release timing is critical to radial glia cell cycle synchronisation, may help us to understand normal and pathological brain development. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Cell reprogramming modelled as transitions in a hierarchy of cell cycles

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    Hannam, Ryan; Annibale, Alessia; Kühn, Reimer

    2017-01-01

    We construct a model of cell reprogramming (the conversion of fully differentiated cells to a state of pluripotency, known as induced pluripotent stem cells, or iPSCs) which builds on key elements of cell biology viz. cell cycles and cell lineages. Although reprogramming has been demonstrated experimentally, much of the underlying processes governing cell fate decisions remain unknown. This work aims to bridge this gap by modelling cell types as a set of hierarchically related dynamical attractors representing cell cycles. Stages of the cell cycle are characterised by the configuration of gene expression levels, and reprogramming corresponds to triggering transitions between such configurations. Two mechanisms were found for reprogramming in a two level hierarchy: cycle specific perturbations and a noise induced switching. The former corresponds to a directed perturbation that induces a transition into a cycle-state of a different cell type in the potency hierarchy (mainly a stem cell) whilst the latter is a priori undirected and could be induced, e.g. by a (stochastic) change in the cellular environment. These reprogramming protocols were found to be effective in large regimes of the parameter space and make specific predictions concerning reprogramming dynamics which are broadly in line with experimental findings. (paper)

  5. Modeling of Complex Life Cycle Prediction Based on Cell Division

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    Fucheng Zhang

    2017-01-01

    Full Text Available Effective fault diagnosis and reasonable life expectancy are of great significance and practical engineering value for the safety, reliability, and maintenance cost of equipment and working environment. At present, the life prediction methods of the equipment are equipment life prediction based on condition monitoring, combined forecasting model, and driven data. Most of them need to be based on a large amount of data to achieve the problem. For this issue, we propose learning from the mechanism of cell division in the organism. We have established a moderate complexity of life prediction model across studying the complex multifactor correlation life model. In this paper, we model the life prediction of cell division. Experiments show that our model can effectively simulate the state of cell division. Through the model of reference, we will use it for the equipment of the complex life prediction.

  6. Details Matter: Noise and Model Structure Set the Relationship between Cell Size and Cell Cycle Timing

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    Felix Barber

    2017-11-01

    Full Text Available Organisms across all domains of life regulate the size of their cells. However, the means by which this is done is poorly understood. We study two abstracted “molecular” models for size regulation: inhibitor dilution and initiator accumulation. We apply the models to two settings: bacteria like Escherichia coli, that grow fully before they set a division plane and divide into two equally sized cells, and cells that form a bud early in the cell division cycle, confine new growth to that bud, and divide at the connection between that bud and the mother cell, like the budding yeast Saccharomyces cerevisiae. In budding cells, delaying cell division until buds reach the same size as their mother leads to very weak size control, with average cell size and standard deviation of cell size increasing over time and saturating up to 100-fold higher than those values for cells that divide when the bud is still substantially smaller than its mother. In budding yeast, both inhibitor dilution or initiator accumulation models are consistent with the observation that the daughters of diploid cells add a constant volume before they divide. This “adder” behavior has also been observed in bacteria. We find that in bacteria an inhibitor dilution model produces adder correlations that are not robust to noise in the timing of DNA replication initiation or in the timing from initiation of DNA replication to cell division (the C+D period. In contrast, in bacteria an initiator accumulation model yields robust adder correlations in the regime where noise in the timing of DNA replication initiation is much greater than noise in the C + D period, as reported previously (Ho and Amir, 2015. In bacteria, division into two equally sized cells does not broaden the size distribution.

  7. A data integration approach for cell cycle analysis oriented to model simulation in systems biology

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    Mosca Ettore

    2007-08-01

    Full Text Available Abstract Background The cell cycle is one of the biological processes most frequently investigated in systems biology studies and it involves the knowledge of a large number of genes and networks of protein interactions. A deep knowledge of the molecular aspect of this biological process can contribute to making cancer research more accurate and innovative. In this context the mathematical modelling of the cell cycle has a relevant role to quantify the behaviour of each component of the systems. The mathematical modelling of a biological process such as the cell cycle allows a systemic description that helps to highlight some features such as emergent properties which could be hidden when the analysis is performed only from a reductionism point of view. Moreover, in modelling complex systems, a complete annotation of all the components is equally important to understand the interaction mechanism inside the network: for this reason data integration of the model components has high relevance in systems biology studies. Description In this work, we present a resource, the Cell Cycle Database, intended to support systems biology analysis on the Cell Cycle process, based on two organisms, yeast and mammalian. The database integrates information about genes and proteins involved in the cell cycle process, stores complete models of the interaction networks and allows the mathematical simulation over time of the quantitative behaviour of each component. To accomplish this task, we developed, a web interface for browsing information related to cell cycle genes, proteins and mathematical models. In this framework, we have implemented a pipeline which allows users to deal with the mathematical part of the models, in order to solve, using different variables, the ordinary differential equation systems that describe the biological process. Conclusion This integrated system is freely available in order to support systems biology research on the cell cycle and

  8. Multiparameter Cell Cycle Analysis.

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    Jacobberger, James W; Sramkoski, R Michael; Stefan, Tammy; Woost, Philip G

    2018-01-01

    Cell cycle cytometry and analysis are essential tools for studying cells of model organisms and natural populations (e.g., bone marrow). Methods have not changed much for many years. The simplest and most common protocol is DNA content analysis, which is extensively published and reviewed. The next most common protocol, 5-bromo-2-deoxyuridine S phase labeling detected by specific antibodies, is also well published and reviewed. More recently, S phase labeling using 5'-ethynyl-2'-deoxyuridine incorporation and a chemical reaction to label substituted DNA has been established as a basic, reliable protocol. Multiple antibody labeling to detect epitopes on cell cycle regulated proteins, which is what this chapter is about, is the most complex of these cytometric cell cycle assays, requiring knowledge of the chemistry of fixation, the biochemistry of antibody-antigen reactions, and spectral compensation. However, because this knowledge is relatively well presented methodologically in many papers and reviews, this chapter will present a minimal Methods section for one mammalian cell type and an extended Notes section, focusing on aspects that are problematic or not well described in the literature. Most of the presented work involves how to segment the data to produce a complete, progressive, and compartmentalized cell cycle analysis from early G1 to late mitosis (telophase). A more recent development, using fluorescent proteins fused with proteins or peptides that are degraded by ubiquitination during specific periods of the cell cycle, termed "Fucci" (fluorescent, ubiquitination-based cell cycle indicators) provide an analysis similar in concept to multiple antibody labeling, except in this case cells can be analyzed while living and transgenic organisms can be created to perform cell cycle analysis ex or in vivo (Sakaue-Sawano et al., Cell 132:487-498, 2007). This technology will not be discussed.

  9. Analysis of X-ray induced cell-cycle perturbations in mouse osteosarcoma cells: a two-signal cell-cycle model

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    Meeteren, A. van; Wijk, R. van; Stap, J.; Deys, B.F.

    1984-01-01

    The effects of X-irradiation on mouse osteosarcoma cells have been studied by time-lapse cinematography and the resulting pedigrees have been analysed statistically. It is shown that the irradiation treatment causes three types of cell kinetic lesions: cell death (disintegration), cell sterilization (failure to divide) and proliferation delay. The first two lesions are the most important with regard to survival of the irradiated cell in a clonal assay. Of these two lesions, sterilization appears to be highly correlated for sister cells, while this is not true for cell disintegration. This indicates that cell survival in a clonal assay may be a function of the ratio of the incidences of these two types of lesions. The X-ray-induced proliferation delay was studied in terms of intermitotic time distributions, mother-daughter correlation and sibling correlation in relation to the current cell-cycle phase at the time of treatment. This analysis shows that the effects of irradiation on these cell-cycle characteristics is highly cell-cycle-dependent. A qualitative model to account for the observations is presented. (author)

  10. Analysis of X-ray induced cell-cycle perturbations in mouse osteosarcoma cells: a two-signal cell-cycle model

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    Meeteren, A van; Wijk, R van [Rijksuniversiteit Utrecht (Netherlands); Stap, J; Deys, B F [Amsterdam Univ. (Netherlands)

    1984-03-01

    The effects of X-irradiation on mouse osteosarcoma cells have been studied by time-lapse cinematography and the resulting pedigrees have been analysed statistically. It is shown that the irradiation treatment causes three types of cell kinetic lesions: cell death (disintegration), cell sterilization (failure to divide) and proliferation delay. The first two lesions are the most important with regard to survival of the irradiated cell in a clonal assay. Of these two lesions, sterilization appears to be highly correlated for sister cells, while this is not true for cell disintegration. This indicates that cell survival in a clonal assay may be a function of the ratio of the incidences of these two types of lesions. The X-ray-induced proliferation delay was studied in terms of intermitotic time distributions, mother-daughter correlation and sibling correlation in relation to the current cell-cycle phase at the time of treatment. This analysis shows that the effects of irradiation on these cell-cycle characteristics is highly cell-cycle-dependent. A qualitative model to account for the observations is presented.

  11. Animal Models for Studying the In Vivo Functions of Cell Cycle CDKs.

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    Risal, Sanjiv; Adhikari, Deepak; Liu, Kui

    2016-01-01

    Multiple Cdks (Cdk4, Cdk6, and Cdk2) and a mitotic Cdk (Cdk1) are involved in cell cycle progression in mammals. Cyclins, Cdk inhibitors, and phosphorylations (both activating and inhibitory) at different cellular levels tightly modulate the activities of these kinases. Based on the results of biochemical studies, it was long believed that different Cdks functioned at specific stages during cell cycle progression. However, deletion of all three interphase Cdks in mice affected cell cycle entry and progression only in certain specialized cells such as hematopoietic cells, beta cells of the pancreas, pituitary lactotrophs, and cardiomyocytes. These genetic experiments challenged the prevailing biochemical model and established that Cdks function in a cell-specific, but not a stage-specific, manner during cell cycle entry and the progression of mitosis. Recent in vivo studies have further established that Cdk1 is the only Cdk that is both essential and sufficient for driving the resumption of meiosis during mouse oocyte maturation. These genetic studies suggest a minimal-essential cell cycle model in which Cdk1 is the central regulator of cell cycle progression. Cdk1 can compensate for the loss of the interphase Cdks by forming active complexes with A-, B-, E-, and D-type Cyclins in a stepwise manner. Thus, Cdk1 plays an essential role in both mitosis and meiosis in mammals, whereas interphase Cdks are dispensable.

  12. Eukaryotic Cell Cycle as a Test Case for Modeling Cellular Regulation in a Collaborative Problem-Solving Environment

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    2007-03-01

    computer models of cell cycle regulation in a variety of organisms, including yeast cells, amphibian embryos, bacterial cells and human cells. These...and meiosis ), but they do not nullify the central role played by irreversible, alternating START and FINISH transitions in the cell cycle. 32...AFRL-IF-RS-TR-2007-69 Final Technical Report March 2007 EUKARYOTIC CELL CYCLE AS A TEST CASE FOR MODELING CELLULAR REGULATION IN A

  13. ODE, RDE and SDE models of cell cycle dynamics and clustering in yeast.

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    Boczko, Erik M; Gedeon, Tomas; Stowers, Chris C; Young, Todd R

    2010-07-01

    Biologists have long observed periodic-like oxygen consumption oscillations in yeast populations under certain conditions, and several unsatisfactory explanations for this phenomenon have been proposed. These ‘autonomous oscillations’ have often appeared with periods that are nearly integer divisors of the calculated doubling time of the culture. We hypothesize that these oscillations could be caused by a form of cell cycle synchronization that we call clustering. We develop some novel ordinary differential equation models of the cell cycle. For these models, and for random and stochastic perturbations, we give both rigorous proofs and simulations showing that both positive and negative growth rate feedback within the cell cycle are possible agents that can cause clustering of populations within the cell cycle. It occurs for a variety of models and for a broad selection of parameter values. These results suggest that the clustering phenomenon is robust and is likely to be observed in nature. Since there are necessarily an integer number of clusters, clustering would lead to periodic-like behaviour with periods that are nearly integer divisors of the period of the cell cycle. Related experiments have shown conclusively that cell cycle clustering occurs in some oscillating yeast cultures.

  14. Cell cycle regulation of DNA polymerase beta in rotenone-based Parkinson's disease models.

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    Hongcai Wang

    Full Text Available In Parkinson's disease (PD, neuronal cells undergo mitotic catastrophe and endoreduplication prior to cell death; however, the regulatory mechanisms remain to be defined. In this study, we investigated cell cycle regulation of DNA polymerase β (poly β in rotenone-based dopaminergic cellular and animal models. Incubation with a low concentration (0.25 µM of rotenone for 1.5 to 7 days resulted in a flattened cell body and decreased DNA replication during S phase, whereas a high concentration (2 µM of rotenone exposure resulted in enlarged, multi-nucleated cells and converted the mitotic cycle into endoreduplication. Consistently, DNA poly β, which is mainly involved in DNA repair synthesis, was upregulated to a high level following exposure to 2 µM rotenone. The abrogation of DNA poly β by siRNA transfection or dideoxycytidine (DDC treatment attenuated the rotenone-induced endoreduplication. The cell cycle was reactivated in cyclin D-expressing dopaminergic neurons from the substantia nigra (SN of rats following stereotactic (ST infusion of rotenone. Increased DNA poly β expression was observed in the substantia nigra pars compacta (SNc and the substantia nigra pars reticulate (SNr of rotenone-treated rats. Collectively, in the in vitro model of rotenone-induced mitotic catastrophe, the overexpression of DNA poly β promotes endoreduplication; in the in vivo model, the upregulation of DNA poly β and cell cycle reentry were also observed in the adult rat substantia nigra. Therefore, the cell cycle regulation of DNA poly β may be involved in the pathological processes of PD, which results in the induction of endoreduplication.

  15. Stochastic E2F activation and reconciliation of phenomenological cell-cycle models.

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    Lee, Tae J; Yao, Guang; Bennett, Dorothy C; Nevins, Joseph R; You, Lingchong

    2010-09-21

    The transition of the mammalian cell from quiescence to proliferation is a highly variable process. Over the last four decades, two lines of apparently contradictory, phenomenological models have been proposed to account for such temporal variability. These include various forms of the transition probability (TP) model and the growth control (GC) model, which lack mechanistic details. The GC model was further proposed as an alternative explanation for the concept of the restriction point, which we recently demonstrated as being controlled by a bistable Rb-E2F switch. Here, through a combination of modeling and experiments, we show that these different lines of models in essence reflect different aspects of stochastic dynamics in cell cycle entry. In particular, we show that the variable activation of E2F can be described by stochastic activation of the bistable Rb-E2F switch, which in turn may account for the temporal variability in cell cycle entry. Moreover, we show that temporal dynamics of E2F activation can be recast into the frameworks of both the TP model and the GC model via parameter mapping. This mapping suggests that the two lines of phenomenological models can be reconciled through the stochastic dynamics of the Rb-E2F switch. It also suggests a potential utility of the TP or GC models in defining concise, quantitative phenotypes of cell physiology. This may have implications in classifying cell types or states.

  16. A Model of Yeast Cell-Cycle Regulation Based on a Standard Component Modeling Strategy for Protein Regulatory Networks.

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    Teeraphan Laomettachit

    Full Text Available To understand the molecular mechanisms that regulate cell cycle progression in eukaryotes, a variety of mathematical modeling approaches have been employed, ranging from Boolean networks and differential equations to stochastic simulations. Each approach has its own characteristic strengths and weaknesses. In this paper, we propose a "standard component" modeling strategy that combines advantageous features of Boolean networks, differential equations and stochastic simulations in a framework that acknowledges the typical sorts of reactions found in protein regulatory networks. Applying this strategy to a comprehensive mechanism of the budding yeast cell cycle, we illustrate the potential value of standard component modeling. The deterministic version of our model reproduces the phenotypic properties of wild-type cells and of 125 mutant strains. The stochastic version of our model reproduces the cell-to-cell variability of wild-type cells and the partial viability of the CLB2-dbΔ clb5Δ mutant strain. Our simulations show that mathematical modeling with "standard components" can capture in quantitative detail many essential properties of cell cycle control in budding yeast.

  17. A data-driven, mathematical model of mammalian cell cycle regulation.

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    Michael C Weis

    Full Text Available Few of >150 published cell cycle modeling efforts use significant levels of data for tuning and validation. This reflects the difficultly to generate correlated quantitative data, and it points out a critical uncertainty in modeling efforts. To develop a data-driven model of cell cycle regulation, we used contiguous, dynamic measurements over two time scales (minutes and hours calculated from static multiparametric cytometry data. The approach provided expression profiles of cyclin A2, cyclin B1, and phospho-S10-histone H3. The model was built by integrating and modifying two previously published models such that the model outputs for cyclins A and B fit cyclin expression measurements and the activation of B cyclin/Cdk1 coincided with phosphorylation of histone H3. The model depends on Cdh1-regulated cyclin degradation during G1, regulation of B cyclin/Cdk1 activity by cyclin A/Cdk via Wee1, and transcriptional control of the mitotic cyclins that reflects some of the current literature. We introduced autocatalytic transcription of E2F, E2F regulated transcription of cyclin B, Cdc20/Cdh1 mediated E2F degradation, enhanced transcription of mitotic cyclins during late S/early G2 phase, and the sustained synthesis of cyclin B during mitosis. These features produced a model with good correlation between state variable output and real measurements. Since the method of data generation is extensible, this model can be continually modified based on new correlated, quantitative data.

  18. A new cell culture model to genetically dissect the complete human papillomavirus life cycle.

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    Bienkowska-Haba, Malgorzata; Luszczek, Wioleta; Myers, Julia E; Keiffer, Timothy R; DiGiuseppe, Stephen; Polk, Paula; Bodily, Jason M; Scott, Rona S; Sapp, Martin

    2018-03-01

    Herein, we describe a novel infection model that achieves highly efficient infection of primary keratinocytes with human papillomavirus type 16 (HPV16). This cell culture model does not depend on immortalization and is amenable to extensive genetic analyses. In monolayer cell culture, the early but not late promoter was active and yielded a spliced viral transcript pattern similar to HPV16-immortalized keratinocytes. However, relative levels of the E8^E2 transcript increased over time post infection suggesting the expression of this viral repressor is regulated independently of other early proteins and that it may be important for the shift from the establishment to the maintenance phase of the viral life cycle. Both the early and the late promoter were strongly activated when infected cells were subjected to differentiation by growth in methylcellulose. When grown as organotypic raft cultures, HPV16-infected cells expressed late E1^E4 and L1 proteins and replication foci were detected, suggesting that they supported the completion of the viral life cycle. As a proof of principle that the infection system may be used for genetic dissection of viral factors, we analyzed E1, E6 and E7 translation termination linker mutant virus for establishment of infection and genome maintenance. E1 but not E6 and E7 was essential to establish infection. Furthermore, E6 but not E7 was required for episomal genome maintenance. Primary keratinocytes infected with wild type HPV16 immortalized, whereas keratinocytes infected with E6 and E7 knockout virus began to senesce 25 to 35 days post infection. The novel infection model provides a powerful genetic tool to study the role of viral proteins throughout the viral life cycle but especially for immediate early events and enables us to compare low- and high-risk HPV types in the context of infection.

  19. A new cell culture model to genetically dissect the complete human papillomavirus life cycle.

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    Malgorzata Bienkowska-Haba

    2018-03-01

    Full Text Available Herein, we describe a novel infection model that achieves highly efficient infection of primary keratinocytes with human papillomavirus type 16 (HPV16. This cell culture model does not depend on immortalization and is amenable to extensive genetic analyses. In monolayer cell culture, the early but not late promoter was active and yielded a spliced viral transcript pattern similar to HPV16-immortalized keratinocytes. However, relative levels of the E8^E2 transcript increased over time post infection suggesting the expression of this viral repressor is regulated independently of other early proteins and that it may be important for the shift from the establishment to the maintenance phase of the viral life cycle. Both the early and the late promoter were strongly activated when infected cells were subjected to differentiation by growth in methylcellulose. When grown as organotypic raft cultures, HPV16-infected cells expressed late E1^E4 and L1 proteins and replication foci were detected, suggesting that they supported the completion of the viral life cycle. As a proof of principle that the infection system may be used for genetic dissection of viral factors, we analyzed E1, E6 and E7 translation termination linker mutant virus for establishment of infection and genome maintenance. E1 but not E6 and E7 was essential to establish infection. Furthermore, E6 but not E7 was required for episomal genome maintenance. Primary keratinocytes infected with wild type HPV16 immortalized, whereas keratinocytes infected with E6 and E7 knockout virus began to senesce 25 to 35 days post infection. The novel infection model provides a powerful genetic tool to study the role of viral proteins throughout the viral life cycle but especially for immediate early events and enables us to compare low- and high-risk HPV types in the context of infection.

  20. A novel quantitative model of cell cycle progression based on cyclin-dependent kinases activity and population balances.

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    Pisu, Massimo; Concas, Alessandro; Cao, Giacomo

    2015-04-01

    Cell cycle regulates proliferative cell capacity under normal or pathologic conditions, and in general it governs all in vivo/in vitro cell growth and proliferation processes. Mathematical simulation by means of reliable and predictive models represents an important tool to interpret experiment results, to facilitate the definition of the optimal operating conditions for in vitro cultivation, or to predict the effect of a specific drug in normal/pathologic mammalian cells. Along these lines, a novel model of cell cycle progression is proposed in this work. Specifically, it is based on a population balance (PB) approach that allows one to quantitatively describe cell cycle progression through the different phases experienced by each cell of the entire population during its own life. The transition between two consecutive cell cycle phases is simulated by taking advantage of the biochemical kinetic model developed by Gérard and Goldbeter (2009) which involves cyclin-dependent kinases (CDKs) whose regulation is achieved through a variety of mechanisms that include association with cyclins and protein inhibitors, phosphorylation-dephosphorylation, and cyclin synthesis or degradation. This biochemical model properly describes the entire cell cycle of mammalian cells by maintaining a sufficient level of detail useful to identify check point for transition and to estimate phase duration required by PB. Specific examples are discussed to illustrate the ability of the proposed model to simulate the effect of drugs for in vitro trials of interest in oncology, regenerative medicine and tissue engineering. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. A Stochastic Model of the Yeast Cell Cycle Reveals Roles for Feedback Regulation in Limiting Cellular Variability.

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    Barik, Debashis; Ball, David A; Peccoud, Jean; Tyson, John J

    2016-12-01

    The cell division cycle of eukaryotes is governed by a complex network of cyclin-dependent protein kinases (CDKs) and auxiliary proteins that govern CDK activities. The control system must function reliably in the context of molecular noise that is inevitable in tiny yeast cells, because mistakes in sequencing cell cycle events are detrimental or fatal to the cell or its progeny. To assess the effects of noise on cell cycle progression requires not only extensive, quantitative, experimental measurements of cellular heterogeneity but also comprehensive, accurate, mathematical models of stochastic fluctuations in the CDK control system. In this paper we provide a stochastic model of the budding yeast cell cycle that accurately accounts for the variable phenotypes of wild-type cells and more than 20 mutant yeast strains simulated in different growth conditions. We specifically tested the role of feedback regulations mediated by G1- and SG2M-phase cyclins to minimize the noise in cell cycle progression. Details of the model are informed and tested by quantitative measurements (by fluorescence in situ hybridization) of the joint distributions of mRNA populations in yeast cells. We use the model to predict the phenotypes of ~30 mutant yeast strains that have not yet been characterized experimentally.

  2. A Stochastic Model of the Yeast Cell Cycle Reveals Roles for Feedback Regulation in Limiting Cellular Variability.

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    Debashis Barik

    2016-12-01

    Full Text Available The cell division cycle of eukaryotes is governed by a complex network of cyclin-dependent protein kinases (CDKs and auxiliary proteins that govern CDK activities. The control system must function reliably in the context of molecular noise that is inevitable in tiny yeast cells, because mistakes in sequencing cell cycle events are detrimental or fatal to the cell or its progeny. To assess the effects of noise on cell cycle progression requires not only extensive, quantitative, experimental measurements of cellular heterogeneity but also comprehensive, accurate, mathematical models of stochastic fluctuations in the CDK control system. In this paper we provide a stochastic model of the budding yeast cell cycle that accurately accounts for the variable phenotypes of wild-type cells and more than 20 mutant yeast strains simulated in different growth conditions. We specifically tested the role of feedback regulations mediated by G1- and SG2M-phase cyclins to minimize the noise in cell cycle progression. Details of the model are informed and tested by quantitative measurements (by fluorescence in situ hybridization of the joint distributions of mRNA populations in yeast cells. We use the model to predict the phenotypes of ~30 mutant yeast strains that have not yet been characterized experimentally.

  3. Dynamic modelling and characterisation of a solid oxide fuel cell integrated in a gas turbine cycle

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    Thorud, Bjoern

    2005-07-01

    This thesis focuses on three main areas within the field of SOFC/GT-technology: 1) Development of a dynamic SOFC/GT model. 2) Model calibration and sensitivity study. 3) Assessment of the dynamic properties of a SOFC/GT power plant. The SOFC/GT model developed in this thesis describes a pressurised tubular Siemens Westinghouse-type SOFC, which is integrated in a gas turbine cycle. The process further includes a plate-fin recuperator for stack air preheating, a prereformer, an anode exhaust gas recycling loop for steam/carbon-ratio control, an afterburner and a shell-tube heat exchanger for air preheating. The fuel cell tube, the recuperator and the shell-tube heat exchanger are spatially distributed models. The SOFC model is further thermally integrated with the prereformer. The compressor and turbine models are based on performance maps as a general representation of the characteristics. In addition, a shaft model which incorporates moment of inertia is included to account for gas turbine transients. The SOFC model is calibrated against experimentally obtained data from a single-cell experiment performed on a Siemens Westinghouse tubular SOFC. The agreement between the model and the experimental results is good. The sensitivity study revealed that the degree of prereforming is of great importance with respect to the axial temperature distribution of the fuel cell. Types of malfunctions are discussed prior to the dynamic behaviour study. The dynamic study of the SOFC/GT process is performed by simulating small and large load changes according to three different strategies; 1) Load change at constant mean fuel cell temperature. 2) Load change at constant turbine inlet temperature. 3) Load change at constant shaft speed. Of these three strategies, the constant mean fuel cell temperature strategy appears to be the most rapid load change method. Furthermore, this strategy implies the lowest degree of thermal cycling, the smoothest fuel cell temperature distribution and

  4. Impaired Cell Cycle Regulation in a Natural Equine Model of Asthma.

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    Alicja Pacholewska

    Full Text Available Recurrent airway obstruction (RAO is a common and potentially debilitating lower airway disease in horses, which shares many similarities with human asthma. In susceptible horses RAO exacerbation is caused by environmental allergens and irritants present in hay dust. The objective of this study was the identification of genes and pathways involved in the pathology of RAO by global transcriptome analyses in stimulated peripheral blood mononuclear cells (PBMCs. We performed RNA-seq on PBMCs derived from 40 RAO affected and 45 control horses belonging to three cohorts of Warmblood horses: two half-sib families and one group of unrelated horses. PBMCs were stimulated with hay dust extract, lipopolysaccharides, a recombinant parasite antigen, or left unstimulated. The total dataset consisted of 561 individual samples. We detected significant differences in the expression profiles between RAO and control horses. Differential expression (DE was most marked upon stimulation with hay dust extract. An important novel finding was a strong upregulation of CXCL13 together with many genes involved in cell cycle regulation in stimulated samples from RAO affected horses, in addition to changes in the expression of several HIF-1 transcription factor target genes. The RAO condition alters systemic changes observed as differential expression profiles of PBMCs. Those changes also depended on the cohort and stimulation of the samples and were dominated by genes involved in immune cell trafficking, development, and cell cycle regulation. Our findings indicate an important role of CXCL13, likely macrophage or Th17 derived, and the cell cycle regulator CDC20 in the immune response in RAO.

  5. Neutral space analysis for a Boolean network model of the fission yeast cell cycle network

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    Gonzalo A Ruz

    2014-01-01

    Full Text Available BACKGROUND: Interactions between genes and their products give rise to complex circuits known as gene regulatory networks (GRN that enable cells to process information and respond to external stimuli. Several important processes for life, depend of an accurate and context-specific regulation of gene expression, such as the cell cycle, which can be analyzed through its GRN, where deregulation can lead to cancer in animals or a directed regulation could be applied for biotechnological processes using yeast. An approach to study the robustness of GRN is through the neutral space. In this paper, we explore the neutral space of a Schizosaccharomyces pombe (fission yeast cell cycle network through an evolution strategy to generate a neutral graph, composed of Boolean regulatory networks that share the same state sequences of the fission yeast cell cycle. RESULTS: Through simulations it was found that in the generated neutral graph, the functional networks that are not in the wildtype connected component have in general a Hamming distance more than 3 with the wildtype, and more than 10 between the other disconnected functional networks. Significant differences were found between the functional networks in the connected component of the wildtype network and the rest of the network, not only at a topological level, but also at the state space level, where significant differences in the distribution of the basin of attraction for the G1 fixed point was found for deterministic updating schemes. CONCLUSIONS: In general, functional networks in the wildtype network connected component, can mutate up to no more than 3 times, then they reach a point of no return where the networks leave the connected component of the wildtype. The proposed method to construct a neutral graph is general and can be used to explore the neutral space of other biologically interesting networks, and also formulate new biological hypotheses studying the functional networks in the

  6. Cell Cycle Control by PTEN.

    Science.gov (United States)

    Brandmaier, Andrew; Hou, Sheng-Qi; Shen, Wen H

    2017-07-21

    Continuous and error-free chromosome inheritance through the cell cycle is essential for genomic stability and tumor suppression. However, accumulation of aberrant genetic materials often causes the cell cycle to go awry, leading to malignant transformation. In response to genotoxic stress, cells employ diverse adaptive mechanisms to halt or exit the cell cycle temporarily or permanently. The intrinsic machinery of cycling, resting, and exiting shapes the cellular response to extrinsic stimuli, whereas prevalent disruption of the cell cycle machinery in tumor cells often confers resistance to anticancer therapy. Phosphatase and tensin homolog (PTEN) is a tumor suppressor and a guardian of the genome that is frequently mutated or deleted in human cancer. Moreover, it is increasingly evident that PTEN deficiency disrupts the fundamental processes of genetic transmission. Cells lacking PTEN exhibit cell cycle deregulation and cell fate reprogramming. Here, we review the role of PTEN in regulating the key processes in and out of cell cycle to optimize genomic integrity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Effects of radiation on the cell division cycle. Using yeasts as models

    International Nuclear Information System (INIS)

    Mann, C.; Marsolier, M.C.

    2000-01-01

    The living organisms, since the appearance on earth of the simplest of them, are submitted to numerous attacks having different origin. They use response systems to the DNA damages coming from these attacks and especially radiations. The cell knows how to take stock of the situation, at different moment of its life, to slow down, eventually to stop its cycle before continuing, after repairing of its DNA and divided itself. These mechanisms have kept a remarkable similarity during the evolution. The study of these systems among yeasts is a precious help to understand the corresponding systems for man and to evaluate the limits but also the possibilities, particularly, in oncology. (N.C.)

  8. Cell cycle gene expression under clinorotation

    Science.gov (United States)

    Artemenko, Olga

    2016-07-01

    Cyclins and cyclin-dependent kinase (CDK) are main regulators of the cell cycle of eukaryotes. It's assumes a significant change of their level in cells under microgravity conditions and by other physical factors actions. The clinorotation use enables to determine the influence of gravity on simulated events in the cell during the cell cycle - exit from the state of quiet stage and promotion presynthetic phase (G1) and DNA synthesis phase (S) of the cell cycle. For the clinorotation effect study on cell proliferation activity is the necessary studies of molecular mechanisms of cell cycle regulation and development of plants under altered gravity condition. The activity of cyclin D, which is responsible for the events of the cell cycle in presynthetic phase can be controlled by the action of endogenous as well as exogenous factors, but clinorotation is one of the factors that influence on genes expression that regulate the cell cycle.These data can be used as a model for further research of cyclin - CDK complex for study of molecular mechanisms regulation of growth and proliferation. In this investigation we tried to summarize and analyze known literature and own data we obtained relatively the main regulators of the cell cycle in altered gravity condition.

  9. In vitro recapitulation of the urea cycle using murine embryonic stem cell-derived in vitro liver model.

    Science.gov (United States)

    Tamai, Miho; Aoki, Mami; Nishimura, Akihito; Morishita, Koji; Tagawa, Yoh-ichi

    2013-12-01

    Ammonia, a toxic metabolite, is converted to urea in hepatocytes via the urea cycle, a process necessary for cell/organismal survival. In liver, hepatocytes, polygonal and multipolar structures, have a few sides which face hepatic sinusoids and adjacent hepatocytes to form intercellular bile canaliculi connecting to the ductules. The critical nature of this three-dimensional environment should be related to the maintenance of hepatocyte function such as urea synthesis. Recently, we established an in vitro liver model derived from murine embryonic stem cells, IVL(mES), which included the hepatocyte layer and a surrounding sinusoid vascular-like network. The IVL(mES) culture, where the hepatocyte is polarized in a similar fashion to its in vivo counterpart, could successfully recapitulate in vivo results. L-Ornithine is an intermediate of the urea cycle, but supplemental L-ornithine does not activate the urea cycle in the apolar primary hepatocyte of monolayer culture. In the IVL(mES), supplemental L-ornithine could activate the urea cycle, and also protect against ammonium/alcohol-induced hepatocyte death. While the IVL(mES) displays architectural and functional properties similar to the liver, primary hepatocyte of monolayer culture fail to model critical functional aspects of liver physiology. We propose that the IVL(mES) will represent a useful, humane alternative to animal studies for drug toxicity and mechanistic studies of liver injury.

  10. Cell growth and division cycle

    International Nuclear Information System (INIS)

    Darzynkiewicz, Z.

    1986-01-01

    The concept of the cell cycle in its present form was introduced more than three decades ago. Studying incorporation of DNA precursors by autoradiography, these authors observed that DNA synthesis in individual cells was discontinuous and occupied a discrete portion of the cell life (S phase). Mitotic division was seen to occur after a certain period of time following DNA replication. A distinct time interval between mitosis and DNA replication was also apparent. Thus, the cell cycle was subdivided into four consecutive phases, G/sub 1/, S, G/sub 2/, and M. The G/sub 1/ and G/sub 2/ phases represented the ''gaps'' between mitosis and the start of DNA replication, and between the end of DNA replication and the onset of mitosis, respectively. The cell cycle was defined as the interval between the midpoint of mitosis and the midpoint of the subsequent mitosis of the daughter cell(s). The authors' present knowledge on the cell cycle benefited mostly from the development of four different techniques: autoradiography, time-lapse cinematography, cell synchronization and flow cytometry. Of these, autoradiography has been the most extensively used, especially during the past two decades. By providing a means to analyse incorporation of precursors of DNA, RNA or proteins by individual cells and, in combination with various techniques of cell synchronization, autoradiography yielded most of the data fundamental to the current understanding of the cell cycle-related phenomena. Kinetics of cell progression through the cell cycle could be analysed in great detail after development of such sophisticated autoradiographic approaches as measurements of the fraction of labeled mitoses (''FLM curves'') or multiple sequential cell labelling with /sup 3/H- and /sup 14/C-TdR

  11. Altered cell cycle-related gene expression in brain and lymphocytes from a transgenic mouse model of Alzheimer's disease [amyloid precursor protein/presenilin 1 (PS1)].

    Science.gov (United States)

    Esteras, Noemí; Bartolomé, Fernando; Alquézar, Carolina; Antequera, Desireé; Muñoz, Úrsula; Carro, Eva; Martín-Requero, Ángeles

    2012-09-01

    Cumulative evidence indicates that aberrant re-expression of many cell cycle-related proteins and inappropriate neuronal cell cycle control are critical events in Alzheimer's disease (AD) pathogenesis. Evidence of cell cycle activation in post-mitotic neurons has also been observed in murine models of AD, despite the fact that most of these mice do not show massive loss of neuronal bodies. Dysfunction of the cell cycle appears to affect cells other than neurons, as peripheral cells, such as lymphocytes and fibroblasts from patients with AD, show an altered response to mitogenic stimulation. We sought to determine whether cell cycle disturbances are present simultaneously in both brain and peripheral cells from the amyloid precursor protein (APP)/presenilin 1 (PS1) mouse model of AD, in order to validate the use of peripheral cells from patients not only to study cell cycle abnormalities as a pathogenic feature of AD, but also as a means to test novel therapeutic approaches. By using cell cycle pathway-specific RT(2)Profiler™ PCR Arrays, we detected changes in a number of cell cycle-related genes in brain as well as in lymphocytes from APP/PS1 mice. Moreover, we found enhanced 5'-bromo-2'-deoxyuridine incorporation into DNA in lymphocytes from APP/PS1 mice, and increased expression of the cell proliferation marker proliferating cell nuclear antigen (PCNA), and the cyclin-dependent kinase (CDK) inhibitor Cdkn2a, as detected by immunohistochemistry in cortical neurons of the APP/PS1 mice. Taken together, the cell cycle-related changes in brain and blood cells reported here support the mitosis failure hypothesis in AD and validate the use of peripheral cells as surrogate tissue to study the molecular basis of AD pathogenesis. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  12. Model-based investigation of the circadian clock and cell cycle coupling in mouse embryonic fibroblasts: Prediction of RevErb-α up-regulation during mitosis

    OpenAIRE

    Traynard , Pauline; Feillet , Céline; Soliman , Sylvain; Delaunay , Franck; Fages , François

    2016-01-01

    International audience; Experimental observations have put in evidence autonomous self-sustained circadian oscillators in most mammalian cells, and proved the existence of molecular links between the circadian clock and the cell cycle. Some mathematical models have also been built to assess conditions of control of the cell cycle by the circadian clock. However, recent studies in individual NIH3T3 fibroblasts have shown an unexpected acceleration of the circadian clock together with the cell ...

  13. Model-based deconvolution of cell cycle time-series data reveals gene expression details at high resolution.

    Directory of Open Access Journals (Sweden)

    Dan Siegal-Gaskins

    2009-08-01

    Full Text Available In both prokaryotic and eukaryotic cells, gene expression is regulated across the cell cycle to ensure "just-in-time" assembly of select cellular structures and molecular machines. However, present in all time-series gene expression measurements is variability that arises from both systematic error in the cell synchrony process and variance in the timing of cell division at the level of the single cell. Thus, gene or protein expression data collected from a population of synchronized cells is an inaccurate measure of what occurs in the average single-cell across a cell cycle. Here, we present a general computational method to extract "single-cell"-like information from population-level time-series expression data. This method removes the effects of 1 variance in growth rate and 2 variance in the physiological and developmental state of the cell. Moreover, this method represents an advance in the deconvolution of molecular expression data in its flexibility, minimal assumptions, and the use of a cross-validation analysis to determine the appropriate level of regularization. Applying our deconvolution algorithm to cell cycle gene expression data from the dimorphic bacterium Caulobacter crescentus, we recovered critical features of cell cycle regulation in essential genes, including ctrA and ftsZ, that were obscured in population-based measurements. In doing so, we highlight the problem with using population data alone to decipher cellular regulatory mechanisms and demonstrate how our deconvolution algorithm can be applied to produce a more realistic picture of temporal regulation in a cell.

  14. Quadratic reactivity fuel cycle model

    International Nuclear Information System (INIS)

    Lewins, J.D.

    1985-01-01

    For educational purposes it is highly desirable to provide simple yet realistic models for fuel cycle and fuel economy. In particular, a lumped model without recourse to detailed spatial calculations would be very helpful in providing the student with a proper understanding of the purposes of fuel cycle calculations. A teaching model for fuel cycle studies based on a lumped model assuming the summability of partial reactivities with a linear dependence of reactivity usefully illustrates fuel utilization concepts. The linear burnup model does not satisfactorily represent natural enrichment reactors. A better model, showing the trend of initial plutonium production before subsequent fuel burnup and fission product generation, is a quadratic fit. The study of M-batch cycles, reloading 1/Mth of the core at end of cycle, is now complicated by nonlinear equations. A complete account of the asymptotic cycle for any order of M-batch refueling can be given and compared with the linear model. A complete account of the transient cycle can be obtained readily in the two-batch model and this exact solution would be useful in verifying numerical marching models. It is convenient to treat the parabolic fit rho = 1 - tau 2 as a special case of the general quadratic fit rho = 1 - C/sub tau/ - (1 - C)tau 2 in suitably normalized reactivity and cycle time units. The parabolic results are given in this paper

  15. Model-based investigation of the circadian clock and cell cycle coupling in mouse embryonic fibroblasts: Prediction of RevErb-α up-regulation during mitosis.

    Science.gov (United States)

    Traynard, Pauline; Feillet, Céline; Soliman, Sylvain; Delaunay, Franck; Fages, François

    2016-11-01

    Experimental observations have put in evidence autonomous self-sustained circadian oscillators in most mammalian cells, and proved the existence of molecular links between the circadian clock and the cell cycle. Some mathematical models have also been built to assess conditions of control of the cell cycle by the circadian clock. However, recent studies in individual NIH3T3 fibroblasts have shown an unexpected acceleration of the circadian clock together with the cell cycle when the culture medium is enriched with growth factors, and the absence of such acceleration in confluent cells. In order to explain these observations, we study a possible entrainment of the circadian clock by the cell cycle through a regulation of clock genes around the mitosis phase. We develop a computational model and a formal specification of the observed behavior to investigate the conditions of entrainment in period and phase. We show that either the selective activation of RevErb-α or the selective inhibition of Bmal1 transcription during the mitosis phase, allow us to fit the experimental data on both period and phase, while a uniform inhibition of transcription during mitosis seems incompatible with the phase data. We conclude on the arguments favoring the RevErb-α up-regulation hypothesis and on some further predictions of the model. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. Epigenetic dynamics across the cell cycle

    DEFF Research Database (Denmark)

    Kheir, Tony Bou; Lund, Anders H.

    2010-01-01

    Progression of the mammalian cell cycle depends on correct timing and co-ordination of a series of events, which are managed by the cellular transcriptional machinery and epigenetic mechanisms governing genome accessibility. Epigenetic chromatin modifications are dynamic across the cell cycle...... a correct inheritance of epigenetic chromatin modifications to daughter cells. In this chapter, we summarize the current knowledge on the dynamics of epigenetic chromatin modifications during progression of the cell cycle....

  17. Elucidating the Role of CaMKK in Cell Cycle and Cell Fate using a C. elegans model

    Science.gov (United States)

    2000-07-01

    domain) or the Aspergillus homologue, anCaMKB (48% overall)(Figure 2). To functionally compare the C. elegans proteins with their mammalian homologues...subunit on the yeast proteome . EMBO J 18, 4157-68 (1999). 14 19. H. Tokumitsu et aL, Substrate recognition by Ca2+/Calmodulin-dependent protein kinase...2 Nicholas School of the Environment Duke University, Durham, NC 27710 Ethan@Duke.Edu In a variety of models, from Xenopus oocytes to Aspergillus to

  18. Cell cycle phases in the unequal mother/daughter cell cycles of Saccharomyces cerevisiae.

    Science.gov (United States)

    Brewer, B J; Chlebowicz-Sledziewska, E; Fangman, W L

    1984-11-01

    During cell division in the yeast Saccharomyces cerevisiae mother cells produce buds (daughter cells) which are smaller and have longer cell cycles. We performed experiments to compare the lengths of cell cycle phases in mothers and daughters. As anticipated from earlier indirect observations, the longer cell cycle time of daughter cells is accounted for by a longer G1 interval. The S-phase and the G2-phase are of the same duration in mother and daughter cells. An analysis of five isogenic strains shows that cell cycle phase lengths are independent of cell ploidy and mating type.

  19. Cell cycle control by components of cell anchorage

    OpenAIRE

    Gad, Annica

    2005-01-01

    Extracellular factors, such as growth factors and cell anchorage to the extracellular matrix, control when and where cells may proliferate. This control is abolished when a normal cell transforms into a tumour cell. The control of cell proliferation by cell anchorage was elusive and less well studied than the control by growth factors. Therefore, we aimed to clarify at what points in the cell cycle and through which molecular mechanisms cell anchorage controls cell cycle pro...

  20. A Method to Design Synthetic Cell-Cycle Networks

    International Nuclear Information System (INIS)

    Ke-Ke, Miao

    2009-01-01

    The interactions among proteins, DNA and RNA in an organism form elaborate cell-cycle networks which govern cell growth and proliferation. Understanding the common structure of cell-cycle networks will be of great benefit to science research. Here, inspired by the importance of the cell-cycle regulatory network of yeast which has been studied intensively, we focus on small networks with 11 nodes, equivalent to that of the cell-cycle regulatory network used by Li et al. [Proc. Natl. Acad. Sci. USA 101(2004)4781] Using a Boolean model, we study the correlation between structure and function, and a possible common structure. It is found that cascade-like networks with a great number of interactions between nodes are stable. Based on these findings, we are able to construct synthetic networks that have the same functions as the cell-cycle regulatory network. (condensed matter: structure, mechanical and thermal properties)

  1. The Hamburg oceanic carbon cycle circulation model. Cycle 1

    International Nuclear Information System (INIS)

    Maier-Reimer, E.; Heinze, C.

    1992-02-01

    The carbon cycle model calculates the prognostic fields of oceanic geochemical carbon cycle tracers making use of a 'frozen' velocity field provided by a run of the LSG oceanic circulation model (see the corresponding manual, LSG=Large Scale Geostrophic). The carbon cycle model includes a crude approximation of interactions between sediment and bottom layer water. A simple (meridionally diffusive) one layer atmosphere model allows to calculate the CO 2 airborne fraction resulting from the oceanic biogeochemical interactions. (orig.)

  2. Therapeutic Cell-Cycle-Decoy Efficacy of a Telomerase-Dependent Adenovirus in an Orthotopic Model of Chemotherapy-Resistant Human Stomach Carcinomatosis Peritonitis Visualized With FUCCI Imaging.

    Science.gov (United States)

    Yano, Shuya; Takehara, Kiyoto; Tazawa, Hiroshi; Kishimoto, Hiroyuki; Urata, Yasuo; Kagawa, Shunsuke; Fujiwara, Toshiyoshi; Hoffman, Robert M

    2017-11-01

    We have established an orthotopic nude-mouse model of gastric cancer carcinomatosis peritonitis, a recalcitrant disease in human patients. Human MKN45 poorly-differentiated human gastric cancer cells developed carcinomatosis peritonitis upon orthotopic transplantation in nude mice. The MKN45 cells expressed the fluorescent ubiquitination-based cell cycle indicator (FUCCI) that color codes the phases of the cell cycle. The intra-peritoneal tumors and ascites contained mostly quiescent G 1 /G o cancer cells visualized as red by FUCCI imaging. Cisplatinum (CDDP) treatment did not reduce bloody ascites, and larger tumors formed in the peritoneal cavity after CDDP treatment in an early-stage carcinomatosis peritonitis orthotopic mouse model. Paclitaxel-treated mice had reduced ascites, but also had large tumor masses in the peritonium after treatment with cancer cells mostly in G 0 /G 1 , visualized by FUCCI red. In contrast, OBP-301 telomerase-dependent adenovirus-treated mice had no ascites and only small tumor nodules consisting of cancer cells mostly in S/G 2 phases in the early-stage carcinomatosis peritonitis model, visualized by FUCCI green. Furthermore, OBP-301 significantly reduced the size of tumors (P < 0.01) and ascites even in a late-stage carcinomatosis peritonitis model. These results suggest that quiescent peritoneally-disseminated gastric cancer cells are resistant to conventional chemotherapy, but OBP-301 significantly reduced the weight of the tumors and increased survival, suggesting clinical potential. J. Cell. Biochem. 118: 3635-3642, 2017. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  3. Temporal fluxomics reveals oscillations in TCA cycle flux throughout the mammalian cell cycle.

    Science.gov (United States)

    Ahn, Eunyong; Kumar, Praveen; Mukha, Dzmitry; Tzur, Amit; Shlomi, Tomer

    2017-11-06

    Cellular metabolic demands change throughout the cell cycle. Nevertheless, a characterization of how metabolic fluxes adapt to the changing demands throughout the cell cycle is lacking. Here, we developed a temporal-fluxomics approach to derive a comprehensive and quantitative view of alterations in metabolic fluxes throughout the mammalian cell cycle. This is achieved by combining pulse-chase LC-MS-based isotope tracing in synchronized cell populations with computational deconvolution and metabolic flux modeling. We find that TCA cycle fluxes are rewired as cells progress through the cell cycle with complementary oscillations of glucose versus glutamine-derived fluxes: Oxidation of glucose-derived flux peaks in late G1 phase, while oxidative and reductive glutamine metabolism dominates S phase. These complementary flux oscillations maintain a constant production rate of reducing equivalents and oxidative phosphorylation flux throughout the cell cycle. The shift from glucose to glutamine oxidation in S phase plays an important role in cell cycle progression and cell proliferation. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

  4. Lactobacillus Decelerates Cervical Epithelial Cell Cycle Progression

    Science.gov (United States)

    Vielfort, Katarina; Weyler, Linda; Söderholm, Niklas; Engelbrecht, Mattias; Löfmark, Sonja; Aro, Helena

    2013-01-01

    We investigated cell cycle progression in epithelial cervical ME-180 cells during colonization of three different Lactobacillus species utilizing live cell microscopy, bromodeoxyuridine incorporation assays, and flow cytometry. The colonization of these ME-180 cells by L. rhamnosus and L. reuteri, originating from human gastric epithelia and saliva, respectively, was shown to reduce cell cycle progression and to cause host cells to accumulate in the G1 phase of the cell cycle. The G1 phase accumulation in L. rhamnosus-colonized cells was accompanied by the up-regulation and nuclear accumulation of p21. By contrast, the vaginal isolate L. crispatus did not affect cell cycle progression. Furthermore, both the supernatants from the lactic acid-producing L. rhamnosus colonies and lactic acid added to cell culture media were able to reduce the proliferation of ME-180 cells. In this study, we reveal the diversity of the Lactobacillus species to affect host cell cycle progression and demonstrate that L. rhamnosus and L. reuteri exert anti-proliferative effects on human cervical carcinoma cells. PMID:23675492

  5. Lactobacillus decelerates cervical epithelial cell cycle progression.

    Directory of Open Access Journals (Sweden)

    Katarina Vielfort

    Full Text Available We investigated cell cycle progression in epithelial cervical ME-180 cells during colonization of three different Lactobacillus species utilizing live cell microscopy, bromodeoxyuridine incorporation assays, and flow cytometry. The colonization of these ME-180 cells by L. rhamnosus and L. reuteri, originating from human gastric epithelia and saliva, respectively, was shown to reduce cell cycle progression and to cause host cells to accumulate in the G1 phase of the cell cycle. The G1 phase accumulation in L. rhamnosus-colonized cells was accompanied by the up-regulation and nuclear accumulation of p21. By contrast, the vaginal isolate L. crispatus did not affect cell cycle progression. Furthermore, both the supernatants from the lactic acid-producing L. rhamnosus colonies and lactic acid added to cell culture media were able to reduce the proliferation of ME-180 cells. In this study, we reveal the diversity of the Lactobacillus species to affect host cell cycle progression and demonstrate that L. rhamnosus and L. reuteri exert anti-proliferative effects on human cervical carcinoma cells.

  6. Protein tyrosine nitration in the cell cycle

    International Nuclear Information System (INIS)

    Jia, Min; Mateoiu, Claudia; Souchelnytskyi, Serhiy

    2011-01-01

    Highlights: → Enrichment of 3-nitrotyrosine containing proteins from cells synchronized in different phases of the cell cycle. → Identification of 76 tyrosine nitrated proteins that change expression during the cell cycle. → Nineteen identified proteins were previously described as regulators of cell proliferation. -- Abstract: Nitration of tyrosine residues in proteins is associated with cell response to oxidative/nitrosative stress. Tyrosine nitration is relatively low abundant post-translational modification that may affect protein functions. Little is known about the extent of protein tyrosine nitration in cells during progression through the cell cycle. Here we report identification of proteins enriched for tyrosine nitration in cells synchronized in G0/G1, S or G2/M phases of the cell cycle. We identified 27 proteins in cells synchronized in G0/G1 phase, 37 proteins in S phase synchronized cells, and 12 proteins related to G2/M phase. Nineteen of the identified proteins were previously described as regulators of cell proliferation. Thus, our data indicate which tyrosine nitrated proteins may affect regulation of the cell cycle.

  7. Performances of Saft Lithium-Ion Cells in LEO Cycling

    Directory of Open Access Journals (Sweden)

    Prevot D.

    2017-01-01

    The article will thus present the whole LEO cycling results available for the two cells, and will provide afterwards the correlation status of Saft Li-ion Model (SLIM with all the experimental data acquired.

  8. Cellular Clocks : Coupled Circadian Dispatch and Cell Division Cycles

    NARCIS (Netherlands)

    Merrow, Martha; Roenneberg, Till

    2004-01-01

    Gating of cell division by the circadian clock is well known, yet its mechanism is little understood. Genetically tractable model systems have led to new hypotheses and questions concerning the coupling of these two cellular cycles.

  9. Modelling the Krebs cycle and oxidative phosphorylation.

    Science.gov (United States)

    Korla, Kalyani; Mitra, Chanchal K

    2014-01-01

    The Krebs cycle and oxidative phosphorylation are the two most important sets of reactions in a eukaryotic cell that meet the major part of the total energy demands of a cell. In this paper, we present a computer simulation of the coupled reactions using open source tools for simulation. We also show that it is possible to model the Krebs cycle with a simple black box with a few inputs and outputs. However, the kinetics of the internal processes has been modelled using numerical tools. We also show that the Krebs cycle and oxidative phosphorylation together can be combined in a similar fashion - a black box with a few inputs and outputs. The Octave script is flexible and customisable for any chosen set-up for this model. In several cases, we had no explicit idea of the underlying reaction mechanism and the rate determining steps involved, and we have used the stoichiometric equations that can be easily changed as and when more detailed information is obtained. The script includes the feedback regulation of the various enzymes of the Krebs cycle. For the electron transport chain, the pH gradient across the membrane is an essential regulator of the kinetics and this has been modelled empirically but fully consistent with experimental results. The initial conditions can be very easily changed and the simulation is potentially very useful in a number of cases of clinical importance.

  10. Transcriptional Waves in the Yeast Cell Cycle

    OpenAIRE

    Oliva, Anna; Rosebrock, Adam; Ferrezuelo, Francisco; Pyne, Saumyadipta; Chen, Haiying; Skiena, Steve; Futcher, Bruce; Leatherwood, Janet

    2005-01-01

    Many genes are regulated as an innate part of the eukaryotic cell cycle, and a complex transcriptional network helps enable the cyclic behavior of dividing cells. This transcriptional network has been studied in Saccharomyces cerevisiae (budding yeast) and elsewhere. To provide more perspective on these regulatory mechanisms, we have used microarrays to measure gene expression through the cell cycle of Schizosaccharomyces pombe (fission yeast). The 750 genes with the most significant oscillat...

  11. Distinct mechanisms act in concert to mediate cell cycle arrest.

    Science.gov (United States)

    Toettcher, Jared E; Loewer, Alexander; Ostheimer, Gerard J; Yaffe, Michael B; Tidor, Bruce; Lahav, Galit

    2009-01-20

    In response to DNA damage, cells arrest at specific stages in the cell cycle. This arrest must fulfill at least 3 requirements: it must be activated promptly; it must be sustained as long as damage is present to prevent loss of genomic information; and after the arrest, cells must re-enter into the appropriate cell cycle phase to ensure proper ploidy. Multiple molecular mechanisms capable of arresting the cell cycle have been identified in mammalian cells; however, it is unknown whether each mechanism meets all 3 requirements or whether they act together to confer specific functions to the arrest. To address this question, we integrated mathematical models describing the cell cycle and the DNA damage signaling networks and tested the contributions of each mechanism to cell cycle arrest and re-entry. Predictions from this model were then tested with quantitative experiments to identify the combined action of arrest mechanisms in irradiated cells. We find that different arrest mechanisms serve indispensable roles in the proper cellular response to DNA damage over time: p53-independent cyclin inactivation confers immediate arrest, whereas p53-dependent cyclin downregulation allows this arrest to be sustained. Additionally, p21-mediated inhibition of cyclin-dependent kinase activity is indispensable for preventing improper cell cycle re-entry and endoreduplication. This work shows that in a complex signaling network, seemingly redundant mechanisms, acting in a concerted fashion, can achieve a specific cellular outcome.

  12. Regulation of cell cycle progression by cell-cell and cell-matrix forces

    NARCIS (Netherlands)

    Uroz, Marina; Wistorf, Sabrina; Serra-Picamal, Xavier; Conte, Vito; Sales-Pardo, Marta; Roca-Cusachs, Pere; Guimerà, Roger; Trepat, Xavier

    2018-01-01

    It has long been proposed that the cell cycle is regulated by physical forces at the cell-cell and cell-extracellular matrix (ECM) interfaces 1-12 . However, the evolution of these forces during the cycle has never been measured in a tissue, and whether this evolution affects cell cycle progression

  13. The LifeCycle model

    DEFF Research Database (Denmark)

    Krink, Thiemo; Løvbjerg, Morten

    2002-01-01

    genetic algorithms (GAs), particle swarm optimisation (PSOs), and stochastic hill climbing to create a generally well-performing search heuristics. In the LifeCycle model, we consider candidate solutions and their fitness as individuals, which, based on their recent search progress, can decide to become...... either a GA individual, a particle of a PSO, or a single stochastic hill climber. First results from a comparison of our new approach with the single search algorithms indicate a generally good performance in numerical optimization....

  14. Cell Cycle Deregulation in Ewing's Sarcoma Pathogenesis

    Science.gov (United States)

    Kowalewski, Ashley A.; Randall, R. Lor; Lessnick, Stephen L.

    2011-01-01

    Ewing's sarcoma is a highly aggressive pediatric tumor of bone that usually contains the characteristic chromosomal translocation t(11;22)(q24;q12). This translocation encodes the oncogenic fusion protein EWS/FLI, which acts as an aberrant transcription factor to deregulate target genes necessary for oncogenesis. One key feature of oncogenic transformation is dysregulation of cell cycle control. It is therefore likely that EWS/FLI and other cooperating mutations in Ewing's sarcoma modulate the cell cycle to facilitate tumorigenesis. This paper will summarize current published data associated with deregulation of the cell cycle in Ewing's sarcoma and highlight important questions that remain to be answered. PMID:21052502

  15. Cell Cycle Deregulation in Ewing's Sarcoma Pathogenesis

    Directory of Open Access Journals (Sweden)

    Ashley A. Kowalewski

    2011-01-01

    Full Text Available Ewing's sarcoma is a highly aggressive pediatric tumor of bone that usually contains the characteristic chromosomal translocation t(11;22(q24;q12. This translocation encodes the oncogenic fusion protein EWS/FLI, which acts as an aberrant transcription factor to deregulate target genes necessary for oncogenesis. One key feature of oncogenic transformation is dysregulation of cell cycle control. It is therefore likely that EWS/FLI and other cooperating mutations in Ewing's sarcoma modulate the cell cycle to facilitate tumorigenesis. This paper will summarize current published data associated with deregulation of the cell cycle in Ewing's sarcoma and highlight important questions that remain to be answered.

  16. Regulation of the cell cycle by irradiation

    International Nuclear Information System (INIS)

    Akashi, Makoto

    1995-01-01

    The molecular mechanism of cell proliferation is extremely complex; deregulation results in neoplastic transformation. In eukaryotes, proliferation of cells is finely regulated through the cell cycle. Studies have shown that the cell cycle is regulated by s series of enzymes known as cyclin-dependent kinases (CDKs). The activities of CDKs are controlled by their association with regulatory subunits, cyclins; the expression of cyclins and the activation of the different cyclin-CDK complexes are required for the cell to cycle. Thus, the cell cycle is regulated by activating and inhibiting phosphorylation of the CDK subunits and this program has internal check points at different stages of the cell cycle. When cells are exposed to external insults such as DNA damaging agents, negative regulation of the cell cycle occurs; arrest in either G1 or G2 stage is induced to prevent the cells from prematurely entering into the next stage before DNA is repaired. Recently, a potent inhibitor of CDKs, which inhibits the phosphorylation of retinoblastoma susceptibility (Rb) gene product by cyclin A-CDK2, cyclin E-CDK2, cyclin D1-CDK4, and cyclin D2-CDK4 complexes has been identified. This protein named WAF1, Sdi1, Cip1, or p21 (a protein of Mr 21,000) contains a p53-binding site in its promoter and studies have reported that the expression of WAF1 was directly regulated by p53; cells with loss of p53 activity due to mutational alteration were unable to induce WAF1. This chapter will be focused on the mechanisms of the cell cycle including inhibitors of CDKs, and the induction of WAF1 by irradiation through a pathway independent of p53 will be also described. (author)

  17. Cell Cycle Related Differentiation of Bone Marrow Cells into Lung Cells

    Energy Technology Data Exchange (ETDEWEB)

    Dooner, Mark; Aliotta, Jason M.; Pimental, Jeffrey; Dooner, Gerri J.; Abedi, Mehrdad; Colvin, Gerald; Liu, Qin; Weier, Heinz-Ulli; Dooner, Mark S.; Quesenberry, Peter J.

    2007-12-31

    Green-fluorescent protein (GFP) labeled marrow cells transplanted into lethally irradiated mice can be detected in the lungs of transplanted mice and have been shown to express lung specific proteins while lacking the expression of hematopoietic markers. We have studied marrow cells induced to transit cell cycle by exposure to IL-3, IL-6, IL-11 and steel factor at different times of culture corresponding to different phases of cell cycle. We have found that marrow cells at the G1/S interface have a 3-fold increase in cells which assume a lung phenotype and that this increase is no longer seen in late S/G2. These cells have been characterized as GFP{sup +} CD45{sup -} and GFP{sup +} cytokeratin{sup +}. Thus marrow cells with the capacity to convert into cells with a lung phenotype after transplantation show a reversible increase with cytokine induced cell cycle transit. Previous studies have shown the phenotype of bone marrow stem cells fluctuates reversibly as these cells traverse cell cycle, leading to a continuum model of stem cell regulation. The present studies indicate that marrow stem cell production of nonhematopoietic cells also fluctuates on a continuum.

  18. Chromatin association of UHRF1 during the cell cycle

    KAUST Repository

    Al-Gashgari, Bothayna

    2017-05-01

    Ubiquitin-like with PHD and RING Finger domains 1 (UHRF1) is a nuclear protein that associates with chromatin. Regardless of the various functions of UHRF1 in the cell, one of its more important functions is its role in the maintenance of DNA methylation patterns by the recruitment of DNMT1. Studies on UHRF1 based on this function have revealed the importance of UHRF1 during the cell cycle. Moreover, based on different studies various factors were described to be involved in the regulation of UHRF1 with different functionalities that can control its binding affinity to different targets on chromatin. These factors are regulated differently in a cell cycle specific manner. In light of this, we propose that UHRF1 has different binding behaviors during the cell cycle in regard to its association with chromatin. In this project, we first analyzed the binding behavior of endogenous UHRF1 from different unsynchronized cell systems in pull-down assays with peptides and oligonucleotides. Moreover, to analyze UHRF1 binding behavior during the cell cycle, we used two different approaches. First we sorted Jurkat and HT1080 cells based on their cell cycle stage using FACS analysis. Additionally, we synchronized HeLa cells to different stages of the cell cycle by chemical treatments, and used extracts from cellsorting and cell synchronization experiments for pull-down assays. We observed that UHRF1 in different cell systems has different preferences in regard to its binding to H3 unmodified and H3K9me3. Moreover, we detected that UHRF1, in general, displays different patterns between different stages of cell cycle; however, we cannot draw a final model for UHRF1 binding pattern during cell cycle.

  19. Repressive histone methylation regulates cardiac myocyte cell cycle exit.

    Science.gov (United States)

    El-Nachef, Danny; Oyama, Kyohei; Wu, Yun-Yu; Freeman, Miles; Zhang, Yiqiang; Robb MacLellan, W

    2018-05-22

    Mammalian cardiac myocytes (CMs) stop proliferating soon after birth and subsequent heart growth comes from hypertrophy, limiting the adult heart's regenerative potential after injury. The molecular events that mediate CM cell cycle exit are poorly understood. To determine the epigenetic mechanisms limiting CM cycling in adult CMs (ACMs) and whether trimethylation of lysine 9 of histone H3 (H3K9me3), a histone modification associated with repressed chromatin, is required for the silencing of cell cycle genes, we developed a transgenic mouse model where H3K9me3 is specifically removed in CMs by overexpression of histone demethylase, KDM4D. Although H3K9me3 is found across the genome, its loss in CMs preferentially disrupts cell cycle gene silencing. KDM4D binds directly to cell cycle genes and reduces H3K9me3 levels at these promotors. Loss of H3K9me3 preferentially leads to increased cell cycle gene expression resulting in enhanced CM cycling. Heart mass was increased in KDM4D overexpressing mice by postnatal day 14 (P14) and continued to increase until 9-weeks of age. ACM number, but not size, was significantly increased in KDM4D expressing hearts, suggesting CM hyperplasia accounts for the increased heart mass. Inducing KDM4D after normal development specifically in ACMs resulted in increased cell cycle gene expression and cycling. We demonstrated that H3K9me3 is required for CM cell cycle exit and terminal differentiation in ACMs. Depletion of H3K9me3 in adult hearts prevents and reverses permanent cell cycle exit and allows hyperplastic growth in adult hearts in vivo. Copyright © 2017. Published by Elsevier Ltd.

  20. Cell cycle arrest induced by radiation

    International Nuclear Information System (INIS)

    Okaichi, Yasuo; Matsumoto, Hideki; Ohnishi, Takeo

    1994-01-01

    It is known that various chemical reactions, such as cell cycle arrest, DNA repair and cell killing, can occur within the cells when exposed to ionizing radiation and ultraviolet radiation. Thus protein dynamics involved in such chemical reactions has received considerable attention. In this article, cell cycle regulation is first discussed in terms of the G2/M-phase and the G1/S-phase. Then, radiation-induced cell cycle arrest is reviewed. Cell cycle regulation mechanism involved in the G2 arrest, which is well known to occur when exposed to radiation, has recently been investigated using yeasts. In addition, recent study has yielded a noticeable finding that the G1 arrest can occur with intracellular accumulation of p53 product following ionization radiation. p53 is also shown to play an extremely important role in both DNA repair and cell killing due to DNA damage. Studies on the role of genes in protein groups induced by radiation will hold promise for the elucidation of cell cycle mechanism. (N.K.) 57 refs

  1. 2-Aminopurine overrides multiple cell cycle checkpoints in BHK cells.

    OpenAIRE

    Andreassen, P R; Margolis, R L

    1992-01-01

    BHK cells blocked at any of several points in the cell cycle override their drug-induced arrest and proceed in the cycle when exposed concurrently to the protein kinase inhibitor 2-aminopurine (2-AP). For cells arrested at various points in interphase, 2-AP-induced cell cycle progression is made evident by arrival of the drug-treated cell population in mitosis. Cells that have escaped from mimosine G1 arrest, from hydroxyurea or aphidicolin S-phase arrest, or from VM-26-induced G2 arrest subs...

  2. Cell Cycle Regulation of Stem Cells by MicroRNAs.

    Science.gov (United States)

    Mens, Michelle M J; Ghanbari, Mohsen

    2018-06-01

    MicroRNAs (miRNAs) are a class of small non-coding RNA molecules involved in the regulation of gene expression. They are involved in the fine-tuning of fundamental biological processes such as proliferation, differentiation, survival and apoptosis in many cell types. Emerging evidence suggests that miRNAs regulate critical pathways involved in stem cell function. Several miRNAs have been suggested to target transcripts that directly or indirectly coordinate the cell cycle progression of stem cells. Moreover, previous studies have shown that altered expression levels of miRNAs can contribute to pathological conditions, such as cancer, due to the loss of cell cycle regulation. However, the precise mechanism underlying miRNA-mediated regulation of cell cycle in stem cells is still incompletely understood. In this review, we discuss current knowledge of miRNAs regulatory role in cell cycle progression of stem cells. We describe how specific miRNAs may control cell cycle associated molecules and checkpoints in embryonic, somatic and cancer stem cells. We further outline how these miRNAs could be regulated to influence cell cycle progression in stem cells as a potential clinical application.

  3. Studies on regulation of the cell cycle in fission yeast.

    Directory of Open Access Journals (Sweden)

    Miroslava Požgajová

    2015-05-01

    Full Text Available All living organisms including plants and animals are composed of millions of cells. These cells perform different functions for the organism although they possess the same chromosomes and carry the same genetic information. Thus, to be able to understand multicellular organism we need to understand the life cycle of individual cells from which the organism comprises. The cell cycle is the life cycle of a single cell in the plant or animal body. It involves series of events in which components of the cell doubles and afterwards equally segregate into daughter cells. Such process ensures growth of the organism, and specialized reductional cell division which leads to production of gamets, assures sexual reproduction. Cell cycle is divided in the G1, S, G2 and M phase. Two gap-phases (G1 and G2 separate S phase (or synthesis and M phase which stays either for mitosis or meiosis. Essential for normal life progression and reproduction is correct chromosome segregation during mitosis and meiosis. Defects in the division program lead to aneuploidy, which in turn leads to birth defects, miscarriages or cancer. Even thou, researchers invented much about the regulation of the cell cycle, there is still long way to understand the complexity of the regulatory machineries that ensure proper segregation of chromosomes. In this paper we would like to describe techniques and materials we use for our studies on chromosome segregation in the model organism Schizosaccharomyces pombe.

  4. Fuel cell hybrid taxi life cycle analysis

    Energy Technology Data Exchange (ETDEWEB)

    Baptista, Patricia, E-mail: patricia.baptista@ist.utl.pt [IDMEC-Instituto Superior Tecnico, Universidade Tecnica de Lisboa, Av. Rovisco Pais, 1, 1049-001 Lisboa (Portugal); Ribau, Joao; Bravo, Joao; Silva, Carla [IDMEC-Instituto Superior Tecnico, Universidade Tecnica de Lisboa, Av. Rovisco Pais, 1, 1049-001 Lisboa (Portugal); Adcock, Paul; Kells, Ashley [Intelligent Energy, Charnwood Building, HolywellPark, Ashby Road, Loughborough, LE11 3GR (United Kingdom)

    2011-09-15

    A small fleet of classic London Taxis (Black cabs) equipped with hydrogen fuel cell power systems is being prepared for demonstration during the 2012 London Olympics. This paper presents a Life Cycle Analysis for these vehicles in terms of energy consumption and CO{sub 2} emissions, focusing on the impacts of alternative vehicle technologies for the Taxi, combining the fuel life cycle (Tank-to-Wheel and Well-to-Tank) and vehicle materials Cradle-to-Grave. An internal combustion engine diesel taxi was used as the reference vehicle for the currently available technology. This is compared to battery and fuel cell vehicle configurations. Accordingly, the following energy pathways are compared: diesel, electricity and hydrogen (derived from natural gas steam reforming). Full Life Cycle Analysis, using the PCO-CENEX drive cycle, (derived from actual London Taxi drive cycles) shows that the fuel cell powered vehicle configurations have lower energy consumption (4.34 MJ/km) and CO{sub 2} emissions (235 g/km) than both the ICE Diesel (9.54 MJ/km and 738 g/km) and the battery electric vehicle (5.81 MJ/km and 269 g/km). - Highlights: > A Life Cycle Analysis of alternative vehicle technologies for the London Taxi was performed. > The hydrogen powered vehicles have the lowest energy consumption and CO{sub 2} emissions results. > A hydrogen powered solution can be a sustainable alternative in a full life cycle framework.

  5. Fuel cell hybrid taxi life cycle analysis

    International Nuclear Information System (INIS)

    Baptista, Patricia; Ribau, Joao; Bravo, Joao; Silva, Carla; Adcock, Paul; Kells, Ashley

    2011-01-01

    A small fleet of classic London Taxis (Black cabs) equipped with hydrogen fuel cell power systems is being prepared for demonstration during the 2012 London Olympics. This paper presents a Life Cycle Analysis for these vehicles in terms of energy consumption and CO 2 emissions, focusing on the impacts of alternative vehicle technologies for the Taxi, combining the fuel life cycle (Tank-to-Wheel and Well-to-Tank) and vehicle materials Cradle-to-Grave. An internal combustion engine diesel taxi was used as the reference vehicle for the currently available technology. This is compared to battery and fuel cell vehicle configurations. Accordingly, the following energy pathways are compared: diesel, electricity and hydrogen (derived from natural gas steam reforming). Full Life Cycle Analysis, using the PCO-CENEX drive cycle, (derived from actual London Taxi drive cycles) shows that the fuel cell powered vehicle configurations have lower energy consumption (4.34 MJ/km) and CO 2 emissions (235 g/km) than both the ICE Diesel (9.54 MJ/km and 738 g/km) and the battery electric vehicle (5.81 MJ/km and 269 g/km). - Highlights: → A Life Cycle Analysis of alternative vehicle technologies for the London Taxi was performed. → The hydrogen powered vehicles have the lowest energy consumption and CO 2 emissions results. → A hydrogen powered solution can be a sustainable alternative in a full life cycle framework.

  6. Cell cycle sibling rivalry: Cdc2 vs. Cdk2.

    Science.gov (United States)

    Kaldis, Philipp; Aleem, Eiman

    2005-11-01

    It has been long believed that the cyclin-dependent kinase 2 (Cdk2) binds to cyclin E or cyclin A and exclusively promotes the G1/S phase transition and that Cdc2/cyclin B complexes play a major role in mitosis. We now provide evidence that Cdc2 binds to cyclin E (in addition to cyclin A and B) and is able to promote the G1/S transition. This new concept indicates that both Cdk2 and/or Cdc2 can drive cells through G1/S phase in parallel. In this review we discuss the classic cell cycle model and how results from knockout mice provide new evidence that refute this model. We focus on the roles of Cdc2 and p27 in regulating the mammalian cell cycle and propose a new model for cell cycle regulation that accommodates these novel findings.

  7. A nuclear glutathione cycle within the cell cycle.

    Science.gov (United States)

    Diaz Vivancos, Pedro; Wolff, Tonja; Markovic, Jelena; Pallardó, Federico V; Foyer, Christine H

    2010-10-15

    The complex antioxidant network of plant and animal cells has the thiol tripeptide GSH at its centre to buffer ROS (reactive oxygen species) and facilitate cellular redox signalling which controls growth, development and defence. GSH is found in nearly every compartment of the cell, including the nucleus. Transport between the different intracellular compartments is pivotal to the regulation of cell proliferation. GSH co-localizes with nuclear DNA at the early stages of proliferation in plant and animal cells. Moreover, GSH recruitment and sequestration in the nucleus during the G1- and S-phases of the cell cycle has a profound impact on cellular redox homoeostasis and on gene expression. For example, the abundance of transcripts encoding stress and defence proteins is decreased when GSH is sequestered in the nucleus. The functions of GSHn (nuclear GSH) are considered in the present review in the context of whole-cell redox homoeostasis and signalling, as well as potential mechanisms for GSH transport into the nucleus. We also discuss the possible role of GSHn as a regulator of nuclear proteins such as histones and PARP [poly(ADP-ribose) polymerase] that control genetic and epigenetic events. In this way, a high level of GSH in the nucleus may not only have an immediate effect on gene expression patterns, but also contribute to how cells retain a memory of the cellular redox environment that is transferred through generations.

  8. A cell culture model for Nosema ceranae and Nosema apis allows new insights into the life cycle of these important honey bee-pathogenic microsporidia.

    Science.gov (United States)

    Gisder, Sebastian; Möckel, Nadine; Linde, Andreas; Genersch, Elke

    2011-02-01

    The population of managed honey bees has been dramatically declining in the recent past in many regions of the world. Consensus now seems to be that pathogens and parasites (e.g. the ectoparasitic mite Varroa destructor, the microsporidium Nosema ceranae and viruses) play a major role in this demise. However, little is known about host-pathogen interactions for bee pathogens and attempts to develop novel strategies to combat bee diseases have been hampered by this gap in our knowledge. One reason for this dire situation is the complete lack of cell cultures for the propagation and study of bee pathogens. Here we present a cell culture model for two honey bee-pathogenic microsporidian species, Nosema apis and N. ceranae. Our cell culture system is based on a lepidopteran cell line, which proved to be susceptible to infection by both N. ceranae and N. apis and enabled us to illustrate the entire life cycle of these microsporidia. We observed hitherto undescribed spindle-shaped meronts and confirmed our findings in infected bees. Our cell culture model provides a previously unavailable means to explore the nature of interactions between the honey bee and its pathogen complex at a mechanistic level and will allow the development of novel treatment strategies.

  9. The Dynamical Mechanisms of the Cell Cycle Size Checkpoint

    International Nuclear Information System (INIS)

    Feng Shi-Fu; Yang Ling; Yan Jie; Liu Zeng-Rong

    2012-01-01

    Cell division must be tightly coupled to cell growth in order to maintain cell size, whereas the mechanisms of how initialization of mitosis is regulated by cell size remain to be elucidated. We develop a mathematical model of the cell cycle, which incorporates cell growth to investigate the dynamical properties of the size checkpoint in embryos of Xenopus laevis. We show that the size checkpoint is naturally raised from a saddle-node bifurcation, and in a mutant case, the cell loses its size control ability due to the loss of this saddle-node point

  10. [Circadian rhythm variation of the clock genes Per1 and cell cycle related genes in different stages of carcinogenesis of buccal mucosa in animal model].

    Science.gov (United States)

    Tan, Xuemei; Ye, Hua; Yang, Kai; Chen, Dan; Tang, Hong

    2015-07-01

    To investigate the expression and circadian rhythm variation of biological clock gene Per1 and cell cycle genes p53, CyclinD1, cyclin-dependent kinases (CDK1), CyclinB1 in different stages of carcinogenesis in buccal mucosa and its relationship with the development of buccal mucosa carcinoma. Ninety golden hamsters were housed under 12 hours light-12 hours dark cycles, and the model of buccal squamous cell carcinoma was established by using the dimethylbenzanthracene (DMBA) to smear the golden hamster buccal mucosa. Before the DMBA was used and after DMBA was used 6 weeks and 14 weeks respectively, the golden hamsters were sacrificed at 6 different time points (5 rats per time point) within 24 hour, including 4, 8, 12, 16, 20 and 24 hour after lights onset (HALO), and the normal buccal mucosa, precancerous lesions and cancer tissue were obtained, respectively. HE stained sections were prepared to observe the canceration of each tissue. Real time RT-PCR was used to detect the mRNA expression of Per1, p53, CyclinD1, CDK1 and CyclinB1, and a cosine analysis method was applied to determine the circadian rhythm variation of Per1, p53, CyclinD1, CDK1 and CyclinB1 mRNA expression, which were characterized by median, amplitude and acrophase. The expression of Per1, p53, CDK1 and CyclinD1 mRNA in 6 different time points within 24 hours in the tissues of three different stages of carcinogenesis had circadian rhythm, respectively. However, the CyclinB1 mRNA was expressed with circadian rhythm just in normal and cancer tissue (P circadian rhythm was in disorder (P > 0.05). As the development of carcinoma, the median of Per1 and p53 mRNA expression were significantly decreased (P circadian rhythm of clock gene Per1 and cell cycle genes p53, CyclinD1, CDK1, CyclinB1 expression remarkably varied with the occurrence and development of carcinoma. Further research into the interaction between circadian and cell cycle of two cycle activity and relationship with the carcinogenesis may

  11. Do lipids shape the eukaryotic cell cycle?

    Science.gov (United States)

    Furse, Samuel; Shearman, Gemma C

    2018-01-01

    Successful passage through the cell cycle presents a number of structural challenges to the cell. Inceptive studies carried out in the last five years have produced clear evidence of modulations in the lipid profile (sometimes referred to as the lipidome) of eukaryotes as a function of the cell cycle. This mounting body of evidence indicates that lipids play key roles in the structural transformations seen across the cycle. The accumulation of this evidence coincides with a revolution in our understanding of how lipid composition regulates a plethora of biological processes ranging from protein activity through to cellular signalling and membrane compartmentalisation. In this review, we discuss evidence from biological, chemical and physical studies of the lipid fraction across the cell cycle that demonstrate that lipids are well-developed cellular components at the heart of the biological machinery responsible for managing progress through the cell cycle. Furthermore, we discuss the mechanisms by which this careful control is exercised. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  12. Complex Systems Analysis of Cell Cycling Models in Carcinogenesis:II. Cell Genome and Interactome, Neoplastic Non-random Transformation Models in Topoi with Lukasiewicz-Logic and MV Algebras

    CERN Document Server

    Baianu, I C

    2004-01-01

    Quantitative Biology, abstract q-bio.OT/0406045 From: I.C. Baianu Dr. [view email] Date (v1): Thu, 24 Jun 2004 02:45:13 GMT (164kb) Date (revised v2): Fri, 2 Jul 2004 00:58:06 GMT (160kb) Complex Systems Analysis of Cell Cycling Models in Carcinogenesis: II. Authors: I.C. Baianu Comments: 23 pages, 1 Figure Report-no: CC04 Subj-class: Other Carcinogenesis is a complex process that involves dynamically inter-connected modular sub-networks that evolve under the influence of micro-environmentally induced perturbations, in non-random, pseudo-Markov chain processes. An appropriate n-stage model of carcinogenesis involves therefore n-valued Logic treatments of nonlinear dynamic transformations of complex functional genomes and cell interactomes. Lukasiewicz Algebraic Logic models of genetic networks and signaling pathways in cells are formulated in terms of nonlinear dynamic systems with n-state components that allow for the generalization of previous, Boolean or "fuzzy", logic models of genetic activities in vivo....

  13. In vitro short-term exposure to air pollution PM{sub 2.5-0.3} induced cell cycle alterations and genetic instability in a human lung cell coculture model

    Energy Technology Data Exchange (ETDEWEB)

    Abbas, Imane [Université de Lille, Lille (France); EA4492-UCEIV, Université du Littoral-Côte d’Opale, Dunkerque (France); Lebanese Atomic Energy Commission – CNRS, Beirut (Lebanon); Verdin, Anthony [Université de Lille, Lille (France); EA4492-UCEIV, Université du Littoral-Côte d’Opale, Dunkerque (France); Escande, Fabienne [Centre de Biologie Pathologie, Centre Hospitalier Régional et Universitaire, Lille (France); Saint-Georges, Françoise [Université de Lille, Lille (France); Groupement Hospitalier de l’Institut Catholique de Lille, Lille (France); Cazier, Fabrice [Université de Lille, Lille (France); Centre Commun de Mesures, Université du Littoral-Côte d’Opale, Dunkerque (France); Mulliez, Philippe [Université de Lille, Lille (France); Groupement Hospitalier de l’Institut Catholique de Lille, Lille (France); Courcot, Dominique; Shirali, Pirouz [Université de Lille, Lille (France); EA4492-UCEIV, Université du Littoral-Côte d’Opale, Dunkerque (France); Gosset, Pierre [Université de Lille, Lille (France); Groupement Hospitalier de l’Institut Catholique de Lille, Lille (France); and others

    2016-05-15

    Although its adverse health effects of air pollution particulate matter (PM2.5) are well-documented and often related to oxidative stress and pro-inflammatory response, recent evidence support the role of the remodeling of the airway epithelium involving the regulation of cell death processes. Hence, the overarching goals of the present study were to use an in vitro coculture model, based on human AM and L132 cells to study the possible alteration of TP53-RB gene signaling pathways (i.e. cell cycle phases, gene expression of TP53, BCL2, BAX, P21, CCND1, and RB, and protein concentrations of their active forms), and genetic instability (i.e. LOH and/or MSI) in the PM{sub 2.5-0.3}-exposed coculture model. PM{sub 2.5-0.3} exposure of human AM from the coculture model induced marked cell cycle alterations after 24 h, as shown by increased numbers of L132 cells in subG1 and S+G2 cell cycle phases, indicating apoptosis and proliferation. Accordingly, activation of the TP53-RB gene signaling pathways after the coculture model exposure to PM{sub 2.5-0.3} was reported in the L132 cells. Exposure of human AM from the coculture model to PM{sub 2.5-0.3} resulted in MS alterations in 3p chromosome multiple critical regions in L132 cell population. Hence, in vitro short-term exposure of the coculture model to PM{sub 2.5-0.3} induced cell cycle alterations relying on the sequential occurrence of molecular abnormalities from TP53-RB gene signaling pathway activation and genetic instability. - Highlights: • Better knowledge on health adverse effects of air pollution PM{sub 2.5}. • Human alveolar macrophage and normal human epithelial lung cell coculture. • Molecular abnormalities from TP53-RB gene signaling pathway. • Loss of heterozygosity and microsatellite instability. • Pathologic changes in morphology and number of cells in relation to airway remodeling.

  14. Efficacy of a Cell-Cycle Decoying Killer Adenovirus on 3-D Gelfoam®-Histoculture and Tumor-Sphere Models of Chemo-Resistant Stomach Carcinomatosis Visualized by FUCCI Imaging.

    Directory of Open Access Journals (Sweden)

    Shuya Yano

    Full Text Available Stomach cancer carcinomatosis peritonitis (SCCP is a recalcitrant disease. The goal of the present study was to establish an in vitro-in vivo-like imageable model of SCCP to develop cell-cycle-based therapeutics of SCCP. We established 3-D Gelfoam® histoculture and tumor-sphere models of SCCP. FUCCI-expressing MKN-45 stomach cancer cells were transferred to express the fluorescence ubiquinized cell-cycle indicator (FUCCI. FUCCI-expressing MKN-45 cells formed spheres on agarose or on Gelfoam® grew into tumor-like structures with G0/G1 cancer cells in the center and S/G2 cancer cells located in the surface as indicated by FUCCI imaging when the cells fluoresced red or green, respectively. We treated FUCCI-expressing cancer cells forming SCCP tumors in Gelfoam® histoculture with OBP-301, cisplatinum (CDDP, or paclitaxel. CDDP or paclitaxel killed only cycling cancer cells and were ineffective against G1/G2 MKN-45 cells in tumors growing on Gelfoam®. In contrast, the telomerase-dependent adenovirus OBP-301 decoyed the MKN-45 cells in tumors on Gelfoam® to cycle from G0/G1 phase to S/G2 phase and reduced their viability. CDDP- or paclitaxel-treated MKN-45 tumors remained quiescent and did not change in size. In contrast, OB-301 reduced the size of the MKN-45 tumors on Gelfoam®. We examined the cell cycle-related proteins using Western blotting. CDDP increased the expression of p53 and p21 indicating cell cycle arrest. In contrast, OBP-301 decreased the expression of p53 and p21 Furthermore, OBP-301 increased the expression of E2F and pAkt as further indication of cell cycle decoy. This 3-D Gelfoam® histoculture and FUCCI imaging are powerful tools to discover effective therapy of SCCP such as OBP-301.

  15. Efficacy of a Cell-Cycle Decoying Killer Adenovirus on 3-D Gelfoam®-Histoculture and Tumor-Sphere Models of Chemo-Resistant Stomach Carcinomatosis Visualized by FUCCI Imaging

    Science.gov (United States)

    Yano, Shuya; Takehara, Kiyoto; Tazawa, Hiroshi; Kishimoto, Hiroyuki; Urata, Yasuo; Kagawa, Shunsuke; Fujiwara, Toshiyoshi; Hoffman, Robert M.

    2016-01-01

    Stomach cancer carcinomatosis peritonitis (SCCP) is a recalcitrant disease. The goal of the present study was to establish an in vitro-in vivo-like imageable model of SCCP to develop cell-cycle-based therapeutics of SCCP. We established 3-D Gelfoam® histoculture and tumor-sphere models of SCCP. FUCCI-expressing MKN-45 stomach cancer cells were transferred to express the fluorescence ubiquinized cell-cycle indicator (FUCCI). FUCCI-expressing MKN-45 cells formed spheres on agarose or on Gelfoam® grew into tumor-like structures with G0/G1 cancer cells in the center and S/G2 cancer cells located in the surface as indicated by FUCCI imaging when the cells fluoresced red or green, respectively. We treated FUCCI-expressing cancer cells forming SCCP tumors in Gelfoam® histoculture with OBP-301, cisplatinum (CDDP), or paclitaxel. CDDP or paclitaxel killed only cycling cancer cells and were ineffective against G1/G2 MKN-45 cells in tumors growing on Gelfoam®. In contrast, the telomerase-dependent adenovirus OBP-301 decoyed the MKN-45 cells in tumors on Gelfoam® to cycle from G0/G1 phase to S/G2 phase and reduced their viability. CDDP- or paclitaxel-treated MKN-45 tumors remained quiescent and did not change in size. In contrast, OB-301 reduced the size of the MKN-45 tumors on Gelfoam®. We examined the cell cycle-related proteins using Western blotting. CDDP increased the expression of p53 and p21 indicating cell cycle arrest. In contrast, OBP-301 decreased the expression of p53 and p21 Furthermore, OBP-301 increased the expression of E2F and pAkt as further indication of cell cycle decoy. This 3-D Gelfoam® histoculture and FUCCI imaging are powerful tools to discover effective therapy of SCCP such as OBP-301. PMID:27673332

  16. Cell cycle kinetics and radiation therapy

    International Nuclear Information System (INIS)

    Mendelsohn, M.L.

    1975-01-01

    Radiation therapy as currently practiced involves the subtle largely empirical art of balancing the recurrence of cancer due to undertreatment against severe damage to local tissues due to overtreatment. Therapeutic results too often fall short of desired success rates; yet, the therapist is continually tantalized to the likelihood that a slight shift of therapeutic ratio favoring normal tissue over cancer would have a profoundly beneficial effect. The application of cell cycle kinetics to radiation therapy is one hope for improving the therapeutic ratio; but, as I will try to show, kinetic approaches are complex, poorly understood, and presently too elusive to elicit confidence or to be used clinically. Their promise lies in their diversity and in the magnitude of our ignorance about how they work and how they should be used. Potentially useful kinetic approaches to therapy can be grouped into three classes. The first class takes advantage of intracyclic differential sensitivity, an effect involving the metabolism and biology of the cell cycle; its strategies are based on synchronization of cells over intervals of hours to days. The second class involves the distinction between cycling and noncycling cells; its strategies are based on the resistance of noncycling cells to cycle-linked radiation sensitizers and chemotherapeutic agents. The third class uses cell repopulation between fractions; its strategies are based on the relative growth rates of tumor and relevant normal tissue before and after perturbation

  17. Cell Cycle Inhibition To Treat Sleeping Sickness

    Directory of Open Access Journals (Sweden)

    Conrad L. Epting

    2017-09-01

    Full Text Available African trypanosomiasis is caused by infection with the protozoan parasite Trypanosoma brucei. During infection, this pathogen divides rapidly to high density in the bloodstream of its mammalian host in a manner similar to that of leukemia. Like all eukaryotes, T. brucei has a cell cycle involving the de novo synthesis of DNA regulated by ribonucleotide reductase (RNR, which catalyzes the conversion of ribonucleotides into their deoxy form. As an essential enzyme for the cell cycle, RNR is a common target for cancer chemotherapy. We hypothesized that inhibition of RNR by genetic or pharmacological means would impair parasite growth in vitro and prolong the survival of infected animals. Our results demonstrate that RNR inhibition is highly effective in suppressing parasite growth both in vitro and in vivo. These results support drug discovery efforts targeting the cell cycle, not only for African trypanosomiasis but possibly also for other infections by eukaryotic pathogens.

  18. Repeated cycles of 5-fluorouracil chemotherapy impaired anti-tumor functions of cytotoxic T cells in a CT26 tumor-bearing mouse model.

    Science.gov (United States)

    Wu, Yanhong; Deng, Zhenling; Wang, Huiru; Ma, Wenbo; Zhou, Chunxia; Zhang, Shuren

    2016-09-20

    Recently, the immunostimulatory roles of chemotherapeutics have been increasingly revealed, although bone marrow suppression is still a common toxicity of chemotherapy. While the numbers and ratios of different immune subpopulations are analyzed after chemotherapy, changes to immune status after each cycle of treatment are less studied and remain unclear. To determine the tumor-specific immune status and functions after different cycles of chemotherapy, we treated CT26 tumor-bearing mice with one to four cycles of 5-fluorouracil (5-FU). Overall survival was not improved when more than one cycle of 5-FU was administered. Here we present data concerning the immune statuses after one and three cycles of chemotherapy. We analyzed the amount of spleen cells from mice treated with one and three cycles of 5-FU as well as assayed their proliferation and cytotoxicity against the CT26 tumor cell line. We found that the absolute numbers of CD8 T-cells and NK cells were not influenced significantly after either one or three cycles of chemotherapy. However, after three cycles of 5-FU, proliferated CD8 T-cells were decreased, and CT26-specific cytotoxicity and IFN-γ secretion of spleen cells were impaired in vitro. After one cycle of 5-FU, there was a greater percentage of tumor infiltrating CD8 T-cells. In addition, more proliferated CD8 T-cells, enhanced tumor-specific cytotoxicity as well as IFN-γ secretion of spleen cells against CT26 in vitro were observed. Given the increased expression of immunosuppressive factors, such as PD-L1 and TGF-β, we assessed the effect of early introduction of immunotherapy in combination with chemotherapy. We found that mice treated with cytokine induced killer cells and PD-L1 monoclonal antibodies after one cycle of 5-FU had a better anti-tumor performance than those treated with chemotherapy or immunotherapy alone. These data suggest that a single cycle of 5-FU treatment promoted an anti-tumor immune response, whereas repeated chemotherapy

  19. Cell-cycle phase specificity of chloroethylnitrosoureas

    International Nuclear Information System (INIS)

    Linfoot, P.A.

    1986-01-01

    Although the cancer chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) is considered a non-cell cycle phase specific drug, it has been shown to produce differential cell killing in G 1 , S, and G 2 /M phase cells, with S phase cells appearing relatively resistant. Studies of cell cycle phase specific cell killing produced by nitrosoureas with different chemical reactivities, clearly indicated that the ability of compounds to cross-link DNA was important in determining their phase specificity. Cells that lacked guanine O 6 -alkytransferase activity showed similar patterns of BCNU phase specificity regardless of their intrinsic sensitivity to BCNU. DNA inter-strand cross-linking, as measured by alkaline elution, was similar in cells exposed to BCNU in G 1 or S phase. 3 H [1-chloroethyl-1nitrosourea] binding to DNA was the same in G 1 , S and G 2 /M phase cells indicating that phase-specific differences in drug uptake and intracellular drug dose were not responsible for phase specific cell kill. These studies suggest that cross-link lesions, other than DNA inter-strand cross-links, and/or effects on DNA repair, other than guanine O 6 -alkyltransferase, are additional important determinants of BCNU phase specific cell killing

  20. A signature-based method for indexing cell cycle phase distribution from microarray profiles

    Directory of Open Access Journals (Sweden)

    Mizuno Hideaki

    2009-03-01

    Full Text Available Abstract Background The cell cycle machinery interprets oncogenic signals and reflects the biology of cancers. To date, various methods for cell cycle phase estimation such as mitotic index, S phase fraction, and immunohistochemistry have provided valuable information on cancers (e.g. proliferation rate. However, those methods rely on one or few measurements and the scope of the information is limited. There is a need for more systematic cell cycle analysis methods. Results We developed a signature-based method for indexing cell cycle phase distribution from microarray profiles under consideration of cycling and non-cycling cells. A cell cycle signature masterset, composed of genes which express preferentially in cycling cells and in a cell cycle-regulated manner, was created to index the proportion of cycling cells in the sample. Cell cycle signature subsets, composed of genes whose expressions peak at specific stages of the cell cycle, were also created to index the proportion of cells in the corresponding stages. The method was validated using cell cycle datasets and quiescence-induced cell datasets. Analyses of a mouse tumor model dataset and human breast cancer datasets revealed variations in the proportion of cycling cells. When the influence of non-cycling cells was taken into account, "buried" cell cycle phase distributions were depicted that were oncogenic-event specific in the mouse tumor model dataset and were associated with patients' prognosis in the human breast cancer datasets. Conclusion The signature-based cell cycle analysis method presented in this report, would potentially be of value for cancer characterization and diagnostics.

  1. Relation Between the Cell Volume and the Cell Cycle Dynamics in Mammalian cell

    International Nuclear Information System (INIS)

    Magno, A.C.G.; Oliveira, I.L.; Hauck, J.V.S.

    2016-01-01

    The main goal of this work is to add and analyze an equation that represents the volume in a dynamical model of the mammalian cell cycle proposed by Gérard and Goldbeter (2011) [1]. The cell division occurs when the cyclinB/Cdkl complex is totally degraded (Tyson and Novak, 2011)[2] and it reaches a minimum value. At this point, the cell is divided into two newborn daughter cells and each one will contain the half of the cytoplasmic content of the mother cell. The equations of our base model are only valid if the cell volume, where the reactions occur, is constant. Whether the cell volume is not constant, that is, the rate of change of its volume with respect to time is explicitly taken into account in the mathematical model, then the equations of the original model are no longer valid. Therefore, every equations were modified from the mass conservation principle for considering a volume that changes with time. Through this approach, the cell volume affects all model variables. Two different dynamic simulation methods were accomplished: deterministic and stochastic. In the stochastic simulation, the volume affects every model's parameters which have molar unit, whereas in the deterministic one, it is incorporated into the differential equations. In deterministic simulation, the biochemical species may be in concentration units, while in stochastic simulation such species must be converted to number of molecules which are directly proportional to the cell volume. In an effort to understand the influence of the new equation a stability analysis was performed. This elucidates how the growth factor impacts the stability of the model's limit cycles. In conclusion, a more precise model, in comparison to the base model, was created for the cell cycle as it now takes into consideration the cell volume variation (paper)

  2. Control points within the cell cycle

    International Nuclear Information System (INIS)

    Van't Hof, J.

    1984-01-01

    Evidence of the temporal order of chromosomal DNA replication argues favorably for the view that the cell cycle is controlled by genes acting in sequence whose time of expression is determined by mitosis and the amount of nuclear DNA (2C vs 4C) in the cell. Gl and G2 appear to be carbohydrate dependent in that cells starved of either carbohydrate of phosphate fail to make these transitions. Cells deprived of nitrate, however, fail only at Gl to S transition indicating that the controls that operate in G1 differ from those that operate in G2. 46 references, 5 figures

  3. The Design Space of the Embryonic Cell Cycle Oscillator.

    Science.gov (United States)

    Mattingly, Henry H; Sheintuch, Moshe; Shvartsman, Stanislav Y

    2017-08-08

    One of the main tasks in the analysis of models of biomolecular networks is to characterize the domain of the parameter space that corresponds to a specific behavior. Given the large number of parameters in most models, this is no trivial task. We use a model of the embryonic cell cycle to illustrate the approaches that can be used to characterize the domain of parameter space corresponding to limit cycle oscillations, a regime that coordinates periodic entry into and exit from mitosis. Our approach relies on geometric construction of bifurcation sets, numerical continuation, and random sampling of parameters. We delineate the multidimensional oscillatory domain and use it to quantify the robustness of periodic trajectories. Although some of our techniques explore the specific features of the chosen system, the general approach can be extended to other models of the cell cycle engine and other biomolecular networks. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  4. Cell cycle and apoptosis genes in atherosclerosis

    NARCIS (Netherlands)

    Boesten, Lianne Simone Mirjam

    2006-01-01

    The work described in this thesis was aimed at identifying the role of cell cycle and apoptosis genes in atherosclerosis. Atherosclerosis is the primary cause of cardiovascular disease, a disorder occurring in the large and medium-sized arteries of the body. Although in the beginning 90s promising

  5. Dynamic ubiquitin signaling in cell cycle regulation.

    Science.gov (United States)

    Gilberto, Samuel; Peter, Matthias

    2017-08-07

    The cell division cycle is driven by a collection of enzymes that coordinate DNA duplication and separation, ensuring that genomic information is faithfully and perpetually maintained. The activity of the effector proteins that perform and coordinate these biological processes oscillates by regulated expression and/or posttranslational modifications. Ubiquitylation is a cardinal cellular modification and is long known for driving cell cycle transitions. In this review, we emphasize emerging concepts of how ubiquitylation brings the necessary dynamicity and plasticity that underlie the processes of DNA replication and mitosis. New studies, often focusing on the regulation of chromosomal proteins like DNA polymerases or kinetochore kinases, are demonstrating that ubiquitylation is a versatile modification that can be used to fine-tune these cell cycle events, frequently through processes that do not involve proteasomal degradation. Understanding how the increasing variety of identified ubiquitin signals are transduced will allow us to develop a deeper mechanistic perception of how the multiple factors come together to faithfully propagate genomic information. Here, we discuss these and additional conceptual challenges that are currently under study toward understanding how ubiquitin governs cell cycle regulation. © 2017 Gilberto and Peter.

  6. A spatio-temporal simulation model of the response of solid tumours to radiotherapy in vivo: parametric validation concerning oxygen enhancement ratio and cell cycle duration

    International Nuclear Information System (INIS)

    Antipas, Vassilis P; Stamatakos, Georgios S; Uzunoglu, Nikolaos K; Dionysiou, Dimitra D; Dale, Roger G

    2004-01-01

    Advanced bio-simulation methods are expected to substantially improve radiotherapy treatment planning. To this end a novel spatio-temporal patient-specific simulation model of the in vivo response of malignant tumours to radiotherapy schemes has been recently developed by our group. This paper discusses recent improvements to the model: an optimized algorithm leading to conformal shrinkage of the tumour as a response to radiotherapy, the introduction of the oxygen enhancement ratio (OER), a realistic initial cell phase distribution and finally an advanced imaging-based algorithm simulating the neovascularization field. A parametric study of the influence of the cell cycle duration T c , OER, OER β for the beta LQ parameter on tumour growth, shrinkage and response to irradiation under two different fractionation schemes has been made. The model has been applied to two glioblastoma multiforme (GBM) cases, one with wild type (wt) and another one with mutated (mt) p53 gene. Furthermore, the model has been applied to a hypothetical GBM tumour with α and β values corresponding to those of generic radiosensitive tumours. According to the model predictions, a whole tumour with shorter T c tends to repopulate faster, as is to be expected. Furthermore, a higher OER value for the dormant cells leads to a more radioresistant whole tumour. A small variation of the OER β value does not seem to play a major role in the tumour response. Accelerated fractionation proved to be superior to the standard scheme for the whole range of the OER values considered. Finally, the tumour with mt p53 was shown to be more radioresistant compared to the tumour with wt p53. Although all simulation predictions agree at least qualitatively with the clinical experience and literature, a long-term clinical adaptation and quantitative validation procedure is in progress

  7. Cell cycle regulation in human embryonic stem cells: links to adaptation to cell culture.

    Science.gov (United States)

    Barta, Tomas; Dolezalova, Dasa; Holubcova, Zuzana; Hampl, Ales

    2013-03-01

    Cell cycle represents not only a tightly orchestrated mechanism of cell replication and cell division but it also plays an important role in regulation of cell fate decision. Particularly in the context of pluripotent stem cells or multipotent progenitor cells, regulation of cell fate decision is of paramount importance. It has been shown that human embryonic stem cells (hESCs) show unique cell cycle characteristics, such as short doubling time due to abbreviated G1 phase; these properties change with the onset of differentiation. This review summarizes the current understanding of cell cycle regulation in hESCs. We discuss cell cycle properties as well as regulatory machinery governing cell cycle progression of undifferentiated hESCs. Additionally, we provide evidence that long-term culture of hESCs is accompanied by changes in cell cycle properties as well as configuration of several cell cycle regulatory molecules.

  8. The cell cycle as a brake for β-cell regeneration from embryonic stem cells.

    Science.gov (United States)

    El-Badawy, Ahmed; El-Badri, Nagwa

    2016-01-13

    The generation of insulin-producing β cells from stem cells in vitro provides a promising source of cells for cell transplantation therapy in diabetes. However, insulin-producing cells generated from human stem cells show deficiency in many functional characteristics compared with pancreatic β cells. Recent reports have shown molecular ties between the cell cycle and the differentiation mechanism of embryonic stem (ES) cells, assuming that cell fate decisions are controlled by the cell cycle machinery. Both β cells and ES cells possess unique cell cycle machinery yet with significant contrasts. In this review, we compare the cell cycle control mechanisms in both ES cells and β cells, and highlight the fundamental differences between pluripotent cells of embryonic origin and differentiated β cells. Through critical analysis of the differences of the cell cycle between these two cell types, we propose that the cell cycle of ES cells may act as a brake for β-cell regeneration. Based on these differences, we discuss the potential of modulating the cell cycle of ES cells for the large-scale generation of functionally mature β cells in vitro. Further understanding of the factors that modulate the ES cell cycle will lead to new approaches to enhance the production of functional mature insulin-producing cells, and yield a reliable system to generate bona fide β cells in vitro.

  9. Cell-cycle synchronisation of bloodstream forms of Trypanosoma brucei using Vybrant DyeCycle Violet-based sorting.

    Science.gov (United States)

    Kabani, Sarah; Waterfall, Martin; Matthews, Keith R

    2010-01-01

    Studies on the cell-cycle of Trypanosoma brucei have revealed several unusual characteristics that differ from the model eukaryotic organisms. However, the inability to isolate homogenous populations of parasites in distinct cell-cycle stages has limited the analysis of trypanosome cell division and complicated the understanding of mutant phenotypes with possible impact on cell-cycle related events. Although hydroxyurea-induced cell-cycle arrest in procyclic and bloodstream forms has been applied recently with success, such block-release protocols can complicate the analysis of cell-cycle regulated events and have the potential to disrupt important cell-cycle checkpoints. An alternative approach based on flow cytometry of parasites stained with Vybrant DyeCycle Orange circumvents this problem, but is restricted to procyclic form parasites. Here, we apply Vybrant Dyecycle Violet staining coupled with flow cytometry to effectively select different cell-cycle stages of bloodstream form trypanosomes. Moreover, the sorted parasites remain viable, although synchrony is rapidly lost. This method enables cell-cycle enrichment of populations of trypanosomes in their mammal infective stage, particularly at the G1 phase.

  10. Cell cycle regulation of hematopoietic stem or progenitor cells.

    Science.gov (United States)

    Hao, Sha; Chen, Chen; Cheng, Tao

    2016-05-01

    The highly regulated process of blood production is achieved through the hierarchical organization of hematopoietic stem cell (HSC) subsets and their progenies, which differ in self-renewal and differentiation potential. Genetic studies in mice have demonstrated that cell cycle is tightly controlled by the complex interplay between extrinsic cues and intrinsic regulatory pathways involved in HSC self-renewal and differentiation. Deregulation of these cellular programs may transform HSCs or hematopoietic progenitor cells (HPCs) into disease-initiating stem cells, and can result in hematopoietic malignancies such as leukemia. While previous studies have shown roles for some cell cycle regulators and related signaling pathways in HSCs and HPCs, a more complete picture regarding the molecular mechanisms underlying cell cycle regulation in HSCs or HPCs is lacking. Based on accumulated studies in this field, the present review introduces the basic components of the cell cycle machinery and discusses their major cellular networks that regulate the dormancy and cell cycle progression of HSCs. Knowledge on this topic would help researchers and clinicians to better understand the pathogenesis of relevant blood disorders and to develop new strategies for therapeutic manipulation of HSCs.

  11. Benzophenone-1 stimulated the growth of BG-1 ovarian cancer cells by cell cycle regulation via an estrogen receptor alpha-mediated signaling pathway in cellular and xenograft mouse models

    International Nuclear Information System (INIS)

    Park, Min-Ah; Hwang, Kyung-A; Lee, Hye-Rim; Yi, Bo-Rim; Jeung, Eui-Bae; Choi, Kyung-Chul

    2013-01-01

    Highlights: ► BP-1 induced cell growth was reversed by an ER antagonist in BG-1 cells. ► BP-1 up-regulated the mRNA expression of cyclin D1. ► Up-regulation of cyclin D1 by BP-1 was reversed by an ER antagonist. ► BP-1 is a potential endocrine disruptor that exerts estrogenic effects. - Abstract: 2,4-Dihydroxybenzophenone (benzophenone-1; BP-1) is an UV stabilizer primarily used to prevent polymer degradation and deterioration in quality due to UV irradiation. Recently, BP-1 has been reported to bioaccumulate in human bodies by absorption through the skin and has the potential to induce health problems including endocrine disruption. In the present study, we examined the xenoestrogenic effect of BP-1 on BG-1 human ovarian cancer cells expressing estrogen receptors (ERs) and relevant xenografted animal models in comparison with 17-β estradiol (E2). In in vitro cell viability assay, BP-1 (10 −8 –10 −5 M) significantly increased BG-1 cell growth the way E2 did. The mechanism underlying the BG-1 cell proliferation was proved to be related with the up-regulation of cyclin D1, a cell cycle progressor, by E2 or BP-1. Both BP-1 and E2 induced cell growth and up-regulation of cyclin D1 were reversed by co-treatment with ICI 182,780, an ER antagonist, suggesting that BP-1 may mediate the cancer cell proliferation via an ER-dependent pathway like E2. On the other hand, the expression of p21, a regulator of cell cycle progression at G 1 phase, was not altered by BP-1 though it was down-regulated by E2. In xenograft mouse models transplanted with BG-1 cells, BP-1 or E2 treatment significantly increased the tumor mass formation compared to a vehicle (corn oil) within 8 weeks. In histopathological analysis, the tumor sections of E2 or BP-1 group displayed extensive cell formations with high density and disordered arrangement, which were supported by the increased number of BrdUrd positive nuclei and the over-expression of cyclin D1 protein. Taken together, these

  12. Cell cycle control by a minimal Cdk network.

    Directory of Open Access Journals (Sweden)

    Claude Gérard

    2015-02-01

    Full Text Available In present-day eukaryotes, the cell division cycle is controlled by a complex network of interacting proteins, including members of the cyclin and cyclin-dependent protein kinase (Cdk families, and the Anaphase Promoting Complex (APC. Successful progression through the cell cycle depends on precise, temporally ordered regulation of the functions of these proteins. In light of this complexity, it is surprising that in fission yeast, a minimal Cdk network consisting of a single cyclin-Cdk fusion protein can control DNA synthesis and mitosis in a manner that is indistinguishable from wild type. To improve our understanding of the cell cycle regulatory network, we built and analysed a mathematical model of the molecular interactions controlling the G1/S and G2/M transitions in these minimal cells. The model accounts for all observed properties of yeast strains operating with the fusion protein. Importantly, coupling the model's predictions with experimental analysis of alternative minimal cells, we uncover an explanation for the unexpected fact that elimination of inhibitory phosphorylation of Cdk is benign in these strains while it strongly affects normal cells. Furthermore, in the strain without inhibitory phosphorylation of the fusion protein, the distribution of cell size at division is unusually broad, an observation that is accounted for by stochastic simulations of the model. Our approach provides novel insights into the organization and quantitative regulation of wild type cell cycle progression. In particular, it leads us to propose a new mechanistic model for the phenomenon of mitotic catastrophe, relying on a combination of unregulated, multi-cyclin-dependent Cdk activities.

  13. COMPUTATIONAL MODELING OF SIGNALING PATHWAYS MEDIATING CELL CYCLE AND APOPTOTIC RESPONSES TO IONIZING RADIATION MEDIATED DNA DAMAGE

    Science.gov (United States)

    Demonstrated of the use of a computational systems biology approach to model dose response relationships. Also discussed how the biologically motivated dose response models have only limited reference to the underlying molecular level. Discussed the integration of Computational S...

  14. Cell mass and cell cycle dynamics of an asynchronous budding yeast population

    DEFF Research Database (Denmark)

    Lencastre Fernandes, Rita; Carlquist, Magnus; Lundin, Luisa

    2013-01-01

    of model predictions for cell property distributions against experimental data is scarce. This study focuses on the experimental and mathematical description of the dynamics of cell size and cell cycle position distributions, of a population of Saccharomyces cerevisiae, in response to the substrate...

  15. Modeling of DNA damage-cluster, cell-cycle and repair pathway dependent radiosensitivity after low- and high-LET irradiation

    International Nuclear Information System (INIS)

    Guenther, Paul

    2017-01-01

    irradiation. This method is able to qualitatively predict the influence of the cell-cycle and the radiation quality on radiosensitivity. Based on this, two approaches for the LEM prediction of the Relative Biological Effectiveness (RBE) are compared. The first approach predicts the RBE based on the survival of asynchronous cells. The second approach predicts the RBE from the sum of survival curves of the subpopulations, which contribute to the asynchronous cell population. Both approaches lead to qualitatively similar results. In the context of describing the microscopic dose deposition of ion irradiation by the amorphous track structure, two questions are addressed: 1. Is it possible to improve the prediction of cell survival after ion irradiation by a more sophisticated composition of the direct and indirect effect? 2. is the amorphous track structure an appropriate model of the dose deposition regarding the DNA damage clustering on the nm-scale or is it necessary to evaluate single ionizations on the molecular level? Regarding the first question, it is shown that a more detailed evaluation of the direct and indirect effect improves the agreement of the LEM predictions to data. Concerning the second question, it is shown that the amorphous track structure can be used for the prediction of DNA damage induction on the nm-scale similar to an ab initio Monte Carlo simulation. In the context of cell-survival modeling, the relevant length scale for DNA damage-clustering is often discussed. The iDSBs und cDSBs used in the GLOBLE and LEM are referring to DNA damage clustering on the μm-scale. There are also models which predict the cell survival after ion irradiation based on complex DNA-damage-clusters on the nm-scale. This work shows, that complex DNA damage-clusters on the μm-scale are correlated to damage clusters on the nm-scale. Therefore, it is possible to predict the cell survival after ion irradiation based on both scales. However, the cell survival after photon

  16. Lobaplatin arrests cell cycle progression in human hepatocellular carcinoma cells

    Directory of Open Access Journals (Sweden)

    Chen Chang-Jie

    2010-10-01

    Full Text Available Abstract Background Hepatocellular carcinoma (HCC still is a big burden for China. In recent years, the third-generation platinum compounds have been proposed as potential active agents for HCC. However, more experimental and clinical data are warranted to support the proposal. In the present study, the effect of lobaplatin was assessed in five HCC cell lines and the underlying molecular mechanisms in terms of cell cycle kinetics were explored. Methods Cytotoxicity of lobaplatin to human HCC cell lines was examined using MTT cell proliferation assay. Cell cycle distribution was determined by flow cytometry. Expression of cell cycle-regulated genes was examined at both the mRNA (RT-PCR and protein (Western blot levels. The phosphorylation status of cyclin-dependent kinases (CDKs and retinoblastoma (Rb protein was also examined using Western blot analysis. Results Lobaplatin inhibited proliferation of human HCC cells in a dose-dependent manner. For the most sensitive SMMC-7721 cells, lobaplatin arrested cell cycle progression in G1 and G2/M phases time-dependently which might be associated with the down-regulation of cyclin B, CDK1, CDC25C, phosphorylated CDK1 (pCDK1, pCDK4, Rb, E2F, and pRb, and the up-regulation of p53, p21, and p27. Conclusion Cytotoxicity of lobaplatin in human HCC cells might be due to its ability to arrest cell cycle progression which would contribute to the potential use of lobaplatin for the management of HCC.

  17. Canthin-6-one induces cell death, cell cycle arrest and differentiation in human myeloid leukemia cells.

    Science.gov (United States)

    Vieira Torquato, Heron F; Ribeiro-Filho, Antonio C; Buri, Marcus V; Araújo Júnior, Roberto T; Pimenta, Renata; de Oliveira, José Salvador R; Filho, Valdir C; Macho, Antonio; Paredes-Gamero, Edgar J; de Oliveira Martins, Domingos T

    2017-04-01

    Canthin-6-one is a natural product isolated from various plant genera and from fungi with potential antitumor activity. In the present study, we evaluate the antitumor effects of canthin-6-one in human myeloid leukemia lineages. Kasumi-1 lineage was used as a model for acute myeloid leukemia. Cells were treated with canthin-6-one and cell death, cell cycle and differentiation were evaluated in both total cells (Lin + ) and leukemia stem cell population (CD34 + CD38 - Lin -/low ). Among the human lineages tested, Kasumi-1 was the most sensitive to canthin-6-one. Canthin-6-one induced cell death with apoptotic (caspase activation, decrease of mitochondrial potential) and necrotic (lysosomal permeabilization, double labeling of annexin V/propidium iodide) characteristics. Moreover, canthin-6-one induced cell cycle arrest at G 0 /G 1 (7μM) and G 2 (45μM) evidenced by DNA content, BrdU incorporation and cyclin B1/histone 3 quantification. Canthin-6-one also promoted differentiation of Kasumi-1, evidenced by an increase in the expression of myeloid markers (CD11b and CD15) and the transcription factor PU.1. Furthermore, a reduction of the leukemic stem cell population and clonogenic capability of stem cells were observed. These results show that canthin-6-one can affect Kasumi-1 cells by promoting cell death, cell cycle arrest and cell differentiation depending on concentration used. Canthin-6-one presents an interesting cytotoxic activity against leukemic cells and represents a promising scaffold for the development of molecules for anti-leukemic applications, especially by its anti-leukemic stem cell activity. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Modeling the Nuclear Fuel Cycle

    International Nuclear Information System (INIS)

    Jacobson, Jacob J.; Dunzik-Gougar, Mary Lou; Juchau, Christopher A.

    2010-01-01

    A review of existing nuclear fuel cycle systems analysis codes was performed to determine if any existing codes meet technical and functional requirements defined for a U.S. national program supporting the global and domestic assessment, development and deployment of nuclear energy systems. The program would be implemented using an interconnected architecture of different codes ranging from the fuel cycle analysis code, which is the subject of the review, to fundamental physical and mechanistic codes. Four main functions are defined for the code: (1) the ability to characterize and deploy individual fuel cycle facilities and reactors in a simulation, while discretely tracking material movements, (2) the capability to perform an uncertainty analysis for each element of the fuel cycle and an aggregate uncertainty analysis, (3) the inclusion of an optimization engine able to optimize simultaneously across multiple objective functions, and (4) open and accessible code software and documentation to aid in collaboration between multiple entities and facilitate software updates. Existing codes, categorized as annualized or discrete fuel tracking codes, were assessed according to the four functions and associated requirements. These codes were developed by various government, education and industrial entities to fulfill particular needs. In some cases, decisions were made during code development to limit the level of detail included in a code to ease its use or to focus on certain aspects of a fuel cycle to address specific questions. The review revealed that while no two of the codes are identical, they all perform many of the same basic functions. No code was able to perform defined function 2 or several requirements of functions 1 and 3. Based on this review, it was concluded that the functions and requirements will be met only with development of a new code, referred to as GENIUS.

  19. Hydration and dehydration cycles in polymer electrolyte fuel cells operated with wet anode and dry cathode feed: A neutron imaging and modeling study

    Science.gov (United States)

    García-Salaberri, P. A.; Sánchez, D. G.; Boillat, P.; Vera, M.; Friedrich, K. A.

    2017-08-01

    Proper water management plays an essential role in the performance and durability of Polymer Electrolyte Fuel Cells (PEFCs), but it is challenged by the variety of water transport phenomena that take place in these devices. Previous experimental work has shown the existence of fluctuations between low and high current density levels in PEFCs operated with wet hydrogen and dry air feed. The alternation between both performance states is accompanied by strong changes in the high frequency resistance, suggesting a cyclic hydration and dehydration of the membrane. This peculiar scenario is examined here considering liquid water distributions from neutron imaging and predictions from a 3D two-phase non-isothermal model. The results show that the hydration-dehydration cycles are triggered by the periodic condensation and shedding of liquid water at the anode inlet. The input of liquid water humidifies the anode channel and offsets the membrane dry-out induced by the dry air stream, thus leading to the high-performance state. When liquid water is flushed out of the anode channel, the dehydration process takes over, and the cell comes back to the low-performance state. The predicted amplitude of the current oscillations grows with decreasing hydrogen and increasing air flow rates, in agreement with previous experimental data.

  20. A combined gas cooled nuclear reactor and fuel cell cycle

    Science.gov (United States)

    Palmer, David J.

    Rising oil costs, global warming, national security concerns, economic concerns and escalating energy demands are forcing the engineering communities to explore methods to address these concerns. It is the intention of this thesis to offer a proposal for a novel design of a combined cycle, an advanced nuclear helium reactor/solid oxide fuel cell (SOFC) plant that will help to mitigate some of the above concerns. Moreover, the adoption of this proposal may help to reinvigorate the Nuclear Power industry while providing a practical method to foster the development of a hydrogen economy. Specifically, this thesis concentrates on the importance of the U.S. Nuclear Navy adopting this novel design for its nuclear electric vessels of the future with discussion on efficiency and thermodynamic performance characteristics related to the combined cycle. Thus, the goals and objectives are to develop an innovative combined cycle that provides a solution to the stated concerns and show that it provides superior performance. In order to show performance, it is necessary to develop a rigorous thermodynamic model and computer program to analyze the SOFC in relation with the overall cycle. A large increase in efficiency over the conventional pressurized water reactor cycle is realized. Both sides of the cycle achieve higher efficiencies at partial loads which is extremely important as most naval vessels operate at partial loads as well as the fact that traditional gas turbines operating alone have poor performance at reduced speeds. Furthermore, each side of the cycle provides important benefits to the other side. The high temperature exhaust from the overall exothermic reaction of the fuel cell provides heat for the reheater allowing for an overall increase in power on the nuclear side of the cycle. Likewise, the high temperature helium exiting the nuclear reactor provides a controllable method to stabilize the fuel cell at an optimal temperature band even during transients helping

  1. Dynamics of the cell-cycle network under genome-rewiring perturbations

    International Nuclear Information System (INIS)

    Katzir, Yair; Elhanati, Yuval; Braun, Erez; Averbukh, Inna

    2013-01-01

    The cell-cycle progression is regulated by a specific network enabling its ordered dynamics. Recent experiments supported by computational models have shown that a core of genes ensures this robust cycle dynamics. However, much less is known about the direct interaction of the cell-cycle regulators with genes outside of the cell-cycle network, in particular those of the metabolic system. Following our recent experimental work, we present here a model focusing on the dynamics of the cell-cycle core network under rewiring perturbations. Rewiring is achieved by placing an essential metabolic gene exclusively under the regulation of a cell-cycle's promoter, forcing the cell-cycle network to function under a multitasking challenging condition; operating in parallel the cell-cycle progression and a metabolic essential gene. Our model relies on simple rate equations that capture the dynamics of the relevant protein–DNA and protein–protein interactions, while making a clear distinction between these two different types of processes. In particular, we treat the cell-cycle transcription factors as limited ‘resources’ and focus on the redistribution of resources in the network during its dynamics. This elucidates the sensitivity of its various nodes to rewiring interactions. The basic model produces the correct cycle dynamics for a wide range of parameters. The simplicity of the model enables us to study the interface between the cell-cycle regulation and other cellular processes. Rewiring a promoter of the network to regulate a foreign gene, forces a multitasking regulatory load. The higher the load on the promoter, the longer is the cell-cycle period. Moreover, in agreement with our experimental results, the model shows that different nodes of the network exhibit variable susceptibilities to the rewiring perturbations. Our model suggests that the topology of the cell-cycle core network ensures its plasticity and flexible interface with other cellular processes

  2. Life-Cycle Models for Survivable Systems

    National Research Council Canada - National Science Library

    Linger, Richard

    2002-01-01

    .... Current software development life-cycle models are not focused on creating survivable systems, and exhibit shortcomings when the goal is to develop systems with a high degree of assurance of survivability...

  3. Phase resetting reveals network dynamics underlying a bacterial cell cycle.

    Science.gov (United States)

    Lin, Yihan; Li, Ying; Crosson, Sean; Dinner, Aaron R; Scherer, Norbert F

    2012-01-01

    Genomic and proteomic methods yield networks of biological regulatory interactions but do not provide direct insight into how those interactions are organized into functional modules, or how information flows from one module to another. In this work we introduce an approach that provides this complementary information and apply it to the bacterium Caulobacter crescentus, a paradigm for cell-cycle control. Operationally, we use an inducible promoter to express the essential transcriptional regulatory gene ctrA in a periodic, pulsed fashion. This chemical perturbation causes the population of cells to divide synchronously, and we use the resulting advance or delay of the division times of single cells to construct a phase resetting curve. We find that delay is strongly favored over advance. This finding is surprising since it does not follow from the temporal expression profile of CtrA and, in turn, simulations of existing network models. We propose a phenomenological model that suggests that the cell-cycle network comprises two distinct functional modules that oscillate autonomously and couple in a highly asymmetric fashion. These features collectively provide a new mechanism for tight temporal control of the cell cycle in C. crescentus. We discuss how the procedure can serve as the basis for a general approach for probing network dynamics, which we term chemical perturbation spectroscopy (CPS).

  4. Impact of cycling cells and cell cycle regulation on Hydra regeneration.

    Science.gov (United States)

    Buzgariu, Wanda; Wenger, Yvan; Tcaciuc, Nina; Catunda-Lemos, Ana-Paula; Galliot, Brigitte

    2018-01-15

    Hydra tissues are made from three distinct populations of stem cells that continuously cycle and pause in G2 instead of G1. To characterize the role of cell proliferation after mid-gastric bisection, we have (i) used flow cytometry and classical markers to monitor cell cycle modulations, (ii) quantified the transcriptomic regulations of 202 genes associated with cell proliferation during head and foot regeneration, and (iii) compared the impact of anti-proliferative treatments on regeneration efficiency. We confirm two previously reported events: an early mitotic wave in head-regenerating tips, when few cell cycle genes are up-regulated, and an early-late wave of proliferation on the second day, preceded by the up-regulation of 17 cell cycle genes. These regulations appear more intense after mid-gastric bisection than after decapitation, suggesting a position-dependent regulation of cell proliferation during head regeneration. Hydroxyurea, which blocks S-phase progression, delays head regeneration when applied before but not after bisection. This result is consistent with the fact that the Hydra central region is enriched in G2-paused adult stem cells, poised to divide upon injury, thus forming a necessary constitutive pro-blastema. However a prolonged exposure to hydroxyurea does not block regeneration as cells can differentiate apical structures without traversing S-phase, and also escape in few days the hydroxyurea-induced S-phase blockade. Thus Hydra head regeneration, which is a fast event, is highly plastic, relying on large stocks of adult stem cells paused in G2 at amputation time, which immediately divide to proliferate and/or differentiate apical structures even when S-phase is blocked. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Cell cycle delays in synchronized cell populations following irradiation with heavy ions

    International Nuclear Information System (INIS)

    Scholz, M.

    1992-11-01

    Mammalian cells subjected to irradiation with heavy ions were investigated for cell cycle delays. The ions used for this purpose included Ne ions in the LET range of 400 keV/μm just as well as uranium ions of 16225 keV/μm. The qualitative changes in cell cycle progression seen after irradiation with Ne ions (400 keV/μm) were similar to those observed in connection with X-rays. Following irradiation with extremely heavy ions (lead, uranium) the majority of cells were even at 45 hours still found to be in the S phase or G 2 M phase of the first cycle. The delay cross section 'σ-delay' was introduced as a quantity that would permit quantitative comparisons to be carried out between the changes in cell progression and other effects of radiation. In order to evaluate the influence of the number of hits on the radiation effect observed, the size of the cell nucleus was precisely determined with reference to the cycle phase and local cell density. A model to simulate those delay effects was designed in such a way that account is taken of this probability of hit and that the results can be extrapolated from the delay effects after X-irradiation. On the basis of the various probabilities of hit for cells at different cycle stages a model was developed to ascertain the intensified effect following fractionated irradiation with heavy ions. (orig./MG) [de

  6. Nuclear fuel cycle modelling using MESSAGE

    International Nuclear Information System (INIS)

    Guiying Zhang; Dongsheng Niu; Guoliang Xu; Hui Zhang; Jue Li; Lei Cao; Zeqin Guo; Zhichao Wang; Yutong Qiu; Yanming Shi; Gaoliang Li

    2017-01-01

    In order to demonstrate the possibilities of application of MESSAGE tool for the modelling of a Nuclear Energy System at the national level, one of the possible open nuclear fuel cycle options based on thermal reactors has been modelled using MESSAGE. The steps of the front-end and back-end of nuclear fuel cycle and nuclear reactor operation are described. The optimal structure for Nuclear Power Development and optimal schedule for introducing various reactor technologies and fuel cycle options; infrastructure facilities, nuclear material flows and waste, investments and other costs are demonstrated. (author)

  7. Timing robustness in the budding and fission yeast cell cycles.

    KAUST Repository

    Mangla, Karan

    2010-02-01

    Robustness of biological models has emerged as an important principle in systems biology. Many past analyses of Boolean models update all pending changes in signals simultaneously (i.e., synchronously), making it impossible to consider robustness to variations in timing that result from noise and different environmental conditions. We checked previously published mathematical models of the cell cycles of budding and fission yeast for robustness to timing variations by constructing Boolean models and analyzing them using model-checking software for the property of speed independence. Surprisingly, the models are nearly, but not totally, speed-independent. In some cases, examination of timing problems discovered in the analysis exposes apparent inaccuracies in the model. Biologically justified revisions to the model eliminate the timing problems. Furthermore, in silico random mutations in the regulatory interactions of a speed-independent Boolean model are shown to be unlikely to preserve speed independence, even in models that are otherwise functional, providing evidence for selection pressure to maintain timing robustness. Multiple cell cycle models exhibit strong robustness to timing variation, apparently due to evolutionary pressure. Thus, timing robustness can be a basis for generating testable hypotheses and can focus attention on aspects of a model that may need refinement.

  8. Alteration of cell cycle progression by Sindbis virus infection

    Energy Technology Data Exchange (ETDEWEB)

    Yi, Ruirong; Saito, Kengo [Department of Molecular Virology, Graduate School of Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8670 (Japan); Isegawa, Naohisa [Laboratory Animal Center, Graduate School of Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8670 (Japan); Shirasawa, Hiroshi, E-mail: sirasawa@faculty.chiba-u.jp [Department of Molecular Virology, Graduate School of Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8670 (Japan)

    2015-07-10

    We examined the impact of Sindbis virus (SINV) infection on cell cycle progression in a cancer cell line, HeLa, and a non-cancerous cell line, Vero. Cell cycle analyses showed that SINV infection is able to alter the cell cycle progression in both HeLa and Vero cells, but differently, especially during the early stage of infection. SINV infection affected the expression of several cell cycle regulators (CDK4, CDK6, cyclin E, p21, cyclin A and cyclin B) in HeLa cells and caused HeLa cells to accumulate in S phase during the early stage of infection. Monitoring SINV replication in HeLa and Vero cells expressing cell cycle indicators revealed that SINV which infected HeLa cells during G{sub 1} phase preferred to proliferate during S/G{sub 2} phase, and the average time interval for viral replication was significantly shorter in both HeLa and Vero cells infected during G{sub 1} phase than in cells infected during S/G{sub 2} phase. - Highlights: • SINV infection was able to alter the cell cycle progression of infected cancer cells. • SINV infection can affect the expression of cell cycle regulators. • SINV infection exhibited a preference for the timing of viral replication among the cell cycle phases.

  9. Alteration of cell cycle progression by Sindbis virus infection

    International Nuclear Information System (INIS)

    Yi, Ruirong; Saito, Kengo; Isegawa, Naohisa; Shirasawa, Hiroshi

    2015-01-01

    We examined the impact of Sindbis virus (SINV) infection on cell cycle progression in a cancer cell line, HeLa, and a non-cancerous cell line, Vero. Cell cycle analyses showed that SINV infection is able to alter the cell cycle progression in both HeLa and Vero cells, but differently, especially during the early stage of infection. SINV infection affected the expression of several cell cycle regulators (CDK4, CDK6, cyclin E, p21, cyclin A and cyclin B) in HeLa cells and caused HeLa cells to accumulate in S phase during the early stage of infection. Monitoring SINV replication in HeLa and Vero cells expressing cell cycle indicators revealed that SINV which infected HeLa cells during G 1 phase preferred to proliferate during S/G 2 phase, and the average time interval for viral replication was significantly shorter in both HeLa and Vero cells infected during G 1 phase than in cells infected during S/G 2 phase. - Highlights: • SINV infection was able to alter the cell cycle progression of infected cancer cells. • SINV infection can affect the expression of cell cycle regulators. • SINV infection exhibited a preference for the timing of viral replication among the cell cycle phases

  10. Mice deleted for cell division cycle 73 gene develop parathyroid and uterine tumours: model for the hyperparathyroidism-jaw tumour syndrome.

    Science.gov (United States)

    Walls, G V; Stevenson, M; Lines, K E; Newey, P J; Reed, A A C; Bowl, M R; Jeyabalan, J; Harding, B; Bradley, K J; Manek, S; Chen, J; Wang, P; Williams, B O; Teh, B T; Thakker, R V

    2017-07-13

    The hyperparathyroidism-jaw tumour (HPT-JT) syndrome is an autosomal dominant disorder characterized by occurrence of parathyroid tumours, often atypical adenomas and carcinomas, ossifying jaw fibromas, renal tumours and uterine benign and malignant neoplasms. HPT-JT is caused by mutations of the cell division cycle 73 (CDC73) gene, located on chromosome 1q31.2 and encodes a 531 amino acid protein, parafibromin. To facilitate in vivo studies of Cdc73 in tumourigenesis we generated conventional (Cdc73 +/- ) and conditional parathyroid-specific (Cdc73 +/L /PTH-Cre and Cdc73 L/L /PTH-Cre) mouse models. Mice were aged to 18-21 months and studied for survival, tumour development and proliferation, and serum biochemistry, and compared to age-matched wild-type (Cdc73 +/+ and Cdc73 +/+ /PTH-Cre) littermates. Survival of Cdc73 +/- mice, when compared to Cdc73 +/+ mice was reduced (Cdc73 +/- =80%; Cdc73 +/+ =90% at 18 months of age, Pfourfold higher than that in parathyroid glands of wild-type littermates (P<0.0001). Cdc73 +/- , Cdc73 +/L /PTH-Cre and Cdc73 L/L /PTH-Cre mice had higher mean serum calcium concentrations than wild-type littermates, and Cdc73 +/- mice also had increased mean serum parathyroid hormone (PTH) concentrations. Parathyroid tumour development, and elevations in serum calcium and PTH, were similar in males and females. Cdc73 +/- mice did not develop bone or renal tumours but female Cdc73 +/- mice, at 18 months of age, had uterine neoplasms comprising squamous metaplasia, adenofibroma and adenomyoma. Uterine neoplasms, myometria and jaw bones of Cdc73 +/- mice had increased proliferation rates that were 2-fold higher than in Cdc73 +/+ mice (P<0.05). Thus, our studies, which have established mouse models for parathyroid tumours and uterine neoplasms that develop in the HPT-JT syndrome, provide in vivo models for future studies of these tumours.

  11. Heteroclinic cycles in the repressilator model

    International Nuclear Information System (INIS)

    Kuznetsov, A.; Afraimovich, V.

    2012-01-01

    Highlights: ► We conduct analysis at infinity in the phase space of the repressilator model. ► We study two models with the original linear and a new saturable degradation terms. ► We link the evolution of an oscillatory solution with a heteroclinic cycle. ► The transition studied here presents a new bifurcation scenario. - Abstract: A repressilator is a synthetic regulatory network that produces self-sustained oscillations. We analyze the evolution of the oscillatory solution in the repressilator model. We have established a connection between the evolution of the oscillatory solution and formation of a heteroclinic cycle at infinity. The convergence of the limit cycle to the heteroclinic cycle occurs very differently compared to the well-studied cases. The transition studied here presents a new bifurcation scenario.

  12. The WAM model cycle 4

    International Nuclear Information System (INIS)

    Guenther, H.; Hasselmann, S.; Janssen, P.A.E.M.

    1992-10-01

    The WAM-model is a third generation wave model which solves the wave transport equation explicitly without any presumptions on the shape of the wave spectrum. It represents the physics of the wave evolution in accordance with our knowledge today for the full set of degrees of freedom of a 2d wave spectrum. The model runs for any given regional or global grid with a prescribed topographic dataset. The grid resolution can be arbitrary in space and time. The propagation can be done on a latitudinal-longitudinal or on a carthesian grid. The model outputs the significant wave height, mean wave direction and frequency, the swell wave height and mean direction, wind stress fields corrected by including the wave induces stress and the drag coefficient at each grid point at chosen output times, and also the 2d wave spectrum at chosen grid points and output times. (orig.)

  13. Cycling indices for ecosystem models

    International Nuclear Information System (INIS)

    Carney, J.H.; Gardner, R.H.; Mankin, J.B.; DeAngelis, D.L.

    1979-01-01

    The study of ecosystems is aided by representing structural and functional groups of organisms or processes as discrete components. A complex compartment model will explicitly map pathways from one compartment to another and specify transfer rates. This quantitative description allows insight into the dynamics of flow of nutrients, toxic chemicals, radionuclides, or energy. Three new indices that calculate compartment-specific probabilities of occurrence and recycling and illustrate the problem of applying these indices to ecosystem models are presented

  14. P27 in cell cycle control and cancer

    DEFF Research Database (Denmark)

    Møller, Michael Boe

    2000-01-01

    In order to survive, cells need tight control of cell cycle progression. The control mechanisms are often lost in human cancer cells. The cell cycle is driven forward by cyclin-dependent kinases (CDKs). The CDK inhibitors (CKIs) are important regulators of the CDKs. As the name implies, CKIs were...

  15. Interlink between cholesterol & cell cycle in prostate carcinoma

    Directory of Open Access Journals (Sweden)

    Govind Singh

    2017-01-01

    Interpretation & conclusions: The present findings along with increased expression of cell cycle protein cyclin E in the cell nucleus of the tumour tissue suggested the possibility of an intriguing role of cholesterol in the mechanism of cell cycle process of prostate cell proliferation.

  16. A protocol to assess cell cycle and apoptosis in human and mouse pluripotent cells

    Directory of Open Access Journals (Sweden)

    Edel Michael J

    2011-04-01

    Full Text Available Abstract Embryonic stem cells (ESC and induced pluripotent stem cells (iPSCs present a great opportunity to treat and model human disease as a cell replacement therapy. There is a growing pressure to understand better the signal transduction pathways regulating pluripotency and self-renewal of these special cells in order to deliver a safe and reliable cell based therapy in the near future. Many signal transduction pathways converge on two major cell functions associated with self-renewal and pluripotency: control of the cell cycle and apoptosis, although a standard method is lacking across the field. Here we present a detailed protocol to assess the cell cycle and apoptosis of ESC and iPSCs as a single reference point offering an easy to use standard approach across the field.

  17. Cdk1 activity acts as a quantitative platform for coordinating cell cycle progression with periodic transcription

    Science.gov (United States)

    Banyai, Gabor; Baïdi, Feriel; Coudreuse, Damien; Szilagyi, Zsolt

    2016-01-01

    Cell proliferation is regulated by cyclin-dependent kinases (Cdks) and requires the periodic expression of particular gene clusters in different cell cycle phases. However, the interplay between the networks that generate these transcriptional oscillations and the core cell cycle machinery remains largely unexplored. In this work, we use a synthetic regulable Cdk1 module to demonstrate that periodic expression is governed by quantitative changes in Cdk1 activity, with different clusters directly responding to specific activity levels. We further establish that cell cycle events neither participate in nor interfere with the Cdk1-driven transcriptional program, provided that cells are exposed to the appropriate Cdk1 activities. These findings contrast with current models that propose self-sustained and Cdk1-independent transcriptional oscillations. Our work therefore supports a model in which Cdk1 activity serves as a quantitative platform for coordinating cell cycle transitions with the expression of critical genes to bring about proper cell cycle progression. PMID:27045731

  18. Modeling the Rock Glacier Cycle

    Science.gov (United States)

    Anderson, R. S.; Anderson, L. S.

    2016-12-01

    Rock glaciers are common in many mountain ranges in which the ELA lies above the peaks. They represent some of the most identifiable components of today's cryosphere in these settings. Their oversteepened snouts pose often-overlooked hazards to travel in alpine terrain. Rock glaciers are supported by avalanches and by rockfall from steep headwalls. The winter's avalanche cone must be sufficiently thick not to melt entirely in the summer. The spatial distribution of rock glaciers reflects this dependence on avalanche sources; they are most common on lee sides of ridges where wind-blown snow augments the avalanche source. In the absence of rockfall, this would support a short, cirque glacier. Depending on the relationship between rockfall and avalanche patterns, "talus-derived" and "glacier-derived" rock glaciers are possible. Talus-derived: If the spatial distribution of rock delivery is similar to the avalanche pattern, the rock-ice mixture will travel an englacial path that is downward through the short accumulation zone before turning upward in the ablation zone. Advected debris is then delivered to the base of a growing surface debris layer that reduces the ice melt rate. The physics is identical to the debris-covered glacier case. Glacier-derived: If on the other hand rockfall from the headwall rolls beyond the avalanche cone, it is added directly to the ablation zone of the glacier. The avalanche accumulation zone then supports a pure ice core to the rock glacier. We have developed numerical models designed to capture the full range of glacier to debris-covered glacier to rock glacier behavior. The hundreds of meter lengths, tens of meters thicknesses, and meter per year speeds of rock glaciers are well described by the models. The model can capture both "talus-derived" and "glacier-derived" rock glaciers. We explore the dependence of glacier behavior on climate histories. As climate warms, a pure ice debris-covered glacier can transform to a much shorter rock

  19. Glacial Cycles and ice-sheet modelling

    NARCIS (Netherlands)

    Oerlemans, J.

    1982-01-01

    An attempt is made to simulate the Pleistocene glacial cycles with a numerical model of the Northern Hemisphere ice sheets. This model treats the vertically-integrated ice flow along a meridian, including computation of bedrock adjustment and temperature distribution in the ice. Basal melt water is

  20. A low protein diet during pregnancy provokes a lasting shift of hepatic expression of genes related to cell cycle throughout ontogenesis in a porcine model

    Directory of Open Access Journals (Sweden)

    Oster Michael

    2012-03-01

    Full Text Available Abstract Background In rodent models and in humans the impact of gestational diets on the offspring's phenotype was shown experimentally and epidemiologically. Adverse environmental conditions during fetal development provoke an intrauterine adaptive response termed 'fetal programming', which may lead to both persistently biased responsiveness to extrinsic factors and permanent consequences for the organismal phenotype. This leads to the hypothesis that the offspring's transcriptome exhibits short-term and long-term changes, depending on the maternal diet. In order to contribute to a comprehensive inventory of genes and functional networks that are targets of nutritional programming initiated during fetal life, we applied whole-genome microarrays for expression profiling in a longitudinal experimental design covering prenatal, perinatal, juvenile, and adult ontogenetic stages in a porcine model. Pregnant sows were fed either a gestational low protein diet (LP, 6% CP or an adequate protein diet (AP, 12% CP. All offspring was nursed by foster sows receiving standard diets. After weaning, all offspring was fed standard diets ad libitum. Results Analyses of the hepatic gene expression of the offspring at prenatal (94 dies post conceptionem, dpc and postnatal stages (1, 28, 188 dies post natum, dpn included comparisons between dietary groups within stages as well as comparisons between ontogenetic stages within diets to separate diet-specific transcriptional changes and maturation processes. We observed differential expression of genes related to lipid metabolism (e.g. Fatty acid metabolism, Biosynthesis of steroids, Synthesis and degradation of ketone bodies, FA elongation in mitochondria, Bile acid synthesis and cell cycle regulation (e.g. Mitotic roles of PLK, G1/S checkpoint regulation, G2/M DNA damage checkpoint regulation. Notably, at stage 1 dpn no regulation of a distinct pathway was found in LP offspring. Conclusions The transcriptomic

  1. KOH concentration effect on cycle life of nickel-hydrogen cells. III - Cycle life test

    Science.gov (United States)

    Lim, H. S.; Verzwyvelt, S. A.

    1988-01-01

    A cycle life test of Ni/H2 cells containing electrolytes of various KOH concentrations and a sintered type nickel electrode was carried out at 23 C using a 45 min accelerated low earth orbit (LEO) cycle regime at 80 percent depth of discharge. One of three cells containing 26 percent KOH has achieved over 28,000 cycles, and the other two 19,000 cycles, without a sign of failure. Two other cells containing 31 percent KOH electrolyte, which is the concentration presently used in aerospace cells, failed after 2,979 and 3,620 cycles. This result indicates that the cycle life of the present type of Ni/H2 cells may be extended by a factor of 5 to 10 simply by lowering the KOH concentration. Long cycle life of a Ni/H2 battery at high depth-of-discharge operation is desired, particularly for an LEO spacecraft application. Typically, battery life of about 30,000 cycles is required for a five year mission in an LEO. Such a cycle life with presently available cells can be assured only at a very low depth-of-discharge operation. Results of testing already show that the cycle life of an Ni/H2 cell is tremendously improved by simply using an electrolyte of low KOH concentration.

  2. Molecular biological mechanism II. Molecular mechanisms of cell cycle regulation

    International Nuclear Information System (INIS)

    Jung, T.

    2000-01-01

    The cell cycle in eukaryotes is regulated by central cell cycle controlling protein kinase complexes. These protein kinase complexes consist of a catalytic subunit from the cyclin-dependent protein kinase family (CDK), and a regulatory subunit from the cyclin family. Cyclins are characterised by their periodic cell cycle related synthesis and destruction. Each cell cycle phase is characterised by a specific set of CDKs and cyclins. The activity of CDK/cyclin complexes is mainly regulated on four levels. It is controlled by specific phosphorylation steps, the synthesis and destruction of cyclins, the binding of specific inhibitor proteins, and by active control of their intracellular localisation. At several critical points within the cell cycle, named checkpoints, the integrity of the cellular genome is monitored. If damage to the genome or an unfinished prior cell cycle phase is detected, the cell cycle progression is stopped. These cell cycle blocks are of great importance to secure survival of cells. Their primary importance is to prevent the manifestation and heritable passage of a mutated genome to daughter cells. Damage sensing, DNA repair, cell cycle control and apoptosis are closely linked cellular defence mechanisms to secure genome integrity. Disregulation in one of these defence mechanisms are potentially correlated with an increased cancer risk and therefore in at least some cases with an increased radiation sensitivity. (orig.) [de

  3. Modelling the CDK-dependent transcription cycle in fission yeast.

    Science.gov (United States)

    Sansó, Miriam; Fisher, Robert P

    2013-12-01

    CDKs (cyclin-dependent kinases) ensure directionality and fidelity of the eukaryotic cell division cycle. In a similar fashion, the transcription cycle is governed by a conserved subfamily of CDKs that phosphorylate Pol II (RNA polymerase II) and other substrates. A genetic model organism, the fission yeast Schizosaccharomyces pombe, has yielded robust models of cell-cycle control, applicable to higher eukaryotes. From a similar approach combining classical and chemical genetics, fundamental principles of transcriptional regulation by CDKs are now emerging. In the present paper, we review the current knowledge of each transcriptional CDK with respect to its substrate specificity, function in transcription and effects on chromatin modifications, highlighting the important roles of CDKs in ensuring quantity and quality control over gene expression in eukaryotes.

  4. Chaotic and stable perturbed maps: 2-cycles and spatial models

    Science.gov (United States)

    Braverman, E.; Haroutunian, J.

    2010-06-01

    As the growth rate parameter increases in the Ricker, logistic and some other maps, the models exhibit an irreversible period doubling route to chaos. If a constant positive perturbation is introduced, then the Ricker model (but not the classical logistic map) experiences period doubling reversals; the break of chaos finally gives birth to a stable two-cycle. We outline the maps which demonstrate a similar behavior and also study relevant discrete spatial models where the value in each cell at the next step is defined only by the values at the cell and its nearest neighbors. The stable 2-cycle in a scalar map does not necessarily imply 2-cyclic-type behavior in each cell for the spatial generalization of the map.

  5. Cell cycle control by the thyroid hormone in neuroblastoma cells

    International Nuclear Information System (INIS)

    Garcia-Silva, Susana; Perez-Juste, German; Aranda, Ana

    2002-01-01

    The thyroid hormone (T3) blocks proliferation and induces differentiation of neuroblastoma N2a-β cells that overexpress the β1 isoform of the T3 receptor. An element in the region responsible for premature termination of transcription mediates a rapid repression of c-myc gene expression by T3. The hormone also causes a decrease of cyclin D1 gene transcription, and is able to antagonize the activation of the cyclin D1 promoter by Ras. In addition, a strong and sustained increase of the levels of the cyclin kinase inhibitor (CKI) p27 Kip1 are found in T3-treated cells. The increased levels of p27 Kip1 lead to a marked inhibition of the kinase activity of the cyclin-CDK2 complexes. As a consequence of these changes, retinoblastoma proteins are hypophosphorylated in T3-treated N2a-β cells, and progression through the restriction point in the cell cycle is blocked

  6. Cell cycle checkpoints: reversible when possible, irreversible when needed

    NARCIS (Netherlands)

    Krenning, L.

    2015-01-01

    Cell cycle checkpoints are reversible in nature, and can prevent progression into the next cell cycle phase if needed. In the case of DNA damage, cells can prevent progression from G1 into S phase, and from G2 into mitosis in the presence of DNA double strand breaks. Following DNA repair, these

  7. Modeling the hydrological cycle on Mars

    Directory of Open Access Journals (Sweden)

    Ghada Machtoub

    2012-03-01

    Full Text Available The study provides a detailed analysis of the hydrological cycle on Mars simulated with a newly developed microphysical model, incorporated in a spectral Mars General Circulation Model. The modeled hydrological cycle is compared well with simulations of other global climate models. The simulated seasonal migration ofwater vapor, circulation instability, and the high degree of temporal variability of localized water vapor outbursts are shown closely consistent with recent observations. The microphysical parameterization provides a significant improvement in the modeling of ice clouds evolved over the tropics and major ancient volcanoes on Mars. The most significant difference between the simulations presented here and other GCM results is the level at which the water ice clouds are found. The model findings also support interpretation of observed thermal anomalies in the Martian tropics during northern spring and summer seasons.

  8. Cell cycle controls: potential targets for chemical carcinogens?

    OpenAIRE

    Afshari, C A; Barrett, J C

    1993-01-01

    The progression of the cell cycle is controlled by the action of both positive and negative growth regulators. The key players in this activity include a family of cyclins and cyclin-dependent kinases, which are themselves regulated by other kinases and phosphatases. Maintenance of balanced cell cycle controls may be directly linked to genomic stability. Loss of the check-points involved in cell cycle control may result in unrepaired DNA damage during DNA synthesis or mitosis leading to genet...

  9. Protein kinase C signaling and cell cycle regulation

    OpenAIRE

    Black, Adrian R.; Black, Jennifer D.

    2013-01-01

    A link between T cell proliferation and the protein kinase C (PKC) family of serine/threonine kinases has been recognized for about thirty years. However, despite the wealth of information on PKC-mediated control of T cell activation, understanding of the effects of PKCs on the cell cycle machinery in this cell type remains limited. Studies in other systems have revealed important cell cycle-specific effects of PKC signaling that can either positively or negatively impact proliferation. Th...

  10. MODELLING OF NON-ROAD TRANSIENT CYCLE

    Directory of Open Access Journals (Sweden)

    Martin Kotus

    2013-12-01

    Full Text Available The paper describes the modeling of NRTC (Non-Road Transient Cycle test procedure based on previously measured characteristics of fuel consumption, carbon monoxide (CO, carbon dioxide (CO2, hydrocarbons (HC, nitrogen oxides (NOx and particulates (PM production. It makes possible to compare the current technical condition of an internal combustion engine of an agricultural tractor with its previous state or other tractor’s engine. Based on measured characteristics, it is also possible to model any other cycle without further measurements (NRSC test procedure, cycle for specific conditions – mountain tractor, etc.. The result may thus contribute to improving the environment by reducing the production of harmful substances emitted into the air and save money due to reduced fuel consumption.

  11. Architecture and inherent robustness of a bacterial cell-cycle control system.

    Science.gov (United States)

    Shen, Xiling; Collier, Justine; Dill, David; Shapiro, Lucy; Horowitz, Mark; McAdams, Harley H

    2008-08-12

    A closed-loop control system drives progression of the coupled stalked and swarmer cell cycles of the bacterium Caulobacter crescentus in a near-mechanical step-like fashion. The cell-cycle control has a cyclical genetic circuit composed of four regulatory proteins with tight coupling to processive chromosome replication and cell division subsystems. We report a hybrid simulation of the coupled cell-cycle control system, including asymmetric cell division and responses to external starvation signals, that replicates mRNA and protein concentration patterns and is consistent with observed mutant phenotypes. An asynchronous sequential digital circuit model equivalent to the validated simulation model was created. Formal model-checking analysis of the digital circuit showed that the cell-cycle control is robust to intrinsic stochastic variations in reaction rates and nutrient supply, and that it reliably stops and restarts to accommodate nutrient starvation. Model checking also showed that mechanisms involving methylation-state changes in regulatory promoter regions during DNA replication increase the robustness of the cell-cycle control. The hybrid cell-cycle simulation implementation is inherently extensible and provides a promising approach for development of whole-cell behavioral models that can replicate the observed functionality of the cell and its responses to changing environmental conditions.

  12. Real Business-cycle Model with Habits

    DEFF Research Database (Denmark)

    Khorunzhina, Natalia

    2015-01-01

    This paper empirically investigates the ability of a real business-cycle model with nonseparabilities in consumption and leisure and external habits both in consumption and leisure to fit the postwar US data. The results indicate a strong but fast-dying habit in leisure, and a somewhat weaker...

  13. CFTSIM-ITER dynamic fuel cycle model

    International Nuclear Information System (INIS)

    Busigin, A.; Gierszewski, P.

    1998-01-01

    Dynamic system models have been developed for specific tritium systems with considerable detail and for integrated fuel cycles with lesser detail (e.g. D. Holland, B. Merrill, Analysis of tritium migration and deposition in fusion reactor systems, Proceedings of the Ninth Symposium Eng. Problems of Fusion Research (1981); M.A. Abdou, E. Vold, C. Gung, M. Youssef, K. Shin, DT fuel self-sufficiency in fusion reactors, Fusion Technol. (1986); G. Spannagel, P. Gierszewski, Dynamic tritium inventory of a NET/ITER fuel cycle with lithium salt solution blanket, Fusion Eng. Des. (1991); W. Kuan, M.A. Abdou, R.S. Willms, Dynamic simulation of a proposed ITER tritium processing system, Fusion Technol. (1995)). In order to provide a tool to understand and optimize the behavior of the ITER fuel cycle, a dynamic fuel cycle model called CFTSIM is under development. The CFTSIM code incorporates more detailed ITER models, specifically for the important isotope separation system, and also has an easier-to-use graphical interface. This paper provides an overview of CFTSIM Version 1.0. The models included are those with significant and varying tritium inventories over a test campaign: fueling, plasma and first wall, pumping, fuel cleanup, isotope separation and storage. An illustration of the results is shown. (orig.)

  14. Cell-cycle research with synchronous cultures: an evaluation

    Science.gov (United States)

    Helmstetter, C. E.; Thornton, M.; Grover, N. B.

    2001-01-01

    The baby-machine system, which produces new-born Escherichia coli cells from cultures immobilized on a membrane, was developed many years ago in an attempt to attain optimal synchrony with minimal disturbance of steady-state growth. In the present article, we put forward a model to describe the behaviour of cells produced by this method, and provide quantitative evaluation of the parameters involved, at each of four different growth rates. Considering the high level of selection achievable with this technique and the natural dispersion in interdivision times, we believe that the output of the baby machine is probably close to optimal in terms of both quality and persistence of synchrony. We show that considerable information on events in the cell cycle can be obtained from populations with age distributions very much broader than those achieved with the baby machine and differing only modestly from steady state. The data presented here, together with the long and fruitful history of findings employing the baby-machine technique, suggest that minimisation of stress on cells is the single most important factor for successful cell-cycle analysis.

  15. Cell cycle phase of nondividing cells in aging human cell cultures determined by DNA content and chromosomal constitution

    International Nuclear Information System (INIS)

    Yanishevsky, R.M.

    1975-01-01

    Human diploid cell cultures, strain WI-38, have a finite proliferative capacity and have been proposed as a model of biological aging. To identify the cell cycle phase of the nondividing cells, cultures of various ages were exposed to 3 Hdt for 48 hours to label dividing cells, then the cycle phase was identified for individual cells by one of two methods, and finally, the proliferative status of the same cells was scored by autoradiographic evidence of 3 HdT uptake. The methods to identify the cycle phase were: determination of DNA strain content by Feulgen scanning cytophotometry, and determination of chromosome constitution by the technique of premature chromosome condensation (PCC). Preliminary experiments showed the effect of continuous exposure to various levels of 3 HdT on cell growth. High levels of 3 HdT inhibited cell cycle traverse: the cell number and labeling index curves reached a plateau; the cell volume increased; the cells accumulated with 4C DNA contents and it appeared that they blocked in G 2 phase. This pattern is consistent with a radiation effect. (U.S.)

  16. A model for global cycling of tritium

    International Nuclear Information System (INIS)

    Killough, G.G.; Kocher, D.C.

    1988-01-01

    Dynamic compartment models are widely used to describe global cycling of radionuclides for purposes of dose estimation. In this paper the authors present a new global tritium model that reproduces environmental time-series data on concentrations in precipitation, ocean surface waters, and surface fresh waters in the northern hemisphere, concentrations of atmospheric tritium in the southern hemisphere, and the latitude dependence of tritium in both hemispheres. Names TRICYCLE (for TRItium CYCLE) the model is based on the global hydrologic cycle and includes hemispheric stratospheric compartments, disaggregation of the troposphere and ocean surface waters into eight latitude zones, consideration of the different concentrations of atmospheric tritium over land and over the ocean, and a diffusive model for transport in the ocean. TRICYCLE reproduces the environmental data if it is assumed that about 50% of the tritium from atmospheric weapons testing was injected directly into the northern stratosphere as HTO. The model's latitudinal disaggregation permits taking into account the distribution of population. For a uniformly distributed release of HTO into the worldwide troposphere, TRICYCLE predicts a collective dose commitment to the world population that exceeds the NCRP model's corresponding prediction by a factor of three

  17. A model for global cycling of tritium

    International Nuclear Information System (INIS)

    Killough, G.G.; Kocher, D.C.

    1988-01-01

    Dynamic compartment models are widely used to describe global cycling of radionuclides for purposes of dose estimation. In this paper, we present a new global tritium model that reproduces environmental time-series data on concentrations in precipitation, ocean surface waters, and surface fresh waters in the northern hemisphere, concentrations of atmospheric tritium in the soutehrn hemisphere, and the latitude dependence of tritium in both hemispheres. Named TRICYCLE for Tritium CYCLE, the model is based on the global hydrologic cycle and includes hemisphereic stratospheric compartments, disaggregation of the troposphere and ocean surface waters into eight latitudezones, consideration of the different concentrations of atmospheric tritium over land and over the ocean, and a diffusive model for transport in the ocean. TRICYCLE reproduces the environmental data if we assume that about 50% of the tritium from atmospheric weapons testing was injected directly into the northern stratosphere as HTO. The models latitudinal disaggregation permits taking into account the distribution of population. For a unfiormaly distributed release of HTO into the worldwide troposphere, TRICYCLE predicts a collective dose commitment to the world population that exceeds the corresponding prediction by the NCRP model by about a factor of 3. 11 refs., 5 figs., 1 tab

  18. Playing with the cell cycle to build the spinal cord.

    Science.gov (United States)

    Molina, Angie; Pituello, Fabienne

    2017-12-01

    A fundamental issue in nervous system development and homeostasis is to understand the mechanisms governing the balance between the maintenance of proliferating progenitors versus their differentiation into post-mitotic neurons. Accumulating data suggest that the cell cycle and core regulators of the cell cycle machinery play a major role in regulating this fine balance. Here, we focus on the interplay between the cell cycle and cellular and molecular events governing spinal cord development. We describe the existing links between the cell cycle and interkinetic nuclear migration (INM). We show how the different morphogens patterning the neural tube also regulate the cell cycle machinery to coordinate proliferation and patterning. We give examples of how cell cycle core regulators regulate transcriptionally, or post-transcriptionally, genes involved in controlling the maintenance versus the differentiation of neural progenitors. Finally, we describe the changes in cell cycle kinetics occurring during neural tube patterning and at the time of neuronal differentiation, and we discuss future research directions to better understand the role of the cell cycle in cell fate decisions. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Modeling Cycle Dependence in Credit Insurance

    Directory of Open Access Journals (Sweden)

    Anisa Caja

    2014-03-01

    Full Text Available Business and credit cycles have an impact on credit insurance, as they do on other businesses. Nevertheless, in credit insurance, the impact of the systemic risk is even more important and can lead to major losses during a crisis. Because of this, the insurer surveils and manages policies almost continuously. The management actions it takes limit the consequences of a downturning cycle. However, the traditional modeling of economic capital does not take into account this important feature of credit insurance. This paper proposes a model aiming to estimate future losses of a credit insurance portfolio, while taking into account the insurer’s management actions. The model considers the capacity of the credit insurer to take on less risk in the case of a cycle downturn, but also the inverse, in the case of a cycle upturn; so, losses are predicted with a more dynamic perspective. According to our results, the economic capital is over-estimated when not considering the management actions of the insurer.

  20. Combined cycling and calendar capacity fade modeling of a Nickel-Manganese-Cobalt Oxide Cell with real-life profile validation

    DEFF Research Database (Denmark)

    de Hoog, Joris; Timmermans, Jean-Marc; Stroe, Daniel-Ioan

    2017-01-01

    This paper presents the development of a semi-empirical combined lifetime model for a Nickel Manganese Cobalt Oxide (NMC) cathode and a graphite anode based cell, considered as one of the most promising candidates for the automotive industry. The development of this model was based on a thorough...

  1. Limit Cycles in Predator-Prey Models

    OpenAIRE

    Puchuri Medina, Liliana

    2017-01-01

    The classic Lotka-Volterra model belongs to a family of differential equations known as “Generalized Lotka-Volterra”, which is part of a classification of four models of quadratic fields with center. These models have been studied to address the Hilbert infinitesimal problem, which consists in determine the number of limit cycles of a perturbed hamiltonian system with center. In this work, we first present an alternative proof of the existence of centers in Lotka-Volterra predator-prey models...

  2. Simulated Carbon Cycling in a Model Microbial Mat.

    Science.gov (United States)

    Decker, K. L.; Potter, C. S.

    2006-12-01

    We present here the novel addition of detailed organic carbon cycling to our model of a hypersaline microbial mat ecosystem. This ecosystem model, MBGC (Microbial BioGeoChemistry), simulates carbon fixation through oxygenic and anoxygenic photosynthesis, and the release of C and electrons for microbial heterotrophs via cyanobacterial exudates and also via a pool of dead cells. Previously in MBGC, the organic portion of the carbon cycle was simplified into a black-box rate of accumulation of simple and complex organic compounds based on photosynthesis and mortality rates. We will discuss the novel inclusion of fermentation as a source of carbon and electrons for use in methanogenesis and sulfate reduction, and the influence of photorespiration on labile carbon exudation rates in cyanobacteria. We will also discuss the modeling of decomposition of dead cells and the ultimate release of inorganic carbon. The detailed modeling of organic carbon cycling is important to the accurate representation of inorganic carbon flux through the mat, as well as to accurate representation of growth models of the heterotrophs under different environmental conditions. Because the model ecosystem is an analog of ancient microbial mats that had huge impacts on the atmosphere of early earth, this MBGC can be useful as a biological component to either early earth models or models of other planets that potentially harbor life.

  3. The Information Warfare Life Cycle Model

    Directory of Open Access Journals (Sweden)

    Brett van Niekerk

    2011-11-01

    Full Text Available Information warfare (IW is a dynamic and developing concept, which constitutes a number of disciplines. This paper aims to develop a life cycle model for information warfare that is applicable to all of the constituent disciplines. The model aims to be scalable and applicable to civilian and military incidents where information warfare tactics are employed. Existing information warfare models are discussed, and a new model is developed from the common aspects of these existing models. The proposed model is then applied to a variety of incidents to test its applicability and scalability. The proposed model is shown to be applicable to multiple disciplines of information warfare and is scalable, thus meeting the objectives of the model.

  4. The Information Warfare Life Cycle Model

    Directory of Open Access Journals (Sweden)

    Brett van Niekerk

    2011-03-01

    Full Text Available Information warfare (IW is a dynamic and developing concept, which constitutes a number of disciplines. This paper aims to develop a life cycle model for information warfare that is applicable to all of the constituent disciplines. The model aims to be scalable and applicable to civilian and military incidents where information warfare tactics are employed. Existing information warfare models are discussed, and a new model is developed from the common aspects of these existing models. The proposed model is then applied to a variety of incidents to test its applicability and scalability. The proposed model is shown to be applicable to multiple disciplines of information warfare and is scalable, thus meeting the objectives of the model.

  5. Benzyl Isothiocyanate Inhibits Prostate Cancer Development in the Transgenic Adenocarcinoma Mouse Prostate (TRAMP Model, Which Is Associated with the Induction of Cell Cycle G1 Arrest

    Directory of Open Access Journals (Sweden)

    Han Jin Cho

    2016-02-01

    Full Text Available Benzyl isothiocyanate (BITC is a hydrolysis product of glucotropaeolin, a compound found in cruciferous vegetables, and has been shown to have anti-tumor properties. In the present study, we investigated whether BITC inhibits the development of prostate cancer in the transgenic adenocarcinoma mouse prostate (TRAMP mice. Five-week old, male TRAMP mice and their nontransgenic littermates were gavage-fed with 0, 5, or 10 mg/kg of BITC every day for 19 weeks. The weight of the genitourinary tract increased markedly in TRAMP mice and this increase was suppressed significantly by BITC feeding. H and E staining of the dorsolateral lobes of the prostate demonstrated that well-differentiated carcinoma (WDC was a predominant feature in the TRAMP mice. The number of lobes with WDC was reduced by BITC feeding while that of lobes with prostatic intraepithelial neoplasia was increased. BITC feeding reduced the number of cells expressing Ki67 (a proliferation marker, cyclin A, cyclin D1, and cyclin-dependent kinase (CDK2 in the prostatic tissue. In vitro cell culture results revealed that BITC decreased DNA synthesis, as well as CDK2 and CDK4 activity in TRAMP-C2 mouse prostate cancer cells. These results indicate that inhibition of cell cycle progression contributes to the inhibition of prostate cancer development in TRAMP mice treated with BITC.

  6. Modeling and analysis of advanced binary cycles

    Energy Technology Data Exchange (ETDEWEB)

    Gawlik, K.

    1997-12-31

    A computer model (Cycle Analysis Simulation Tool, CAST) and a methodology have been developed to perform value analysis for small, low- to moderate-temperature binary geothermal power plants. The value analysis method allows for incremental changes in the levelized electricity cost (LEC) to be determined between a baseline plant and a modified plant. Thermodynamic cycle analyses and component sizing are carried out in the model followed by economic analysis which provides LEC results. The emphasis of the present work is on evaluating the effect of mixed working fluids instead of pure fluids on the LEC of a geothermal binary plant that uses a simple Organic Rankine Cycle. Four resources were studied spanning the range of 265{degrees}F to 375{degrees}F. A variety of isobutane and propane based mixtures, in addition to pure fluids, were used as working fluids. This study shows that the use of propane mixtures at a 265{degrees}F resource can reduce the LEC by 24% when compared to a base case value that utilizes commercial isobutane as its working fluid. The cost savings drop to 6% for a 375{degrees}F resource, where an isobutane mixture is favored. Supercritical cycles were found to have the lowest cost at all resources.

  7. Segmentation and classification of cell cycle phases in fluorescence imaging.

    Science.gov (United States)

    Ersoy, Ilker; Bunyak, Filiz; Chagin, Vadim; Cardoso, M Christina; Palaniappan, Kannappan

    2009-01-01

    Current chemical biology methods for studying spatiotemporal correlation between biochemical networks and cell cycle phase progression in live-cells typically use fluorescence-based imaging of fusion proteins. Stable cell lines expressing fluorescently tagged protein GFP-PCNA produce rich, dynamically varying sub-cellular foci patterns characterizing the cell cycle phases, including the progress during the S-phase. Variable fluorescence patterns, drastic changes in SNR, shape and position changes and abundance of touching cells require sophisticated algorithms for reliable automatic segmentation and cell cycle classification. We extend the recently proposed graph partitioning active contours (GPAC) for fluorescence-based nucleus segmentation using regional density functions and dramatically improve its efficiency, making it scalable for high content microscopy imaging. We utilize surface shape properties of GFP-PCNA intensity field to obtain descriptors of foci patterns and perform automated cell cycle phase classification, and give quantitative performance by comparing our results to manually labeled data.

  8. Variety in intracellular diffusion during the cell cycle

    DEFF Research Database (Denmark)

    Selhuber-Unkel, C.; Yde, P.; Berg-Sørensen, Kirstine

    2009-01-01

    During the cell cycle, the organization of the cytoskeletal network undergoes dramatic changes. In order to reveal possible changes of the viscoelastic properties in the intracellular space during the cell cycle we investigated the diffusion of endogenous lipid granules within the fission yeast...... Schizosaccharomyces Pombe using optical tweezers. The cell cycle was divided into interphase and mitotic cell division, and the mitotic cell division was further subdivided in its stages. During all stages of the cell cycle, the granules predominantly underwent subdiffusive motion, characterized by an exponent...... a that is also linked to the viscoelastic moduli of the cytoplasm. The exponent a was significantly smaller during interphase than during any stage of the mitotic cell division, signifying that the cytoplasm was more elastic during interphase than during division. We found no significant differences...

  9. Rethinking cell-cycle-dependent gene expression in Schizosaccharomyces pombe.

    Science.gov (United States)

    Cooper, Stephen

    2017-11-01

    Three studies of gene expression during the division cycle of Schizosaccharomyces pombe led to the proposal that a large number of genes are expressed at particular times during the S. pombe cell cycle. Yet only a small fraction of genes proposed to be expressed in a cell-cycle-dependent manner are reproducible in all three published studies. In addition to reproducibility problems, questions about expression amplitudes, cell-cycle timing of expression, synchronization artifacts, and the problem with methods for synchronizing cells must be considered. These problems and complications prompt the idea that caution should be used before accepting the conclusion that there are a large number of genes expressed in a cell-cycle-dependent manner in S. pombe.

  10. Connecting the nucleolus to the cell cycle and human disease.

    Science.gov (United States)

    Tsai, Robert Y L; Pederson, Thoru

    2014-08-01

    Long known as the center of ribosome synthesis, the nucleolus is connected to cell cycle regulation in more subtle ways. One is a surveillance system that reacts promptly when rRNA synthesis or processing is impaired, halting cell cycle progression. Conversely, the nucleolus also acts as a first-responder to growth-related stress signals. Here we review emerging concepts on how these "infraribosomal" links between the nucleolus and cell cycle progression operate in both forward and reverse gears. We offer perspectives on how new cancer therapeutic designs that target this infraribosomal mode of cell growth control may shape future clinical progress. © FASEB.

  11. Single-cell analysis of transcription kinetics across the cell cycle

    Science.gov (United States)

    Skinner, Samuel O; Xu, Heng; Nagarkar-Jaiswal, Sonal; Freire, Pablo R; Zwaka, Thomas P; Golding, Ido

    2016-01-01

    Transcription is a highly stochastic process. To infer transcription kinetics for a gene-of-interest, researchers commonly compare the distribution of mRNA copy-number to the prediction of a theoretical model. However, the reliability of this procedure is limited because the measured mRNA numbers represent integration over the mRNA lifetime, contribution from multiple gene copies, and mixing of cells from different cell-cycle phases. We address these limitations by simultaneously quantifying nascent and mature mRNA in individual cells, and incorporating cell-cycle effects in the analysis of mRNA statistics. We demonstrate our approach on Oct4 and Nanog in mouse embryonic stem cells. Both genes follow similar two-state kinetics. However, Nanog exhibits slower ON/OFF switching, resulting in increased cell-to-cell variability in mRNA levels. Early in the cell cycle, the two copies of each gene exhibit independent activity. After gene replication, the probability of each gene copy to be active diminishes, resulting in dosage compensation. DOI: http://dx.doi.org/10.7554/eLife.12175.001 PMID:26824388

  12. Division of labour between Myc and G1 cyclins in cell cycle commitment and pace control.

    Science.gov (United States)

    Dong, Peng; Maddali, Manoj V; Srimani, Jaydeep K; Thélot, François; Nevins, Joseph R; Mathey-Prevot, Bernard; You, Lingchong

    2014-09-01

    A body of evidence has shown that the control of E2F transcription factor activity is critical for determining cell cycle entry and cell proliferation. However, an understanding of the precise determinants of this control, including the role of other cell-cycle regulatory activities, has not been clearly defined. Here, recognizing that the contributions of individual regulatory components could be masked by heterogeneity in populations of cells, we model the potential roles of individual components together with the use of an integrated system to follow E2F dynamics at the single-cell level and in real time. These analyses reveal that crossing a threshold amplitude of E2F accumulation determines cell cycle commitment. Importantly, we find that Myc is critical in modulating the amplitude, whereas cyclin D/E activities have little effect on amplitude but do contribute to the modulation of duration of E2F activation, thereby affecting the pace of cell cycle progression.

  13. Estrogen receptor alpha is cell cycle-regulated and regulates the cell cycle in a ligand-dependent fashion.

    Science.gov (United States)

    JavanMoghadam, Sonia; Weihua, Zhang; Hunt, Kelly K; Keyomarsi, Khandan

    2016-06-17

    Estrogen receptor alpha (ERα) has been implicated in several cell cycle regulatory events and is an important predictive marker of disease outcome in breast cancer patients. Here, we aimed to elucidate the mechanism through which ERα influences proliferation in breast cancer cells. Our results show that ERα protein is cell cycle-regulated in human breast cancer cells and that the presence of 17-β-estradiol (E2) in the culture medium shortened the cell cycle significantly (by 4.5 hours, P cycle duration were observed in the S and G2/M phases, whereas the G1 phase was indistinguishable under liganded and unliganded conditions. In addition, ERα knockdown in MCF-7 cells accelerated mitotic exit, whereas transfection of ERα-negative MDA-MB-231 cells with exogenous ERα significantly shortened the S and G2/M phases (by 9.1 hours, P cycle progression through the S and G2/M phases than fulvestrant does, presumably because of the destabilizing effect of fulvestrant on ERα protein. Together, these results show that ERα modulates breast cancer cell proliferation by regulating events during the S and G2/M phases of the cell cycle in a ligand-dependent fashion. These results provide the rationale for an effective treatment strategy that includes a cell cycle inhibitor in combination with a drug that lowers estrogen levels, such as an aromatase inhibitor, and an antiestrogen that does not result in the degradation of ERα, such as tamoxifen.

  14. The Cell Cycle: An Activity Using Paper Plates to Represent Time Spent in Phases of the Cell Cycle

    Science.gov (United States)

    Scherer, Yvette D.

    2014-01-01

    In this activity, students are given the opportunity to combine skills in math and geometry for a biology lesson in the cell cycle. Students utilize the data they collect and analyze from an online onion-root-tip activity to create a paper-plate time clock representing a 24-hour cell cycle. By dividing the paper plate into appropriate phases of…

  15. Numerical simulation of the hair formation -modeling of hair cycle

    Science.gov (United States)

    Kajihara, Narumichi; Nagayama, Katsuya

    2018-01-01

    In the recent years, the fields of study of anti-aging, health and beauty, cosmetics, and hair diseases have attracted significant attention. In particular, human hair is considered to be an important aspect with regard to an attractive appearance. To this end, many workers have sought to understand the formation mechanism of the hair root. However, observing growth in the hair root is difficult, and a detailed mechanism of the process has not yet been elucidated. Hair repeats growth, retraction, and pause cycles (hair cycle) in a repetitive process. In the growth phase, hair is formed through processes of cell proliferation and differentiation (keratinization). During the retraction phase, hair growth stops, and during the resting period, hair fall occurs and new hair grows. This hair cycle is believed to affect the elongation rate, thickness, strength, and shape of hair. Therefore, in this study, we introduce a particle model as a new method to elucidate the unknown process of hair formation, and to model the hair formation process accompanying the proliferation and differentiation of the hair root cells in all three dimensions. In addition, to the growth period, the retraction and the resting periods are introduced to realize the hair cycle using this model.

  16. Soil Carbon and Nitrogen Cycle Modeling

    Science.gov (United States)

    Woo, D.; Chaoka, S.; Kumar, P.; Quijano, J. C.

    2012-12-01

    Second generation bioenergy crops, such as miscanthus (Miscantus × giganteus) and switchgrass (Panicum virgatum), are regarded as clean energy sources, and are an attractive option to mitigate the human-induced climate change. However, the global climate change and the expansion of perennial grass bioenergy crops have the power to alter the biogeochemical cycles in soil, especially, soil carbon storages, over long time scales. In order to develop a predictive understanding, this study develops a coupled hydrological-soil nutrient model to simulate soil carbon responses under different climate scenarios such as: (i) current weather condition, (ii) decreased precipitation by -15%, and (iii) increased temperature up to +3C for four different crops, namely miscanthus, switchgrass, maize, and natural prairie. We use Precision Agricultural Landscape Modeling System (PALMS), version 5.4.0, to capture biophysical and hydrological components coupled with a multilayer carbon and ¬nitrogen cycle model. We apply the model at daily time scale to the Energy Biosciences Institute study site, located in the University of Illinois Research Farms, in Urbana, Illinois. The atmospheric forcing used to run the model was generated stochastically from parameters obtained using available data recorded in Bondville Ameriflux Site. The model simulations are validated with observations of drainage and nitrate and ammonium concentrations recorded in drain tiles during 2011. The results of this study show (1) total soil carbon storage of miscanthus accumulates most noticeably due to the significant amount of aboveground plant carbon, and a relatively high carbon to nitrogen ratio and lignin content, which reduce the litter decomposition rate. Also, (2) the decreased precipitation contributes to the enhancement of total soil carbon storage and soil nitrogen concentration because of the reduced microbial biomass pool. However, (3) an opposite effect on the cycle is introduced by the increased

  17. Cell cycle-dependent induction of autophagy, mitophagy and reticulophagy.

    Science.gov (United States)

    Tasdemir, Ezgi; Maiuri, M Chiara; Tajeddine, Nicolas; Vitale, Ilio; Criollo, Alfredo; Vicencio, José Miguel; Hickman, John A; Geneste, Olivier; Kroemer, Guido

    2007-09-15

    When added to cells, a variety of autophagy inducers that operate through distinct mechanisms and target different organelles for autophagic destruction (mitochondria in mitophagy, endoplasmic reticulum in reticulophagy) rarely induce autophagic vacuolization in more than 50% or the cells. Here we show that this heterogeneity may be explained by cell cycle-specific effects. The BH3 mimetic ABT737, lithium, rapamycin, tunicamycin or nutrient depletion stereotypically induce autophagy preferentially in the G(1) and S phases of the cell cycle, as determined by simultaneous monitoring of cell cycle markers and the cytoplasmic aggregation of GFP-LC3 in autophagic vacuoles. These results point to a hitherto neglected crosstalk between autophagic vacuolization and cell cycle regulation.

  18. Brucella abortus Cell Cycle and Infection Are Coordinated.

    Science.gov (United States)

    De Bolle, Xavier; Crosson, Sean; Matroule, Jean-Yves; Letesson, Jean-Jacques

    2015-12-01

    Brucellae are facultative intracellular pathogens. The recent development of methods and genetically engineered strains allowed the description of cell-cycle progression of Brucella abortus, including unipolar growth and the ordered initiation of chromosomal replication. B. abortus cell-cycle progression is coordinated with intracellular trafficking in the endosomal compartments. Bacteria are first blocked at the G1 stage, growth and chromosome replication being resumed shortly before reaching the intracellular proliferation compartment. The control mechanisms of cell cycle are similar to those reported for the bacterium Caulobacter crescentus, and they are crucial for survival in the host cell. The development of single-cell analyses could also be applied to other bacterial pathogens to investigate their cell-cycle progression during infection. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. An isopycnic ocean carbon cycle model

    Directory of Open Access Journals (Sweden)

    K. M. Assmann

    2010-02-01

    Full Text Available The carbon cycle is a major forcing component in the global climate system. Modelling studies, aiming to explain recent and past climatic changes and to project future ones, increasingly include the interaction between the physical and biogeochemical systems. Their ocean components are generally z-coordinate models that are conceptually easy to use but that employ a vertical coordinate that is alien to the real ocean structure. Here, we present first results from a newly-developed isopycnic carbon cycle model and demonstrate the viability of using an isopycnic physical component for this purpose. As expected, the model represents well the interior ocean transport of biogeochemical tracers and produces realistic tracer distributions. Difficulties in employing a purely isopycnic coordinate lie mainly in the treatment of the surface boundary layer which is often represented by a bulk mixed layer. The most significant adjustments of the ocean biogeochemistry model HAMOCC, for use with an isopycnic coordinate, were in the representation of upper ocean biological production. We present a series of sensitivity studies exploring the effect of changes in biogeochemical and physical processes on export production and nutrient distribution. Apart from giving us pointers for further model development, they highlight the importance of preformed nutrient distributions in the Southern Ocean for global nutrient distributions. The sensitivity studies show that iron limitation for biological particle production, the treatment of light penetration for biological production, and the role of diapycnal mixing result in significant changes of nutrient distributions and liniting factors of biological production.

  20. Endothelial cell subpopulations in vitro: cell volume, cell cycle, and radiosensitivity

    International Nuclear Information System (INIS)

    Rubin, D.B.; Drab, E.A.; Bauer, K.D.

    1989-01-01

    Vascular endothelial cells (EC) are important clinical targets of radiation and other forms of free radical/oxidant stresses. In this study, we found that the extent of endothelial damage may be determined by the different cytotoxic responses of EC subpopulations. The following characteristics of EC subpopulations were examined: (1) cell volume; (2) cell cycle position; and (3) cytotoxic indexes for both acute cell survival and proliferative capacity after irradiation (137Cs, gamma, 0-10 Gy). EC cultured from bovine aortas were separated by centrifugal elutriation into subpopulations of different cell volumes. Through flow cytometry, we found that cell volume was related to the cell cycle phase distribution. The smallest EC were distributed in G1 phase and the larger cells were distributed in either early S, middle S, or late S + G2M phases. Cell cycle phase at the time of irradiation was not associated with acute cell loss. However, distribution in the cell cycle did relate to cell survival based on proliferative capacity (P less than 0.01). The order of increasing radioresistance was cells in G1 (D0 = 110 cGy), early S (135 cGy), middle S (145 cGy), and late S + G2M phases (180 cGy). These findings (1) suggest an age-related response to radiation in a nonmalignant differentiated cell type and (2) demonstrate EC subpopulations in culture

  1. Growth versus immunity--a redirection of the cell cycle?

    Science.gov (United States)

    Eichmann, Ruth; Schäfer, Patrick

    2015-08-01

    Diseases caused by plant pathogens significantly reduce growth and yield in agricultural crop production. Raising immunity in crops is therefore a major aim in breeding programs. However, efforts to enhance immunity are challenged by the occurrence of growth inhibition triggered by immunity that can be as detrimental as diseases. In this review, we will propose molecular models to explain the inhibitory growth-immunity crosstalk. We will briefly discuss why the resource reallocation model might not represent the driving force for the observed growth-immunity trade-offs. We suggest a model in which immunity redirects and initiates hormone signalling activities that can impair plant growth by antagonising cell cycle regulation and meristem activities. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. Thermodynamic Investigation of an Integrated Gasification Plant with Solid Oxide Fuel Cell and Steam Cycles

    DEFF Research Database (Denmark)

    Rokni, Masoud

    2012-01-01

    A gasification plant is integrated on the top of a solid oxide fuel cell (SOFC) cycle, while a steam turbine (ST) cycle is used as a bottoming cycle for the SOFC plant. The gasification plant was fueled by woodchips to produce biogas and the SOFC stacks were fired with biogas. The produced gas...... generator (HRSG). The steam cycle was modeled with a simple single pressure level. In addition, a hybrid recuperator was used to recover more energy from the HRSG and send it back to the SOFC cycle. Thus two different configurations were investigated to study the plants characteristic. Such system...

  3. Modeling of the Global Water Cycle - Analytical Models

    Science.gov (United States)

    Yongqiang Liu; Roni Avissar

    2005-01-01

    Both numerical and analytical models of coupled atmosphere and its underlying ground components (land, ocean, ice) are useful tools for modeling the global and regional water cycle. Unlike complex three-dimensional climate models, which need very large computing resources and involve a large number of complicated interactions often difficult to interpret, analytical...

  4. Protein kinase C signaling and cell cycle regulation

    Directory of Open Access Journals (Sweden)

    Adrian R Black

    2013-01-01

    Full Text Available A link between T cell proliferation and the protein kinase C (PKC family of serine/threonine kinases has been recognized for about thirty years. However, despite the wealth of information on PKC-mediated control of T cell activation, understanding of the effects of PKCs on the cell cycle machinery in this cell type remains limited. Studies in other systems have revealed important cell cycle-specific effects of PKC signaling that can either positively or negatively impact proliferation. The outcome of PKC activation is highly context-dependent, with the precise cell cycle target(s and overall effects determined by the specific isozyme involved, the timing of PKC activation, the cell type, and the signaling environment. Although PKCs can regulate all stages of the cell cycle, they appear to predominantly affect G0/G1 and G2. PKCs can modulate multiple cell cycle regulatory molecules, including cyclins, cyclin-dependent kinases (cdks, cdk inhibitors and cdc25 phosphatases; however, evidence points to Cip/Kip cdk inhibitors and D-type cyclins as key mediators of PKC-regulated cell cycle-specific effects. Several PKC isozymes can target Cip/Kip proteins to control G0/G1→S and/or G2→M transit, while effects on D-type cyclins regulate entry into and progression through G1. Analysis of PKC signaling in T cells has largely focused on its roles in T cell activation; thus, observed cell cycle effects are mainly positive. A prominent role is emerging for PKCθ, with non-redundant functions of other isozymes also described. Additional evidence points to PKCδ as a negative regulator of the cell cycle in these cells. As in other cell types, context-dependent effects of individual isozymes have been noted in T cells, and Cip/Kip cdk inhibitors and D-type cyclins appear to be major PKC targets. Future studies are anticipated to take advantage of the similarities between these various systems to enhance understanding of PKC-mediated cell cycle regulation in

  5. Inheritance of Cell-Cycle Duration in the Presence of Periodic Forcing

    Science.gov (United States)

    Mosheiff, Noga; Martins, Bruno M. C.; Pearl-Mizrahi, Sivan; Grünberger, Alexander; Helfrich, Stefan; Mihalcescu, Irina; Kohlheyer, Dietrich; Locke, James C. W.; Glass, Leon; Balaban, Nathalie Q.

    2018-04-01

    Periodic forcing of nonlinear oscillators leads to a large number of dynamic behaviors. The coupling of the cell cycle to the circadian clock provides a biological realization of such forcing. A previous model of forcing leads to nontrivial relations between correlations along cell lineages. Here, we present a simplified two-dimensional nonlinear map for the periodic forcing of the cell cycle. Using high-throughput single-cell microscopy, we have studied the correlations between cell-cycle duration in discrete lineages of several different organisms, including those with known coupling to a circadian clock and those without known coupling to a circadian clock. The model reproduces the paradoxical correlations and predicts new features that can be compared with the experimental data. By fitting the model to the data, we extract the important parameters that govern the dynamics. Interestingly, the model reproduces bimodal distributions for cell-cycle duration, as well as the gating of cell division by the phase of the clock, without having been explicitly fed into the model. In addition, the model predicts that circadian coupling may increase cell-to-cell variability in a clonal population of cells. In agreement with this prediction, deletion of the circadian clock reduces variability. Our results show that simple correlations can identify systems under periodic forcing and that studies of nonlinear coupling of biological oscillators provide insight into basic cellular processes of growth.

  6. Analysis of the Budding Yeast Cell Cycle by Flow Cytometry.

    Science.gov (United States)

    Rosebrock, Adam P

    2017-01-03

    DNA synthesis is one of the landmark events in the cell cycle: G 1 cells have one copy of the genome, S phase cells are actively engaged in DNA synthesis, and G 2 cells have twice as much nuclear DNA as G 1 cells. Cellular DNA content can be measured by staining with a fluorescent dye followed by a flow-cytometric readout. This method provides a quantitative measurement of cell cycle position on a cell-by-cell basis at high speed. Using flow cytometry, tens of thousands of single-cell measurements can be generated in a few seconds. This protocol details staining of cells of the budding yeast Saccharomyces cerevisiae for flow cytometry using Sytox Green dye in a method that can be scaled widely-from one sample to many thousands and operating on inputs ranging from 1 million to more than 100 million cells. Flow cytometry is preferred over light microscopy or Coulter analyses for the analysis of the cell cycle as DNA content and cell cycle position are being directly measured. © 2017 Cold Spring Harbor Laboratory Press.

  7. The Mammalian Cell Cycle Regulates Parvovirus Nuclear Capsid Assembly

    Science.gov (United States)

    Riolobos, Laura; Domínguez, Carlos; Kann, Michael; Almendral, José M.

    2015-01-01

    It is unknown whether the mammalian cell cycle could impact the assembly of viruses maturing in the nucleus. We addressed this question using MVM, a reference member of the icosahedral ssDNA nuclear parvoviruses, which requires cell proliferation to infect by mechanisms partly understood. Constitutively expressed MVM capsid subunits (VPs) accumulated in the cytoplasm of mouse and human fibroblasts synchronized at G0, G1, and G1/S transition. Upon arrest release, VPs translocated to the nucleus as cells entered S phase, at efficiencies relying on cell origin and arrest method, and immediately assembled into capsids. In synchronously infected cells, the consecutive virus life cycle steps (gene expression, proteins nuclear translocation, capsid assembly, genome replication and encapsidation) proceeded tightly coupled to cell cycle progression from G0/G1 through S into G2 phase. However, a DNA synthesis stress caused by thymidine irreversibly disrupted virus life cycle, as VPs became increasingly retained in the cytoplasm hours post-stress, forming empty capsids in mouse fibroblasts, thereby impairing encapsidation of the nuclear viral DNA replicative intermediates. Synchronously infected cells subjected to density-arrest signals while traversing early S phase also blocked VPs transport, resulting in a similar misplaced cytoplasmic capsid assembly in mouse fibroblasts. In contrast, thymidine and density arrest signals deregulating virus assembly neither perturbed nuclear translocation of the NS1 protein nor viral genome replication occurring under S/G2 cycle arrest. An underlying mechanism of cell cycle control was identified in the nuclear translocation of phosphorylated VPs trimeric assembly intermediates, which accessed a non-conserved route distinct from the importin α2/β1 and transportin pathways. The exquisite cell cycle-dependence of parvovirus nuclear capsid assembly conforms a novel paradigm of time and functional coupling between cellular and virus life

  8. Cell-cycle inhibition by Helicobacter pylori L-asparaginase.

    Directory of Open Access Journals (Sweden)

    Claudia Scotti

    Full Text Available Helicobacter pylori (H. pylori is a major human pathogen causing chronic gastritis, peptic ulcer, gastric cancer, and mucosa-associated lymphoid tissue lymphoma. One of the mechanisms whereby it induces damage depends on its interference with proliferation of host tissues. We here describe the discovery of a novel bacterial factor able to inhibit the cell-cycle of exposed cells, both of gastric and non-gastric origin. An integrated approach was adopted to isolate and characterise the molecule from the bacterial culture filtrate produced in a protein-free medium: size-exclusion chromatography, non-reducing gel electrophoresis, mass spectrometry, mutant analysis, recombinant protein expression and enzymatic assays. L-asparaginase was identified as the factor responsible for cell-cycle inhibition of fibroblasts and gastric cell lines. Its effect on cell-cycle was confirmed by inhibitors, a knockout strain and the action of recombinant L-asparaginase on cell lines. Interference with cell-cycle in vitro depended on cell genotype and was related to the expression levels of the concurrent enzyme asparagine synthetase. Bacterial subcellular distribution of L-asparaginase was also analysed along with its immunogenicity. H. pylori L-asparaginase is a novel antigen that functions as a cell-cycle inhibitor of fibroblasts and gastric cell lines. We give evidence supporting a role in the pathogenesis of H. pylori-related diseases and discuss its potential diagnostic application.

  9. Verteporfin inhibits papillary thyroid cancer cells proliferation and cell cycle through ERK1/2 signaling pathway

    Science.gov (United States)

    Liao, Tian; Wei, Wen-Jun; Wen, Duo; Hu, Jia-Qian; Wang, Yu; Ma, Ben; Cao, Yi-Min; Xiang, Jun; Guan, Qing; Chen, Jia-Ying; Sun, Guo-Hua; Zhu, Yong-Xue; Li, Duan-Shu; Ji, Qing-Hai

    2018-01-01

    Verteporfin, a FDA approved second-generation photosensitizer, has been demonstrated to have anticancer activity in various tumors, but not including papillary thyroid cancer (PTC). In current pre-clinical pilot study, we investigate the effect of verteporfin on proliferation, apoptosis, cell cycle and tumor growth of PTC. Our results indicate verteporfin attenuates cell proliferation, arrests cell cycle in G2/S phase and induces apoptosis of PTC cells. Moreover, treatment of verteporfin dramatically suppresses tumor growth from PTC cells in xenograft mouse model. We further illustrate that exposure to MEK inhibitor U0126 inactivates phosphorylation of ERK1/2 and MEK in verteporfin-treated PTC cells. These data suggest verteporfin exhibits inhibitory effect on PTC cells proliferation and cell cycle partially via ERK1/2 signalling pathway, which strongly encourages the further application of verteporfin in the treatment against PTC. PMID:29721041

  10. Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression.

    Science.gov (United States)

    Chauhan, Neha; Visram, Myriam; Cristobal-Sarramian, Alvaro; Sarkleti, Florian; Kohlwein, Sepp D

    2015-03-10

    Cell growth and division requires the precise duplication of cellular DNA content but also of membranes and organelles. Knowledge about the cell-cycle-dependent regulation of membrane and storage lipid homeostasis is only rudimentary. Previous work from our laboratory has shown that the breakdown of triacylglycerols (TGs) is regulated in a cell-cycle-dependent manner, by activation of the Tgl4 lipase by the major cyclin-dependent kinase Cdc28. The lipases Tgl3 and Tgl4 are required for efficient cell-cycle progression during the G1/S (Gap1/replication phase) transition, at the onset of bud formation, and their absence leads to a cell-cycle delay. We now show that defective lipolysis activates the Swe1 morphogenesis checkpoint kinase that halts cell-cycle progression by phosphorylation of Cdc28 at tyrosine residue 19. Saturated long-chain fatty acids and phytosphingosine supplementation rescue the cell-cycle delay in the Tgl3/Tgl4 lipase-deficient strain, suggesting that Swe1 activity responds to imbalanced sphingolipid metabolism, in the absence of TG degradation. We propose a model by which TG-derived sphingolipids are required to activate the protein phosphatase 2A (PP2A(Cdc55)) to attenuate Swe1 phosphorylation and its inhibitory effect on Cdc28 at the G1/S transition of the cell cycle.

  11. Comparative analysis of Goodwin's business cycle models

    Science.gov (United States)

    Antonova, A. O.; Reznik, S.; Todorov, M. D.

    2016-10-01

    We compare the behavior of solutions of Goodwin's business cycle equation in the form of neutral delay differential equation with fixed delay (NDDE model) and in the form of the differential equations of 3rd, 4th and 5th orders (ODE model's). Such ODE model's (Taylor series expansion of NDDE in powers of θ) are proposed in N. Dharmaraj and K. Vela Velupillai [6] for investigation of the short periodic sawthooth oscillations in NDDE. We show that the ODE's of 3rd, 4th and 5th order may approximate the asymptotic behavior of only main Goodwin's mode, but not the sawthooth modes. If the order of the Taylor series expansion exceeds 5, then the approximate ODE becomes unstable independently of time lag θ.

  12. Modeling closed nuclear fuel cycles processes

    Energy Technology Data Exchange (ETDEWEB)

    Shmidt, O.V. [A.A. Bochvar All-Russian Scientific Research Institute for Inorganic Materials, Rogova, 5a street, Moscow, 123098 (Russian Federation); Makeeva, I.R. [Zababakhin All-Russian Scientific Research Institute of Technical Physics, Vasiliev street 13, Snezhinsk, Chelyabinsk region, 456770 (Russian Federation); Liventsov, S.N. [Tomsk Polytechnic University, Tomsk, Lenin Avenue, 30, 634050 (Russian Federation)

    2016-07-01

    Computer models of processes are necessary for determination of optimal operating conditions for closed nuclear fuel cycle (NFC) processes. Computer models can be quickly changed in accordance with new and fresh data from experimental research. 3 kinds of process simulation are necessary. First, the VIZART software package is a balance model development used for calculating the material flow in technological processes. VIZART involves taking into account of equipment capacity, transport lines and storage volumes. Secondly, it is necessary to simulate the physico-chemical processes that are involved in the closure of NFC. The third kind of simulation is the development of software that allows the optimization, diagnostics and control of the processes which implies real-time simulation of product flows on the whole plant or on separate lines of the plant. (A.C.)

  13. Models of life: epigenetics, diversity and cycles

    Science.gov (United States)

    Sneppen, Kim

    2017-04-01

    This review emphasizes aspects of biology that can be understood through repeated applications of simple causal rules. The selected topics include perspectives on gene regulation, phage lambda development, epigenetics, microbial ecology, as well as model approaches to diversity and to punctuated equilibrium in evolution. Two outstanding features are repeatedly described. One is the minimal number of rules to sustain specific states of complex systems for a long time. The other is the collapse of such states and the subsequent dynamical cycle of situations that restitute the system to a potentially new metastable state.

  14. Modeling the element cycle of aquatic plants

    International Nuclear Information System (INIS)

    Asaeda, Takashi

    2007-01-01

    Aquatic plants play an important role in element cycles in wetlands and the efficiency of the process is extremely related to their proportional biomass allocation to above- and belowground organs. Therefore, the framework of most macrophyte productivity models is usually similar with a mass-balance approach consisting of gross production, respiration and mortality losses and the translocation between organs. These growth models are incorporated with decomposition models to evaluate the annual cycle of elements. Perennial emergent macrophytes with a relatively large biomass have a particularly important role in element cycles. Their phenological stages, such as the beginning of hibernation of belowground rhizome systems, emergence of new shoots in spring with resources stocked in the rhizomes, flowering, downward translocation of photosynthetic products later on and then the mortality of the aboveground system in late autumn, depend on the environmental conditions, basically the nutrients, water depth, climatic variations, etc. Although some species retain standing dead shoots for a long time, dead shoots easily fall into water, starting to decompose in the immediate aftermath. However, their decomposition rates in the water are relatively low, causing to accumulate large amounts of organic sediments on the bottom. Together with the deposition of allochthonous suspended matters in the stand, this process decreases the water depth, transforming wetlands gradually into land. The depth of penetration of roots into the sediments to uptake nutrients and water is extremely site specific, however, in water-logged areas, the maximum penetrable depth may be approximately estimated by considering the ability of oxygen transport into the rhizome system. The growth of perennial submerged plants is also estimated by a process similar to that of emergent macrophytes. However, compared with emergent macrophytes, the root system of submerged macrophytes is weaker, and the nutrient

  15. Modeling of a combined cycle power plant

    International Nuclear Information System (INIS)

    Faridah Mohamad Idris

    2001-01-01

    The combined cycle power plant is a non-linear, closed loop system, which consists of high-pressure (HP) superheater, HP evaporator, HP economizer, low-pressure (LP) evaporator, HP drum, HP deaerator, condenser, HP and LP steam turbine and gas turbine. The two types of turbines in the plant for example the gas turbine and the HP and LP steam turbines operate concurrently to generate power to the plant. The exhaust gas which originate from the combustion chamber drives the gas turbine, after which it flows into the heat recovery steam generator (HRSG) to generate superheated steam to be used in driving the HP and LP steam turbines. In this thesis, the combined cycle power plant is modeled at component level using the physical method. Assuming that there is delay in transport, except for the gas turbine system, the mass and heat balances are applied on the components of the plant to derive the governing equations of the components. These time dependent equations, which are of first order differential types, are then solved for the mass and enthalpy of the components. The solutions were simulated using Matlab Simulink using measured plant data. Where necessary there is no plant data available, approximated data were used. The generalized regression neural networks are also used to generate extra sets of simulation data for the HRSG system. Comparisons of the simulation results with its corresponding plant data showed good agreements between the two and indicated that the models developed for the components could be used to represent the combined cycle power plant under study. (author)

  16. Keith's MAGIC: Cloning and the Cell Cycle.

    Science.gov (United States)

    Wells, D N

    2013-10-01

    Abstract Professor Keith Campbell's critical contribution to the discovery that a somatic cell from an adult animal can be fully reprogrammed by oocyte factors to form a cloned individual following nuclear transfer (NT)(Wilmut et al., 1997 ) overturned a dogma concerning the reversibility of cell fate that many scientists had considered to be biologically impossible. This seminal experiment proved the totipotency of adult somatic nuclei and finally confirmed that adult cells could differentiate without irreversible changes to the genetic material.

  17. The cell cycle of the planctomycete Gemmata obscuriglobus with respect to cell compartmentalization

    Directory of Open Access Journals (Sweden)

    Fuerst John A

    2009-01-01

    Full Text Available Abstract Background Gemmata obscuriglobus is a distinctive member of the divergent phylum Planctomycetes, all known members of which are peptidoglycan-less bacteria with a shared compartmentalized cell structure and divide by a budding process. G. obscuriglobus in addition shares the unique feature that its nucleoid DNA is surrounded by an envelope consisting of two membranes forming an analogous structure to the membrane-bounded nucleoid of eukaryotes and therefore G. obscuriglobus forms a special model for cell biology. Draft genome data for G. obscuriglobus as well as complete genome sequences available so far for other planctomycetes indicate that the key bacterial cell division protein FtsZ is not present in these planctomycetes, so the cell division process in planctomycetes is of special comparative interest. The membrane-bounded nature of the nucleoid in G. obscuriglobus also suggests that special mechanisms for the distribution of this nuclear body to the bud and for distribution of chromosomal DNA might exist during division. It was therefore of interest to examine the cell division cycle in G. obscuriglobus and the process of nucleoid distribution and nuclear body formation during division in this planctomycete bacterium via light and electron microscopy. Results Using phase contrast and fluorescence light microscopy, and transmission electron microscopy, the cell division cycle of G. obscuriglobus was determined. During the budding process, the bud was formed and developed in size from one point of the mother cell perimeter until separation. The matured daughter cell acted as a new mother cell and started its own budding cycle while the mother cell can itself initiate budding repeatedly. Fluorescence microscopy of DAPI-stained cells of G. obscuriglobus suggested that translocation of the nucleoid and formation of the bud did not occur at the same time. Confocal laser scanning light microscopy applied to cells stained for membranes as

  18. Distinguishing between stochasticity and determinism: Examples from cell cycle duration variability.

    Science.gov (United States)

    Pearl Mizrahi, Sivan; Sandler, Oded; Lande-Diner, Laura; Balaban, Nathalie Q; Simon, Itamar

    2016-01-01

    We describe a recent approach for distinguishing between stochastic and deterministic sources of variability, focusing on the mammalian cell cycle. Variability between cells is often attributed to stochastic noise, although it may be generated by deterministic components. Interestingly, lineage information can be used to distinguish between variability and determinism. Analysis of correlations within a lineage of the mammalian cell cycle duration revealed its deterministic nature. Here, we discuss the sources of such variability and the possibility that the underlying deterministic process is due to the circadian clock. Finally, we discuss the "kicked cell cycle" model and its implication on the study of the cell cycle in healthy and cancerous tissues. © 2015 WILEY Periodicals, Inc.

  19. Molecular Cogs: Interplay between Circadian Clock and Cell Cycle.

    Science.gov (United States)

    Gaucher, Jonathan; Montellier, Emilie; Sassone-Corsi, Paolo

    2018-05-01

    The cell cycle and the circadian clock operate as biological oscillators whose timed functions are tightly regulated. Accumulating evidence illustrates the presence of molecular links between these two oscillators. This mutual interplay utilizes various coupling mechanisms, such as the use of common regulators. The connection between these two cyclic systems has unique interest in the context of aberrant cell proliferation since both of these oscillators are frequently misregulated in cancer cells. Further studies will provide deeper understanding of the detailed molecular connections between the cell cycle and the circadian clock and may also serve as a basis for the design of innovative therapeutic strategies. Copyright © 2018 Elsevier Ltd. All rights reserved.

  20. Automation life-cycle cost model

    Science.gov (United States)

    Gathmann, Thomas P.; Reeves, Arlinda J.; Cline, Rick; Henrion, Max; Ruokangas, Corinne

    1992-01-01

    The problem domain being addressed by this contractual effort can be summarized by the following list: Automation and Robotics (A&R) technologies appear to be viable alternatives to current, manual operations; Life-cycle cost models are typically judged with suspicion due to implicit assumptions and little associated documentation; and Uncertainty is a reality for increasingly complex problems and few models explicitly account for its affect on the solution space. The objectives for this effort range from the near-term (1-2 years) to far-term (3-5 years). In the near-term, the envisioned capabilities of the modeling tool are annotated. In addition, a framework is defined and developed in the Decision Modelling System (DEMOS) environment. Our approach is summarized as follows: Assess desirable capabilities (structure into near- and far-term); Identify useful existing models/data; Identify parameters for utility analysis; Define tool framework; Encode scenario thread for model validation; and Provide transition path for tool development. This report contains all relevant, technical progress made on this contractual effort.

  1. The timing of T cell priming and cycling

    Directory of Open Access Journals (Sweden)

    Reinhard eObst

    2015-11-01

    Full Text Available The proliferation of specific lymphocytes is the central tenet of the clonal selection paradigm. Antigen recognition by T cells triggers a series of events that produces expanded clones of differentiated effector cells. TCR signaling events are detectable within seconds and minutes and are likely to continue for hours and days in vivo. Here, I review the work done on the importance of TCR signals in the later part of the expansion phase of the primary T cell response, primarily regarding the regulation of the cell cycle in CD4+ and CD8+ cells. The results suggest a degree of programming by early signals for effector differentiation, particularly in the CD8+ T cell compartment, with optimal expansion supported by persistent antigen presentation later on. Differences to CD4+ T cell expansion and new avenues towards a molecular understanding of cell cycle regulation in lymphocytes are discussed.

  2. Thermally regenerative hydrogen/oxygen fuel cell power cycles

    Science.gov (United States)

    Morehouse, J. H.

    1986-01-01

    Two innovative thermodynamic power cycles are analytically examined for future engineering feasibility. The power cycles use a hydrogen-oxygen fuel cell for electrical energy production and use the thermal dissociation of water for regeneration of the hydrogen and oxygen. The TDS (thermal dissociation system) uses a thermal energy input at over 2000 K to thermally dissociate the water. The other cycle, the HTE (high temperature electrolyzer) system, dissociates the water using an electrolyzer operating at high temperature (1300 K) which receives its electrical energy from the fuel cell. The primary advantages of these cycles is that they are basically a no moving parts system, thus having the potential for long life and high reliability, and they have the potential for high thermal efficiency. Both cycles are shown to be classical heat engines with ideal efficiency close to Carnot cycle efficiency. The feasibility of constructing actual cycles is investigated by examining process irreversibilities and device efficiencies for the two types of cycles. The results show that while the processes and devices of the 2000 K TDS exceed current technology limits, the high temperature electrolyzer system appears to be a state-of-the-art technology development. The requirements for very high electrolyzer and fuel cell efficiencies are seen as determining the feasbility of the HTE system, and these high efficiency devices are currently being developed. It is concluded that a proof-of-concept HTE system experiment can and should be conducted.

  3. Dual Pressure versus Hybrid Recuperation in an Integrated Solid Oxide Fuel Cell Cycle – Steam Cycle

    DEFF Research Database (Denmark)

    Rokni, Masoud

    2014-01-01

    A SOFC (solid oxide fuel cell) cycle running on natural gas was integrated with a ST (steam turbine) cycle. The fuel is desulfurized and pre-reformed before entering the SOFC. A burner was used to combust the remaining fuel after the SOFC stacks. The off-gases from the burner were used to produce...... pressure configuration steam cycle combined with SOFC cycle (SOFC-ST) was new and has not been studied previously. In each of the configuration, a hybrid recuperator was used to recovery the remaining energy of the off-gases after the HRSG. Thus, four different plants system setups were compared to each...... other to reveal the most superior concept with respect to plant efficiency and power. It was found that in order to increase the plant efficiency considerably, it was enough to use a single pressure with a hybrid recuperator instead of a dual pressure Rankine cycle....

  4. Development and applications of GREET 2.7 -- The Transportation Vehicle-Cycle Model

    International Nuclear Information System (INIS)

    Burnham, A.; Wang, M. Q.; Wu, Y.

    2006-01-01

    Argonne National Laboratory has developed a vehicle-cycle module for the Greenhouse gases, Regulated Emissions, and Energy use in Transportation (GREET) model. The fuel-cycle GREET model has been cited extensively and contains data on fuel cycles and vehicle operations. The vehicle-cycle model evaluates the energy and emission effects associated with vehicle material recovery and production, vehicle component fabrication, vehicle assembly, and vehicle disposal/recycling. With the addition of the vehicle-cycle module, the GREET model now provides a comprehensive, lifecycle-based approach to compare the energy use and emissions of conventional and advanced vehicle technologies (e.g., hybrid electric vehicles and fuel cell vehicles). This report details the development and application of the GREET 2.7 model. The current model includes six vehicles--a conventional material and a lightweight material version of a mid-size passenger car with the following powertrain systems: internal combustion engine, internal combustion engine with hybrid configuration, and fuel cell with hybrid configuration. The model calculates the energy use and emissions that are required for vehicle component production; battery production; fluid production and use; and vehicle assembly, disposal, and recycling. This report also presents vehicle-cycle modeling results. In order to put these results in a broad perspective, the fuel-cycle model (GREET 1.7) was used in conjunction with the vehicle-cycle model (GREET 2.7) to estimate total energy-cycle results

  5. Development and applications of GREET 2.7 -- The Transportation Vehicle-CycleModel.

    Energy Technology Data Exchange (ETDEWEB)

    Burnham, A.; Wang, M. Q.; Wu, Y.

    2006-12-20

    Argonne National Laboratory has developed a vehicle-cycle module for the Greenhouse gases, Regulated Emissions, and Energy use in Transportation (GREET) model. The fuel-cycle GREET model has been cited extensively and contains data on fuel cycles and vehicle operations. The vehicle-cycle model evaluates the energy and emission effects associated with vehicle material recovery and production, vehicle component fabrication, vehicle assembly, and vehicle disposal/recycling. With the addition of the vehicle-cycle module, the GREET model now provides a comprehensive, lifecycle-based approach to compare the energy use and emissions of conventional and advanced vehicle technologies (e.g., hybrid electric vehicles and fuel cell vehicles). This report details the development and application of the GREET 2.7 model. The current model includes six vehicles--a conventional material and a lightweight material version of a mid-size passenger car with the following powertrain systems: internal combustion engine, internal combustion engine with hybrid configuration, and fuel cell with hybrid configuration. The model calculates the energy use and emissions that are required for vehicle component production; battery production; fluid production and use; and vehicle assembly, disposal, and recycling. This report also presents vehicle-cycle modeling results. In order to put these results in a broad perspective, the fuel-cycle model (GREET 1.7) was used in conjunction with the vehicle-cycle model (GREET 2.7) to estimate total energy-cycle results.

  6. NONO couples the circadian clock to the cell cycle.

    Science.gov (United States)

    Kowalska, Elzbieta; Ripperger, Juergen A; Hoegger, Dominik C; Bruegger, Pascal; Buch, Thorsten; Birchler, Thomas; Mueller, Anke; Albrecht, Urs; Contaldo, Claudio; Brown, Steven A

    2013-01-29

    Mammalian circadian clocks restrict cell proliferation to defined time windows, but the mechanism and consequences of this interrelationship are not fully understood. Previously we identified the multifunctional nuclear protein NONO as a partner of circadian PERIOD (PER) proteins. Here we show that it also conveys circadian gating to the cell cycle, a connection surprisingly important for wound healing in mice. Specifically, although fibroblasts from NONO-deficient mice showed approximately normal circadian cycles, they displayed elevated cell doubling and lower cellular senescence. At a molecular level, NONO bound to the p16-Ink4A cell cycle checkpoint gene and potentiated its circadian activation in a PER protein-dependent fashion. Loss of either NONO or PER abolished this activation and circadian expression of p16-Ink4A and eliminated circadian cell cycle gating. In vivo, lack of NONO resulted in defective wound repair. Because wound healing defects were also seen in multiple circadian clock-deficient mouse lines, our results therefore suggest that coupling of the cell cycle to the circadian clock via NONO may be useful to segregate in temporal fashion cell proliferation from tissue organization.

  7. Metformin inhibits cell cycle progression of B-cell chronic lymphocytic leukemia cells.

    Science.gov (United States)

    Bruno, Silvia; Ledda, Bernardetta; Tenca, Claudya; Ravera, Silvia; Orengo, Anna Maria; Mazzarello, Andrea Nicola; Pesenti, Elisa; Casciaro, Salvatore; Racchi, Omar; Ghiotto, Fabio; Marini, Cecilia; Sambuceti, Gianmario; DeCensi, Andrea; Fais, Franco

    2015-09-08

    B-cell chronic lymphocytic leukemia (CLL) was believed to result from clonal accumulation of resting apoptosis-resistant malignant B lymphocytes. However, it became increasingly clear that CLL cells undergo, during their life, iterative cycles of re-activation and subsequent clonal expansion. Drugs interfering with CLL cell cycle entry would be greatly beneficial in the treatment of this disease. 1, 1-Dimethylbiguanide hydrochloride (metformin), the most widely prescribed oral hypoglycemic agent, inexpensive and well tolerated, has recently received increased attention for its potential antitumor activity. We wondered whether metformin has apoptotic and anti-proliferative activity on leukemic cells derived from CLL patients. Metformin was administered in vitro either to quiescent cells or during CLL cell activation stimuli, provided by classical co-culturing with CD40L-expressing fibroblasts. At doses that were totally ineffective on normal lymphocytes, metformin induced apoptosis of quiescent CLL cells and inhibition of cell cycle entry when CLL were stimulated by CD40-CD40L ligation. This cytostatic effect was accompanied by decreased expression of survival- and proliferation-associated proteins, inhibition of signaling pathways involved in CLL disease progression and decreased intracellular glucose available for glycolysis. In drug combination experiments, metformin lowered the apoptotic threshold and potentiated the cytotoxic effects of classical and novel antitumor molecules. Our results indicate that, while CLL cells after stimulation are in the process of building their full survival and cycling armamentarium, the presence of metformin affects this process.

  8. Cell cycles and proliferation patterns in Haematococcus pluvialis

    Science.gov (United States)

    Zhang, Chunhui; Liu, Jianguo; Zhang, Litao

    2017-09-01

    Most studies on Haematococcus pluvialis have been focused on cell growth and astaxanthin accumulation; far less attention has been paid to cell cycles and proliferation patterns. The purpose of this study was to clarify cell cycles and proliferation patterns in H. pluvialis microscopically using a camera and video recorder system. The complicated life history of H. pluvialis can be divided into two stages: the motile stage and the non-motile stage. All the cells can be classified into forms as follows: motile cell, nonmotile cell, zoospore and aplanospore. The main cell proliferation, both in the motile phase and non-motile phase in H. pluvialis, is by asexual reproduction. Under normal growth conditions, a motile cell usually produces two, sometimes four, and exceptionally eight zoospores. Under unfavorable conditions, the motile cell loses its flagella and transforms into a non-motile cell, and the non-motile cell usually produces 2, 4 or 8 aplanospores, and occasionally 20-32 aplanospores, which further develop into non-motile cells. Under suitable conditions, the non-motile cell is also able to release zoospores. The larger non-motile cells produce more than 16 zoospores, and the smaller ones produce 4 or 8 zoospores. Vegetative reproduction is by direct cell division in the motile phase and by occasional cell budding in the non-motile phase. There is, as yet, no convincing direct evidence for sexual reproduction.

  9. Plant Characteristics of an Integrated Solid Oxide Fuel Cell Cycle and a Steam Cycle

    DEFF Research Database (Denmark)

    Rokni, Masoud

    2010-01-01

    Plant characteristics of a system containing a solid oxide fuel cell (SOFC) cycle on the top of a Rankine cycle were investigated. Natural gas (NG) was used as the fuel for the plant. A desulfurization reactor removes the sulfur content in the fuel, while a pre-reformer broke down the heavier...... recovery steam generator (HRSG). The remaining energy of the off-gases was recycled back to the topping cycle for further utilization. Several parameter studies were carried out to investigate the sensitivity of the suggested plant. It was shown that the operation temperature of the desulfurization unit...

  10. Business cycles and the financial performance of fuel cell companies

    International Nuclear Information System (INIS)

    Henriques, I.; Sadorsky, P.

    2005-01-01

    Fuel cells are expected to play a major role in a hydrogen powered world. They will provide power to homes, modes of transportation and appliances. Hydrogen is the most abundant element in nature, but it must be extracted in order to be usable. It can be produced from oil, natural gas and coal or from renewable sources such as biomass, thermal or nuclear reactions. Fuel cells running on hydrogen extracted from non renewable resources have an efficiency of 30 per cent, which is twice as efficient as an internal combustion engine. The greatest barrier to mass commercialization is the cost of making hydrogen-powered auto engines. Also, an infrastructure must be developed to refill hydrogen cars. One solution is to build a hydrogen highway using the existing natural gas grid to produce hydrogen and sell it at existing filling stations. The cost of building 12,000 refueling pumps in urban areas which will provide access to 70 per cent of America's population is estimated at $10 to $15 billion. This paper described the vector autoregression (VAR) model which empirically examines the relationship between financial performance of fuel cell companies and business cycles. It was used to measure how sensitive the financial performance of fuel cell companies are to changes in macroeconomic activity. A four variable VAR model was developed to examine the relationship between stock prices, oil prices and interest rates. It was shown that the stock prices of fuel cell companies are affected by shocks to technology stock prices and oil prices, with the former having a longer lasting impact. These results add to the growing literature that oil price movements are not as important as once thought. 15 refs., 3 tabs., 3 figs

  11. Discovery of a Splicing Regulator Required for Cell Cycle Progression

    Energy Technology Data Exchange (ETDEWEB)

    Suvorova, Elena S.; Croken, Matthew; Kratzer, Stella; Ting, Li-Min; Conde de Felipe, Magnolia; Balu, Bharath; Markillie, Lye Meng; Weiss, Louis M.; Kim, Kami; White, Michael W.

    2013-02-01

    In the G1 phase of the cell division cycle, eukaryotic cells prepare many of the resources necessary for a new round of growth including renewal of the transcriptional and protein synthetic capacities and building the machinery for chromosome replication. The function of G1 has an early evolutionary origin and is preserved in single and multicellular organisms, although the regulatory mechanisms conducting G1 specific functions are only understood in a few model eukaryotes. Here we describe a new G1 mutant from an ancient family of apicomplexan protozoans. Toxoplasma gondii temperature-sensitive mutant 12-109C6 conditionally arrests in the G1 phase due to a single point mutation in a novel protein containing a single RNA-recognition-motif (TgRRM1). The resulting tyrosine to asparagine amino acid change in TgRRM1 causes severe temperature instability that generates an effective null phenotype for this protein when the mutant is shifted to the restrictive temperature. Orthologs of TgRRM1 are widely conserved in diverse eukaryote lineages, and the human counterpart (RBM42) can functionally replace the missing Toxoplasma factor. Transcriptome studies demonstrate that gene expression is downregulated in the mutant at the restrictive temperature due to a severe defect in splicing that affects both cell cycle and constitutively expressed mRNAs. The interaction of TgRRM1 with factors of the tri-SNP complex (U4/U6 & U5 snRNPs) indicate this factor may be required to assemble an active spliceosome. Thus, the TgRRM1 family of proteins is an unrecognized and evolutionarily conserved class of splicing regulators. This study demonstrates investigations into diverse unicellular eukaryotes, like the Apicomplexa, have the potential to yield new insights into important mechanisms conserved across modern eukaryotic kingdoms.

  12. The cell cycle-regulated genes of Schizosaccharomyces pombe.

    Science.gov (United States)

    Oliva, Anna; Rosebrock, Adam; Ferrezuelo, Francisco; Pyne, Saumyadipta; Chen, Haiying; Skiena, Steve; Futcher, Bruce; Leatherwood, Janet

    2005-07-01

    Many genes are regulated as an innate part of the eukaryotic cell cycle, and a complex transcriptional network helps enable the cyclic behavior of dividing cells. This transcriptional network has been studied in Saccharomyces cerevisiae (budding yeast) and elsewhere. To provide more perspective on these regulatory mechanisms, we have used microarrays to measure gene expression through the cell cycle of Schizosaccharomyces pombe (fission yeast). The 750 genes with the most significant oscillations were identified and analyzed. There were two broad waves of cell cycle transcription, one in early/mid G2 phase, and the other near the G2/M transition. The early/mid G2 wave included many genes involved in ribosome biogenesis, possibly explaining the cell cycle oscillation in protein synthesis in S. pombe. The G2/M wave included at least three distinctly regulated clusters of genes: one large cluster including mitosis, mitotic exit, and cell separation functions, one small cluster dedicated to DNA replication, and another small cluster dedicated to cytokinesis and division. S. pombe cell cycle genes have relatively long, complex promoters containing groups of multiple DNA sequence motifs, often of two, three, or more different kinds. Many of the genes, transcription factors, and regulatory mechanisms are conserved between S. pombe and S. cerevisiae. Finally, we found preliminary evidence for a nearly genome-wide oscillation in gene expression: 2,000 or more genes undergo slight oscillations in expression as a function of the cell cycle, although whether this is adaptive, or incidental to other events in the cell, such as chromatin condensation, we do not know.

  13. The cell cycle-regulated genes of Schizosaccharomyces pombe.

    Directory of Open Access Journals (Sweden)

    Anna Oliva

    2005-07-01

    Full Text Available Many genes are regulated as an innate part of the eukaryotic cell cycle, and a complex transcriptional network helps enable the cyclic behavior of dividing cells. This transcriptional network has been studied in Saccharomyces cerevisiae (budding yeast and elsewhere. To provide more perspective on these regulatory mechanisms, we have used microarrays to measure gene expression through the cell cycle of Schizosaccharomyces pombe (fission yeast. The 750 genes with the most significant oscillations were identified and analyzed. There were two broad waves of cell cycle transcription, one in early/mid G2 phase, and the other near the G2/M transition. The early/mid G2 wave included many genes involved in ribosome biogenesis, possibly explaining the cell cycle oscillation in protein synthesis in S. pombe. The G2/M wave included at least three distinctly regulated clusters of genes: one large cluster including mitosis, mitotic exit, and cell separation functions, one small cluster dedicated to DNA replication, and another small cluster dedicated to cytokinesis and division. S. pombe cell cycle genes have relatively long, complex promoters containing groups of multiple DNA sequence motifs, often of two, three, or more different kinds. Many of the genes, transcription factors, and regulatory mechanisms are conserved between S. pombe and S. cerevisiae. Finally, we found preliminary evidence for a nearly genome-wide oscillation in gene expression: 2,000 or more genes undergo slight oscillations in expression as a function of the cell cycle, although whether this is adaptive, or incidental to other events in the cell, such as chromatin condensation, we do not know.

  14. Effect of fenhexamid and cyprodinil on the expression of cell cycle- and metastasis-related genes via an estrogen receptor-dependent pathway in cellular and xenografted ovarian cancer models

    International Nuclear Information System (INIS)

    Go, Ryeo-Eun; Kim, Cho-Won; Choi, Kyung-Chul

    2015-01-01

    ABSTRACT: Fenhexamid and cyprodinil are antifungal agents (pesticides) used for agriculture, and are present at measurable amounts in fruits and vegetables. In the current study, the effects of fenhexamid and cyprodinil on cancer cell proliferation and metastasis were examined. Additionally, the protein expression levels of cyclin D1 and cyclin E as well as cathepsin D were analyzed in BG-1 ovarian cancer cells that express estrogen receptors (ERs). The cells were cultured with 0.1% dimethyl sulfoxide (DMSO; control), 17β-estradiol (E2; 10 −9 M), and fenhexamid or cyprodinil (10 –5 –10 −7 M). Results of a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that fenhexamid and cyprodinil increased BG-1 cell proliferation about 1.5 to 2 times similar to E2 (5 times) compared to the control. When the cells were co-treated with ICI 182,780 (10 −8 M), an ER antagonist, the proliferation of pesticide-treated BG-1 cells was decreased to the level of the control. A wound healing assay revealed that the pesticides reduced the disrupted area in the BG-1 cell monolayer similar to E2. Protein levels of cyclin D1 and E as well as cathepsin D were increased by fenhexamid and cyprodinil. This effect was reversed by co-treatment with ICI 182,780. In a xenograft mouse model with transplanted BG-1 cells, cyprodinil significantly increased tumor mass formation about 2 times as did E2 (6 times) compared to the vehicle (0.1% DMSO) over an 80-day period. In contrast, fenhexamid did not promote ovarian tumor formation in this mouse model. Cyprodinil also induced cell proliferation along with the expression of proliferating cell nuclear antigen (PCNA) and cathepsin D in tumor tissues similar to E2. Taken together, these results imply that fenhexamid and cyprodinil may have disruptive effects on ER-expressing cancer by altering the cell cycle- and metastasis-related gene expression via an ER-dependent pathway. - Highlights: • Fenhexamid and

  15. Neurosecretory cells of the amygdaloid complex during estrous cycle.

    Science.gov (United States)

    Akhmadeev, A V; Kalimullina, L B

    2005-02-01

    Ultrastructure of neurosecretory cells of the dorsomedial nucleus of the cerebral amygdaloid complex (one of the main zones of sexual dimorphism) was studied in different phases of the estrous cycle. The characteristics of the "light" and "dark" cells change depending on the concentrations of sex steroids during estrus and metestrus.

  16. Temporal controls of the asymmetric cell division cycle in Caulobacter crescentus.

    Directory of Open Access Journals (Sweden)

    Shenghua Li

    2009-08-01

    Full Text Available The asymmetric cell division cycle of Caulobacter crescentus is orchestrated by an elaborate gene-protein regulatory network, centered on three major control proteins, DnaA, GcrA and CtrA. The regulatory network is cast into a quantitative computational model to investigate in a systematic fashion how these three proteins control the relevant genetic, biochemical and physiological properties of proliferating bacteria. Different controls for both swarmer and stalked cell cycles are represented in the mathematical scheme. The model is validated against observed phenotypes of wild-type cells and relevant mutants, and it predicts the phenotypes of novel mutants and of known mutants under novel experimental conditions. Because the cell cycle control proteins of Caulobacter are conserved across many species of alpha-proteobacteria, the model we are proposing here may be applicable to other genera of importance to agriculture and medicine (e.g., Rhizobium, Brucella.

  17. Temporal controls of the asymmetric cell division cycle in Caulobacter crescentus.

    Science.gov (United States)

    Li, Shenghua; Brazhnik, Paul; Sobral, Bruno; Tyson, John J

    2009-08-01

    The asymmetric cell division cycle of Caulobacter crescentus is orchestrated by an elaborate gene-protein regulatory network, centered on three major control proteins, DnaA, GcrA and CtrA. The regulatory network is cast into a quantitative computational model to investigate in a systematic fashion how these three proteins control the relevant genetic, biochemical and physiological properties of proliferating bacteria. Different controls for both swarmer and stalked cell cycles are represented in the mathematical scheme. The model is validated against observed phenotypes of wild-type cells and relevant mutants, and it predicts the phenotypes of novel mutants and of known mutants under novel experimental conditions. Because the cell cycle control proteins of Caulobacter are conserved across many species of alpha-proteobacteria, the model we are proposing here may be applicable to other genera of importance to agriculture and medicine (e.g., Rhizobium, Brucella).

  18. Temporal remodeling of the cell cycle accompanies differentiation in the Drosophila germline.

    Science.gov (United States)

    Hinnant, Taylor D; Alvarez, Arturo A; Ables, Elizabeth T

    2017-09-01

    Development of multicellular organisms relies upon the coordinated regulation of cellular differentiation and proliferation. Growing evidence suggests that some molecular regulatory pathways associated with the cell cycle machinery also dictate cell fate; however, it remains largely unclear how the cell cycle is remodeled in concert with cell differentiation. During Drosophila oogenesis, mature oocytes are created through a series of precisely controlled division and differentiation steps, originating from a single tissue-specific stem cell. Further, germline stem cells (GSCs) and their differentiating progeny remain in a predominantly linear arrangement as oogenesis proceeds. The ability to visualize the stepwise events of differentiation within the context of a single tissue make the Drosophila ovary an exceptional model for study of cell cycle remodeling. To describe how the cell cycle is remodeled in germ cells as they differentiate in situ, we used the Drosophila Fluorescence Ubiquitin-based Cell Cycle Indicator (Fly-FUCCI) system, in which degradable versions of GFP::E2f1 and RFP::CycB fluorescently label cells in each phase of the cell cycle. We found that the lengths of the G1, S, and G2 phases of the cell cycle change dramatically over the course of differentiation, and identified the 4/8-cell cyst as a key developmental transition state in which cells prepare for specialized cell cycles. Our data suggest that the transcriptional activator E2f1, which controls the transition from G1 to S phase, is a key regulator of mitotic divisions in the early germline. Our data support the model that E2f1 is necessary for proper GSC proliferation, self-renewal, and daughter cell development. In contrast, while E2f1 degradation by the Cullin 4 (Cul4)-containing ubiquitin E3 ligase (CRL4) is essential for developmental transitions in the early germline, our data do not support a role for E2f1 degradation as a mechanism to limit GSC proliferation or self-renewal. Taken

  19. Cell cycle-tailored targeting of metastatic melanoma: Challenges and opportunities.

    Science.gov (United States)

    Haass, Nikolas K; Gabrielli, Brian

    2017-07-01

    The advent of targeted therapies of metastatic melanoma, such as MAPK pathway inhibitors and immune checkpoint antagonists, has turned dermato-oncology from the "bad guy" to the "poster child" in oncology. Current targeted therapies are effective, although here is a clear need to develop combination therapies to delay the onset of resistance. Many antimelanoma drugs impact on the cell cycle but are also dependent on certain cell cycle phases resulting in cell cycle phase-specific drug insensitivity. Here, we raise the question: Have combination trials been abandoned prematurely as ineffective possibly only because drug scheduling was not optimized? Firstly, if both drugs of a combination hit targets in the same melanoma cell, cell cycle-mediated drug insensitivity should be taken into account when planning combination therapies, timing of dosing schedules and choice of drug therapies in solid tumors. Secondly, if the combination is designed to target different tumor cell subpopulations of a heterogeneous tumor, one drug effective in a particular subpopulation should not negatively impact on the other drug targeting another subpopulation. In addition to the role of cell cycle stage and progression on standard chemotherapeutics and targeted drugs, we discuss the utilization of cell cycle checkpoint control defects to enhance chemotherapeutic responses or as targets themselves. We propose that cell cycle-tailored targeting of metastatic melanoma could further improve therapy outcomes and that our real-time cell cycle imaging 3D melanoma spheroid model could be utilized as a tool to measure and design drug scheduling approaches. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Establishment of human papillomavirus infection requires cell cycle progression.

    Directory of Open Access Journals (Sweden)

    Dohun Pyeon

    2009-02-01

    Full Text Available Human papillomaviruses (HPVs are DNA viruses associated with major human cancers. As such there is a strong interest in developing new means, such as vaccines and microbicides, to prevent HPV infections. Developing the latter requires a better understanding of the infectious life cycle of HPVs. The HPV infectious life cycle is closely linked to the differentiation state of the stratified epithelium it infects, with progeny virus only made in the terminally differentiating suprabasal compartment. It has long been recognized that HPV must first establish its infection within the basal layer of stratified epithelium, but why this is the case has not been understood. In part this restriction might reflect specificity of expression of entry receptors. However, this hypothesis could not fully explain the differentiation restriction of HPV infection, since many cell types can be infected with HPVs in monolayer cell culture. Here, we used chemical biology approaches to reveal that cell cycle progression through mitosis is critical for HPV infection. Using infectious HPV16 particles containing the intact viral genome, G1-synchronized human keratinocytes as hosts, and early viral gene expression as a readout for infection, we learned that the recipient cell must enter M phase (mitosis for HPV infection to take place. Late M phase inhibitors had no effect on infection, whereas G1, S, G2, and early M phase cell cycle inhibitors efficiently prevented infection. We conclude that host cells need to pass through early prophase for successful onset of transcription of the HPV encapsidated genes. These findings provide one reason why HPVs initially establish infections in the basal compartment of stratified epithelia. Only this compartment of the epithelium contains cells progressing through the cell cycle, and therefore it is only in these cells that HPVs can establish their infection. By defining a major condition for cell susceptibility to HPV infection, these

  1. sensitivity analysis on flexible road pavement life cycle cost model

    African Journals Online (AJOL)

    user

    of sensitivity analysis on a developed flexible pavement life cycle cost model using varying discount rate. The study .... organizations and specific projects needs based. Life-cycle ... developed and completed urban road infrastructure corridor ...

  2. Integrated corporate structure life cycle management modeling and organization

    OpenAIRE

    Naumenko, M.; Morozova, L.

    2011-01-01

    Integrated business structure presented as complementary pool of its participants skills. The methodical approach to integrated business structure life cycle modeling proposed. Recommendations of enterprises life cycles stages correlate are submitted.

  3. Cell Division, a new open access online forum for and from the cell cycle community

    Directory of Open Access Journals (Sweden)

    Kaldis Philipp

    2006-04-01

    Full Text Available Abstract Cell Division is a new, open access, peer-reviewed online journal that publishes cutting-edge articles, commentaries and reviews on all exciting aspects of cell cycle control in eukaryotes. A major goal of this new journal is to publish timely and significant studies on the aberrations of the cell cycle network that occur in cancer and other diseases.

  4. Radiotherapy and chemotherapy after partial synchronization of cell cycle

    International Nuclear Information System (INIS)

    Hermann, H.J.; Ammon, J.; Nuevemann, M.; Zum Winkel, K.; Technische Hochschule Aachen

    1977-01-01

    Apart from densely ionising radiations, radiotherapy and chemotherapy after partial synchronisation of the cell cycle are, at the moment, the only way to improve the efficiency of a treatment of malignant tumours. The new principle is based on the finding that tumour cells are more sensitive to radiation or chemotherapy in a certain metabolic situation. Partial synchronisation of the cell cycle makes it possible to enrich tumour cells in a certain metabolic state. In order to show the efficiency of such a measure, several methods can be used. Recently, impulse cytophotometry has been replacing these methods, since it permits a quick, simple, and individual control of the synchronisation effect. However, there has not been any clinical experiment yet to prove that tumour cells show a maximum sensitivity to radio- and chemotherapy in the G 2 -M-phase. This is why a number of patients with malignant tumours which could not be operated or treated with the usual radiotherapy or polychemotherapy were treated according to this new therapeutic principle. The results obtained in 233 cases encourage the specialists to continue the experiments. The indication of a treatment after partial synchronisation of the cell cycle should be based on the tumour spread as documented according to the TNM-system. Only when these guidelines are followed will it be possible to explain the problems still unsolved in the principle of radiotherapy and chemotherapy after partial synchronisation of the cell cycle and to carry out radio- and chemotherapy with improved efficiency in the future. (orig./MG) [de

  5. Cell cycle related /sup 125/IUDR-induced-division delay

    International Nuclear Information System (INIS)

    Scheniderman, M.H.; Hofer, K.G.

    1987-01-01

    A series of experiments were run to determine if /sup 125/I-decays, in /sup 125/IUdR labeled DNA, specifically accumulated at 1, 3, 5, 7 and 9 hours after plating labeled mitotic cells caused a change in the rate or time of cell entry into mitosis. To accomplish this, a pool of labeled mitotic cells was selected in mitosis and plated in replicate flasks. /sup 125/I decays were accumulated in groups of cells by cooling (4 0 C) for 2 hours starting at the designated times. After rewarding, colcemid was added to arrest cells in mitosis. The rate of cell progression into mitosis for each cell cycle time of accumulation was determined by scoring the mitotic index of cells sampled as a function of time after addition of the colcemid. The results are summarized: (1) Decays from /sup 125/I in /sup 125/I(UdR) labeled DNA reduced the rate of cell progression into mitosis and delayed the time of initiation of mitosis. (2) The reduced rate of progression and the delayed time of initiation of mitosis were independent of the cell cycle time that /sup 125/I-decays were accumulated. (3) The reduced rate of progression after cell cycle accumulation of /sup 125/I decay was statistically indistinguishable from the corresponding controls. (4) The delayed initiation of mitosis after specific cell cycle accumulation of /sup 125/I- decays was greater than the corresponding control. The relationship of these data to DNA and non-DNA division delay target(s) is emphasized

  6. Cell cycle in egg cell and its progression during zygotic development in rice.

    Science.gov (United States)

    Sukawa, Yumiko; Okamoto, Takashi

    2018-03-01

    Rice egg is arrested at G1 phase probably by OsKRP2. After fusion with sperm, karyogamy, OsWEE1-mediated parental DNA integrity in zygote nucleus, zygote progresses cell cycle to produce two-celled embryo. In angiosperms, female and male gametes exist in gametophytes after the complementation of meiosis and the progression of nuclear/cell division of the haploid cell. Within the embryo sac, the egg cell is specially differentiated for fertilization and subsequent embryogenesis, and cellular programs for embryonic development, such as restarting the cell cycle and de novo gene expression, are halted. There is only limited knowledge about how the cell cycle in egg cells restarts toward zygotic division, although the conversion of the cell cycle from a quiescent and arrested state to an active state is the most evident transition of cell status from egg cell to zygote. This is partly due to the difficulty in direct access and analysis of egg cells, zygotes and early embryos, which are deeply embedded in ovaries. In this study, precise relative DNA amounts in the nuclei of egg cells, developing zygotes and cells of early embryos were measured, and the cell cycle of a rice egg cell was estimated as the G1 phase with a 1C DNA level. In addition, increases in DNA content in zygote nuclei via karyogamy and DNA replication were also detectable according to progression of the cell cycle. In addition, expression profiles for cell cycle-related genes in egg cells and zygotes were also addressed, and it was suggested that OsKRP2 and OsWEE1 function in the inhibition of cell cycle progression in egg cells and in checkpoint of parental DNA integrity in zygote nucleus, respectively.

  7. Angular-dependent light scattering from cancer cells in different phases of the cell cycle.

    Science.gov (United States)

    Lin, Xiaogang; Wan, Nan; Weng, Lingdong; Zhou, Yong

    2017-10-10

    Cancer cells in different phases of the cell cycle result in significant differences in light scattering properties. In order to harvest cancer cells in particular phases of the cell cycle, we cultured cancer cells through the process of synchronization. Flow cytometric analysis was applied to check the results of cell synchronization and prepare for light scattering measurements. Angular-dependent light scattering measurements of cancer cells arrested in the G1, S, and G2 phases have been performed. Based on integral calculations for scattering intensities from 5° to 10° and from 110° to 150°, conclusions have been reached. Clearly, the sizes of the cancer cells in different phases of the cell cycle dominated the forward scatter. Accompanying the increase of cell size with the progression of the cell cycle, the forward scattering intensity also increased. Meanwhile, the DNA content of cancer cells in every phase of the cell cycle is responsible for light scattering at large scatter angles. The higher the DNA content of cancer cells was, the greater the positive effect on the high-scattering intensity. As expected, understanding the relationships between the light scattering from cancer cells and cell cycles will aid in the development of cancer diagnoses. Also, it may assist in the guidance of antineoplastic drugs clinically.

  8. Identification of a novel EGF-sensitive cell cycle checkpoint

    International Nuclear Information System (INIS)

    Walker, Francesca; Zhang Huihua; Burgess, Antony W.

    2007-01-01

    The site of action of growth factors on mammalian cell cycle has been assigned to the boundary between the G1 and S phases. We show here that Epidermal Growth Factor (EGF) is also required for mitosis. BaF/3 cells expressing the EGFR (BaF/wtEGFR) synthesize DNA in response to EGF, but arrest in S-phase. We have generated a cell line (BaF/ERX) with defective downregulation of the EGFR and sustained activation of EGFR signalling pathways: these cells undergo mitosis in an EGF-dependent manner. The transit of BaF/ERX cells through G2/M strictly requires activation of EGFR and is abolished by AG1478. This phenotype is mimicked by co-expression of ErbB2 in BaF/wtEGFR cells, and abolished by inhibition of the EGFR kinase, suggesting that sustained signalling of the EGFR, through impaired downregulation of the EGFR or heterodimerization, is required for completion of the cycle. We have confirmed the role of EGFR signalling in the G2/M phase of the cell cycle using a human tumor cell line which overexpresses the EGFR and is dependent on EGFR signalling for growth. These findings unmask an EGF-sensitive checkpoint, helping to understand the link between sustained EGFR signalling, proliferation and the acquisition of a radioresistant phenotype in cancer cells

  9. Labeling of lectin receptors during the cell cycle.

    Science.gov (United States)

    Garrido, J

    1976-12-01

    Labeling of lectin receptors during the cell cycle. (Localizabión de receptores para lectinas durante el ciclo celular). Arch. Biol. Med. Exper. 10: 100-104, 1976. The topographic distribution of specific cell surface receptors for concanavalin A and wheat germ agglutinin was studied by ultrastructural labeling in the course of the cell cycle. C12TSV5 cells were synchronized by double thymidine block or mechanical selection (shakeoff). They were labeled by means of lectin-peroxidase techniques while in G1 S, G2 and M phases of the cycle. The results obtained were similar for both lectins employed. Interphase cells (G1 S, G2) present a stlihtly discontinous labeling pattern that is similar to the one observed on unsynchronized cells of the same line. Cells in mitosis, on the contrary, present a highly discontinous distribution of reaction product. This pattern disappears after the cells enters G1 and is not present on mitotic cells fixed in aldehyde prior to labeling.

  10. A New Dynamic Model for Nuclear Fuel Cycle System Analysis

    International Nuclear Information System (INIS)

    Choi, Sungyeol; Ko, Won Il

    2014-01-01

    The evaluation of mass flow is a complex process where numerous parameters and their complex interaction are involved. Given that many nuclear power countries have light and heavy water reactors and associated fuel cycle technologies, the mass flow analysis has to consider a dynamic transition from the open fuel cycle to other cycles over decades or a century. Although an equilibrium analysis provides insight concerning the end-states of fuel cycle transitions, it cannot answer when we need specific management options, whether the current plan can deliver these options when needed, and how fast the equilibrium can be achieved. As a pilot application, the government brought several experts together to conduct preliminary evaluations for nuclear fuel cycle options in 2010. According to Table 1, they concluded that the closed nuclear fuel cycle has long-term advantages over the open fuel cycle. However, it is still necessary to assess these options in depth and to optimize transition paths of these long-term options with advanced dynamic fuel cycle models. A dynamic simulation model for nuclear fuel cycle systems was developed and its dynamic mass flow analysis capability was validated against the results of existing models. This model can reflects a complex combination of various fuel cycle processes and reactor types, from once-through to multiple recycling, within a single nuclear fuel cycle system. For the open fuel cycle, the results of the developed model are well matched with the results of other models

  11. A Dominant-Negative PPARγ Mutant Promotes Cell Cycle Progression and Cell Growth in Vascular Smooth Muscle Cells

    Directory of Open Access Journals (Sweden)

    Joey Z. Liu

    2009-01-01

    Full Text Available PPARγ ligands have been shown to have antiproliferative effects on many cell types. We herein report that a synthetic dominant-negative (DN PPARγ mutant functions like a growth factor to promote cell cycle progression and cell proliferation in human coronary artery smooth muscle cells (CASMCs. In quiescent CASMCs, adenovirus-expressed DN-PPARγ promoted G1→S cell cycle progression, enhanced BrdU incorporation, and increased cell proliferation. DN-PPARγ expression also markedly enhanced positive regulators of the cell cycle, increasing Rb and CDC2 phosphorylation and the expression of cyclin A, B1, D1, and MCM7. Conversely, overexpression of wild-type (WT or constitutively-active (CA PPARγ inhibited cell cycle progression and the activity and expression of positive regulators of the cell cycle. DN-PPARγ expression, however, did not up-regulate positive cell cycle regulators in PPARγ-deficient cells, strongly suggesting that DN-PPARγ effects on cell cycle result from blocking the function of endogenous wild-type PPARγ. DN-PPARγ expression enhanced phosphorylation of ERK MAPKs. Furthermore, the ERK specific-inhibitor PD98059 blocked DN-PPARγ-induced phosphorylation of Rb and expression of cyclin A and MCM7. Our data thus suggest that DN-PPARγ promotes cell cycle progression and cell growth in CASMCs by modulating fundamental cell cycle regulatory proteins and MAPK mitogenic signaling pathways in vascular smooth muscle cells (VSMCs.

  12. Dynamical principles of cell-cycle arrest: Reversible, irreversible, and mixed strategies

    Science.gov (United States)

    Pfeuty, Benjamin

    2012-08-01

    Living cells often alternate between proliferating and nonproliferating states as part of individual or collective strategies to adapt to complex and changing environments. To this aim, they have evolved a biochemical regulatory network enabling them to switch between cell-division cycles (i.e., oscillatory state) and cell-cycle arrests (i.e., steady state) in response to extracellular cues. This can be achieved by means of a variety of bifurcation mechanisms that potentially give rise to qualitatively distinct cell-cycle arrest properties. In this paper, we study the dynamics of a minimal biochemical network model in which a cell-division oscillator and a differentiation switch mutually antagonize. We identify the existence of three biologically plausible bifurcation scenarios organized around a codimension-four swallowtail-homoclinic singularity. As a result, the model exhibits a broad repertoire of cell-cycle arrest properties in terms of reversibility of these arrests, tunability of interdivision time, and ability to track time-varying signals. This dynamic versatility would explain the diversity of cell-cycle arrest strategies developed in different living species and functional contexts.

  13. α-Mangostin Induces Apoptosis and Cell Cycle Arrest in Oral Squamous Cell Carcinoma Cell

    Directory of Open Access Journals (Sweden)

    Hyun-Ho Kwak

    2016-01-01

    Full Text Available Mangosteen has long been used as a traditional medicine and is known to have antibacterial, antioxidant, and anticancer effects. Although the effects of α-mangostin, a natural compound extracted from the pericarp of mangosteen, have been investigated in many studies, there is limited data on the effects of the compound in human oral squamous cell carcinoma (OSCC. In this study, α-mangostin was assessed as a potential anticancer agent against human OSCC cells. α-Mangostin inhibited cell proliferation and induced cell death in OSCC cells in a dose- and time-dependent manner with little to no effect on normal human PDLF cells. α-Mangostin treatment clearly showed apoptotic evidences such as nuclear fragmentation and accumulation of annexin V and PI-positive cells on OSCC cells. α-Mangostin treatment also caused the collapse of mitochondrial membrane potential and the translocation of cytochrome c from the mitochondria into the cytosol. The expressions of the mitochondria-related proteins were activated by α-mangostin. Treatment with α-mangostin also induced G1 phase arrest and downregulated cell cycle-related proteins (CDK/cyclin. Hence, α-mangostin specifically induces cell death and inhibits proliferation in OSCC cells via the intrinsic apoptosis pathway and cell cycle arrest at the G1 phase, suggesting that α-mangostin may be an effective agent for the treatment of OSCC.

  14. UV-induced changes in cell cycle and gene expression within rabbit lens epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Sidjanin, D. [Northern Illinois Univ., De Kalb, IL (United States). Dept. of Biological Sciences; Grdina, D. [Argonne National Lab., IL (United States); Woloschak, G.E. [Northern Illinois Univ., De Kalb, IL (United States). Dept. of Biological Sciences

    1994-11-01

    Damage to lens epithelial cells is a probable initiation process in cataract formation induced by ultraviolet radiation. These experiments investigated the ability of 254 nm radiation on cell cycle progression and gene expression in rabbit lens epithelial cell line N/N1003A. No changes in expression of c-fos, c-jun, alpha- tubulin, or vimentin was observed following UV exposure. Using flow cytometry, an accumulation of cells in G1/S phase of the cell cycle 1 hr following exposure. The observed changes in gene expression, especially the decreased histone transcripts reported here may play a role in UV induced inhibition of cell cycle progression.

  15. Cell cycle commitment in budding yeast emerges from the cooperation of multiple bistable switches

    Science.gov (United States)

    Zhang, Tongli; Schmierer, Bernhard; Novák, Béla

    2011-01-01

    The start-transition (START) in the G1 phase marks the point in the cell cycle at which a yeast cell initiates a new round of cell division. Once made, this decision is irreversible and the cell is committed to progressing through the entire cell cycle, irrespective of arrest signals such as pheromone. How commitment emerges from the underlying molecular interaction network is poorly understood. Here, we perform a dynamical systems analysis of an established cell cycle model, which has never been analysed from a commitment perspective. We show that the irreversibility of the START transition and subsequent commitment can be consistently explained in terms of the interplay of multiple bistable molecular switches. By applying an existing mathematical model to a novel problem and by expanding the model in a self-consistent manner, we achieve several goals: we bring together a large number of experimental findings into a coherent theoretical framework; we increase the scope and the applicability of the original model; we give a systems level explanation of how the START transition and the cell cycle commitment arise from the dynamical features of the underlying molecular interaction network; and we make clear, experimentally testable predictions. PMID:22645649

  16. Nuclear-fuel-cycle optimization: methods and modelling techniques

    International Nuclear Information System (INIS)

    Silvennoinen, P.

    1982-01-01

    This book present methods applicable to analyzing fuel-cycle logistics and optimization as well as in evaluating the economics of different reactor strategies. After an introduction to the phases of a fuel cycle, uranium cost trends are assessed in a global perspective. Subsequent chapters deal with the fuel-cycle problems faced by a power utility. The fuel-cycle models cover the entire cycle from the supply of uranium to the disposition of spent fuel. The chapter headings are: Nuclear Fuel Cycle, Uranium Supply and Demand, Basic Model of the LWR (light water reactor) Fuel Cycle, Resolution of Uncertainties, Assessment of Proliferation Risks, Multigoal Optimization, Generalized Fuel-Cycle Models, Reactor Strategy Calculations, and Interface with Energy Strategies. 47 references, 34 figures, 25 tables

  17. CycleBase.org - a comprehensive multi-organism online database of cell-cycle experiments

    DEFF Research Database (Denmark)

    Gauthier, Nicholas Paul; Larsen, Malene Erup; Wernersson, Rasmus

    2007-01-01

    The past decade has seen the publication of a large number of cell-cycle microarray studies and many more are in the pipeline. However, data from these experiments are not easy to access, combine and evaluate. We have developed a centralized database with an easy-to-use interface, Cyclebase...

  18. An apoptotic cell cycle mutant in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Villadsen, Ingrid

    1996-01-01

    The simple eukaryote Saccharomyces cerevisiae has proved to be a useful organism for elucidating the mechanisms that govern cell cycle progression in eukaryotic cells. The excellent in vivo system permits a cell cycle study using temperature sensitive mutants. In addition, it is possible to study...... many genes and gene products from higher eukaryotes in Saccharomyces cerevisiae because many genes and biological processes are homologous or similar in lower and in higher eukaryotes. The highly developed methods of genetics and molecular biology greatly facilitates studies of higher eukaryotic...... processes.Programmmed cell death with apoptosis plays a major role in development and homeostatis in most, if not all, animal cells. Apoptosis is a morphologically distinct form of death, that requires the activation of a highly regulated suicide program. Saccharomyces cerevisiae provides a new system...

  19. Orchestration of DNA Damage Checkpoint Dynamics across the Human Cell Cycle.

    Science.gov (United States)

    Chao, Hui Xiao; Poovey, Cere E; Privette, Ashley A; Grant, Gavin D; Chao, Hui Yan; Cook, Jeanette G; Purvis, Jeremy E

    2017-11-22

    Although molecular mechanisms that prompt cell-cycle arrest in response to DNA damage have been elucidated, the systems-level properties of DNA damage checkpoints are not understood. Here, using time-lapse microscopy and simulations that model the cell cycle as a series of Poisson processes, we characterize DNA damage checkpoints in individual, asynchronously proliferating cells. We demonstrate that, within early G1 and G2, checkpoints are stringent: DNA damage triggers an abrupt, all-or-none cell-cycle arrest. The duration of this arrest correlates with the severity of DNA damage. After the cell passes commitment points within G1 and G2, checkpoint stringency is relaxed. By contrast, all of S phase is comparatively insensitive to DNA damage. This checkpoint is graded: instead of halting the cell cycle, increasing DNA damage leads to slower S phase progression. In sum, we show that a cell's response to DNA damage depends on its exact cell-cycle position and that checkpoints are phase-dependent, stringent or relaxed, and graded or all-or-none. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Cyclebase 3.0: a multi-organism database on cell-cycle regulation and phenotypes.

    Science.gov (United States)

    Santos, Alberto; Wernersson, Rasmus; Jensen, Lars Juhl

    2015-01-01

    The eukaryotic cell division cycle is a highly regulated process that consists of a complex series of events and involves thousands of proteins. Researchers have studied the regulation of the cell cycle in several organisms, employing a wide range of high-throughput technologies, such as microarray-based mRNA expression profiling and quantitative proteomics. Due to its complexity, the cell cycle can also fail or otherwise change in many different ways if important genes are knocked out, which has been studied in several microscopy-based knockdown screens. The data from these many large-scale efforts are not easily accessed, analyzed and combined due to their inherent heterogeneity. To address this, we have created Cyclebase--available at http://www.cyclebase.org--an online database that allows users to easily visualize and download results from genome-wide cell-cycle-related experiments. In Cyclebase version 3.0, we have updated the content of the database to reflect changes to genome annotation, added new mRNA and protein expression data, and integrated cell-cycle phenotype information from high-content screens and model-organism databases. The new version of Cyclebase also features a new web interface, designed around an overview figure that summarizes all the cell-cycle-related data for a gene. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  1. HIV-1 Vif's Capacity To Manipulate the Cell Cycle Is Species Specific.

    Science.gov (United States)

    Evans, Edward L; Becker, Jordan T; Fricke, Stephanie L; Patel, Kishan; Sherer, Nathan M

    2018-04-01

    Cells derived from mice and other rodents exhibit profound blocks to HIV-1 virion production, reflecting species-specific incompatibilities between viral Tat and Rev proteins and essential host factors cyclin T1 (CCNT1) and exportin-1 (XPO1, also known as CRM1), respectively. To determine if mouse cell blocks other than CCNT1 and XPO1 affect HIV's postintegration stages, we studied HIV-1 NL4-3 gene expression in mouse NIH 3T3 cells modified to constitutively express HIV-1-compatible versions of CCNT1 and XPO1 (3T3.CX cells). 3T3.CX cells supported both Rev-independent and Rev-dependent viral gene expression and produced relatively robust levels of virus particles, confirming that CCNT1 and XPO1 represent the predominant blocks to these stages. Unexpectedly, however, 3T3.CX cells were remarkably resistant to virus-induced cytopathic effects observed in human cell lines, which we mapped to the viral protein Vif and its apparent species-specific capacity to induce G 2 /M cell cycle arrest. Vif was able to mediate rapid degradation of human APOBEC3G and the PPP2R5D regulatory B56 subunit of the PP2A phosphatase holoenzyme in mouse cells, thus demonstrating that Vif NL4-3 's modulation of the cell cycle can be functionally uncoupled from some of its other defined roles in CUL5-dependent protein degradation. Vif was also unable to induce G 2 /M cell cycle arrest in other nonhuman cell types, including cells derived from nonhuman primates, leading us to propose that one or more human-specific cofactors underpin Vif's ability to modulate the cell cycle. IMPORTANCE Cells derived from mice and other rodents exhibit profound blocks to HIV-1 replication, thus hindering the development of a low-cost small-animal model for studying HIV/AIDS. Here, we engineered otherwise-nonpermissive mouse cells to express HIV-1-compatible versions of two species-specific host dependency factors, cyclin T1 (CCNT1) and exportin-1 (XPO1) (3T3.CX cells). We show that 3T3.CX cells rescue HIV-1

  2. Evolution of cell cycle control: same molecular machines, different regulation

    DEFF Research Database (Denmark)

    de Lichtenberg, Ulrik; Jensen, Thomas Skøt; Brunak, Søren

    2007-01-01

    Decades of research has together with the availability of whole genomes made it clear that many of the core components involved in the cell cycle are conserved across eukaryotes, both functionally and structurally. These proteins are organized in complexes and modules that are activated or deacti......Decades of research has together with the availability of whole genomes made it clear that many of the core components involved in the cell cycle are conserved across eukaryotes, both functionally and structurally. These proteins are organized in complexes and modules that are activated...... for assembling the same molecular machines just in time for action....

  3. Understanding cell cycle and cell death regulation provides novel weapons against human diseases.

    Science.gov (United States)

    Wiman, K G; Zhivotovsky, B

    2017-05-01

    Cell division, cell differentiation and cell death are the three principal physiological processes that regulate tissue homoeostasis in multicellular organisms. The growth and survival of cells as well as the integrity of the genome are regulated by a complex network of pathways, in which cell cycle checkpoints, DNA repair and programmed cell death have critical roles. Disruption of genomic integrity and impaired regulation of cell death may both lead to uncontrolled cell growth. Compromised cell death can also favour genomic instability. It is becoming increasingly clear that dysregulation of cell cycle and cell death processes plays an important role in the development of major disorders such as cancer, cardiovascular disease, infection, inflammation and neurodegenerative diseases. Research achievements in these fields have led to the development of novel approaches for treatment of various conditions associated with abnormalities in the regulation of cell cycle progression or cell death. A better understanding of how cellular life-and-death processes are regulated is essential for this development. To highlight these important advances, the Third Nobel Conference entitled 'The Cell Cycle and Cell Death in Disease' was organized at Karolinska Institutet in 2016. In this review we will summarize current understanding of cell cycle progression and cell death and discuss some of the recent advances in therapeutic applications in pathological conditions such as cancer, neurological disorders and inflammation. © 2017 The Association for the Publication of the Journal of Internal Medicine.

  4. A comparison of production system life cycle models

    Science.gov (United States)

    Attri, Rajesh; Grover, Sandeep

    2012-09-01

    Companies today need to keep up with the rapidly changing market conditions to stay competitive. The main issues in this paper are related to a company's market and its competitors. The prediction of market behavior is helpful for a manufacturing enterprise to build efficient production systems. However, these predictions are usually not reliable. A production system is required to adapt to changing markets, but such requirement entails higher cost. Hence, analyzing different life cycle models of the production system is necessary. In this paper, different life cycle models of the production system are compared to evaluate the distinctive features and the limitations of each model. Furthermore, the difference between product life cycle and production life cycle is summarized, and the effect of product life cycle on production life cycle is explained. Finally, a production system life cycle model, along with key activities to be performed in each stage, is proposed specifically for the manufacturing sector.

  5. Imaging- and Flow Cytometry-based Analysis of Cell Position and the Cell Cycle in 3D Melanoma Spheroids

    Science.gov (United States)

    Beaumont, Kimberley A.; Anfosso, Andrea; Ahmed, Farzana

    2015-01-01

    Three-dimensional (3D) tumor spheroids are utilized in cancer research as a more accurate model of the in vivo tumor microenvironment, compared to traditional two-dimensional (2D) cell culture. The spheroid model is able to mimic the effects of cell-cell interaction, hypoxia and nutrient deprivation, and drug penetration. One characteristic of this model is the development of a necrotic core, surrounded by a ring of G1 arrested cells, with proliferating cells on the outer layers of the spheroid. Of interest in the cancer field is how different regions of the spheroid respond to drug therapies as well as genetic or environmental manipulation. We describe here the use of the fluorescence ubiquitination cell cycle indicator (FUCCI) system along with cytometry and image analysis using commercial software to characterize the cell cycle status of cells with respect to their position inside melanoma spheroids. These methods may be used to track changes in cell cycle status, gene/protein expression or cell viability in different sub-regions of tumor spheroids over time and under different conditions. PMID:26779761

  6. Changes in oscillatory dynamics in the cell cycle of early Xenopus laevis embryos.

    Directory of Open Access Journals (Sweden)

    Tony Y-C Tsai

    2014-02-01

    Full Text Available During the early development of Xenopus laevis embryos, the first mitotic cell cycle is long (∼85 min and the subsequent 11 cycles are short (∼30 min and clock-like. Here we address the question of how the Cdk1 cell cycle oscillator changes between these two modes of operation. We found that the change can be attributed to an alteration in the balance between Wee1/Myt1 and Cdc25. The change in balance converts a circuit that acts like a positive-plus-negative feedback oscillator, with spikes of Cdk1 activation, to one that acts like a negative-feedback-only oscillator, with a shorter period and smoothly varying Cdk1 activity. Shortening the first cycle, by treating embryos with the Wee1A/Myt1 inhibitor PD0166285, resulted in a dramatic reduction in embryo viability, and restoring the length of the first cycle in inhibitor-treated embryos with low doses of cycloheximide partially rescued viability. Computations with an experimentally parameterized mathematical model show that modest changes in the Wee1/Cdc25 ratio can account for the observed qualitative changes in the cell cycle. The high ratio in the first cycle allows the period to be long and tunable, and decreasing the ratio in the subsequent cycles allows the oscillator to run at a maximal speed. Thus, the embryo rewires its feedback regulation to meet two different developmental requirements during early development.

  7. Stable cycling in discrete-time genetic models.

    OpenAIRE

    Hastings, A

    1981-01-01

    Examples of stable cycling are discussed for two-locus, two-allele, deterministic, discrete-time models with constant fitnesses. The cases that cycle were found by using numerical techniques to search for stable Hopf bifurcations. One consequence of the results is that apparent cases of directional selection may be due to stable cycling.

  8. Stable cycling in discrete-time genetic models.

    Science.gov (United States)

    Hastings, A

    1981-11-01

    Examples of stable cycling are discussed for two-locus, two-allele, deterministic, discrete-time models with constant fitnesses. The cases that cycle were found by using numerical techniques to search for stable Hopf bifurcations. One consequence of the results is that apparent cases of directional selection may be due to stable cycling.

  9. Cell Cycle Regulation by Alternative Polyadenylation of CCND1.

    Science.gov (United States)

    Wang, Qiong; He, Guopei; Hou, Mengmeng; Chen, Liutao; Chen, Shangwu; Xu, Anlong; Fu, Yonggui

    2018-05-01

    Global shortening of 3'UTRs by alternative polyadenylation (APA) has been observed in cancer cells. However, the role of APA in cancer remains unknown. CCND1 is a proto-oncogene that regulates progression through the G1-S phase of the cell cycle; moreover, it has been observed to be switching to proximal APA sites in cancer cells. To investigate the biological function of the APA of CCND1, we edited the weak poly(A) signal (PAS) of the proximal APA site to a canonical PAS using the CRISPR/Cas9 method, which can force the cells to use a proximal APA site. Cell cycle profiling and proliferation assays revealed that the proximal APA sites of CCND1 accelerated the cell cycle and promoted cell proliferation, but UTR-APA and CR-APA act via different molecular mechanisms. These results indicate that PAS editing with CRISPR/Cas9 provides a good method by which to study the biological function of APA.

  10. Petri Net Modeling of Computer Virus Life Cycle | Ikekonwu ...

    African Journals Online (AJOL)

    Virus life cycle, which refers to the stages of development of a computer virus, is presented as a suitable area for the application of Petri nets. Petri nets a powerful modeling tool in the field of dynamic system analysis is applied to model the virus life cycle. Simulation of the derived model is also presented. The intention of ...

  11. PETRI NET MODELING OF COMPUTER VIRUS LIFE CYCLE

    African Journals Online (AJOL)

    Dr Obe

    dynamic system analysis is applied to model the virus life cycle. Simulation of the derived model ... Keywords: Virus lifecycle, Petri nets, modeling. simulation. .... complex process. Figure 2 .... by creating Matlab files for five different computer ...

  12. The Adder Phenomenon Emerges from Independent Control of Pre- and Post-Start Phases of the Budding Yeast Cell Cycle.

    Science.gov (United States)

    Chandler-Brown, Devon; Schmoller, Kurt M; Winetraub, Yonatan; Skotheim, Jan M

    2017-09-25

    Although it has long been clear that cells actively regulate their size, the molecular mechanisms underlying this regulation have remained poorly understood. In budding yeast, cell size primarily modulates the duration of the cell-division cycle by controlling the G1/S transition known as Start. We have recently shown that the rate of progression through Start increases with cell size, because cell growth dilutes the cell-cycle inhibitor Whi5 in G1. Recent phenomenological studies in yeast and bacteria have shown that these cells add an approximately constant volume during each complete cell cycle, independent of their size at birth. These results seem to be in conflict, as the phenomenological studies suggest that cells measure the amount they grow, rather than their size, and that size control acts over the whole cell cycle, rather than specifically in G1. Here, we propose an integrated model that unifies the adder phenomenology with the molecular mechanism of G1/S cell-size control. We use single-cell microscopy to parameterize a full cell-cycle model based on independent control of pre- and post-Start cell-cycle periods. We find that our model predicts the size-independent amount of cell growth during the full cell cycle. This suggests that the adder phenomenon is an emergent property of the independent regulation of pre- and post-Start cell-cycle periods rather than the consequence of an underlying molecular mechanism measuring a fixed amount of growth. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. The recruitability and cell-cycle state of intestinal stem cells

    International Nuclear Information System (INIS)

    Potten, C.S.; Chadwick, C.; Ijiri, K.; Tsubouchi, S.; Hanson, W.R.

    1984-01-01

    Evidence is presented which suggests that the crypts of the small intestine contain at least two discrete but interdependent classes of stem cells, some with discrete cell kinetic properties and some with discrete radiation responses or radiosensitivities. Very low doses of X rays or gamma rays, or neutrons, kill a few cells in the stem cell regions of the crypt in a sensitive dose-dependent manner. Similar doses generate several different cell kinetic responses within either the clonogenic fraction or the cells at the stem cell position within the crypt. The cell kinetic responses range from apparent recruitment of G0 clonogenic cells into cycle, to a marked shortening of the average cell cycle of the cells at the stem cell position. It is suggested that the cell kinetic changes may be the consequence of the cell destruction

  14. Life cycle assessment of hydrogen production and fuel cell systems

    International Nuclear Information System (INIS)

    Dincer, I.

    2007-01-01

    This paper details life cycle assessment (LCA) of hydrogen production and fuel cell system. LCA is a key tool in hydrogen and fuel cell technologies for design, analysis, development; manufacture, applications etc. Energy efficiencies and greenhouse gases and air pollution emissions have been evaluated in all process steps including crude oil and natural gas pipeline transportation, crude oil distillation, natural gas reprocessing, wind and solar electricity generation , hydrogen production through water electrolysis and gasoline and hydrogen distribution and utilization

  15. Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle.

    Science.gov (United States)

    Feillet, Céline; Krusche, Peter; Tamanini, Filippo; Janssens, Roel C; Downey, Mike J; Martin, Patrick; Teboul, Michèle; Saito, Shoko; Lévi, Francis A; Bretschneider, Till; van der Horst, Gijsbertus T J; Delaunay, Franck; Rand, David A

    2014-07-08

    Daily synchronous rhythms of cell division at the tissue or organism level are observed in many species and suggest that the circadian clock and cell cycle oscillators are coupled. For mammals, despite known mechanistic interactions, the effect of such coupling on clock and cell cycle progression, and hence its biological relevance, is not understood. In particular, we do not know how the temporal organization of cell division at the single-cell level produces this daily rhythm at the tissue level. Here we use multispectral imaging of single live cells, computational methods, and mathematical modeling to address this question in proliferating mouse fibroblasts. We show that in unsynchronized cells the cell cycle and circadian clock robustly phase lock each other in a 1:1 fashion so that in an expanding cell population the two oscillators oscillate in a synchronized way with a common frequency. Dexamethasone-induced synchronization reveals additional clock states. As well as the low-period phase-locked state there are distinct coexisting states with a significantly higher period clock. Cells transition to these states after dexamethasone synchronization. The temporal coordination of cell division by phase locking to the clock at a single-cell level has significant implications because disordered circadian function is increasingly being linked to the pathogenesis of many diseases, including cancer.

  16. Positive Feedback Keeps Duration of Mitosis Temporally Insulated from Upstream Cell-Cycle Events.

    Science.gov (United States)

    Araujo, Ana Rita; Gelens, Lendert; Sheriff, Rahuman S M; Santos, Silvia D M

    2016-10-20

    Cell division is characterized by a sequence of events by which a cell gives rise to two daughter cells. Quantitative measurements of cell-cycle dynamics in single cells showed that despite variability in G1-, S-, and G2 phases, duration of mitosis is short and remarkably constant. Surprisingly, there is no correlation between cell-cycle length and mitotic duration, suggesting that mitosis is temporally insulated from variability in earlier cell-cycle phases. By combining live cell imaging and computational modeling, we showed that positive feedback is the molecular mechanism underlying the temporal insulation of mitosis. Perturbing positive feedback gave rise to a sluggish, variable entry and progression through mitosis and uncoupled duration of mitosis from variability in cell cycle length. We show that positive feedback is important to keep mitosis short, constant, and temporally insulated and anticipate it might be a commonly used regulatory strategy to create modularity in other biological systems. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  17. NSA2, a novel nucleolus protein regulates cell proliferation and cell cycle

    International Nuclear Information System (INIS)

    Zhang, Heyu; Ma, Xi; Shi, Taiping; Song, Quansheng; Zhao, Hongshan; Ma, Dalong

    2010-01-01

    NSA2 (Nop seven-associated 2) was previously identified in a high throughput screen of novel human genes associated with cell proliferation, and the NSA2 protein is evolutionarily conserved across different species. In this study, we revealed that NSA2 is broadly expressed in human tissues and cultured cell lines, and located in the nucleolus of the cell. Both of the putative nuclear localization signals (NLSs) of NSA2, also overlapped with nucleolar localization signals (NoLSs), are capable of directing nucleolar accumulation. Moreover, over-expression of the NSA2 protein promoted cell growth in different cell lines and regulated the G1/S transition in the cell cycle. SiRNA silencing of the NSA2 transcript attenuated the cell growth and dramatically blocked the cell cycle in G1/S transition. Our results demonstrated that NSA2 is a nucleolar protein involved in cell proliferation and cell cycle regulation.

  18. Technoeconomy of different solid oxide fuel cell based hybrid cycle

    DEFF Research Database (Denmark)

    Rokni, Masoud

    2014-01-01

    Gas turbine, steam turbine and heat engine (Stirling engine) is used as bottoming cycle for a solid oxide fuel cell plant to compare different plants efficiencies, CO2 emissionsand plants cost in terms of $/kW. Each plant is then integrated with biomass gasification and finally six plants...

  19. Stable Regulation of Cell Cycle Events in Mycobacteria: Insights From Inherently Heterogeneous Bacterial Populations.

    Science.gov (United States)

    Logsdon, Michelle M; Aldridge, Bree B

    2018-01-01

    Model bacteria, such as E. coli and B. subtilis , tightly regulate cell cycle progression to achieve consistent cell size distributions and replication dynamics. Many of the hallmark features of these model bacteria, including lateral cell wall elongation and symmetric growth and division, do not occur in mycobacteria. Instead, mycobacterial growth is characterized by asymmetric polar growth and division. This innate asymmetry creates unequal birth sizes and growth rates for daughter cells with each division, generating a phenotypically heterogeneous population. Although the asymmetric growth patterns of mycobacteria lead to a larger variation in birth size than typically seen in model bacterial populations, the cell size distribution is stable over time. Here, we review the cellular mechanisms of growth, division, and cell cycle progression in mycobacteria in the face of asymmetry and inherent heterogeneity. These processes coalesce to control cell size. Although Mycobacterium smegmatis and Mycobacterium bovis Bacillus Calmette-Guérin (BCG) utilize a novel model of cell size control, they are similar to previously studied bacteria in that initiation of DNA replication is a key checkpoint for cell division. We compare the regulation of DNA replication initiation and strategies used for cell size homeostasis in mycobacteria and model bacteria. Finally, we review the importance of cellular organization and chromosome segregation relating to the physiology of mycobacteria and consider how new frameworks could be applied across the wide spectrum of bacterial diversity.

  20. Stable Regulation of Cell Cycle Events in Mycobacteria: Insights From Inherently Heterogeneous Bacterial Populations

    Directory of Open Access Journals (Sweden)

    Michelle M. Logsdon

    2018-03-01

    Full Text Available Model bacteria, such as E. coli and B. subtilis, tightly regulate cell cycle progression to achieve consistent cell size distributions and replication dynamics. Many of the hallmark features of these model bacteria, including lateral cell wall elongation and symmetric growth and division, do not occur in mycobacteria. Instead, mycobacterial growth is characterized by asymmetric polar growth and division. This innate asymmetry creates unequal birth sizes and growth rates for daughter cells with each division, generating a phenotypically heterogeneous population. Although the asymmetric growth patterns of mycobacteria lead to a larger variation in birth size than typically seen in model bacterial populations, the cell size distribution is stable over time. Here, we review the cellular mechanisms of growth, division, and cell cycle progression in mycobacteria in the face of asymmetry and inherent heterogeneity. These processes coalesce to control cell size. Although Mycobacterium smegmatis and Mycobacterium bovis Bacillus Calmette-Guérin (BCG utilize a novel model of cell size control, they are similar to previously studied bacteria in that initiation of DNA replication is a key checkpoint for cell division. We compare the regulation of DNA replication initiation and strategies used for cell size homeostasis in mycobacteria and model bacteria. Finally, we review the importance of cellular organization and chromosome segregation relating to the physiology of mycobacteria and consider how new frameworks could be applied across the wide spectrum of bacterial diversity.

  1. Effects of γ-radiation on cell growth, cell cycle and promoter methylation of 22 cell cycle genes in the 1321NI astrocytoma cell line.

    Science.gov (United States)

    Alghamian, Yaman; Abou Alchamat, Ghalia; Murad, Hossam; Madania, Ammar

    2017-09-01

    DNA damage caused by radiation initiates biological responses affecting cell fate. DNA methylation regulates gene expression and modulates DNA damage pathways. Alterations in the methylation profiles of cell cycle regulating genes may control cell response to radiation. In this study we investigated the effect of ionizing radiation on the methylation levels of 22 cell cycle regulating genes in correlation with gene expression in 1321NI astrocytoma cell line. 1321NI cells were irradiated with 2, 5 or 10Gy doses then analyzed after 24, 48 and 72h for cell viability using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliu bromide) assay. Flow cytometry were used to study the effect of 10Gy irradiation on cell cycle. EpiTect Methyl II PCR Array was used to identify differentially methylated genes in irradiated cells. Changes in gene expression was determined by qPCR. Azacytidine treatment was used to determine whether DNA methylation affectes gene expression. Our results showed that irradiation decreased cell viability and caused cell cycle arrest at G2/M. Out of 22 genes tested, only CCNF and RAD9A showed some increase in DNA methylation (3.59% and 3.62%, respectively) after 10Gy irradiation, and this increase coincided with downregulation of both genes (by 4 and 2 fold, respectively). with azacytidine confirmed that expression of CCNF and RAD9A genes was regulated by methylation. 1321NI cell line is highly radioresistant and that irradiation of these cells with a 10Gy dose increases DNA methylation of CCNF and RAD9A genes. This dose down-regulates these genes, favoring G2/M arrest. Copyright © 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.

  2. Resveratrol Improves Cell Cycle Arrest in Chronic Prostatitis Rats, by C-kit/SCF Suppression.

    Science.gov (United States)

    He, Yi; Zeng, Huizhi; Yu, Yang; Zhang, Jiashu; Zeng, Xiaona; Gong, Fengtao; Liu, Qi; Yang, Bo

    2017-08-01

    Chronic prostatitis (CP) with complex pathogenesis is difficult for treatment. c-kit has been associated with the control of cell proliferation of prostate cells. This study aims to evaluate the role of resveratrol, an activator of Sirt1, in regulating the expression of c-kit in CP and investigate the consequent effects on cell cycle. Rat model of CP was established through subcutaneous injections of diphtheria-pertussis-tetanus vaccine and subsequently treated with resveratrol. Hematoxylin and eosin staining was performed to identify the histopathological changes in prostates. Western blotting and immunohistochemical staining examined the expression level of c-kit, stem cell factor (SCF), Sirt1, and cell cycle-associated proteins. The model group exhibited severe diffuse chronic inflammation, characterized by leukocyte infiltration and papillary frond protrusion into the gland cavities, and a notable increase in prostatic epithelial height. Gland lumen diameter was also significantly smaller; the activity of c-kit/SCF in the CP rats was increased significantly compared to the control group. Meanwhile, the cell cycle proteins are dysregulated significantly in CP rats. Resveratrol treatment significantly improved these factors by Sirt1 activation. Dysregulation of cell cycle was involved in the pathological processes of CP, which was improved after resveratrol treatment by the downregulation of c-kit/SCF by activating Sirt1.

  3. Proteomic analysis of the response to cell cycle arrests in human myeloid leukemia cells.

    Science.gov (United States)

    Ly, Tony; Endo, Aki; Lamond, Angus I

    2015-01-02

    Previously, we analyzed protein abundance changes across a 'minimally perturbed' cell cycle by using centrifugal elutriation to differentially enrich distinct cell cycle phases in human NB4 cells (Ly et al., 2014). In this study, we compare data from elutriated cells with NB4 cells arrested at comparable phases using serum starvation, hydroxyurea, or RO-3306. While elutriated and arrested cells have similar patterns of DNA content and cyclin expression, a large fraction of the proteome changes detected in arrested cells are found to reflect arrest-specific responses (i.e., starvation, DNA damage, CDK1 inhibition), rather than physiological cell cycle regulation. For example, we show most cells arrested in G2 by CDK1 inhibition express abnormally high levels of replication and origin licensing factors and are likely poised for genome re-replication. The protein data are available in the Encyclopedia of Proteome Dynamics (

  4. Chemical dissection of the cell cycle: probes for cell biology and anti-cancer drug development.

    Science.gov (United States)

    Senese, S; Lo, Y C; Huang, D; Zangle, T A; Gholkar, A A; Robert, L; Homet, B; Ribas, A; Summers, M K; Teitell, M A; Damoiseaux, R; Torres, J Z

    2014-10-16

    Cancer cell proliferation relies on the ability of cancer cells to grow, transition through the cell cycle, and divide. To identify novel chemical probes for dissecting the mechanisms governing cell cycle progression and cell division, and for developing new anti-cancer therapeutics, we developed and performed a novel cancer cell-based high-throughput chemical screen for cell cycle modulators. This approach identified novel G1, S, G2, and M-phase specific inhibitors with drug-like properties and diverse chemotypes likely targeting a broad array of processes. We further characterized the M-phase inhibitors and highlight the most potent M-phase inhibitor MI-181, which targets tubulin, inhibits tubulin polymerization, activates the spindle assembly checkpoint, arrests cells in mitosis, and triggers a fast apoptotic cell death. Importantly, MI-181 has broad anti-cancer activity, especially against BRAF(V600E) melanomas.

  5. Discrete gene replication events drive coupling between the cell cycle and circadian clocks.

    Science.gov (United States)

    Paijmans, Joris; Bosman, Mark; Ten Wolde, Pieter Rein; Lubensky, David K

    2016-04-12

    Many organisms possess both a cell cycle to control DNA replication and a circadian clock to anticipate changes between day and night. In some cases, these two rhythmic systems are known to be coupled by specific, cross-regulatory interactions. Here, we use mathematical modeling to show that, additionally, the cell cycle generically influences circadian clocks in a nonspecific fashion: The regular, discrete jumps in gene-copy number arising from DNA replication during the cell cycle cause a periodic driving of the circadian clock, which can dramatically alter its behavior and impair its function. A clock built on negative transcriptional feedback either phase-locks to the cell cycle, so that the clock period tracks the cell division time, or exhibits erratic behavior. We argue that the cyanobacterium Synechococcus elongatus has evolved two features that protect its clock from such disturbances, both of which are needed to fully insulate it from the cell cycle and give it its observed robustness: a phosphorylation-based protein modification oscillator, together with its accompanying push-pull read-out circuit that responds primarily to the ratios of different phosphoform concentrations, makes the clock less susceptible to perturbations in protein synthesis; the presence of multiple, asynchronously replicating copies of the same chromosome diminishes the effect of replicating any single copy of a gene.

  6. SAMHD1 controls cell cycle status, apoptosis and HIV-1 infection in monocytic THP-1 cells

    International Nuclear Information System (INIS)

    Bonifati, Serena; Daly, Michele B.; St Gelais, Corine; Kim, Sun Hee; Hollenbaugh, Joseph A.; Shepard, Caitlin; Kennedy, Edward M.; Kim, Dong-Hyun; Schinazi, Raymond F.; Kim, Baek; Wu, Li

    2016-01-01

    SAMHD1 limits HIV-1 infection in non-dividing myeloid cells by decreasing intracellular dNTP pools. HIV-1 restriction by SAMHD1 in these cells likely prevents activation of antiviral immune responses and modulates viral pathogenesis, thus highlighting a critical role of SAMHD1 in HIV-1 physiopathology. Here, we explored the function of SAMHD1 in regulating cell proliferation, cell cycle progression and apoptosis in monocytic THP-1 cells. Using the CRISPR/Cas9 technology, we generated THP-1 cells with stable SAMHD1 knockout. We found that silencing of SAMHD1 in cycling cells stimulates cell proliferation, redistributes cell cycle population in the G_1/G_0 phase and reduces apoptosis. These alterations correlated with increased dNTP levels and more efficient HIV-1 infection in dividing SAMHD1 knockout cells relative to control. Our results suggest that SAMHD1, through its dNTPase activity, affects cell proliferation, cell cycle distribution and apoptosis, and emphasize a key role of SAMHD1 in the interplay between cell cycle regulation and HIV-1 infection.

  7. SAMHD1 controls cell cycle status, apoptosis and HIV-1 infection in monocytic THP-1 cells

    Energy Technology Data Exchange (ETDEWEB)

    Bonifati, Serena [Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH (United States); Daly, Michele B. [Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA (United States); St Gelais, Corine; Kim, Sun Hee [Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH (United States); Hollenbaugh, Joseph A.; Shepard, Caitlin [Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA (United States); Kennedy, Edward M. [Department of Molecular Genetics and Microbiology, Duke University, Durham, NC (United States); Kim, Dong-Hyun [Department of Pharmacy, School of Pharmacy, Kyung-Hee University, Seoul (Korea, Republic of); Schinazi, Raymond F. [Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA (United States); Kim, Baek, E-mail: baek.kim@emory.edu [Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA (United States); Department of Pharmacy, School of Pharmacy, Kyung-Hee University, Seoul (Korea, Republic of); Wu, Li, E-mail: wu.840@osu.edu [Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH (United States)

    2016-08-15

    SAMHD1 limits HIV-1 infection in non-dividing myeloid cells by decreasing intracellular dNTP pools. HIV-1 restriction by SAMHD1 in these cells likely prevents activation of antiviral immune responses and modulates viral pathogenesis, thus highlighting a critical role of SAMHD1 in HIV-1 physiopathology. Here, we explored the function of SAMHD1 in regulating cell proliferation, cell cycle progression and apoptosis in monocytic THP-1 cells. Using the CRISPR/Cas9 technology, we generated THP-1 cells with stable SAMHD1 knockout. We found that silencing of SAMHD1 in cycling cells stimulates cell proliferation, redistributes cell cycle population in the G{sub 1}/G{sub 0} phase and reduces apoptosis. These alterations correlated with increased dNTP levels and more efficient HIV-1 infection in dividing SAMHD1 knockout cells relative to control. Our results suggest that SAMHD1, through its dNTPase activity, affects cell proliferation, cell cycle distribution and apoptosis, and emphasize a key role of SAMHD1 in the interplay between cell cycle regulation and HIV-1 infection.

  8. Outside-in control -Does plant cell wall integrity regulate cell cycle progression?

    Science.gov (United States)

    Gigli-Bisceglia, Nora; Hamann, Thorsten

    2018-04-13

    During recent years it has become accepted that plant cell walls are not inert objects surrounding all plant cells but are instead highly dynamic, plastic structures. They are involved in a large number of cell biological processes and contribute actively to plant growth, development and interaction with environment. Therefore, it is not surprising that cellular processes can control plant cell wall integrity while, simultaneously, cell wall integrity can influence cellular processes. In yeast and animal cells such a bi-directional relationship also exists between the yeast/animal extra-cellular matrices and the cell cycle. In yeast, the cell wall integrity maintenance mechanism and a dedicated plasmamembrane integrity checkpoint are mediating this relationship. Recent research has yielded insights into the mechanism controlling plant cell wall metabolism during cytokinesis. However, knowledge regarding putative regulatory pathways controlling adaptive modifications in plant cell cycle activity in response to changes in the state of the plant cell wall are not yet identified. In this review, we summarize similarities and differences in regulatory mechanisms coordinating extra cellular matrices and cell cycle activity in animal and yeast cells, discuss the available evidence supporting the existence of such a mechanism in plants and suggest that the plant cell wall integrity maintenance mechanism might also control cell cycle activity in plant cells. This article is protected by copyright. All rights reserved.

  9. Optimizing design of converters using power cycling lifetime models

    DEFF Research Database (Denmark)

    Nielsen, Rasmus Ørndrup; Munk-Nielsen, Stig

    2015-01-01

    Converter power cycling lifetime depends heavily on converter operation point. A lifetime model of a single power module switched mode power supply with wide input voltage range is shown. A lifetime model is created using a power loss model, a thermal model and a model for power cycling capability...... with a given mission profile. A method to improve the expected lifetime of the converter is presented, taking into account switching frequency, input voltage and transformer turns ratio....

  10. The cancer-germline antigen SSX2 causes cell cycle arrest and DNA damage in cancer cells

    DEFF Research Database (Denmark)

    Greve, Katrine Buch Vidén; Lindgreen, Jonas; Terp, Mikkel Green

    2011-01-01

    The SSX family of cancer and germline antigens is mainly expressed in the germ cells of healthy individuals as well as wide range of cancers and is therefore potential targets for immunotherapy. However, little is known about the role of SSX proteins in tumorigenesis and normal cell function. Here......, we show that SSX2 is involved in regulation of cancer cell growth. We found that ectopic expression of SSX2 in melanoma and colon cancer cells strongly reduced cell growth and induced apoptosis in vitro. Importantly, in a xenograft mouse model, the growth of tumors derived from SSX2 overexpressing...... melanoma cells was severely reduced compared to those derived from the isogenic parental cell line. Cell cycle analysis showed that SSX2 caused an accumulation of cells arrested in G1. Consistent with this, we observed a marked decrease in cells expressing the proliferation marker Ki67 and concomitantly...

  11. Effects of [3H]UdR on the cell-cycle progression of L1210 cells

    International Nuclear Information System (INIS)

    Darzynkiewicz, Z.; Carter, S.; Kimmel, M.

    1984-01-01

    Tritium-labelled uridine (( 3 H)UdR)perturbs progression of L1210 cells through the mitotic cycle. A slowdown of G 2 cells is observed 2 hr after addition of 0.5-5.0 μci/ml of ( 3 H)UdR into cultures. At 2.5-5.0 μCi/ml of ( 3 H)UdR a slowdown of cell progression through S is also apparent. Additionally, there is an increase in the number of cells with DNA values higher than 4C in cultures growing in the presence of ( 3 H)UdR for 8-24 hr. A pulse of ( 3 H)UdR of 2 hr duration labels predominantly (95%) cellular RNA. The first cell-cycle effects (G 2 slowdown) are observed when the amount of the incorporated ( 3 H)UdR is such that, on average there are fewer than thirty-six ( 3 H) decays per cell which corresponds to approximately 12-19 rads. The S-phase slowdown is seen at a dose of incorporated ( 3 H)UdR twice as high as that inducing G 2 effects. The specific localization of ( 3 H)UdR in nucleoli, peripheral nucleoplasm and in cytoplasm, as well as differences in the kinetics of the incorporation in relation to phases of the cell cycle are discussed. Mathematical modelling of the cell-cycle effects of ( 3 H)UdR is provided. (author)

  12. Cell cycle dependent changes in the plasma membrane organization of mammalian cells.

    Science.gov (United States)

    Denz, Manuela; Chiantia, Salvatore; Herrmann, Andreas; Mueller, Peter; Korte, Thomas; Schwarzer, Roland

    2017-03-01

    Lipid membranes are major structural elements of all eukaryotic and prokaryotic organisms. Although many aspects of their biology have been studied extensively, their dynamics and lateral heterogeneity are still not fully understood. Recently, we observed a cell-to-cell variability in the plasma membrane organization of CHO-K1 cells (Schwarzer et al., 2014). We surmised that cell cycle dependent changes of the individual cells from our unsynchronized cell population account for this phenomenon. In the present study, this hypothesis was tested. To this aim, CHO-K1 cells were arrested in different cell cycle phases by chemical treatments, and the order of their plasma membranes was determined by various fluorescent lipid analogues using fluorescence lifetime imaging microscopy. Our experiments exhibit significant differences in the membrane order of cells arrested in the G2/M or S phase compared to control cells. Our single-cell analysis also enabled the specific selection of mitotic cells, which displayed a significant increase of the membrane order compared to the control. In addition, the lipid raft marker GPImYFP was used to study the lateral organization of cell cycle arrested cells as well as mitotic cells and freely cycling samples. Again, significant differences were found between control and arrested cells and even more pronounced between control and mitotic cells. Our data demonstrate a direct correlation between cell cycle progression and plasma membrane organization, underlining that cell-to-cell heterogeneities of membrane properties have to be taken into account in cellular studies especially at the single-cell level. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Cell cycle analysis in patients with Fanconi anemia from Serbia

    Directory of Open Access Journals (Sweden)

    Ćirković Sanja

    2013-01-01

    Full Text Available Fanconi anemia (FA is a rare autosomal recessive disorder, characterized by progressive bone marrow failure, chromosomal instability and cell cycle blockage in the G2 phase. The hypersensitivity of FA cells can be additionally induced with specific alkylating agents such as diepoxybutane (DEB and mitomycin C, which is used in differential diagnosis of FA. Among 72 patients with clinical suspicion of FA, who were diagnosed at the Mother and Child Health Care Institute of Serbia “Dr Vukan Cupic” and the University Children’s Hospital (2004 - 2011, in 10 patients the diagnosis of FA was confirmed on the basis of an increased chromosome sensitivity to DEB. Five out of 10 FA patients were available for further flow cytometric analysis of cell cycle. We examined cell cycle blockage in G2 phase in untreated and with DEB treated lymphocyte cultures from FA patients and from the healthy persons, as control group. All five patients affected with FA, showed an increased DEB induced G2-phase-blockage which was over two times higher than in controls. The percentage of FA cells arrested in G2 phase was between 4,41% and 10,45% with mean value (MV of 7,76%, but in the control group this range was lower: 1,56% - 4,11% (MV: 2.84%, with no overlapping. FA patients showed an increased spontaneous arrest in G2 phase, as well, comparing to healthy controls (MV: 14,63% vs. 5,82%. Cell cycle assay of G2 phase blockage could be used as an additional diagnostic tool for confirmation of FA in patients with clinical suspicion of this disease. [Projekat Ministarstva nauke Republike Srbije, br. 173046

  14. Nuclear receptor TLX regulates cell cycle progression in neural stem cells of the developing brain.

    Science.gov (United States)

    Li, Wenwu; Sun, Guoqiang; Yang, Su; Qu, Qiuhao; Nakashima, Kinichi; Shi, Yanhong

    2008-01-01

    TLX is an orphan nuclear receptor that is expressed exclusively in vertebrate forebrains. Although TLX is known to be expressed in embryonic brains, the mechanism by which it influences neural development remains largely unknown. We show here that TLX is expressed specifically in periventricular neural stem cells in embryonic brains. Significant thinning of neocortex was observed in embryonic d 14.5 TLX-null brains with reduced nestin labeling and decreased cell proliferation in the germinal zone. Cell cycle analysis revealed both prolonged cell cycles and increased cell cycle exit in TLX-null embryonic brains. Increased expression of a cyclin-dependent kinase inhibitor p21 and decreased expression of cyclin D1 provide a molecular basis for the deficiency of cell cycle progression in embryonic brains of TLX-null mice. Furthermore, transient knockdown of TLX by in utero electroporation led to precocious cell cycle exit and differentiation of neural stem cells followed by outward migration. Together these results indicate that TLX plays an important role in neural development by regulating cell cycle progression and exit of neural stem cells in the developing brain.

  15. Akt1 intramitochondrial cycling is a crucial step in the redox modulation of cell cycle progression.

    Directory of Open Access Journals (Sweden)

    Valeria Gabriela Antico Arciuch

    2009-10-01

    Full Text Available Akt is a serine/threonine kinase involved in cell proliferation, apoptosis, and glucose metabolism. Akt is differentially activated by growth factors and oxidative stress by sequential phosphorylation of Ser(473 by mTORC2 and Thr(308 by PDK1. On these bases, we investigated the mechanistic connection of H(2O(2 yield, mitochondrial activation of Akt1 and cell cycle progression in NIH/3T3 cell line with confocal microscopy, in vivo imaging, and directed mutagenesis. We demonstrate that modulation by H(2O(2 entails the entrance of cytosolic P-Akt1 Ser(473 to mitochondria, where it is further phosphorylated at Thr(308 by constitutive PDK1. Phosphorylation of Thr(308 in mitochondria determines Akt1 passage to nuclei and triggers genomic post-translational mechanisms for cell proliferation. At high H(2O(2, Akt1-PDK1 association is disrupted and P-Akt1 Ser(473 accumulates in mitochondria in detriment to nuclear translocation; accordingly, Akt1 T308A is retained in mitochondria. Low Akt1 activity increases cytochrome c release to cytosol leading to apoptosis. As assessed by mass spectra, differential H(2O(2 effects on Akt1-PDK interaction depend on the selective oxidation of Cys(310 to sulfenic or cysteic acids. These results indicate that Akt1 intramitochondrial-cycling is central for redox modulation of cell fate.

  16. Lineage-specific interface proteins match up the cell cycle and differentiation in embryo stem cells

    DEFF Research Database (Denmark)

    Re, Angela; Workman, Christopher; Waldron, Levi

    2014-01-01

    The shortage of molecular information on cell cycle changes along embryonic stem cell (ESC) differentiation prompts an in silico approach, which may provide a novel way to identify candidate genes or mechanisms acting in coordinating the two programs. We analyzed germ layer specific gene expression...... changes during the cell cycle and ESC differentiation by combining four human cell cycle transcriptome profiles with thirteen in vitro human ESC differentiation studies. To detect cross-talk mechanisms we then integrated the transcriptome data that displayed differential regulation with protein...... interaction data. A new class of non-transcriptionally regulated genes was identified, encoding proteins which interact systematically with proteins corresponding to genes regulated during the cell cycle or cell differentiation, and which therefore can be seen as interface proteins coordinating the two...

  17. Models of the Organizational Life Cycle: Applications to Higher Education.

    Science.gov (United States)

    Cameron, Kim S.; Whetten, David A.

    1983-01-01

    A review of models of group and organization life cycle development is provided and the applicability of those models for institutions of higher education are discussed. An understanding of the problems and characteristics present in different life cycle stages can help institutions manage transitions more effectively. (Author/MLW)

  18. Checks and balances? DNA replication and the cell cycle in Plasmodium.

    Science.gov (United States)

    Matthews, Holly; Duffy, Craig W; Merrick, Catherine J

    2018-03-27

    It is over 100 years since the life-cycle of the malaria parasite Plasmodium was discovered, yet its intricacies remain incompletely understood - a knowledge gap that may prove crucial for our efforts to control the disease. Phenotypic screens have partially filled the void in the antimalarial drug market, but as compound libraries eventually become exhausted, new medicines will only come from directed drug development based on a better understanding of fundamental parasite biology. This review focusses on the unusual cell cycles of Plasmodium, which may present a rich source of novel drug targets as well as a topic of fundamental biological interest. Plasmodium does not grow by conventional binary fission, but rather by several syncytial modes of replication including schizogony and sporogony. Here, we collate what is known about the various cell cycle events and their regulators throughout the Plasmodium life-cycle, highlighting the differences between Plasmodium, model organisms and other apicomplexan parasites and identifying areas where further study is required. The possibility of DNA replication and the cell cycle as a drug target is also explored. Finally the use of existing tools, emerging technologies, their limitations and future directions to elucidate the peculiarities of the Plasmodium cell cycle are discussed.

  19. Aneuploidy assessed by DNA index influences the effect of iron status on plasma and/or supernatant cytokine levels and progression of cells through the cell cycle in a mouse model.

    Science.gov (United States)

    Kuvibidila, Solo; Porretta, Connie; Baliga, Surendra

    2014-02-01

    Aneuploidy, a condition associated with altered chromosome number, hence DNA index, is frequently seen in many diseases including cancers and affects immunity. Iron, an essential nutrient for humans, modulates the immune function and the proliferation of normal and cancer cells. To determine whether impaired immunity seen in iron-deficient subjects may be related to aneuploidy, we measured spleen cell DNA index, percent of cells in different phases of the cell cycle, plasma and/or supernatant IL-2, IL-10, IL-12, and interferon-gamma in control, pair-fed, iron-deficient, and iron-replete mice (N=20-22/group). The test and control diets differed only in iron content (0.09mmol/kg versus 0.9mmol/kg) and were fed for 68days. Mean levels of hemoglobin and liver iron stores of iron-deficient and iron-replete mice were 40-60% lower than those of control and pair-fed mice (P<0.05). Mean plasma levels of IL-10, interferon-gamma and percent of cells in S+G2/M phases were lower in mice with than in those without aneuploidy (P<0.05). Lowest plasma IL-12 and interferon-gamma concentrations were observed in iron-deficient mice with aneuploidy. Mean percents of cultures with aneuploidy and DNA indexes were higher in iron-deficient and iron-replete than in control and pair-fed mice likely due to delayed cell division (P<0.05). Aneuploidy decreased the concentration of IL-2 and interferon-gamma in baseline cultures while it increased that of interferon-gamma in anti-CD3 treated cultures. Aneuploidic indexes negatively correlated with cytokine levels, percents of cells in S+G2/M phases and indicators of iron status (P<0.05). Although chromosome cytogenetics was not performed, for the first time, we report that increased aneuploidy rate may modulate the immune function during iron-deficiency. Copyright © 2014. Published by Elsevier Ltd.

  20. Redistribution of cell cycle by arsenic trioxide is associated with demethylation and expression changes of cell cycle related genes in acute promyelocytic leukemia cell line (NB4).

    Science.gov (United States)

    Hassani, Saeed; Khaleghian, Ali; Ahmadian, Shahin; Alizadeh, Shaban; Alimoghaddam, Kamran; Ghavamzadeh, Ardeshir; Ghaffari, Seyed H

    2018-01-01

    PML-RARα perturbs the normal epigenetic setting, which is essential to oncogenic transformation in acute promyelocytic leukemia (APL). Transcription induction and recruitment of DNA methyltransferases (DNMTs) by PML-RARα and subsequent hypermethylation are components of this perturbation. Arsenic trioxide (ATO), an important drug in APL therapy, concurrent with degradation of PML-RARα induces cell cycle change and apoptosis. How ATO causes cell cycle alteration has remained largely unexplained. Here, we investigated DNA methylation patterns of cell cycle regulatory genes promoters, the effects of ATO on the methylated genes and cell cycle distribution in an APL cell line, NB4. Analysis of promoter methylation status of 22 cell cycle related genes in NB4 revealed that CCND1, CCNE1, CCNF, CDKN1A, GADD45α, and RBL1 genes were methylated 60.7, 84.6, 58.6, 8.7, 33.4, and 73.7%, respectively, that after treatment with 2 μM ATO for 48 h, turn into 0.6, 13.8, 0.1, 6.6, 10.7, and 54.5% methylated. ATO significantly reduced the expression of DNMT1, 3A, and 3B. ATO induced the expression of CCND1, CCNE1, and GADD45α genes, suppressed the expression of CCNF and CDKN1A genes, which were consistent with decreased number of cells in G1 and S phases and increased number of cells in G2/M phase. In conclusion, demethylation and alteration in the expression level of the cell cycle related genes may be possible mechanisms in ATO-induced cell cycle arrest in APL cells. It may suggest that ATO by demethylation of CCND1 and CCNE1 and their transcriptional activation accelerates G1 and S transition into the G2/M cell cycle arrest.

  1. Modeling of DNA damage-cluster, cell-cycle and repair pathway dependent radiosensitivity after low- and high-LET irradiation; Modellierung der DNA-Schadenscluster-, Zellzyklus- und Reparaturweg-abhaengigen Strahlenempfindlichkeit nach niedrig- und hoch-LET-Bestrahlung

    Energy Technology Data Exchange (ETDEWEB)

    Guenther, Paul

    2017-07-17

    irradiation. This method is able to qualitatively predict the influence of the cell-cycle and the radiation quality on radiosensitivity. Based on this, two approaches for the LEM prediction of the Relative Biological Effectiveness (RBE) are compared. The first approach predicts the RBE based on the survival of asynchronous cells. The second approach predicts the RBE from the sum of survival curves of the subpopulations, which contribute to the asynchronous cell population. Both approaches lead to qualitatively similar results. In the context of describing the microscopic dose deposition of ion irradiation by the amorphous track structure, two questions are addressed: 1. Is it possible to improve the prediction of cell survival after ion irradiation by a more sophisticated composition of the direct and indirect effect? 2. is the amorphous track structure an appropriate model of the dose deposition regarding the DNA damage clustering on the nm-scale or is it necessary to evaluate single ionizations on the molecular level? Regarding the first question, it is shown that a more detailed evaluation of the direct and indirect effect improves the agreement of the LEM predictions to data. Concerning the second question, it is shown that the amorphous track structure can be used for the prediction of DNA damage induction on the nm-scale similar to an ab initio Monte Carlo simulation. In the context of cell-survival modeling, the relevant length scale for DNA damage-clustering is often discussed. The iDSBs und cDSBs used in the GLOBLE and LEM are referring to DNA damage clustering on the μm-scale. There are also models which predict the cell survival after ion irradiation based on complex DNA-damage-clusters on the nm-scale. This work shows, that complex DNA damage-clusters on the μm-scale are correlated to damage clusters on the nm-scale. Therefore, it is possible to predict the cell survival after ion irradiation based on both scales. However, the cell survival after photon

  2. Rising cyclin-CDK levels order cell cycle events.

    Directory of Open Access Journals (Sweden)

    Catherine Oikonomou

    Full Text Available Diverse mitotic events can be triggered in the correct order and time by a single cyclin-CDK. A single regulator could confer order and timing on multiple events if later events require higher cyclin-CDK than earlier events, so that gradually rising cyclin-CDK levels can sequentially trigger responsive events: the "quantitative model" of ordering.This 'quantitative model' makes predictions for the effect of locking cyclin at fixed levels for a protracted period: at low cyclin levels, early events should occur rapidly, while late events should be slow, defective, or highly variable (depending on threshold mechanism. We titrated the budding yeast mitotic cyclin Clb2 within its endogenous expression range to a stable, fixed level and measured time to occurrence of three mitotic events: growth depolarization, spindle formation, and spindle elongation, as a function of fixed Clb2 level. These events require increasingly more Clb2 according to their normal order of occurrence. Events occur efficiently and with low variability at fixed Clb2 levels similar to those observed when the events normally occur. A second prediction of the model is that increasing the rate of cyclin accumulation should globally advance timing of all events. Moderate (<2-fold overexpression of Clb2 accelerates all events of mitosis, resulting in consistently rapid sequential cell cycles. However, this moderate overexpression also causes a significant frequency of premature mitoses leading to inviability, suggesting that Clb2 expression level is optimized to balance the fitness costs of variability and catastrophe.We conclude that mitotic events are regulated by discrete cyclin-CDK thresholds. These thresholds are sequentially triggered as cyclin increases, yielding reliable order and timing. In many biological processes a graded input must be translated into discrete outputs. In such systems, expression of the central regulator is likely to be tuned to an optimum level, as we

  3. Transcriptional and Cell Cycle Alterations Mark Aging of Primary Human Adipose-Derived Stem Cells.

    Science.gov (United States)

    Shan, Xiaoyin; Roberts, Cleresa; Kim, Eun Ji; Brenner, Ariana; Grant, Gregory; Percec, Ivona

    2017-05-01

    Adult stem cells play a critical role in the maintenance of tissue homeostasis and prevention of aging. While the regenerative potential of stem cells with low cellular turnover, such as adipose-derived stem cells (ASCs), is increasingly recognized, the study of chronological aging in ASCs is technically difficult and remains poorly understood. Here, we use our model of chronological aging in primary human ASCs to examine genome-wide transcriptional networks. We demonstrate first that the transcriptome of aging ASCs is distinctly more stable than that of age-matched fibroblasts, and further, that age-dependent modifications in cell cycle progression and translation initiation specifically characterize aging ASCs in conjunction with increased nascent protein synthesis and a distinctly shortened G1 phase. Our results reveal novel chronological aging mechanisms in ASCs that are inherently different from differentiated cells and that may reflect an organismal attempt to meet the increased demands of tissue and organ homeostasis during aging. Stem Cells 2017;35:1392-1401. © 2017 AlphaMed Press.

  4. The cell cycle regulator protein P16 and the cellular senescence of dental follicle cells.

    Science.gov (United States)

    Morsczeck, Christian; Hullmann, Markus; Reck, Anja; Reichert, Torsten E

    2018-02-01

    Cellular senescence is a restricting factor for regenerative therapies with somatic stem cells. We showed previously that the onset of cellular senescence inhibits the osteogenic differentiation in stem cells of the dental follicle (DFCs), although the mechanism remains elusive. Two different pathways are involved in the induction of the cellular senescence, which are driven either by the cell cycle protein P21 or by the cell cycle protein P16. In this study, we investigated the expression of cell cycle proteins in DFCs after the induction of cellular senescence. The induction of cellular senescence was proved by an increased expression of β-galactosidase and an increased population doubling time after a prolonged cell culture. Cellular senescence regulated the expression of cell cycle proteins. The expression of cell cycle protein P16 was up-regulated, which correlates with the induction of cellular senescence markers in DFCs. However, the expression of cyclin-dependent kinases (CDK)2 and 4 and the expression of the cell cycle protein P21 were successively decreased in DFCs. In conclusion, our data suggest that a P16-dependent pathway drives the induction of cellular senescence in DFCs.

  5. Susceptibility of Hep3B cells in different phases of cell cycle to tBid.

    Science.gov (United States)

    Ma, Shi-Hong; Chen, George G; Ye, Caiguo; Leung, Billy C S; Ho, Rocky L K; Lai, Paul B S

    2011-01-01

    tBid is a pro-apoptotic molecule. Apoptosis inducers usually act in a cell cycle-specific fashion. The aim of this study was to elucidate whether effect of tBid on hepatocellular carcinoma (HCC) Hep3B cells was cell cycle phase specific. We synchronized Hep3B cells at G0/G1, S or G2/M phases by chemicals or flow sorting and tested the susceptibility of the cells to recombinant tBid. Cell viability was measured by MTT assay and apoptosis by TUNEL. The results revealed that tBid primarily targeted the cells at G0/G1 phase of cell cycle, and it also increased the cells at the G2/M phase. 5-Fluorouracil (5-FU), on the other hand, arrested Hep3B cells at the G0/G1 phase, but significantly reduced cells at G2/M phase. The levels of cell cycle-related proteins and caspases were altered in line with the change in the cell cycle. The combination of tBid with 5-FU caused more cells to be apoptotic than either agent alone. Therefore, the complementary effect of tBid and 5-FU on different phases of the cell cycle may explain their synergistric effect on Hep3B cells. The elucidation of the phase-specific effect of tBid points to a possible therapeutic option that combines different phase specific agents to overcome resistance of HCC. Copyright © 2010 Elsevier B.V. All rights reserved.

  6. Capsaicin induces cell cycle arrest and apoptosis in human KB cancer cells.

    Science.gov (United States)

    Lin, Chia-Han; Lu, Wei-Cheng; Wang, Che-Wei; Chan, Ya-Chi; Chen, Mu-Kuan

    2013-02-25

    Capsaicin, a pungent phytochemical in a variety of red peppers of the genus Capsicum, has shown an anti-proliferative effect on various human cancer cell lines. In contrast, capsaicin has also been considered to promote the growth of cancer cells. Thus, the effects of capsaicin on various cell types need to be explored. The anti-proliferative effects of capsaicin on human KB cancer cells are still unknown. Therefore, we examined the viability, cell cycle progression, and factors associated with apoptosis in KB cells treated with capsaicin. The cell proliferation/viability and cytotoxicity of KB cells exposed to capsaicin were determined by a sulforhodamine B colorimetric assay and trypan blue exclusion. Apoptosis was detected by Hoechst staining and confirmed by western blot analysis of poly-(ADP-ribose) polymerase cleavage. Cell cycle distribution and changes of the mitochondrial membrane potential were analyzed by flow cytometry. Furthermore, the expression of caspase 3, 8 and 9 was evaluated by immunoblotting. We found that treatment of KB cells with capsaicin significantly reduced cell proliferation/viability and induced cell death in a dose-dependent manner compared with that in the untreated control. Cell cycle analysis indicated that exposure of KB cells to capsaicin resulted in cell cycle arrest at G2/M phase. Capsaicin-induced growth inhibition of KB cells appeared to be associated with induction of apoptosis. Moreover, capsaicin induced disruption of the mitochondrial membrane potential as well as activation of caspase 9, 3 and poly-(ADP-ribose) polymerase in KB cells. Our data demonstrate that capsaicin modulates cell cycle progression and induces apoptosis in human KB cancer cells through mitochondrial membrane permeabilization and caspase activation. These observations suggest an anti-cancer activity of capsaicin.

  7. Phytol isolated from watermelon (Citrullus lanatus) sprouts induces cell death in human T-lymphoid cell line Jurkat cells via S-phase cell cycle arrest.

    Science.gov (United States)

    Itoh, Tomohiro; Ono, Akito; Kawaguchi, Kaori; Teraoka, Sayaka; Harada, Mayo; Sumi, Keitaro; Ando, Masashi; Tsukamasa, Yasuyuki; Ninomiya, Masayuki; Koketsu, Mamoru; Hashizume, Toshiharu

    2018-05-01

    The phytol isolated from watermelon (Citrullus lanatus) sprouts inhibited the growth of a human T-cell leukemia line Jurkat cell and suppressed tumor progression in a xenograft model of human lung adenocarcinoma epithelial cell line A549 in nude mice. To elucidate the mechanisms underlying the phytol-induced cell death in the present study, we examined the changes in cell morphology, DNA fragmentation, and intracellular reactive oxygen species (ROS) levels and performed flow cytometric analysis to evaluate cell cycle stage. There were no significant changes in apoptosis, autophagy, and necrosis marker in cells treated with the phytol. But, we found, for the first time, that phytol remarkably induced S-phase cell cycle arrest accompanied with intracellular ROS production. Western blot analyses showed that phytolinduced S-phase cell cycle arrest was mediated through the decreased expression of cyclins A and D and the downregulations of MAPK and PI3K/Akt. The tumor volume levels in mice treated with phytol were lower than those of non-treatment groups, and it showed very similar suppression compared with those of mice treated with cyclophosphamide. Based on the data of in vitro and in vivo studies and previous studies, we suggest phytol as a potential therapeutic compound for cancer. Copyright © 2018 Elsevier Ltd. All rights reserved.

  8. Linalool Induces Cell Cycle Arrest and Apoptosis in Leukemia Cells and Cervical Cancer Cells through CDKIs

    Directory of Open Access Journals (Sweden)

    Mei-Yin Chang

    2015-11-01

    Full Text Available Plantaginaceae, a popular traditional Chinese medicine, has long been used for treating various diseases from common cold to cancer. Linalool is one of the biologically active compounds that can be isolated from Plantaginaceae. Most of the commonly used cytotoxic anticancer drugs have been shown to induce apoptosis in susceptible tumor cells. However, the signaling pathway for apoptosis remains undefined. In this study, the cytotoxic effect of linalool on human cancer cell lines was investigated. Water-soluble tetrazolium salts (WST-1 based colorimetric cellular cytotoxicity assay, was used to test the cytotoxic ability of linalool against U937 and HeLa cells, and flow cytometry (FCM and genechip analysis were used to investigate the possible mechanism of apoptosis. These results demonstrated that linalool exhibited a good cytotoxic effect on U937 and HeLa cells, with the IC50 value of 2.59 and 11.02 μM, respectively, compared with 5-FU with values of 4.86 and 12.31 μM, respectively. After treating U937 cells with linalool for 6 h, we found an increased sub-G1 peak and a dose-dependent phenomenon, whereby these cells were arrested at the G0/G1 phase. Furthermore, by using genechip analysis, we observed that linalool can promote p53, p21, p27, p16, and p18 gene expression. Therefore, this study verified that linalool can arrest the cell cycle of U937 cells at the G0/G1 phase and can arrest the cell cycle of HeLa cells at the G2/M phase. Its mechanism facilitates the expression of the cyclin-dependent kinases inhibitors (CDKIs p53, p21, p27, p16, and p18, as well as the non-expression of cyclin-dependent kinases (CDKs activity.

  9. Cyclebase 3.0: a multi-organism database on cell-cycle regulation and phenotypes

    DEFF Research Database (Denmark)

    Santos Delgado, Alberto; Wernersson, Rasmus; Jensen, Lars Juhl

    2015-01-01

    3.0, we have updated the content of the database to reflect changes to genome annotation, added new mRNAand protein expression data, and integrated cell-cycle phenotype information from high-content screens and model-organism databases. The new version of Cyclebase also features a new web interface...

  10. Systematic identification of yeast cell cycle transcription factors using multiple data sources

    Directory of Open Access Journals (Sweden)

    Li Wen-Hsiung

    2008-12-01

    Full Text Available Abstract Background Eukaryotic cell cycle is a complex process and is precisely regulated at many levels. Many genes specific to the cell cycle are regulated transcriptionally and are expressed just before they are needed. To understand the cell cycle process, it is important to identify the cell cycle transcription factors (TFs that regulate the expression of cell cycle-regulated genes. Results We developed a method to identify cell cycle TFs in yeast by integrating current ChIP-chip, mutant, transcription factor binding site (TFBS, and cell cycle gene expression data. We identified 17 cell cycle TFs, 12 of which are known cell cycle TFs, while the remaining five (Ash1, Rlm1, Ste12, Stp1, Tec1 are putative novel cell cycle TFs. For each cell cycle TF, we assigned specific cell cycle phases in which the TF functions and identified the time lag for the TF to exert regulatory effects on its target genes. We also identified 178 novel cell cycle-regulated genes, among which 59 have unknown functions, but they may now be annotated as cell cycle-regulated genes. Most of our predictions are supported by previous experimental or computational studies. Furthermore, a high confidence TF-gene regulatory matrix is derived as a byproduct of our method. Each TF-gene regulatory relationship in this matrix is supported by at least three data sources: gene expression, TFBS, and ChIP-chip or/and mutant data. We show that our method performs better than four existing methods for identifying yeast cell cycle TFs. Finally, an application of our method to different cell cycle gene expression datasets suggests that our method is robust. Conclusion Our method is effective for identifying yeast cell cycle TFs and cell cycle-regulated genes. Many of our predictions are validated by the literature. Our study shows that integrating multiple data sources is a powerful approach to studying complex biological systems.

  11. Plant characteristics of an integrated solid oxide fuel cell cycle and a steam cycle

    International Nuclear Information System (INIS)

    Rokni, Masoud

    2010-01-01

    Plant characteristics of a system containing a solid oxide fuel cell (SOFC) cycle on the top of a Rankine cycle were investigated. A desulfurization reactor removes the sulfur content in the fuel, while a pre-reformer broke down the heavier hydrocarbons in an adiabatic steam reformer (ASR). The pre-treated fuel then entered to the anode side of the SOFC. The remaining fuels after the SOFC stacks entered a catalytic burner for further combusting. The burned gases from the burner were then used to produce steam for the Rankine cycle in a heat recovery steam generator (HRSG). The remaining energy of the off-gases was recycled back to the topping cycle for further utilization. Several parameter studies were carried out to investigate the sensitivity of the suggested plant. It was shown that the operation temperature of the desulfurization and the pre-reformer had no effect on the plant efficiency, which was also true when decreasing the anode temperature. However, increasing the cathode temperature had a significant effect on the plant efficiency. In addition, decreasing the SOFC utilization factor from 0.8 to 0.7, increases the plant efficiency by about 6%. An optimal plant efficiency of about 71% was achieved by optimizing the plant.

  12. Plant characteristics of an integrated solid oxide fuel cell cycle and a steam cycle

    Energy Technology Data Exchange (ETDEWEB)

    Rokni, Masoud [Technical University of Denmark, Dept. of Mechanical Engineering, Thermal Energy System, Building 402, 2800 Kgs, Lyngby (Denmark)

    2010-12-15

    Plant characteristics of a system containing a solid oxide fuel cell (SOFC) cycle on the top of a Rankine cycle were investigated. A desulfurization reactor removes the sulfur content in the fuel, while a pre-reformer broke down the heavier hydrocarbons in an adiabatic steam reformer (ASR). The pre-treated fuel then entered to the anode side of the SOFC. The remaining fuels after the SOFC stacks entered a catalytic burner for further combusting. The burned gases from the burner were then used to produce steam for the Rankine cycle in a heat recovery steam generator (HRSG). The remaining energy of the off-gases was recycled back to the topping cycle for further utilization. Several parameter studies were carried out to investigate the sensitivity of the suggested plant. It was shown that the operation temperature of the desulfurization and the pre-reformer had no effect on the plant efficiency, which was also true when decreasing the anode temperature. However, increasing the cathode temperature had a significant effect on the plant efficiency. In addition, decreasing the SOFC utilization factor from 0.8 to 0.7, increases the plant efficiency by about 6%. An optimal plant efficiency of about 71% was achieved by optimizing the plant. (author)

  13. Circadian Clock Synchronization of the Cell Cycle in Zebrafish Occurs through a Gating Mechanism Rather Than a Period-phase Locking Process.

    Science.gov (United States)

    Laranjeiro, Ricardo; Tamai, T Katherine; Letton, William; Hamilton, Noémie; Whitmore, David

    2018-04-01

    Studies from a number of model systems have shown that the circadian clock controls expression of key cell cycle checkpoints, thus providing permissive or inhibitory windows in which specific cell cycle events can occur. However, a major question remains: Is the clock actually regulating the cell cycle through such a gating mechanism or, alternatively, is there a coupling process that controls the speed of cell cycle progression? Using our light-responsive zebrafish cell lines, we address this issue directly by synchronizing the cell cycle in culture simply by changing the entraining light-dark (LD) cycle in the incubator without the need for pharmacological intervention. Our results show that the cell cycle rapidly reentrains to a shifted LD cycle within 36 h, with changes in p21 expression and subsequent S phase timing occurring within the first few hours of resetting. Reentrainment of mitosis appears to lag S phase resetting by 1 circadian cycle. The range of entrainment of the zebrafish clock to differing LD cycles is large, from 16 to 32 hour periods. We exploited this feature to explore cell cycle entrainment at both the population and single cell levels. At the population level, cell cycle length is shortened or lengthened under corresponding T-cycles, suggesting that a 1:1 coupling mechanism is capable of either speeding up or slowing down the cell cycle. However, analysis at the single cell level reveals that this, in fact, is not true and that a gating mechanism is the fundamental method of timed cell cycle regulation in zebrafish. Cell cycle length at the single cell level is virtually unaltered with varying T-cycles.

  14. An Adjusted Discount Rate Model for Fuel Cycle Cost Estimation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, S. K.; Kang, G. B.; Ko, W. I. [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2013-10-15

    Owing to the diverse nuclear fuel cycle options available, including direct disposal, it is necessary to select the optimum nuclear fuel cycles in consideration of the political and social environments as well as the technical stability and economic efficiency of each country. Economic efficiency is therefore one of the significant evaluation standards. In particular, because nuclear fuel cycle cost may vary in each country, and the estimated cost usually prevails over the real cost, when evaluating the economic efficiency, any existing uncertainty needs to be removed when possible to produce reliable cost information. Many countries still do not have reprocessing facilities, and no globally commercialized HLW (High-level waste) repository is available. A nuclear fuel cycle cost estimation model is therefore inevitably subject to uncertainty. This paper analyzes the uncertainty arising out of a nuclear fuel cycle cost evaluation from the viewpoint of a cost estimation model. Compared to the same discount rate model, the nuclear fuel cycle cost of a different discount rate model is reduced because the generation quantity as denominator in Equation has been discounted. Namely, if the discount rate reduces in the back-end process of the nuclear fuel cycle, the nuclear fuel cycle cost is also reduced. Further, it was found that the cost of the same discount rate model is overestimated compared with the different discount rate model as a whole.

  15. An Adjusted Discount Rate Model for Fuel Cycle Cost Estimation

    International Nuclear Information System (INIS)

    Kim, S. K.; Kang, G. B.; Ko, W. I.

    2013-01-01

    Owing to the diverse nuclear fuel cycle options available, including direct disposal, it is necessary to select the optimum nuclear fuel cycles in consideration of the political and social environments as well as the technical stability and economic efficiency of each country. Economic efficiency is therefore one of the significant evaluation standards. In particular, because nuclear fuel cycle cost may vary in each country, and the estimated cost usually prevails over the real cost, when evaluating the economic efficiency, any existing uncertainty needs to be removed when possible to produce reliable cost information. Many countries still do not have reprocessing facilities, and no globally commercialized HLW (High-level waste) repository is available. A nuclear fuel cycle cost estimation model is therefore inevitably subject to uncertainty. This paper analyzes the uncertainty arising out of a nuclear fuel cycle cost evaluation from the viewpoint of a cost estimation model. Compared to the same discount rate model, the nuclear fuel cycle cost of a different discount rate model is reduced because the generation quantity as denominator in Equation has been discounted. Namely, if the discount rate reduces in the back-end process of the nuclear fuel cycle, the nuclear fuel cycle cost is also reduced. Further, it was found that the cost of the same discount rate model is overestimated compared with the different discount rate model as a whole

  16. Verifiable Fuel Cycle Simulation Model (VISION): A Tool for Analyzing Nuclear Fuel Cycle Futures

    International Nuclear Information System (INIS)

    Jacobson, Jacob J.; Piet, Steven J.; Matthern, Gretchen E.; Shropshire, David E.; Jeffers, Robert F.; Yacout, A.M.; Schweitzer, Tyler

    2010-01-01

    The nuclear fuel cycle consists of a set of complex components that are intended to work together. To support the nuclear renaissance, it is necessary to understand the impacts of changes and timing of events in any part of the fuel cycle system such as how the system would respond to each technological change, a series of which moves the fuel cycle from where it is to a postulated future state. The system analysis working group of the United States research program on advanced fuel cycles (formerly called the Advanced Fuel Cycle Initiative) is developing a dynamic simulation model, VISION, to capture the relationships, timing, and changes in and among the fuel cycle components to help develop an understanding of how the overall fuel cycle works. This paper is an overview of the philosophy and development strategy behind VISION. The paper includes some descriptions of the model components and some examples of how to use VISION. For example, VISION users can now change yearly the selection of separation or reactor technologies, the performance characteristics of those technologies, and/or the routing of material among separation and reactor types - with the model still operating on a PC in <5 min.

  17. Radiobilogical cell survival models

    International Nuclear Information System (INIS)

    Zackrisson, B.

    1992-01-01

    A central issue in clinical radiobiological research is the prediction of responses to different radiation qualities. The choice of cell survival and dose-response model greatly influences the results. In this context the relationship between theory and model is emphasized. Generally, the interpretations of experimental data depend on the model. Cell survival models are systematized with respect to their relations to radiobiological theories of cell kill. The growing knowlegde of biological, physical, and chemical mechanisms is reflected in the formulation of new models. The present overview shows that recent modelling has been more oriented towards the stochastic fluctuations connected to radiation energy deposition. This implies that the traditional cell surivival models ought to be complemented by models of stochastic energy deposition processes and repair processes at the intracellular level. (orig.)

  18. Inhibition of exportin-1 function results in rapid cell cycle-associated DNA damage in cancer cells.

    Science.gov (United States)

    Burke, Russell T; Marcus, Joshua M; Orth, James D

    2017-06-13

    Selective inhibitors of nuclear export (SINE) are small molecules in development as anti-cancer agents. The first-in-class SINE, selinexor, is in clinical trials for blood and solid cancers. Selinexor forms a covalent bond with exportin-1 at cysteine-528, and blocks its ability to export cargos. Previous work has shown strong cell cycle effects and drug-induced cell death across many different cancer-derived cell lines. Here, we report strong cell cycle-associated DNA double-stranded break formation upon the treatment of cancer cells with SINE. In multiple cell models, selinexor treatment results in the formation of clustered DNA damage foci in 30-40% of cells within 8 hours that is dependent upon cysteine-528. DNA damage strongly correlates with G1/S-phase and decreased DNA replication. Live cell microscopy reveals an association between DNA damage and cell fate. Cells that form damage in G1-phase more often die or arrest, while those damaged in S/G2-phase frequently progress to cell division. Up to half of all treated cells form damage foci, and most cells that die after being damaged, were damaged in G1-phase. By comparison, non-transformed cell lines show strong cell cycle effects but little DNA damage and less death than cancer cells. Significant drug combination effects occur when selinexor is paired with different classes of agents that either cause DNA damage or that diminish DNA damage repair. These data present a novel effect of exportin-1 inhibition and provide a strong rationale for multiple combination treatments of selinexor with agents that are currently in use for the treatment of different solid cancers.

  19. A life-cycle perspective on automotive fuel cells

    International Nuclear Information System (INIS)

    Simons, Andrew; Bauer, Christian

    2015-01-01

    Highlights: • Individual inventories for each fuel cell system component, current and future. • Environmental and human health burdens from fuel cell production and end-of-life. • Comparison passenger transport in fuel cell and conventional vehicles. • Fuel cell can be more critical to overall burdens than hydrogen production. • Fuel cell developments require radical but possible changes to reduce burdens. - Abstract: The production and end-of-life (EoL) processes for current and future proton exchange membrane fuel cell (PEMFC) systems for road passenger vehicle applications were analysed and quantified in the form of life cycle inventories. The current PEMFC technology is characterised by highly sensitive operating conditions and a high system mass. For each core component of PEMFC there are a range of materials under development and the research aimed to identify those considered realistic for a 2020 future scenario and according to commercial goals of achieving higher performance, increased power density, greater stability and a marked reduction of costs. End-of-life scenarios were developed in consideration of the materials at the focus of recovery efforts. The life cycle impact assessment (LCIA) addressed the production and EoL of the fuel cell systems with inclusion of a sensitivity analysis to assess influences on the results from the key fuel cell parameters. The second part to the LCIA assessed the environmental and human health burdens from passenger transport in a fuel cell vehicle (FCV) with comparison between the 2012 and 2020 fuel cell scenarios and referenced to an internal combustion engine vehicle (ICEV) of Euro5 emission standard. It was seen that whilst the drivetrain (and therefore the fuel cell system) is a major contributor to the emissions in all the indicators shown, the hydrogen use (and therefore the efficiency of the fuel cell system and the method of hydrogen production) can have a far greater influence on the environmental

  20. Cell cycle-dependent Rho GTPase activity dynamically regulates cancer cell motility and invasion in vivo.

    Science.gov (United States)

    Kagawa, Yoshinori; Matsumoto, Shinji; Kamioka, Yuji; Mimori, Koshi; Naito, Yoko; Ishii, Taeko; Okuzaki, Daisuke; Nishida, Naohiro; Maeda, Sakae; Naito, Atsushi; Kikuta, Junichi; Nishikawa, Keizo; Nishimura, Junichi; Haraguchi, Naotsugu; Takemasa, Ichiro; Mizushima, Tsunekazu; Ikeda, Masataka; Yamamoto, Hirofumi; Sekimoto, Mitsugu; Ishii, Hideshi; Doki, Yuichiro; Matsuda, Michiyuki; Kikuchi, Akira; Mori, Masaki; Ishii, Masaru

    2013-01-01

    The mechanism behind the spatiotemporal control of cancer cell dynamics and its possible association with cell proliferation has not been well established. By exploiting the intravital imaging technique, we found that cancer cell motility and invasive properties were closely associated with the cell cycle. In vivo inoculation of human colon cancer cells bearing fluorescence ubiquitination-based cell cycle indicator (Fucci) demonstrated an unexpected phenomenon: S/G2/M cells were more motile and invasive than G1 cells. Microarray analyses showed that Arhgap11a, an uncharacterized Rho GTPase-activating protein (RhoGAP), was expressed in a cell-cycle-dependent fashion. Expression of ARHGAP11A in cancer cells suppressed RhoA-dependent mechanisms, such as stress fiber formation and focal adhesion, which made the cells more prone to migrate. We also demonstrated that RhoA suppression by ARHGAP11A induced augmentation of relative Rac1 activity, leading to an increase in the invasive properties. RNAi-based inhibition of Arhgap11a reduced the invasion and in vivo expansion of cancers. Additionally, analysis of human specimens showed the significant up-regulation of Arhgap11a in colon cancers, which was correlated with clinical invasion status. The present study suggests that ARHGAP11A, a cell cycle-dependent RhoGAP, is a critical regulator of cancer cell mobility and is thus a promising therapeutic target in invasive cancers.

  1. Cell cycle-dependent Rho GTPase activity dynamically regulates cancer cell motility and invasion in vivo.

    Directory of Open Access Journals (Sweden)

    Yoshinori Kagawa

    Full Text Available The mechanism behind the spatiotemporal control of cancer cell dynamics and its possible association with cell proliferation has not been well established. By exploiting the intravital imaging technique, we found that cancer cell motility and invasive properties were closely associated with the cell cycle. In vivo inoculation of human colon cancer cells bearing fluorescence ubiquitination-based cell cycle indicator (Fucci demonstrated an unexpected phenomenon: S/G2/M cells were more motile and invasive than G1 cells. Microarray analyses showed that Arhgap11a, an uncharacterized Rho GTPase-activating protein (RhoGAP, was expressed in a cell-cycle-dependent fashion. Expression of ARHGAP11A in cancer cells suppressed RhoA-dependent mechanisms, such as stress fiber formation and focal adhesion, which made the cells more prone to migrate. We also demonstrated that RhoA suppression by ARHGAP11A induced augmentation of relative Rac1 activity, leading to an increase in the invasive properties. RNAi-based inhibition of Arhgap11a reduced the invasion and in vivo expansion of cancers. Additionally, analysis of human specimens showed the significant up-regulation of Arhgap11a in colon cancers, which was correlated with clinical invasion status. The present study suggests that ARHGAP11A, a cell cycle-dependent RhoGAP, is a critical regulator of cancer cell mobility and is thus a promising therapeutic target in invasive cancers.

  2. Mast cells dysregulate apoptotic and cell cycle genes in mucosal squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Davis Paul

    2006-12-01

    Full Text Available Abstract Background Mucosal squamous cell carcinoma of the head and neck is a disease of high mortality and morbidity. Interactions between the squamous cell carcinoma and the host's local immunity, and how the latter contributes to the biological behavior of the tumor are unclear. In vivo studies have demonstrated sequential mast cell infiltration and degranulation during squamous cell carcinogenesis. The degree of mast cell activation correlates closely with distinct phases of hyperkeratosis, dysplasia, carcinoma in-situ and invasive carcinoma. However, the role of mast cells in carcinogenesis is unclear. Aim This study explores the effects of mast cells on the proliferation and gene expression profile of mucosal squamous cell carcinoma using human mast cell line (HMC-1 and human glossal squamous cell carcinoma cell line (SCC25. Methods HMC-1 and SCC25 were co-cultured in a two-compartment chamber, separated by a polycarbonate membrane. HMC-1 was stimulated to degranulate with calcium ionophore A23187. The experiments were done in quadruplicate. Negative controls were established where SCC25 were cultured alone without HMC-1. At 12, 24, 48 and 72 hours, proliferation and viability of SCC25 were assessed with MTT colorimetric assay. cDNA microarray was employed to study differential gene expression between co-cultured and control SCC25. Results HMC-1/SCC25 co-culture resulted in suppression of growth rate for SCC-25 (34% compared with 110% for the control by 72 hours, p Conclusion We show that mast cells have a direct inhibitory effect on the proliferation of mucosal squamous cell carcinoma in vitro by dysregulating key genes in apoptosis and cell cycle control.

  3. Life-cycle analysis of product integrated polymer solar cells

    DEFF Research Database (Denmark)

    Espinosa Martinez, Nieves; García-Valverde, Rafael; Krebs, Frederik C

    2011-01-01

    A life cycle analysis (LCA) on a product integrated polymer solar module is carried out in this study. These assessments are well-known to be useful in developmental stages of a product in order to identify the bottlenecks for the up-scaling in its production phase for several aspects spanning from...... economics through design to functionality. An LCA study was performed to quantify the energy use and greenhouse gas (GHG) emissions from electricity use in the manufacture of a light-weight lamp based on a plastic foil, a lithium-polymer battery, a polymer solar cell, printed circuitry, blocking diode......, switch and a white light emitting semiconductor diode. The polymer solar cell employed in this prototype presents a power conversion efficiency in the range of 2 to 3% yielding energy payback times (EPBT) in the range of 1.3–2 years. Based on this it is worthwhile to undertake a life-cycle study...

  4. Soaking RNAi in Bombyx mori BmN4-SID1 Cells Arrests Cell Cycle Progression

    Science.gov (United States)

    Mon, Hiroaki; Li, Zhiqing; Kobayashi, Isao; Tomita, Shuichiro; Lee, JaeMan; Sezutsu, Hideki; Tamura, Toshiki; Kusakabe, Takahiro

    2013-01-01

    RNA interference (RNAi) is an evolutionarily conserved mechanism for sequence-specific gene silencing. Previously, the BmN4-SID1 cell expressing Caenorhabditis ele gans SID-1 was established, in which soaking RNAi could induce effective gene silencing. To establish its utility, 6 cell cycle progression related cDNAs, CDK1, MYC, MYB, RNRS, CDT1, and GEMININ, were isolated from the silkworm, Bombyx mori L. (Lepidoptera: Bombycidae), and their expressions were further silenced by soaking RNAi in the BmN4-SID1 cells. The cell cycle progression analysis using flow cytometer demonstrated that the small amount of double stranded RNA was enough to arrest cell cycle progression at the specific cell phases. These data suggest that RNAi in the BmN4-SID1 cells can be used as a powerful tool for loss-of-function analysis of B. mori genes. PMID:24773378

  5. INTERACTION BETWEEN MODELS OF THE LIFE CYCLE OF INDUSTRIAL ENTERPRISE AND CYCLE OF ITS REORGANIZATION

    Directory of Open Access Journals (Sweden)

    Chulkov Vitaliy Olegovich

    2012-10-01

    Full Text Available The objective of this scientific research is to develop a theoretical model of organizational and technology-related processes of reorganization of industrial enterprises, as well as their interaction. Multipoint logic notions of growth and interaction phases are used as research methods. The author describes the basic stages of reorganization, the life cycle of industrial enterprises and the cycle of their transformation. The processes are presented as an infographical image that represents a concentric model of interaction. This concentric model represents interaction between two or more phases. The process is entitled infografical modeling on the polyfunctional level. The concentric model moves both clockwise and anti-clockwise. Basic organizational and technological processes of reorganization of industrial enterprises that include decision making in terms of expediency of reorganization, design, construction, and performance of industrial enterprises at full capacity, and further operation of the industrial enterprise are described in the paper. Attainment of this objective, namely, reorganization of an industrial enterprise, involves a huge amount of resources, including labour resources that need interaction with all parties of reorganization; therefore, the concentric model of interaction describing the basic cycle of reorganization, the life cycle of an industrial enterprise and the cycle of its conversion is a trustworthy representation of this process. The proposed concentric model of interaction should be used in the design of organizational and technology-related processes for integrated consideration of reorganization of enterprises required to understand and improve the efficiency of reorganizations and to control the reorganization of industrial facilities.

  6. SHP1-mediated cell cycle redistribution inhibits radiosensitivity of non-small cell lung cancer

    International Nuclear Information System (INIS)

    Cao, Rubo; Ding, Qian; Li, Pindong; Xue, Jun; Zou, Zhenwei; Huang, Jing; Peng, Gang

    2013-01-01

    Radioresistance is the common cause for radiotherapy failure in non-small cell lung cancer (NSCLC), and the degree of radiosensitivity of tumor cells is different during different cell cycle phases. The objective of the present study was to investigate the effects of cell cycle redistribution in the establishment of radioresistance in NSCLC, as well as the signaling pathway of SH2 containing Tyrosine Phosphatase (SHP1). A NSCLC subtype cell line, radioresistant A549 (A549S1), was induced by high-dose hypofractionated ionizing radiations. Radiosensitivity-related parameters, cell cycle distribution and expression of cell cycle-related proteins and SHP1 were investigated. siRNA was designed to down-regulate SHP1expression. Compared with native A549 cells, the proportion of cells in the S phase was increased, and cells in the G0/G1 phase were consequently decreased, however, the proportion of cells in the G2/M phase did not change in A549S1 cells. Moreover, the expression of SHP1, CDK4 and CylinD1 were significantly increased, while p16 was significantly down-regulated in A549S1 cells compared with native A549 cells. Furthermore, inhibition of SHP1 by siRNA increased the radiosensitivity of A549S1 cells, induced a G0/G1 phase arrest, down-regulated CDK4 and CylinD1expressions, and up-regulated p16 expression. SHP1 decreases the radiosensitivity of NSCLC cells through affecting cell cycle distribution. This finding could unravel the molecular mechanism involved in NSCLC radioresistance

  7. Thermodynamic analysis of an integrated solid oxide fuel cell cycle with a rankine cycle

    International Nuclear Information System (INIS)

    Rokni, Masoud

    2010-01-01

    Hybrid systems consisting of solid oxide fuel cells (SOFC) on the top of a steam turbine (ST) are investigated. The plants are fired by natural gas (NG). A desulfurization reactor removes the sulfur content in the fuel while a pre-reformer breaks down the heavier hydro-carbons. The pre-treated fuel enters then into the anode side of the SOFC. The remaining fuels after the SOFC stacks enter a burner for further burning. The off-gases are then used to produce steam for a Rankine cycle in a heat recovery steam generator (HRSG). Different system setups are suggested. Cyclic efficiencies up to 67% are achieved which is considerably higher than the conventional combined cycles (CC). Both adiabatic steam reformer (ASR) and catalytic partial oxidation (CPO) fuel pre-reformer reactors are considered in this investigation.

  8. Tritium fuel cycle modeling and tritium breeding analysis for CFETR

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Hongli; Pan, Lei; Lv, Zhongliang; Li, Wei; Zeng, Qin, E-mail: zengqin@ustc.edu.cn

    2016-05-15

    Highlights: • A modified tritium fuel cycle model with more detailed subsystems was developed. • The mean residence time method applied to tritium fuel cycle calculation was updated. • Tritium fuel cycle analysis for CFETR was carried out. - Abstract: Attaining tritium self-sufficiency is a critical goal for fusion reactor operated on the D–T fuel cycle. The tritium fuel cycle models were developed to describe the characteristic parameters of the various elements of the tritium cycle as a tool for evaluating the tritium breeding requirements. In this paper, a modified tritium fuel cycle model with more detailed subsystems and an updated mean residence time calculation method was developed based on ITER tritium model. The tritium inventory in fueling system and in plasma, supposed to be important for part of the initial startup tritium inventory, was considered in the updated mean residence time method. Based on the model, the tritium fuel cycle analysis of CFETR (Chinese Fusion Engineering Testing Reactor) was carried out. The most important two parameters, the minimum initial startup tritium inventory (I{sub m}) and the minimum tritium breeding ratio (TBR{sub req}) were calculated. The tritium inventories in steady state and tritium release of subsystems were obtained.

  9. Dihydroartemisinin inhibits the human erythroid cell differentiation by altering the cell cycle

    International Nuclear Information System (INIS)

    Finaurini, Sara; Basilico, Nicoletta; Corbett, Yolanda; D’Alessandro, Sarah; Parapini, Silvia; Olliaro, Piero; Haynes, Richard K.; Taramelli, Donatella

    2012-01-01

    Artemisinin derivatives such as dihydroartemisinin (DHA) induce significant depletion of early embryonic erythroblasts in animal models. We have reported previously that DHA specifically targets pro-erythroblasts and basophilic erythroblasts, when human CD34+ stem cells are differentiated toward the erythroid lineage, indicating that a window of susceptibility to artemisinins may exist also in human developmental erythropoiesis during pregnancy. To better investigate the toxicity of artemisinin derivatives, the structure–activity relationship was evaluated against the K562 leukaemia cell line, used as a model for differentiating early human erythroblasts. All artemisinins derivatives, except deoxyartemisinin, inhibited both spontaneous and induced erythroid differentiation, confirming that the peroxide bridge is responsible for the erythro-toxicity. On the contrary, cell growth was markedly reduced by DHA, artemisone and artesunate but not by artemisinin, 10-deoxoartemisinin or deoxy-artemisinin. The substituent at position C-10 is responsible only for the anti-proliferative effect, since 10-deoxoartemisinin did not reduce cell growth but arrested the differentiation of K562 cells. In particular, the results showed that DHA resulted the most potent and rapidly acting compound of the drug family, causing (i) the decreased expression of GpA surface receptors and the down regulation the γ-globin gene; (ii) the alteration of S phase of cell cycle and (iii) the induction of programmed cell death of early erythroblasts in a dose dependent manner within 24 h. In conclusion, these findings confirm that the active metabolite DHA is responsible for the erythro-toxicity of most of artemisinins used in therapy. Thus, as long as no further clinical data are available, current WHO recommendations of avoiding malaria treatment with artemisinins during the first trimester of pregnancy remain valid.

  10. Static and dynamic modelling of gas turbines in advanced cycles

    Energy Technology Data Exchange (ETDEWEB)

    Gustafsson, Jan-Olof

    1998-12-01

    Gas turbines have been in operation for at least 50 years. The engine is used for propulsion of aircraft and high speed ships. It is used for power production in remote locations and for peak load and emergency situations. Gas turbines have been used in combined cycles for 20 to 30 years. Highly efficient power plants based on gas turbines are a competitive option for the power industry today. The thermal efficiency of the simple cycle gas turbine has increased due to higher turbine inlet temperatures and improved compressor and expander designs. Equally important are the improved cycles in which the gas turbine operates. One example is the combined cycle that uses steam for turbine cooling. Steam is extracted from the bottoming cycle, then used as airfoil coolant in a closed loop and returned to the bottoming cycle. The Evaporative Gas Turbine (EvGT), also known as the Humid Air Turbine (HAT), is another advanced cycle. A mixture of air and water vapour is used as working media. Air from the compressor outlet is humidified and then preheated in a recuperator prior to combustion. The static and dynamic performance is changed when the gas turbine is introduced in an evaporative cycle. The cycle is gaining in popularity, but so far it has not been demonstrated. A Swedish joint program to develop the cycle has been in operation since 1993. As part of the program, a small pilot plant is being erected at the Lund Institute of Technology (LTH). The plant is based on a 600 kW gas turbine, and demonstration of the EvGT cycle started autumn 1998 and will continue, in the present phase, for one year. This thesis presents static and dynamic models for traditional gas turbine components, such as, the compressor, combustor, expander and recuperator. A static model for the humidifier is presented, based on common knowledge for atmospheric humidification. All models were developed for the pilot plant at LTH with the objective to support evaluation of the process and individual

  11. Development of cell-cycle checkpoint therapy for solid tumors.

    Science.gov (United States)

    Tamura, Kenji

    2015-12-01

    Cellular proliferation is tightly controlled by several cell-cycle checkpoint proteins. In cancer, the genes encoding these proteins are often disrupted and cause unrestrained cancer growth. The proteins are over-expressed in many malignancies; thus, they are potential targets for anti-cancer therapies. These proteins include cyclin-dependent kinase, checkpoint kinase, WEE1 kinase, aurora kinase and polo-like kinase. Cyclin-dependent kinase inhibitors are the most advanced cell-cycle checkpoint therapeutics available. For instance, palbociclib (PD0332991) is a first-in-class, oral, highly selective inhibitor of CDK4/6 and, in combination with letrozole (Phase II; PALOMA-1) or with fulvestrant (Phase III; PALOMA-3), it has significantly prolonged progression-free survival, in patients with metastatic estrogen receptor-positive, HER2-negative breast cancer, in comparison with that observed in patients using letrozole, or fulvestrant alone, respectively. In this review, we provide an overview of the current compounds available for cell-cycle checkpoint protein-directed therapy for solid tumors. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  12. Toona Sinensis Extracts Induced Cell Cycle Arrest and Apoptosis in the Human Lung Large Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Cheng-Yuan Wang

    2010-02-01

    Full Text Available Toona sinensis extracts have been shown to exhibit anti-cancer effects in human ovarian cancer cell lines, human promyelocytic leukemia cells and human lung adenocarcinoma. Its safety has also been confirmed in animal studies. However, its anti-cancer properties in human lung large cell carcinoma have not been studied. Here, we used a powder obtained by freeze-drying the super-natant of centrifuged crude extract from Toona sinensis leaves (TSL-1 to treat the human lung carcinoma cell line H661. Cell viability was evaluated by the 3-(4-,5-dimethylthiazol-2-yl-2,5-diphenyl tetrazolium bromide assay. Flow cytometry analysis revealed that TSL-1 blocked H661 cell cycle progression. Western blot analysis showed decreased expression of cell cycle proteins that promote cell cycle progression, including cyclin-dependent kinase 4 and cyclin D1, and increased the expression of proteins that inhibit cell cycle progression, including p27. Furthermore, flow cytometry analysis showed that TSL-1 induced H661 cell apoptosis. Western blot analysis showed that TSL-1 reduced the expression of the anti-apoptotic protein B-cell lymphoma 2, and degraded the DNA repair protein, poly(ADP-ribose polymerase. TSL-1 shows potential as a novel therapeutic agent or for use as an adjuvant for treating human lung large cell carcinoma.

  13. Rates of incorporation of radioactive molecules during the cell cycle

    International Nuclear Information System (INIS)

    Gray, J.W.; Pallavicini, M.G.; George, Y.S.; Groppi, V.; Look, M.; Dean, P.N.

    1981-01-01

    We report measurements of the incorporation of radioactive molecules during short labeling periods, as a function of cell-cycle stage, using a cell-sorter-based technique that does not require cell synchronization. We have determined: (1) tritiated thymidine ( 3 H-TdR) incorporation throughout S-phase in Lewis lung tumor cells in vitro both before and after treatment with cytosine arabinoside; (2) 3 H-TdR incorporation throughout S-phase in KHT tumor cells in vitro and in vivo; (3) 3 H-TdR incorporation throughout S-phase in Chinese hamster ovary cells and compared it with DNA synthesis throughout S-phase; (4) a mathematical expression describing 3 H-TdR incorporation throughout S-phase in Chinese hamster M3-1 cells; and (5) the simultaneous incorporation of 3 H-TdR and 35 S-methionine as they are related to cell size and DNA content in S49 mouse lymphoma cells. In asynchronously growing cells in vitro and in vivo, 3 H-TdR incorporation was generally low in early and late S-phase and highest in mid-S-phase. However, in Lewis lung tumor cells treated with cytosine arabinoside 3 H-TdR incorporation was highest in early and late S-phase and lowest in mid-S-phase. Incorporation of 35 S-methionine increased continuously with cell size and DNA content. Incorporation of 3 H-TdR in CHO cells was proportional to DNA synthesis

  14. Allyl isothiocyanate affects the cell cycle of Arabidopsis thaliana

    Directory of Open Access Journals (Sweden)

    Signe Elisabeth Åsberg

    2015-05-01

    Full Text Available Isothiocyanates (ITCs are degradation products of glucosinolates present in members of the Brassicaceae family acting as herbivore repellents and antimicrobial compounds. Recent results indicate that allyl ITC (AITC has a role in defense responses such as glutathione depletion, ROS generation and stomatal closure. In this study we show that exposure to non-lethal concentrations of AITC causes a shift in the cell cycle distribution of Arabidopsis thaliana leading to accumulation of cells in S-phases and a reduced number of cells in non-replicating phases. Furthermore, transcriptional analysis revealed an AITC-induced up-regulation of the gene encoding cyclin-dependent kinase A while several genes encoding mitotic proteins were down-regulated, suggesting an inhibition of mitotic processes. Interestingly, visualization of DNA synthesis indicated that exposure to AITC reduced the rate of DNA replication. Taken together, these results indicate that non-lethal concentrations of AITC induce cells of A. thaliana to enter the cell cycle and accumulate in S-phases, presumably as a part of a defensive response. Thus, this study suggests that AITC has several roles in plant defense and add evidence to the growing data supporting a multifunctional role of glucosinolates and their degradation products in plants.

  15. H4 histamine receptors mediate cell cycle arrest in growth factor-induced murine and human hematopoietic progenitor cells.

    Directory of Open Access Journals (Sweden)

    Anne-France Petit-Bertron

    Full Text Available The most recently characterized H4 histamine receptor (H4R is expressed preferentially in the bone marrow, raising the question of its role during hematopoiesis. Here we show that both murine and human progenitor cell populations express this receptor subtype on transcriptional and protein levels and respond to its agonists by reduced growth factor-induced cell cycle progression that leads to decreased myeloid, erythroid and lymphoid colony formation. H4R activation prevents the induction of cell cycle genes through a cAMP/PKA-dependent pathway that is not associated with apoptosis. It is mediated specifically through H4R signaling since gene silencing or treatment with selective antagonists restores normal cell cycle progression. The arrest of growth factor-induced G1/S transition protects murine and human progenitor cells from the toxicity of the cell cycle-dependent anticancer drug Ara-C in vitro and reduces aplasia in a murine model of chemotherapy. This first evidence for functional H4R expression in hematopoietic progenitors opens new therapeutic perspectives for alleviating hematotoxic side effects of antineoplastic drugs.

  16. [Sea urchin embryo, DNA-damaged cell cycle checkpoint and the mechanisms initiating cancer development].

    Science.gov (United States)

    Bellé, Robert; Le Bouffant, Ronan; Morales, Julia; Cosson, Bertrand; Cormier, Patrick; Mulner-Lorillon, Odile

    2007-01-01

    Cell division is an essential process for heredity, maintenance and evolution of the whole living kingdom. Sea urchin early development represents an excellent experimental model for the analysis of cell cycle checkpoint mechanisms since embryonic cells contain a functional DNA-damage checkpoint and since the whole sea urchin genome is sequenced. The DNA-damaged checkpoint is responsible for an arrest in the cell cycle when DNA is damaged or incorrectly replicated, for activation of the DNA repair mechanism, and for commitment to cell death by apoptosis in the case of failure to repair. New insights in cancer biology lead to two fundamental concepts about the very first origin of cancerogenesis. Cancers result from dysfunction of DNA-damaged checkpoints and cancers appear as a result of normal stem cell (NCS) transformation into a cancer stem cell (CSC). The second aspect suggests a new definition of "cancer", since CSC can be detected well before any clinical evidence. Since early development starts from the zygote, which is a primary stem cell, sea urchin early development allows analysis of the early steps of the cancerization process. Although sea urchins do not develop cancers, the model is alternative and complementary to stem cells which are not easy to isolate, do not divide in a short time and do not divide synchronously. In the field of toxicology and incidence on human health, the sea urchin experimental model allows assessment of cancer risk from single or combined molecules long before any epidemiologic evidence is available. Sea urchin embryos were used to test the worldwide used pesticide Roundup that contains glyphosate as the active herbicide agent; it was shown to activate the DNA-damage checkpoint of the first cell cycle of development. The model therefore allows considerable increase in risk evaluation of new products in the field of cancer and offers a tool for the discovery of molecular markers for early diagnostic in cancer biology

  17. Cell cycle arrest and the evolution of chronic kidney disease from acute kidney injury.

    Science.gov (United States)

    Canaud, Guillaume; Bonventre, Joseph V

    2015-04-01

    For several decades, acute kidney injury (AKI) was generally considered a reversible process leading to complete kidney recovery if the individual survived the acute illness. Recent evidence from epidemiologic studies and animal models, however, have highlighted that AKI can lead to the development of fibrosis and facilitate the progression of chronic renal failure. When kidney injury is mild and baseline function is normal, the repair process can be adaptive with few long-term consequences. When the injury is more severe, repeated, or to a kidney with underlying disease, the repair can be maladaptive and epithelial cell cycle arrest may play an important role in the development of fibrosis. Indeed, during the maladaptive repair after a renal insult, many tubular cells that are undergoing cell division spend a prolonged period in the G2/M phase of the cell cycle. These tubular cells recruit intracellular pathways leading to the synthesis and the secretion of profibrotic factors, which then act in a paracrine fashion on interstitial pericytes/fibroblasts to accelerate proliferation of these cells and production of interstitial matrix. Thus, the tubule cells assume a senescent secretory phenotype. Characteristic features of these cells may represent new biomarkers of fibrosis progression and the G2/M-arrested cells may represent a new therapeutic target to prevent, delay or arrest progression of chronic kidney disease. Here, we summarize recent advances in our understanding of the biology of the cell cycle and how cell cycle arrest links AKI to chronic kidney disease. © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  18. Fuel cycle assessment: A compendium of models, methodologies, and approaches

    Energy Technology Data Exchange (ETDEWEB)

    1994-07-01

    The purpose of this document is to profile analytical tools and methods which could be used in a total fuel cycle analysis. The information in this document provides a significant step towards: (1) Characterizing the stages of the fuel cycle. (2) Identifying relevant impacts which can feasibly be evaluated quantitatively or qualitatively. (3) Identifying and reviewing other activities that have been conducted to perform a fuel cycle assessment or some component thereof. (4) Reviewing the successes/deficiencies and opportunities/constraints of previous activities. (5) Identifying methods and modeling techniques/tools that are available, tested and could be used for a fuel cycle assessment.

  19. Thermodynamic Analysis of an Integrated Solid Oxide Fuel Cell Cycle with a Rankine Cycle

    DEFF Research Database (Denmark)

    Rokni, Masoud

    2010-01-01

    Hybrid systems consisting of Solid Oxide Fuel Cells (SOFC) on the top of a Steam Turbine (ST) are investigated. The plants are fired by natural gas (NG). A desulfurization reactor removes the sulfur content in the fuel while a pre-reformer breaks down the heavier hydrocarbons. The pre-treated fuel......% are achieved which is considerably higher than the conventional Combined Cycles (CC). Both ASR (Adiabatic Steam Reformer) and CPO (Catalytic Partial Oxidation) fuel pre-reformer reactors are considered in this investigation....

  20. Cell cycle of spermatogonial colony forming stem cells in the CBA mouse after neutron irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Bootsma, A.L. (Rijksuniversiteit Utrecht (Netherlands). Academisch Ziekenhuis); Davids, J.A.G. (Netherlands Energy Research Foundation, Petten (Netherlands))

    1988-03-01

    In the CBA mouse testis, about 10% of the stem cell population is highly resistant to neutron irradiation (D/sub 0/, 0.75 Gy). Following a dose of 1.50 Gy these cells rapidly increase their sensitivity towards a second neutron dose and progress fairly synchronously through their first post-irradiation cell cycle. From experiments in which neutron irradiation was combined with hydroxyurea, it appeared that in this cycle the S-phase is less radiosensitive (D/sub 0/, 0.43 Gy) than the other phases of the cell cycle (D/sub 0/, 0.25 Gy). From experiments in which hydroxyurea was injected twice after irradiation, the speed of inflow of cells in S and the duration of S and the cell cycle could be calculated. Between 32 and 36 hr after irradiation cells start to enter the S-phase at a speed of 30% of the population every 12 hr. At 60 hr 50% of the population has already passed the S-phase while 30% is still in S. The data point to a cell cycle time of about 36 hr, while the S-phase lasts 12 hr at the most. (author).

  1. Experiments and Cycling at the LHC Prototype Half-Cell

    Science.gov (United States)

    Saban, R.; Casas-Cubillos, J.; Coull, L.; Cruikshank, P.; Dahlerup-Petersen, K.; Hilbert, B.; Krainz, G.; Kos, N.; Lebrun, P.; Momal, F.; Misiaen, D.; Parma, V.; Poncet, A.; Riddone, G.; Rijllart, A.; Rodriguez-Mateos, F.; Schmidt, R.; Serio, L.; Wallen, E.; van Weelderen, R.; Williams, L. R.

    1997-05-01

    The first version of the LHC prototype half-cell has been in operation since February 1995. It consists of one quadrupole and three 10-m twin aperture dipole magnets which operate at 1.8 K. This experimental set-up has been used to observe and study phenomena which appear when the systems are assembled in one unit and influence one another. The 18-month long experimental program has validated the cryogenic system and yielded a number of results on cryogenic instrumentation, magnet protection and vacuum in particular under non-standard operating conditions. The program was recently complemented by the cycling experiment: it consisted in powering the magnets following the ramp rates which will be experienced by the magnets during an LHC injection. In order to simulate 10 years of routine operation of LHC, more than 2000 1-hour cycles were performed interleaved with provoked quenches. The objective of this experiment was to reveal eventual flaws in the design of components. The prototype half-cell performed to expectations showing no sign of failure of fatigue of components for more than 2000 cycles until one of the dipoles started exhibiting an erratic quench behavior.

  2. Modelling of diurnal cycle under climate change

    Energy Technology Data Exchange (ETDEWEB)

    Eliseev, A V; Bezmenov, K V; Demchenko, P F; Mokhov, I I; Petoukhov, V K [Russian Academy of Sciences, Moscow (Russian Federation). Inst. of Atmospheric Physics

    1996-12-31

    The observed diurnal temperature range (DTR) displays remarkable change during last 30 years. Land air DTR generally decreases under global climate warming due to more significant night minimum temperature increase in comparison with day maximum temperature increase. Atmosphere hydrological cycle characteristics change under global warming and possible background aerosol atmosphere content change may cause essential errors in the estimation of DTR tendencies of change under global warming. The result of this study is the investigation of cloudiness effect on the DTR and blackbody radiative emissivity diurnal range. It is shown that in some cases (particularly in cold seasons) it results in opposite change in DTR and BD at doubled CO{sub 2} atmosphere content. The influence of background aerosol is the same as the cloudiness one

  3. Modelling of diurnal cycle under climate change

    Energy Technology Data Exchange (ETDEWEB)

    Eliseev, A.V.; Bezmenov, K.V.; Demchenko, P.F.; Mokhov, I.I.; Petoukhov, V.K. [Russian Academy of Sciences, Moscow (Russian Federation). Inst. of Atmospheric Physics

    1995-12-31

    The observed diurnal temperature range (DTR) displays remarkable change during last 30 years. Land air DTR generally decreases under global climate warming due to more significant night minimum temperature increase in comparison with day maximum temperature increase. Atmosphere hydrological cycle characteristics change under global warming and possible background aerosol atmosphere content change may cause essential errors in the estimation of DTR tendencies of change under global warming. The result of this study is the investigation of cloudiness effect on the DTR and blackbody radiative emissivity diurnal range. It is shown that in some cases (particularly in cold seasons) it results in opposite change in DTR and BD at doubled CO{sub 2} atmosphere content. The influence of background aerosol is the same as the cloudiness one

  4. Dihydromyricetin induces cell cycle arrest and apoptosis in melanoma SK-MEL-28 cells.

    Science.gov (United States)

    Zeng, Guofang; Liu, Jie; Chen, Hege; Liu, Bin; Zhang, Qingyu; Li, Mingyi; Zhu, Runzhi

    2014-06-01

    Dihydromyricetin (DHM) exhibits multiple pharmacological activities; however, the role of DHM in anti-melanoma activities and the underlying molecular mechanisms are unclear. The aim of the present study was to evaluate the effects of DHM on cell proliferation, cell cycle distribution and apoptosis in the human melanoma SK-MEL-28 cell line, and to explore the related mechanisms. The effect of DHM on cell proliferation was investigated by MTT assay, and cell cycle distribution was determined by flow cytometry. TUNEL assay was used to evaluate DHM-mediated apoptosis, and western blotting was applied to examine expression levels of p53, p21, Cdc25A, Cdc2, P-Cdc2, Bax, IKK-α, NF-κB p65, p38 and P-p38 proteins. The results revealed that DHM suppressed cell proliferation of SK-MEL-28 cells in a concentration- and time-dependent manner, and caused cell cycle arrest at the G1/S phase. DHM increased the production of p53 and p21 proteins and downregulated the production of Cdc25A, Cdc2 and P-Cdc2 proteins, which induced cell cycle arrest. Additionally, DHM significantly induced the apoptosis of SK-MEL-28 cells, and enhanced the expression levels of Bax proteins and decreased the protein levels of IKK-α, NF-κB (p65) and P-p38. The results suggest that DHM may be a novel and effective candidate agent to inhibit the growth of melanoma.

  5. Nitrogen cycling models and their application to forest harvesting

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, D.W.; Dale, V.H.

    1986-01-01

    The characterization of forest nitrogen- (N-) cycling processes by several N-cycling models (FORCYTE, NITCOMP, FORTNITE, and LINKAGES) is briefly reviewed and evaluated against current knowledge of N cycling in forests. Some important processes (e.g., translocation within trees, N dynamics in decaying leaf litter) appear to be well characterized, whereas others (e.g., N mineralization from soil organic matter, N fixation, N dynamics in decaying wood, nitrification, and nitrate leaching) are poorly characterized, primarily because of a lack of knowledge rather than an oversight by model developers. It is remarkable how well the forest models do work in the absence of data on some key processes. For those systems in which the poorly understood processes could cause major changes in N availability or productivity, the accuracy of model predictions should be examined. However, the development of N-cycling models represents a major step beyond the much simpler, classic conceptual models of forest nutrient cycling developed by early investigators. The new generation of computer models will surely improve as research reveals how key nutrient-cycling processes operate.

  6. Internal cycle modeling and environmental assessment of multiple cycle consumer products

    International Nuclear Information System (INIS)

    Tsiliyannis, C.A.

    2012-01-01

    Highlights: ► Dynamic flow models are presented for remanufactured, reused or recycled products. ► Early loss and stochastic return are included for fast and slow cycling products. ► The reuse-to-input flow ratio (Internal Cycle Factor, ICF) is determined. ► The cycle rate, which is increasing with the ICF, monitors eco-performance. ► Early internal cycle losses diminish the ICF, the cycle rate and performance. - Abstract: Dynamic annual flow models incorporating consumer discard and usage loss and featuring deterministic and stochastic end-of-cycle (EOC) return by the consumer are developed for reused or remanufactured products (multiple cycle products, MCPs), including fast and slow cycling, short and long-lived products. It is shown that internal flows (reuse and overall consumption) increase proportionally to the dimensionless internal cycle factor (ICF) which is related to environmental impact reduction factors. The combined reuse/recycle (or cycle) rate is shown capable for shortcut, albeit effective, monitoring of environmental performance in terms of waste production, virgin material extraction and manufacturing impacts of all MCPs, a task, which physical variables (lifetime, cycling frequency, mean or total number of return trips) and conventional rates, via which environmental policy has been officially implemented (e.g. recycling rate) cannot accomplish. The cycle rate is shown to be an increasing (hyperbolic) function of ICF. The impact of the stochastic EOC return characteristics on total reuse and consumption flows, as well as on eco-performance, is assessed: symmetric EOC return has a small, positive effect on performance compared to deterministic, while early shifted EOC return is more beneficial. In order to be efficient, environmental policy should set higher minimum reuse targets for higher trippage MCPs. The results may serve for monitoring, flow accounting and comparative eco-assessment of MCPs. They may be useful in identifying

  7. Cell-cycle distributions and radiation responses of Chinese hamster cells cultured continuously under hypoxic conditions

    International Nuclear Information System (INIS)

    Tokita, N.; Carpenter, S.G.; Raju, M.R.

    1984-01-01

    Cell-cycle distributions were measured by flow cytometry for Chinese hamster (CHO) cells cultured continuously under hypoxic conditions. DNA histograms showed an accumulation of cells in the early S phase followed by a traverse delay through the S phase, and a G 2 block. During hypoxic culturing, cell viability decreased rapidly to less than 0.1% at 120 h. Radiation responses for cells cultured under these conditions showed an extreme radioresistance at 72 h. Results suggest that hypoxia induces a condition similar to cell synchrony which itself changes the radioresistance of hypoxic cells. (author)

  8. Sulforaphane induces cell cycle arrest and apoptosis in acute lymphoblastic leukemia cells.

    Directory of Open Access Journals (Sweden)

    Koramit Suppipat

    Full Text Available Acute lymphoblastic leukemia (ALL is the most common hematological cancer in children. Although risk-adaptive therapy, CNS-directed chemotherapy, and supportive care have improved the survival of ALL patients, disease relapse is still the leading cause of cancer-related death in children. Therefore, new drugs are needed as frontline treatments in high-risk disease and as salvage agents in relapsed ALL. In this study, we report that purified sulforaphane, a natural isothiocyanate found in cruciferous vegetables, has anti-leukemic properties in a broad range of ALL cell lines and primary lymphoblasts from pediatric T-ALL and pre-B ALL patients. The treatment of ALL leukemic cells with sulforaphane resulted in dose-dependent apoptosis and G2/M cell cycle arrest, which was associated with the activation of caspases (3, 8, and 9, inactivation of PARP, p53-independent upregulation of p21(CIP1/WAF1, and inhibition of the Cdc2/Cyclin B1 complex. Interestingly, sulforaphane also inhibited the AKT and mTOR survival pathways in most of the tested cell lines by lowering the levels of both total and phosphorylated proteins. Finally, the administration of sulforaphane to the ALL xenograft models resulted in a reduction of tumor burden, particularly following oral administration, suggesting a potential role as an adjunctive agent to improve the therapeutic response in high-risk ALL patients with activated AKT signaling.

  9. Cell-cycle regulatory proteins in human wound healing

    DEFF Research Database (Denmark)

    Bartkova, Jirina; Grøn, Birgitte; Dabelsteen, Erik

    2003-01-01

    Proper healing of mucosal wounds requires careful orchestration of epithelial cell migration and proliferation. To elucidate the molecular basis of the lack of cellular proliferation in the migrating 'epithelial tongue' during the re-epithelialization of oral mucosal wounds, the expression of cell......-cycle regulators critical for G(1)-phase progression and S-phase entry was here analysed immunohistochemically. Compared to normal human mucosa, epithelia migrating to cover 2- or 3-day-old wounds made either in vivo or in an organotypic cell culture all showed loss of the proliferation marker Ki67 and cyclins D(1......) and A, and reduced expression of cyclins D(3) and E, the cyclin D-dependent kinase 4 (CDK4), the MCM7 component of DNA replication origin complexes and the retinoblastoma protein pRb. Among the CDK inhibitors (CKIs), p16ink4a and p21Cip1 were moderately increased and decreased, respectively, whereas...

  10. Cell cycle progression in irradiated endothelial cells cultured from bovine aorta

    International Nuclear Information System (INIS)

    Rubin, D.B.; Drab, E.A.; Ward, W.F.; Bauer, K.D.

    1988-01-01

    Logarithmically growing endothelial cells from bovine aortas were exposed to single doses of 0-10 Gy of 60Co gamma rays, and cell cycle phase distribution and progression were examined by flow cytometry and autoradiography. In some experiments, cells were synchronized in the cell cycle with hydroxyurea (1 mM). Cell number in sham-irradiated control cultures doubled in approximately 24 h. Estimated cycle stage times for control cells were 14.4 h for G1 phase, 7.2 h for S phase, and 2.4 h for G2 + M phase. Irradiated cells demonstrated a reduced distribution at the G1/S phase border at 4 h, and an increased distribution in G2 + M phase at 24 h postirradiation. Autoradiographs of irradiated cells after continuous [3H]thymidine labeling indicated a block in G1 phase or at the G1/S-phase border. The duration of the block was dose dependent (2-3 min/cGy). Progression of the endothelial cells through S phase after removal of the hydroxyurea block also was retarded by irradiation, as demonstrated by increased distribution in early S phase and decreased distribution in late S phase. These results indicate that progression of asynchronous cultured bovine aortic endothelial cells through the DNA synthetic cycle is susceptible to radiation inhibition at specific sites in the cycle, resulting in redistribution and partial synchronization of the population. Thus aortic endothelial cells, diploid cells from a normal tissue, resemble many immortal cell types that have been examined in this regard in vitro

  11. The Role of Mining in an Australian Business Cycle Model

    OpenAIRE

    Veroude, Alexandra

    2012-01-01

    The purpose of this paper is to evaluate a business cycle model that includes a mining sector, with the cyclical variations of the Australian Economy. Large quantities of mineral deposits are found in Australia and there exists high demand for these minerals from developing nations. This results in the mining sector contributing to a high proportion of GDP. Surprisingly, the inclusion of a mining sector has not previously been studied in a business cycle model. Australia is a small open econo...

  12. Restriction point control of the mammalian cell cycle via the cyclin E/Cdk2:p27 complex.

    NARCIS (Netherlands)

    Conradie, R.; Bruggeman, F.J.; Ciliberto, A.; Csikasz-Nagby, A.; Novak, B.; Westerhoff, H.V.; Snoep, J.L.

    2010-01-01

    Numerous top-down kinetic models have been constructed to describe the cell cycle. These models have typically been constructed, validated and analyzed using model species (molecular intermediates and proteins) and phenotypic observations, and therefore do not focus on the individual model processes

  13. DMPD: CSF-1 and cell cycle control in macrophages. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 8981359 CSF-1 and cell cycle control in macrophages. Hamilton JA. Mol Reprod Dev. 1...997 Jan;46(1):19-23. (.png) (.svg) (.html) (.csml) Show CSF-1 and cell cycle control in macrophages. PubmedI...D 8981359 Title CSF-1 and cell cycle control in macrophages. Authors Hamilton JA. Publication Mol Reprod Dev

  14. Complex Biological Systems Analysis of Cell Cycling Models in Carcinogenesis: I. The essential roles of modifications in the c-Myc, TP53/p53, p27 and hTERT modules in Cancer Initiation and Progression

    CERN Document Server

    Prisecaru, V I

    2004-01-01

    A new approach to the integration of results from a modular, complex biological systems analysis of nonlinear dynamics in cell cycling network transformations that are leading to carcinogenesis is proposed. Carcinogenesis is a complex process that involves dynamically inter-connected biomolecules in the intercellular, membrane, cytosolic, nuclear and nucleolar compartments that form numerous inter-related pathways referred to as networks. One such network module contains the cell cyclins whose functions are essential to cell cycling and division. Cyclins are proteins that also link to several critical pro-apoptotic and other cell cycling/division components, such as: c-Myc, p27, the tumor suppressor gene TP53 and its product-- the p53 protein with key roles in controlling DNA repair, inducing apoptosis and activating p21 (which can depress cell cyclins if activated), mdm2(with its biosynthesis activated by p53 and also, in its turn, inhibiting p53), p21, the Thomsen-Friedenreich antigen(T- antigen),Rb,Bax, Ba...

  15. Modelling asymmetric persistence over the business cycle

    NARCIS (Netherlands)

    Ph.H.B.F. Franses (Philip Hans); R. Paap (Richard)

    1998-01-01

    textabstractWe address the issue of time varying persistence of shocks to macroeconomic time series variables by proposing a new and parsimonious time series model. Our model assumes that this time varying persistence depends on a linear combination of lagged explanatory variables, where this

  16. Modeling Operating Modes during Plant Life Cycle

    DEFF Research Database (Denmark)

    Jørgensen, Sten Bay; Lind, Morten

    2012-01-01

    Modelling process plants during normal operation requires a set a basic assumptions to define the desired functionalities which lead to fullfillment of the operational goal(-s) for the plant. However during during start-up and shut down as well as during batch operation an ensemble of interrelated...... modes are required to cover the whole operational window of a processs plant including intermediary operating modes. Development of such an model ensemble for a plant would constitute a systematic way of defining the possible plant operating modes and thus provide a platform for also defining a set...... of candidate control structures. The present contribution focuses on development of a model ensemble for a plant with an illustartive example for a bioreactor. Starting from a functional model a process plant may be conceptually designed and qualitative operating models may be developed to cover the different...

  17. Curcumin Induces Autophagy, Apoptosis, and Cell Cycle Arrest in Human Pancreatic Cancer Cells

    Directory of Open Access Journals (Sweden)

    Yaping Zhu

    2017-01-01

    Full Text Available Objective. Curcumin is an active extract from turmeric. The aim of this study was to identify the underlying mechanism of curcumin on PCa cells and the role of autophagy in this process. Methods. The inhibitory effect of curcumin on the growth of PANC1 and BxPC3 cell lines was detected by CCK-8 assay. Cell cycle distribution and apoptosis were tested by flow cytometry. Autophagosomes were tested by cell immunofluorescence assay. The protein expression was detected by Western blot. The correlation between LC3II/Bax and cell viability was analyzed. Results. Curcumin inhibited the cell proliferation in a dose- and time-dependent manner. Curcumin could induce cell cycle arrest at G2/M phase and apoptosis of PCa cells. The autophagosomes were detected in the dosing groups. Protein expression of Bax and LC3II was upregulated, while Bcl2 was downregulated in the high dosing groups of curcumin. There was a significant negative correlation between LC3II/Bax and cell viability. Conclusions. Autophagy could be triggered by curcumin in the treatment of PCa. Apoptosis and cell cycle arrest also participated in this process. These findings imply that curcumin is a multitargeted agent for PCa cells. In addition, autophagic cell death may predominate in the high concentration groups of curcumin.

  18. Cell cycle effects of L-sulforaphane, a major antioxidant from cruciferous vegetables: The role of the anaphase promoting complex.

    Science.gov (United States)

    Shelley, Zhaoping; Royce, Simon G; Ververis, Katherine; Karagiannis, Tom C

    2014-01-01

    L-sulforaphane (LSF) is a natural isothiocyanate found in cruciferous vegetables particularly broccoli. LSF has been identified as a potent antioxidant and anti-cancer agent and is widely known to regulate phase II detoxifying enzymes and induce cell cycle arrest or apoptosis in malignant cells in vitro and in vivo. Previous studies have found significant G2/M cell cycle arrest in response to LSF in various model of cancer and results have mainly been attributed to increased cyclin B1 protein levels and increased p21expression. Using genome-wide mRNA-Seq analysis we provide insights into the molecular mechanisms of action of LSF to identify a key pathway in cell cycle progression - the role of the anaphase promoting complex (APC) pathway. We evaluated gene expression changes in human erythroleukemic K562 cells following treatment with 15 μM LSF for 48h and compared them to immortalized human keratinocytes, human microvascular endothelial cells (HMEC-1) cells and normal human umbilical endothelial cells (HUVEC). We identified disparate gene expression changes in response to LSF between malignant and normal cells and immortalized cell lines. The results highlight significant down-regulation of kinase CDK1 which is suggestive that the existence and activity of APC/CDC20 complex will be inhibited along with its associated down-stream degradation of key cell cycle regulators preventing cell cycle progression from mitotic exit.

  19. Modeling Phosphorus Transport and Cycling in the Greater Everglades Ecosystem

    Science.gov (United States)

    James, A. I.; Grace, K. A.; Jawitz, J. W.; Muller, S.; Munoz-Carpena, R.; Flaig, E. G.

    2005-12-01

    A solute transport model was used to predict phosphorus mobility in the northern Everglades. Over the past several decades, agricultural drainage waters discharged into the northern Everglades, have been enriched in phosphorus (P) relative to the historic rainfall-driven inputs. While methods of reducing total P concentrations in the discharge water have been actively pursued through implementation of agricultural Best Management Practices (BMPs), a major parallel effort has focused on the construction of a network of constructed wetlands for P removal before these waters enter the Everglades. This study describes the development of a water quality model for P transport and cycling and its application to a large constructed wetland: Stormwater Treatment Area 1 West (STA 1W), located southeast of Lake Okeechobee on the eastern perimeter of the Everglades Agricultural Area (EAA). In STA 1W agricultural nutrients such as phosphorus (P) are removed from EAA runoff before entering the adjacent Water Conservation Areas (WCAs) and the Everglades. STA 1W is divided by levees into 4 cells, which are flooded for most of the year; thus the dominant mechanism for flow and transport is overland flow. P is removed either through deposition into sediments or is taken up by plants; in either case the soils end up being significantly enriched in P. The model has been applied and calibrated to several years of water quality data from Cell 4 within STA 1W. Most existing P models have been applied to agricultural/upland systems, with only a few relevant to treatment wetlands such as STA 1W. To ensure sufficient flexibility in selecting appropriate system components and reactions, the model has been designed to incorporate a wide range of user-selectable mechanisms for P uptake and release parameters between soils and inflowing water. The model can track a large number of mobile and nonmobile components and utilizes a Godunov-style operator-splitting technique for the transported

  20. Analytical model for Stirling cycle machine design

    Energy Technology Data Exchange (ETDEWEB)

    Formosa, F. [Laboratoire SYMME, Universite de Savoie, BP 80439, 74944 Annecy le Vieux Cedex (France); Despesse, G. [Laboratoire Capteurs Actionneurs et Recuperation d' Energie, CEA-LETI-MINATEC, Grenoble (France)

    2010-10-15

    In order to study further the promising free piston Stirling engine architecture, there is a need of an analytical thermodynamic model which could be used in a dynamical analysis for preliminary design. To aim at more realistic values, the models have to take into account the heat losses and irreversibilities on the engine. An analytical model which encompasses the critical flaws of the regenerator and furthermore the heat exchangers effectivenesses has been developed. This model has been validated using the whole range of the experimental data available from the General Motor GPU-3 Stirling engine prototype. The effects of the technological and operating parameters on Stirling engine performance have been investigated. In addition to the regenerator influence, the effect of the cooler effectiveness is underlined. (author)

  1. The many faces of the mathematical modeling cycle

    NARCIS (Netherlands)

    Perrenet, J.C.; Zwaneveld, B.

    2012-01-01

    In literature about mathematical modeling a diversity can be seen in ways of presenting the modeling cycle. Every year, students in the Bachelor’s program Applied Mathematics of the Eindhoven University of Technology, after having completed a series of mathematical modeling projects, have been

  2. Thermodynamic investigation of an integrated gasification plant with solid oxide fuel cell and steam cycles

    Energy Technology Data Exchange (ETDEWEB)

    Rokni, Masoud [Technical Univ. of Denmark, Lyngby (Denmark). Dept. of Mechanical Engineering, Thermal Energy System

    2012-07-01

    A gasification plant is integrated on the top of a solid oxide fuel cell (SOFC) cycle, while a steam turbine (ST) cycle is used as a bottoming cycle for the SOFC plant. The gasification plant was fueled by woodchips to produce biogas and the SOFC stacks were fired with biogas. The produced gas was rather clean for feeding to the SOFC stacks after a simple cleaning step. Because all the fuel cannot be burned in the SOFC stacks, a burner was used to combust the remaining fuel. The off-gases from the burner were then used to produce steam for the bottoming steam cycle in a heat recovery steam generator (HRSG). The steam cycle was modeled with a simple single pressure level. In addition, a hybrid recuperator was used to recover more energy from the HRSG and send it back to the SOFC cycle. Thus two different configurations were investigated to study the plants characteristic. Such system integration configurations are completely novel and have not been studied elsewhere. Plant efficiencies of 56% were achieved under normal operation which was considerably higher than the IGCC (Integrated Gasification Combined Cycle) in which a gasification plant is integrated with a gas turbine and a steam turbine. Furthermore, it is shown that under certain operating conditions, plant efficiency of about 62 is also possible to achieve. (orig.)

  3. Centrosome/Cell cycle uncoupling and elimination in the endoreduplicating intestinal cells of C. elegans.

    Directory of Open Access Journals (Sweden)

    Yu Lu

    Full Text Available The centrosome cycle is most often coordinated with mitotic cell division through the activity of various essential cell cycle regulators, consequently ensuring that the centriole is duplicated once, and only once, per cell cycle. However, this coupling can be altered in specific developmental contexts; for example, multi-ciliated cells generate hundreds of centrioles without any S-phase requirement for their biogenesis, while Drosophila follicle cells eliminate their centrosomes as they begin to endoreduplicate. In order to better understand how the centrosome cycle and the cell cycle are coordinated in a developmental context we use the endoreduplicating intestinal cell lineage of C. elegans to address how novel variations of the cell cycle impact this important process. In C. elegans, the larval intestinal cells undergo one nuclear division without subsequent cytokinesis, followed by four endocycles that are characterized by successive rounds of S-phase. We monitored the levels of centriolar/centrosomal markers and found that centrosomes lose their pericentriolar material following the nuclear division that occurs during the L1 stage and is thereafter never re-gained. The centrioles then become refractory to S phase regulators that would normally promote duplication during the first endocycle, after which they are eliminated during the L2 stage. Furthermore, we show that SPD-2 plays a central role in the numeral regulation of centrioles as a potential target of CDK activity. On the other hand, the phosphorylation on SPD-2 by Polo-like kinase, the transcriptional regulation of genes that affect centriole biogenesis, and the ubiquitin/proteasome degradation pathway, contribute collectively to the final elimination of the centrioles during the L2 stage.

  4. Refined life-cycle assessment of polymer solar cells

    DEFF Research Database (Denmark)

    Lenzmann, F.; Kroon, J.; Andriessen, R.

    2011-01-01

    A refined life-cycle assessment of polymer solar cells is presented with a focus on critical components, i.e. the transparent conductive ITO layer and the encapsulation components. This present analysis gives a comprehensive sketch of the full environmental potential of polymer-OPV in comparison...... with other PV technologies. It is shown that on a m2 basis the environmental characteristics of polymer-OPV are highly beneficial, while on a watt-peak and on a kWh basis, these benefits are - at the current level of the development - still (over-)compensated by low module efficiency and limited lifetime...

  5. Maid (GCIP) is involved in cell cycle control of hepatocytes

    DEFF Research Database (Denmark)

    Sonnenberg-Riethmacher, Eva; Wüstefeld, Torsten; Miehe, Michaela

    2007-01-01

    . Therefore, we studied the role of Maid during cell cycle progression after partial hepatectomy (PH). Lack of Maid expression after PH was associated with a delay in G1/S-phase progression as evidenced by delayed cyclinA expression and DNA replication in Maid-deficient mice. However, at later time points......The function of Maid (GCIP), a cyclinD-binding helix-loop-helix protein, was analyzed by targeted disruption in mice. We show that Maid function is not required for normal embryonic development. However, older Maid-deficient mice-in contrast to wild-type controls--develop hepatocellular carcinomas...

  6. Characterization of stem/progenitor cell cycle using murine circumvallate papilla taste bud organoid.

    Science.gov (United States)

    Aihara, Eitaro; Mahe, Maxime M; Schumacher, Michael A; Matthis, Andrea L; Feng, Rui; Ren, Wenwen; Noah, Taeko K; Matsu-ura, Toru; Moore, Sean R; Hong, Christian I; Zavros, Yana; Herness, Scott; Shroyer, Noah F; Iwatsuki, Ken; Jiang, Peihua; Helmrath, Michael A; Montrose, Marshall H

    2015-11-24

    Leucine-rich repeat-containing G-protein coupled receptor 5-expressing (Lgr5(+)) cells have been identified as stem/progenitor cells in the circumvallate papillae, and single cultured Lgr5(+) cells give rise to taste cells. Here we use circumvallate papilla tissue to establish a three-dimensional culture system (taste bud organoids) that develops phenotypic characteristics similar to native tissue, including a multilayered epithelium containing stem/progenitor in the outer layers and taste cells in the inner layers. Furthermore, characterization of the cell cycle of the taste bud progenitor niche reveals striking dynamics of taste bud development and regeneration. Using this taste bud organoid culture system and FUCCI2 transgenic mice, we identify the stem/progenitor cells have at least 5 distinct cell cycle populations by tracking within 24-hour synchronized oscillations of proliferation. Additionally, we demonstrate that stem/progenitor cells have motility to form taste bud organoids. Taste bud organoids provides a system for elucidating mechanisms of taste signaling, disease modeling, and taste tissue regeneration.

  7. Dux4 induces cell cycle arrest at G1 phase through upregulation of p21 expression

    International Nuclear Information System (INIS)

    Xu, Hongliang; Wang, Zhaoxia; Jin, Suqin; Hao, Hongjun; Zheng, Lemin; Zhou, Boda; Zhang, Wei; Lv, He; Yuan, Yun

    2014-01-01

    Highlights: • Dux4 induced TE671 cell proliferation defect and G1 phase arrest. • Dux4 upregulated p21 expression without activating p53. • Silencing p21 rescued Dux4 mediated proliferation defect and cell cycle arrest. • Sp1 binding site was required for Dux4-induced p21 promoter activation. - Abstract: It has been implicated that Dux4 plays crucial roles in development of facioscapulohumeral dystrophy. But the underlying myopathic mechanisms and related down-stream events of this retrogene were far from clear. Here, we reported that overexpression of Dux4 in a cell model TE671 reduced cell proliferation rate, and increased G1 phase accumulation. We also determined the impact of Dux4 on p53/p21 signal pathway, which controls the checkpoint in cell cycle progression. Overexpression of Dux4 increased p21 mRNA and protein level, while expression of p53, phospho-p53 remained unchanged. Silencing p21 rescued Dux4 mediated proliferation defect and cell cycle arrest. Furthermore, we demonstrated that enhanced Dux4 expression increased p21 promoter activity and elevated expression of Sp1 transcription factor. Mutation of Sp1 binding site decreased dux4 induced p21 promoter activation. Chromatin immunoprecipitation (ChIP) assays confirmed the Dux4-induced binding of Sp1 to p21 promoter in vivo. These results suggest that Dux4 might induce proliferation inhibition and G1 phase arrest through upregulation of p21

  8. Macrophage/epithelium cross-talk regulates cell cycle progression and migration in pancreatic progenitors.

    Directory of Open Access Journals (Sweden)

    Kristin Mussar

    Full Text Available Macrophages populate the mesenchymal compartment of all organs during embryogenesis and have been shown to support tissue organogenesis and regeneration by regulating remodeling of the extracellular microenvironment. Whether this mesenchymal component can also dictate select developmental decisions in epithelia is unknown. Here, using the embryonic pancreatic epithelium as model system, we show that macrophages drive the epithelium to execute two developmentally important choices, i.e. the exit from cell cycle and the acquisition of a migratory phenotype. We demonstrate that these developmental decisions are effectively imparted by macrophages activated toward an M2 fetal-like functional state, and involve modulation of the adhesion receptor NCAM and an uncommon "paired-less" isoform of the transcription factor PAX6 in the epithelium. Over-expression of this PAX6 variant in pancreatic epithelia controls both cell motility and cell cycle progression in a gene-dosage dependent fashion. Importantly, induction of these phenotypes in embryonic pancreatic transplants by M2 macrophages in vivo is associated with an increased frequency of endocrine-committed cells emerging from ductal progenitor pools. These results identify M2 macrophages as key effectors capable of coordinating epithelial cell cycle withdrawal and cell migration, two events critical to pancreatic progenitors' delamination and progression toward their differentiated fates.

  9. Dux4 induces cell cycle arrest at G1 phase through upregulation of p21 expression

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Hongliang; Wang, Zhaoxia; Jin, Suqin; Hao, Hongjun [Department of Neurology, Peking University First Hospital, Beijing 100034 (China); Zheng, Lemin [The Institute of Cardiovascular Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides of Health Ministry, Beijing 100191 (China); Zhou, Boda [The Department of Cardiology, Peking University Third Hospital, Beijing 100191 (China); Zhang, Wei; Lv, He [Department of Neurology, Peking University First Hospital, Beijing 100034 (China); Yuan, Yun, E-mail: yuanyun2002@sohu.com [Department of Neurology, Peking University First Hospital, Beijing 100034 (China)

    2014-03-28

    Highlights: • Dux4 induced TE671 cell proliferation defect and G1 phase arrest. • Dux4 upregulated p21 expression without activating p53. • Silencing p21 rescued Dux4 mediated proliferation defect and cell cycle arrest. • Sp1 binding site was required for Dux4-induced p21 promoter activation. - Abstract: It has been implicated that Dux4 plays crucial roles in development of facioscapulohumeral dystrophy. But the underlying myopathic mechanisms and related down-stream events of this retrogene were far from clear. Here, we reported that overexpression of Dux4 in a cell model TE671 reduced cell proliferation rate, and increased G1 phase accumulation. We also determined the impact of Dux4 on p53/p21 signal pathway, which controls the checkpoint in cell cycle progression. Overexpression of Dux4 increased p21 mRNA and protein level, while expression of p53, phospho-p53 remained unchanged. Silencing p21 rescued Dux4 mediated proliferation defect and cell cycle arrest. Furthermore, we demonstrated that enhanced Dux4 expression increased p21 promoter activity and elevated expression of Sp1 transcription factor. Mutation of Sp1 binding site decreased dux4 induced p21 promoter activation. Chromatin immunoprecipitation (ChIP) assays confirmed the Dux4-induced binding of Sp1 to p21 promoter in vivo. These results suggest that Dux4 might induce proliferation inhibition and G1 phase arrest through upregulation of p21.

  10. Macrophage/epithelium cross-talk regulates cell cycle progression and migration in pancreatic progenitors.

    Science.gov (United States)

    Mussar, Kristin; Tucker, Andrew; McLennan, Linsey; Gearhart, Addie; Jimenez-Caliani, Antonio J; Cirulli, Vincenzo; Crisa, Laura

    2014-01-01

    Macrophages populate the mesenchymal compartment of all organs during embryogenesis and have been shown to support tissue organogenesis and regeneration by regulating remodeling of the extracellular microenvironment. Whether this mesenchymal component can also dictate select developmental decisions in epithelia is unknown. Here, using the embryonic pancreatic epithelium as model system, we show that macrophages drive the epithelium to execute two developmentally important choices, i.e. the exit from cell cycle and the acquisition of a migratory phenotype. We demonstrate that these developmental decisions are effectively imparted by macrophages activated toward an M2 fetal-like functional state, and involve modulation of the adhesion receptor NCAM and an uncommon "paired-less" isoform of the transcription factor PAX6 in the epithelium. Over-expression of this PAX6 variant in pancreatic epithelia controls both cell motility and cell cycle progression in a gene-dosage dependent fashion. Importantly, induction of these phenotypes in embryonic pancreatic transplants by M2 macrophages in vivo is associated with an increased frequency of endocrine-committed cells emerging from ductal progenitor pools. These results identify M2 macrophages as key effectors capable of coordinating epithelial cell cycle withdrawal and cell migration, two events critical to pancreatic progenitors' delamination and progression toward their differentiated fates.

  11. Glucose capped silver nanoparticles induce cell cycle arrest in HeLa cells.

    Science.gov (United States)

    Panzarini, Elisa; Mariano, Stefania; Vergallo, Cristian; Carata, Elisabetta; Fimia, Gian Maria; Mura, Francesco; Rossi, Marco; Vergaro, Viviana; Ciccarella, Giuseppe; Corazzari, Marco; Dini, Luciana

    2017-06-01

    This study aims to determine the interaction (uptake and biological effects on cell viability and cell cycle progression) of glucose capped silver nanoparticles (AgNPs-G) on human epithelioid cervix carcinoma (HeLa) cells, in relation to amount, 2×10 3 or 2×10 4 NPs/cell, and exposure time, up to 48h. The spherical and well dispersed AgNPs (30±5nm) were obtained by using glucose as reducing agent in a green synthesis method that ensures to stabilize AgNPs avoiding cytotoxic soluble silver ions Ag + release. HeLa cells take up abundantly and rapidly AgNPs-G resulting toxic to cells in amount and incubation time dependent manner. HeLa cells were arrested at S and G2/M phases of the cell cycle and subG1 population increased when incubated with 2×10 4 AgNPs-G/cell. Mitotic index decreased accordingly. The dissolution experiments demonstrated that the observed effects were due only to AgNPs-G since glucose capping prevents Ag + release. The AgNPs-G influence on HeLa cells viability and cell cycle progression suggest that AgNPs-G, alone or in combination with chemotherapeutics, may be exploited for the development of novel antiproliferative treatment in cancer therapy. However, the possible influence of the cell cycle on cellular uptake of AgNPs-G and the mechanism of AgNPs entry in cells need further investigation. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Bevacizumab inhibits proliferation of choroidal endothelial cells by regulation of the cell cycle.

    Science.gov (United States)

    Rusovici, Raluca; Patel, Chirag J; Chalam, Kakarla V

    2013-01-01

    The purpose of this study was to evaluate cell cycle changes in choroidal endothelial cells treated with varying doses of bevacizumab in the presence of a range of concentrations of vascular endothelial growth factor (VEGF). Bevacizumab, a drug widely used in the treatment of neovascular age-related macular degeneration, choroidal neovascularization, and proliferative diabetic retinopathy, neutralizes all isoforms of VEGF. However, the effect of intravitreal administration of bevacizumab on the choroidal endothelial cell cycle has not been established. Monkey choroidal endothelial (RF/6A) cells were treated with VEGF 50 ng/mL and escalating doses of bevacizumab 0.1-2 mg/mL for 72 hours. Cell cycle changes in response to bevacizumab were analyzed by flow cytometry and propidium iodide staining. Cell proliferation was measured using the WST-1 assay. Morphological changes were recorded by bright field cell microscopy. Bevacizumab inhibited proliferation of choroidal endothelial cells by stabilization of the cell cycle in G0/G1 phase. Cell cycle analysis of VEGF-enriched choroidal endothelial cells revealed a predominant increase in the G2/M population (21.84%, P, 0.01) and a decrease in the G0/G1 phase population (55.08%, P, 0.01). Addition of escalating doses of bevacizumab stabilized VEGF-enriched cells in the G0/G1 phase (55.08%, 54.49%, 56.3%, and 64% [P, 0.01]) and arrested proliferation by inhibiting the G2/M phase (21.84%, 21.46%, 20.59%, 20.94%, and 16.1% [P, 0.01]). The increase in G0/G1 subpopulation in VEGF-enriched and bevacizumab-treated cells compared with VEGF-enriched cells alone was dose-dependent. Bevacizumab arrests proliferation of VEGF-enriched choroidal endothelial cells by stabilizing the cell cycle in the G0/G1 phase and inhibiting the G2/M phase in a dose-dependent fashion.

  13. Change of cell cycle arrest of tumor cell lines after 60Co γ-irradiation

    International Nuclear Information System (INIS)

    Tang Yi; Liu Wenli; Zhou Jianfeng; Gao Qinglei; Wu Jianhong

    2003-01-01

    Objective: To observe the cell cycle arrest changes in peripheral blood mononuclear cells (PBMNCs) of normal persons and several kinds of tumor cell lines after 60 Co γ-irradiation. Methods: PBMNCs of normal persons, HL-60, K562, SiHA and 113 tumor cell lines were irradiated with 60 Co γ-rays at the absorbed doses of 6, 10,15 Gy. Cell cycles changes were checked 6, 12, 24, 48 and 60 h after the irradiation. Results: A stasis state was observed in normal person PBMNCs, 95 percents of which were in G 1 phase, and they still remained stasis after the irradiation. Except the 113 cell line manifesting G 1 phase arrest, all other tumor cell lines showed G 2 /M phase arrest after irradiation. The radiation sensitivity of HL-60 was higher than that of SiHA cell line. Conclusion: Different cell lines have different cell cycle arrest reaction to radiation and their radiation sensitivity are also different

  14. Terrestrial nitrogen cycling in Earth system models revisited

    Science.gov (United States)

    Stocker, Benjamin D; Prentice, I. Colin; Cornell, Sarah; Davies-Barnard, T; Finzi, Adrien; Franklin, Oskar; Janssens, Ivan; Larmola, Tuula; Manzoni, Stefano; Näsholm, Torgny; Raven, John; Rebel, Karin; Reed, Sasha C.; Vicca, Sara; Wiltshire, Andy; Zaehle, Sönke

    2016-01-01

    Understanding the degree to which nitrogen (N) availability limits land carbon (C) uptake under global environmental change represents an unresolved challenge. First-generation ‘C-only’vegetation models, lacking explicit representations of N cycling,projected a substantial and increasing land C sink under rising atmospheric CO2 concentrations. This prediction was questioned for not taking into account the potentially limiting effect of N availability, which is necessary for plant growth (Hungate et al.,2003). More recent global models include coupled C and N cycles in land ecosystems (C–N models) and are widely assumed to be more realistic. However, inclusion of more processes has not consistently improved their performance in capturing observed responses of the global C cycle (e.g. Wenzel et al., 2014). With the advent of a new generation of global models, including coupled C, N, and phosphorus (P) cycling, model complexity is sure to increase; but model reliability may not, unless greater attention is paid to the correspondence of model process representations ande mpirical evidence. It was in this context that the ‘Nitrogen Cycle Workshop’ at Dartington Hall, Devon, UK was held on 1–5 February 2016. Organized by I. Colin Prentice and Benjamin D. Stocker (Imperial College London, UK), the workshop was funded by the European Research Council,project ‘Earth system Model Bias Reduction and assessing Abrupt Climate change’ (EMBRACE). We gathered empirical ecologists and ecosystem modellers to identify key uncertainties in terrestrial C–N cycling, and to discuss processes that are missing or poorly represented in current models.

  15. Optimal design of solid oxide fuel cell, ammonia-water single effect absorption cycle and Rankine steam cycle hybrid system

    Science.gov (United States)

    Mehrpooya, Mehdi; Dehghani, Hossein; Ali Moosavian, S. M.

    2016-02-01

    A combined system containing solid oxide fuel cell-gas turbine power plant, Rankine steam cycle and ammonia-water absorption refrigeration system is introduced and analyzed. In this process, power, heat and cooling are produced. Energy and exergy analyses along with the economic factors are used to distinguish optimum operating point of the system. The developed electrochemical model of the fuel cell is validated with experimental results. Thermodynamic package and main parameters of the absorption refrigeration system are validated. The power output of the system is 500 kW. An optimization problem is defined in order to finding the optimal operating point. Decision variables are current density, temperature of the exhaust gases from the boiler, steam turbine pressure (high and medium), generator temperature and consumed cooling water. Results indicate that electrical efficiency of the combined system is 62.4% (LHV). Produced refrigeration (at -10 °C) and heat recovery are 101 kW and 22.1 kW respectively. Investment cost for the combined system (without absorption cycle) is about 2917 kW-1.

  16. Effects of (/sup 3/H)UdR on the cell-cycle progression of L1210 cells

    Energy Technology Data Exchange (ETDEWEB)

    Darzynkiewicz, Z.; Carter, S.; Kimmel, M. (Memorial Sloan-Kettering Cancer Center, New York (USA))

    1984-11-01

    Tritium-labelled uridine ((/sup 3/H)UdR)perturbs progression of L1210 cells through the mitotic cycle. A slowdown of G/sub 2/ cells is observed 2 hr after addition of 0.5-5.0 ..mu..ci/ml of (/sup 3/H)UdR into cultures. At 2.5-5.0 ..mu..Ci/ml of (/sup 3/H)UdR a slowdown of cell progression through S is also apparent. Additionally, there is an increase in the number of cells with DNA values higher than 4C in cultures growing in the presence of (/sup 3/H)UdR for 8-24 hr. A pulse of (/sup 3/H)UdR of 2 hr duration labels predominantly (95%) cellular RNA. The first cell-cycle effects (G/sub 2/ slowdown) are observed when the amount of the incorporated (/sup 3/H)UdR is such that, on average there are fewer than thirty-six (/sup 3/H) decays per cell which corresponds to approximately 12-19 rads. The S-phase slowdown is seen at a dose of incorporated (/sup 3/H)UdR twice as high as that inducing G/sub 2/ effects. The specific localization of (/sup 3/H)UdR in nucleoli, peripheral nucleoplasm and in cytoplasm, as well as differences in the kinetics of the incorporation in relation to phases of the cell cycle are discussed. Mathematical modelling of the cell-cycle effects of (/sup 3/H)UdR is provided.

  17. Application of Nuclear Volume Measurements to Comprehend the Cell Cycle in Root-Knot Nematode-Induced Giant Cells

    Directory of Open Access Journals (Sweden)

    José Dijair Antonino de Souza Junior

    2017-06-01

    Full Text Available Root-knot nematodes induce galls that contain giant-feeding cells harboring multiple enlarged nuclei within the roots of host plants. It is recognized that the cell cycle plays an essential role in the set-up of a peculiar nuclear organization that seemingly steers nematode feeding site induction and development. Functional studies of a large set of cell cycle genes in transgenic lines of the model host Arabidopsis thaliana have contributed to better understand the role of the cell cycle components and their implication in the establishment of functional galls. Mitotic activity mainly occurs during the initial stages of gall development and is followed by an intense endoreduplication phase imperative to produce giant-feeding cells, essential to form vigorous galls. Transgenic lines overexpressing particular cell cycle genes can provoke severe nuclei phenotype changes mainly at later stages of feeding site development. This can result in chaotic nuclear phenotypes affecting their volume. These aberrant nuclear organizations are hampering gall development and nematode maturation. Herein we report on two nuclear volume assessment methods which provide information on the complex changes occurring in nuclei during giant cell development. Although we observed that the data obtained with AMIRA tend to be more detailed than Volumest (Image J, both approaches proved to be highly versatile, allowing to access 3D morphological changes in nuclei of complex tissues and organs. The protocol presented here is based on standard confocal optical sectioning and 3-D image analysis and can be applied to study any volume and shape of cellular organelles in various complex biological specimens. Our results suggest that an increase in giant cell nuclear volume is not solely linked to increasing ploidy levels, but might result from the accumulation of mitotic defects.

  18. Albumin Suppresses Human Hepatocellular Carcinoma Proliferation and the Cell Cycle

    Directory of Open Access Journals (Sweden)

    Shunsuke Nojiri

    2014-03-01

    Full Text Available Many investigations have revealed that a low recurrence rate of hepatocellular carcinoma (HCC is associated with high serum albumin levels in patients; therefore, high levels of serum albumin are a major indicator of a favorable prognosis. However, the mechanism inhibiting the proliferation of HCC has not yet been elucidated, so we investigated the effect of serum albumin on HCC cell proliferation. Hep3B was cultured in MEM with no serum or containing 5 g/dL human albumin. As control samples, Prionex was added to generate the same osmotic pressure as albumin. After 24-h incubation, the expressions of α-fetoprotein (AFP, p53, p21, and p57 were evaluated with real-time PCR using total RNA extracted from the liver. Protein expressions and the phosphorylation of Rb (retinoblastoma were determined by Western blot analysis using total protein extracted from the liver. For flow cytometric analysis of the cell cycle, FACS analysis was performed. The percentages of cell cycle distribution were evaluated by PI staining, and all samples were analyzed employing FACScalibur (BD with appropriate software (ModFit LT; BD. The cell proliferation assay was performed by counting cells with using a Scepter handy automated cell counter (Millipore. The mRNA levels of AFP relative to Alb(−: Alb(−, Alb(+, and Prionex, were 1, 0.7 ± 0.2 (p < 0.001 for Alb(−, and 1 ± 0.3, respectively. The mRNA levels of p21 were 1, 1.58 ± 0.4 (p = 0.007 for Alb(− and p = 0.004 for Prionex, and 0.8 ± 0.2, respectively. The mRNA levels of p57 were 1, 4.4 ± 1.4 (p = 0.002 for Alb(− and Prionex, and 1.0 ± 0.1, respectively. The protein expression levels of Rb were similar in all culture media. The phosphorylation of P807/811 and P780 of Rb protein was reduced in Alb(+. More cells in the G0/G1 phase and fewer cells in S and G2/M phases were obtained in Alb(+ than in Alb(− (G0/G1: 60.9%, 67.7%, 61.5%; G2/M: 16.5%, 13.1%, 15.6%; S: 22.6%, 19.2%, 23.0%, Alb(−, Alb

  19. Integrated fuel-cycle models for fast breeder reactors

    International Nuclear Information System (INIS)

    Ott, K.O.; Maudlin, P.J.

    1981-01-01

    Breeder-reactor fuel-cycle analysis can be divided into four different areas or categories. The first category concerns questions about the spatial variation of the fuel composition for single loading intervals. Questions of the variations in the fuel composition over several cycles represent a second category. Third, there is a need for a determination of the breeding capability of the reactor. The fourth category concerns the investigation of breeding and long-term fuel logistics. Two fuel-cycle models used to answer questions in the third and fourth area are presented. The space- and time-dependent actinide balance, coupled with criticality and fuel-management constraints, is the basis for both the Discontinuous Integrated Fuel-Cycle Model and the Continuous Integrated Fuel-Cycle Model. The results of the continuous model are compared with results obtained from detailed two-dimensional space and multigroup depletion calculations. The continuous model yields nearly the same results as the detailed calculation, and this is with a comparatively insignificant fraction of the computational effort needed for the detailed calculation. Thus, the integrated model presented is an accurate tool for answering questions concerning reactor breeding capability and long-term fuel logistics. (author)

  20. Tcf3 and cell cycle factors contribute to butyrate resistance in colorectal cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Chiaro, Christopher, E-mail: cchiaro@tcmedc.org [Department of Basic Sciences, The Commonwealth Medical College, 525 Pine Street, Scranton, PA 18509 (United States); Lazarova, Darina L., E-mail: dlazarova@tcmedc.org [Department of Basic Sciences, The Commonwealth Medical College, 525 Pine Street, Scranton, PA 18509 (United States); Bordonaro, Michael, E-mail: mbordonaro@tcmedc.org [Department of Basic Sciences, The Commonwealth Medical College, 525 Pine Street, Scranton, PA 18509 (United States)

    2012-11-09

    Highlights: Black-Right-Pointing-Pointer We investigate mechanisms responsible for butyrate resistance in colon cancer cells. Black-Right-Pointing-Pointer Tcf3 modulates butyrate's effects on Wnt activity and cell growth in resistant cells. Black-Right-Pointing-Pointer Tcf3 modulation of butyrate's effects differ by cell context. Black-Right-Pointing-Pointer Cell cycle factors are overexpressed in the resistant cells. Black-Right-Pointing-Pointer Reversal of altered gene expression can enhance the anti-cancer effects of butyrate. -- Abstract: Butyrate, a fermentation product of dietary fiber, inhibits clonal growth in colorectal cancer (CRC) cells dependent upon the fold induction of Wnt activity. We have developed a CRC cell line (HCT-R) that, unlike its parental cell line, HCT-116, does not respond to butyrate exposure with hyperactivation of Wnt signaling and suppressed clonal growth. PCR array analyses revealed Wnt pathway-related genes, the expression of which differs between butyrate-sensitive HCT-116 CRC cells and their butyrate-resistant HCT-R cell counterparts. We identified overexpression of Tcf3 as being partially responsible for the butyrate-resistant phenotype, as this DNA-binding protein suppresses the hyperinduction of Wnt activity by butyrate. Consequently, Tcf3 knockdown in HCT-R cells restores their sensitivity to the effects of butyrate on Wnt activity and clonal cell growth. Interestingly, the effects of overexpressed Tcf3 differ between HCT-116 and HCT-R cells; thus, in HCT-116 cells Tcf3 suppresses proliferation without rendering the cells resistant to butyrate. In HCT-R cells, however, the overexpression of Tcf3 inhibits Wnt activity, and the cells are still able to proliferate due to the higher expression levels of cell cycle factors, particularly those driving the G{sub 1} to S transition. Knowledge of the molecular mechanisms determining the variable sensitivity of CRC cells to butyrate may assist in developing approaches that

  1. Tcf3 and cell cycle factors contribute to butyrate resistance in colorectal cancer cells

    International Nuclear Information System (INIS)

    Chiaro, Christopher; Lazarova, Darina L.; Bordonaro, Michael

    2012-01-01

    Highlights: ► We investigate mechanisms responsible for butyrate resistance in colon cancer cells. ► Tcf3 modulates butyrate’s effects on Wnt activity and cell growth in resistant cells. ► Tcf3 modulation of butyrate’s effects differ by cell context. ► Cell cycle factors are overexpressed in the resistant cells. ► Reversal of altered gene expression can enhance the anti-cancer effects of butyrate. -- Abstract: Butyrate, a fermentation product of dietary fiber, inhibits clonal growth in colorectal cancer (CRC) cells dependent upon the fold induction of Wnt activity. We have developed a CRC cell line (HCT-R) that, unlike its parental cell line, HCT-116, does not respond to butyrate exposure with hyperactivation of Wnt signaling and suppressed clonal growth. PCR array analyses revealed Wnt pathway-related genes, the expression of which differs between butyrate-sensitive HCT-116 CRC cells and their butyrate-resistant HCT-R cell counterparts. We identified overexpression of Tcf3 as being partially responsible for the butyrate-resistant phenotype, as this DNA-binding protein suppresses the hyperinduction of Wnt activity by butyrate. Consequently, Tcf3 knockdown in HCT-R cells restores their sensitivity to the effects of butyrate on Wnt activity and clonal cell growth. Interestingly, the effects of overexpressed Tcf3 differ between HCT-116 and HCT-R cells; thus, in HCT-116 cells Tcf3 suppresses proliferation without rendering the cells resistant to butyrate. In HCT-R cells, however, the overexpression of Tcf3 inhibits Wnt activity, and the cells are still able to proliferate due to the higher expression levels of cell cycle factors, particularly those driving the G 1 to S transition. Knowledge of the molecular mechanisms determining the variable sensitivity of CRC cells to butyrate may assist in developing approaches that prevent or reverse butyrate resistance.

  2. Radiosensitizing potential of gemcitabine (2',2'-difluoro-2'-deoxycytidine) within the cell cycle in vitro

    International Nuclear Information System (INIS)

    Latz, Detlev; Fleckenstein, Katharina; Eble, Michael; Blatter, Johannes; Wannenmacher, Michael; Weber, Klaus J.

    1998-01-01

    Purpose: Gemcitabine (2',2'-difluorodeoxycytidine; dFdCyd) is a new deoxycitidine analog which exhibits substantial activity against solid tumors and radiosensitizing properties in vitro. To examine cell cycle-specific effects of a combined treatment with gemcitabine and radiation, the in vitro clonogenic survival of two different cell lines was measured for cells from log-phase culture, G1 and S-phase cells. Methods and Materials: Chinese hamster (V79) and human colon carcinoma (Widr) cells were exposed to different radiation doses and for different points of time relative to gemcitabine treatment (2 h). Experiments were also carried out with different cell-cycle populations obtained after mitotic selection (V79) or after serum stimulation of plateau-phase cells (Widr). The resulting survival curves were analyzed according to the LQ model, and mean inactivation doses (MID) and the cell cycle-specific enhancement ratios (ER) were calculated from the survival curve parameters. Results: Effectiveness of combined treatment of log-phase cells was greatest when cells were irradiated at the end of the gemcitabine exposure [ER: 1.28 (V79), 1.24 (Widr)]. For later times after the removal of the drug, radiosensitization declined, approaching independent toxicity. From the time course of interactive-type damage decay half-life values of 75 min (V79) and 92 min (Widr) were derived. Gemcitabine did not radiosensitize G1 Widr cells or V79 cells from the G1/S border, but substantial radiosensitization was observed for the S-phase cell preparations [ER: 1.45 (V79-lateS), 1.57 (Widr)]. Conclusions: Treatment of cells with gemcitabine immediately before irradiation eliminates, or at least greatly reduces, the variation in radiosensitivity during the cell cycle that is manifested by radioresistance during S phase. This reversal of S-phase radioresistance could imply that gemcitabine interferes with the potentially lethal damage repair/fixation pathway. Other approaches have been

  3. Casticin impairs cell growth and induces cell apoptosis via cell cycle arrest in human oral cancer SCC-4 cells.

    Science.gov (United States)

    Chou, Guan-Ling; Peng, Shu-Fen; Liao, Ching-Lung; Ho, Heng-Chien; Lu, Kung-Wen; Lien, Jin-Cherng; Fan, Ming-Jen; La, Kuang-Chi; Chung, Jing-Gung

    2018-02-01

    Casticin, a polymethoxyflavone, present in natural plants, has been shown to have biological activities including anti-cancer activities. Herein, we investigated the anti-oral cancer activity of casticin on SCC-4 cells in vitro. Viable cells, cell cycle distribution, apoptotic cell death, reactive oxygen species (ROS) production, and Ca 2+ production, levels of ΔΨ m and caspase activity were measured by flow cytometric assay. Cell apoptosis associated protein expressions were examined by Western blotting and confocal laser microscopy. Results indicated that casticin induced cell morphological changes, DNA condensation and damage, decreased the total viable cells, induced G 2 /M phase arrest in SCC-4 cells. Casticin promoted ROS and Ca 2+ productions, decreases the levels of ΔΨ m , promoted caspase-3, -8, and -9 activities in SCC-4 cells. Western blotting assay demonstrated that casticin affect protein level associated with G2/M phase arrest and apoptosis. Confocal laser microscopy also confirmed that casticin increased the translocation of AIF and cytochrome c in SCC-4 cells. In conclusion, casticin decreased cell number through G 2 /M phase arrest and the induction of cell apoptosis through caspase- and mitochondria-dependent pathways in SCC-4 cells. © 2017 Wiley Periodicals, Inc.

  4. Advanced Nuclear Fuel Cycle Transitions: Optimization, Modeling Choices, and Disruptions

    Science.gov (United States)

    Carlsen, Robert W.

    Many nuclear fuel cycle simulators have evolved over time to help understan the nuclear industry/ecosystem at a macroscopic level. Cyclus is one of th first fuel cycle simulators to accommodate larger-scale analysis with it liberal open-source licensing and first-class Linux support. Cyclus also ha features that uniquely enable investigating the effects of modeling choices o fuel cycle simulators and scenarios. This work is divided into thre experiments focusing on optimization, effects of modeling choices, and fue cycle uncertainty. Effective optimization techniques are developed for automatically determinin desirable facility deployment schedules with Cyclus. A novel method fo mapping optimization variables to deployment schedules is developed. Thi allows relationships between reactor types and scenario constraints to b represented implicitly in the variable definitions enabling the usage o optimizers lacking constraint support. It also prevents wasting computationa resources evaluating infeasible deployment schedules. Deployed power capacit over time and deployment of non-reactor facilities are also included a optimization variables There are many fuel cycle simulators built with different combinations o modeling choices. Comparing results between them is often difficult. Cyclus flexibility allows comparing effects of many such modeling choices. Reacto refueling cycle synchronization and inter-facility competition among othe effects are compared in four cases each using combinations of fleet of individually modeled reactors with 1-month or 3-month time steps. There are noticeable differences in results for the different cases. The larges differences occur during periods of constrained reactor fuel availability This and similar work can help improve the quality of fuel cycle analysi generally There is significant uncertainty associated deploying new nuclear technologie such as time-frames for technology availability and the cost of buildin advanced reactors

  5. Energy landscape reveals that the budding yeast cell cycle is a robust and adaptive multi-stage process.

    Directory of Open Access Journals (Sweden)

    Cheng Lv

    2015-03-01

    Full Text Available Quantitatively understanding the robustness, adaptivity and efficiency of cell cycle dynamics under the influence of noise is a fundamental but difficult question to answer for most eukaryotic organisms. Using a simplified budding yeast cell cycle model perturbed by intrinsic noise, we systematically explore these issues from an energy landscape point of view by constructing an energy landscape for the considered system based on large deviation theory. Analysis shows that the cell cycle trajectory is sharply confined by the ambient energy barrier, and the landscape along this trajectory exhibits a generally flat shape. We explain the evolution of the system on this flat path by incorporating its non-gradient nature. Furthermore, we illustrate how this global landscape changes in response to external signals, observing a nice transformation of the landscapes as the excitable system approaches a limit cycle system when nutrients are sufficient, as well as the formation of additional energy wells when the DNA replication checkpoint is activated. By taking into account the finite volume effect, we find additional pits along the flat cycle path in the landscape associated with the checkpoint mechanism of the cell cycle. The difference between the landscapes induced by intrinsic and extrinsic noise is also discussed. In our opinion, this meticulous structure of the energy landscape for our simplified model is of general interest to other cell cycle dynamics, and the proposed methods can be applied to study similar biological systems.

  6. Modelling of powder die compaction for press cycle optimization

    Directory of Open Access Journals (Sweden)

    Bayle Jean-Philippe

    2016-01-01

    Full Text Available A new electromechanical press for fuel pellet manufacturing was built last year in partnership between CEA-Marcoule and ChampalleAlcen. This press was developed to shape pellets in a hot cell via remote handling. It has been qualified to show its robustness and to optimize the compaction cycle, thus obtaining a better sintered pellet profile and limiting damage. We will show you how 400 annular pellets have been produced with good geometry's parameters, based on press settings management. These results are according to a good phenomenological pressing knowledge with Finite Element Modeling calculation. Therefore, during die pressing, a modification in the punch displacement sequence induces fluctuation in the axial distribution of frictional forces. The green pellet stress and density gradients are based on these frictional forces between powder and tool, and between grains in the powder, influencing the shape of the pellet after sintering. The pellet shape and diameter tolerances must be minimized to avoid the need for grinding operations. To find the best parameters for the press settings, which enable optimization, FEM calculations were used and different compaction models compared to give the best calculation/physical trial comparisons. These simulations were then used to predict the impact of different parameters when there is a change in the type of powder and the pellet size, or when the behavior of the press changes during the compaction time. In 2016, it is planned to set up the press in a glove box for UO2 manufacturing qualification based on our simulation methodology, before actual hot cell trials in the future.

  7. Software Platform Evaluation - Verifiable Fuel Cycle Simulation (VISION) Model

    International Nuclear Information System (INIS)

    J. J. Jacobson; D. E. Shropshire; W. B. West

    2005-01-01

    The purpose of this Software Platform Evaluation (SPE) is to document the top-level evaluation of potential software platforms on which to construct a simulation model that satisfies the requirements for a Verifiable Fuel Cycle Simulation Model (VISION) of the Advanced Fuel Cycle (AFC). See the Software Requirements Specification for Verifiable Fuel Cycle Simulation (VISION) Model (INEEL/EXT-05-02643, Rev. 0) for a discussion of the objective and scope of the VISION model. VISION is intended to serve as a broad systems analysis and study tool applicable to work conducted as part of the AFCI (including costs estimates) and Generation IV reactor development studies. This document will serve as a guide for selecting the most appropriate software platform for VISION. This is a ''living document'' that will be modified over the course of the execution of this work

  8. Effect of irradiation on cell cycle, cell death and expression of its related proteins in normal human oral keratinocytes

    International Nuclear Information System (INIS)

    Kang, Mi Ae; Heo, Min Suk; Lee, Sam Sun; Oh, Sung Ook; Choi, Soon Chul; Park, Tae Won; Lee, Sul Mi; Jeon, In Seong

    2003-01-01

    To investigate the radiosensitivity of the normal human oral keratinocytes (NHOK), and the effect of irradiation on cell cycle and protein expression. To evaluate the radiosensitivity of NHOK, the number of colonies and cells were counted after irradiation and the SF2 (survival fraction as 2 Gy) value, and the cell survival curve fitted on a linear-quadratic model were obtained. LDH analysis was carried out to evaluate the necrosis of NHOK at 1, 2,3, and 4 days after 2, 10, and 20 Gy irradiation. Cell cycle arrest and the induction of apoptosis were analyzed using flow cytometry at 1, 2, 3, and 4 days after 2, 10, and 20 Gy irradiation. Finally, proteins related cell cycle arrest and apoptosis were analysed by Western blot. The number of survival cell was significantly decreased in a dose-dependent manner. The cell survival curve showed SF2, α, and β values to be 0.568, 0.209, and 0.020 respectively. At 20 Gy irradiated cells showed higher optical density than the control group. After irradiation, apoptosis was not observed but G2 arrest was observed in the NHOK cells. 1 day after 10 Gy irradiation, the expression of p53 remained unchanged, the p21 WAF1/Cip1 increased and the mdm2 decreased. The expression of bax, bcl-2, cyclin B1, and cyclin D remained unchanged. These results indicate that NHOK responds to irradiation by G2 arrest, which is possibly mediated by the expression of p21 WAF1/Cip1 , and that cell necrosis occurs by high dose irradiation.

  9. Identification of Cell Cycle-Regulated Genes by Convolutional Neural Network.

    Science.gov (United States)

    Liu, Chenglin; Cui, Peng; Huang, Tao

    2017-01-01

    The cell cycle-regulated genes express periodically with the cell cycle stages, and the identification and study of these genes can provide a deep understanding of the cell cycle process. Large false positives and low overlaps are big problems in cell cycle-regulated gene detection. Here, a computational framework called DLGene was proposed for cell cycle-regulated gene detection. It is based on the convolutional neural network, a deep learning algorithm representing raw form of data pattern without assumption of their distribution. First, the expression data was transformed to categorical state data to denote the changing state of gene expression, and four different expression patterns were revealed for the reported cell cycle-regulated genes. Then, DLGene was applied to discriminate the non-cell cycle gene and the four subtypes of cell cycle genes. Its performances were compared with six traditional machine learning methods. At last, the biological functions of representative cell cycle genes for each subtype are analyzed. Our method showed better and more balanced performance of sensitivity and specificity comparing to other machine learning algorithms. The cell cycle genes had very different expression pattern with non-cell cycle genes and among the cell-cycle genes, there were four subtypes. Our method not only detects the cell cycle genes, but also describes its expression pattern, such as when its highest expression level is reached and how it changes with time. For each type, we analyzed the biological functions of the representative genes and such results provided novel insight to the cell cycle mechanisms. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Simulation of the Prokaryotic Cell Cycle at http://simon.bio.uva.nl/cellcycle/

    Directory of Open Access Journals (Sweden)

    Arieh Zaritsky

    2012-02-01

    Full Text Available The bacterial Cell Cycle is presented using the Simulation program CCSim, which employs four parameters related to time (inter-division τ, replication C, division D and size (mass at replication initiation Mi, sufficient to describe and compare bacterial cells under various conditions. The parameter values can be altered and the effects of the alterations can be seen. CCSim is easy to use and presents the kinetics of cell growth in a digestible format. Replicating chromosomes and growing bacillary cells are coupled to parameters that affect the cell cycle and animated. It serves as an educational tool to teach bacteriology and to compare experimental observations with the model best describing cell growth thus improve our understanding of regulatory mechanisms. Examples are displayed of transitions between known physiological states that are consistent with experimental results, including one that explains strange observations. The program predicts enhanced division frequencies after a period of slow replication under thymine limitation if a minimal distance (Eclipse exists between successive replisomes, as observed. Missing features and ways to improve, extend and refine CCSim are proposed, for both single cells and random populations under steady-states of exponential growth and during well-defined transitions. Future improvements and extensions are proposed for single cells and populations.

  11. Simulation of the Prokaryotic Cell Cycle at simon.bio.uva.nl/cellcycle/

    Directory of Open Access Journals (Sweden)

    Charles E. Helmstetter

    2012-02-01

    Full Text Available The bacterial Cell Cycle is presented using the Simulation program CCSim, which employs four parameters related to time (inter-division τ, replication C, division D and size (mass at replication initiation Mi, sufficient to describe and compare bacterial cells under various conditions. The parameter values can be altered and the effects of the alterations can be seen. CCSim is easy to use and presents the kinetics of cell growth in a digestible format. Replicating chromosomes and growing bacillary cells are coupled to parameters that affect the cell cycle and animated. It serves as an educational tool to teach bacteriology and to compare experimental observations with the model best describing cell growth thus improve our understanding of regulatory mechanisms. Examples are displayed of transitions between known physiological states that are consistent with experimental results, including one that explains strange observations. The program predicts enhanced division frequencies after a period of slow replication under thymine limitation if a minimal distance (Eclipse exists between successive replisomes, as observed. Missing features and ways to improve, extend and refine CCSim are proposed, for both single cells and random populations under steady-states of exponential growth and during well-defined transitions. Future improvements and extensions are proposed for single cells and populations.

  12. Day/Night Cycle: Mental Models of Primary School Children

    Science.gov (United States)

    Chiras, Andreas

    2008-01-01

    The study investigated the mental models of primary school children related to the day/night cycle. Semi-structure interviews were conducted with 40 fourth-grade and 40 sixth-grade children. Qualitative and quantitative analysis of the data indicated that the majority of the children were classified as having geocentric models. The results also…

  13. A comparison of major petroleum life cycle models | Science ...

    Science.gov (United States)

    Many organizations have attempted to develop an accurate well-to-pump life cycle model of petroleum products in order to inform decision makers of the consequences of its use. Our paper studies five of these models, demonstrating the differences in their predictions and attempting to evaluate their data quality. Carbon dioxide well-to-pump emissions for gasoline showed a variation of 35 %, and other pollutants such as ammonia and particulate matter varied up to 100 %. Differences in allocation do not appear to explain differences in predictions. Effects of these deviations on well-to-wheels passenger vehicle and truck transportation life cycle models may be minimal for effects such as global warming potential (6 % spread), but for respiratory effects of criteria pollutants (41 % spread) and other impact categories, they can be significant. A data quality assessment of the models’ documentation revealed real differences between models in temporal and geographic representativeness, completeness, as well as transparency. Stakeholders may need to consider carefully the tradeoffs inherent when selecting a model to conduct life cycle assessments for systems that make heavy use of petroleum products. This is a qualitative and quantitative comparison of petroleum LCA models intended for an expert audience interested in better understanding the data quality of existing petroleum life cycle models and the quantitative differences between these models.

  14. S-phase-dependent cell cycle disturbances caused by Aleutian mink disease parvovirus

    DEFF Research Database (Denmark)

    Oleksiewicz, M.B.; Alexandersen, Søren

    1997-01-01

    We examined replication of the autonomous parovirus Aleutian mink disease parovirus (ADV) in relation to cell cycle progression of permissive Crandell feline kidney (CRFK) cells. Flow cytometric analysis showed that ADV caused a composite, binary pattern of cell cycle arrest. ADV-induced cell cyc...

  15. Radiation could induce p53-independent and cell cycle - unrelated apoptosis in 5-fluorouracil radiosensitized head and neck carcinoma cells

    International Nuclear Information System (INIS)

    Didelot, C.; Mirjolet, J.F.; Barberi-Heyob, M.; Ramacci, C.; Merlin, J.L.

    2002-01-01

    The effect of chemoresistance induction in radio sensitivity and cellular behavior after irradiation remains misunderstood. This study was designed to understand the relationship between radiation-induced cell cycle arrest, apoptosis, and radiosensitivity in KB cell line and KB3 subline selected after 5-fluorouracil (5FU) exposure. Exposure of KB cells to 5FU led to an increase in radiosensitivity. G 2 /M cell cycle arrest was observed in the two cell lines after irradiation. The radioresistant KB cell line reached the maximum arrest two hours before KB3. The cellular exit from this arrest was found to be related to the wild type p53 protein expression induction. After irradiation, only KB3 cell line underwent apoptosis. This apoptosis induction seemed to be independent of G 2 /M arrest exit, which was carried out later. The difference in radiosensitivity between KB and KB3 subline may result therefore from both a difference in apoptosis induction and a difference in G 2 /M arrest maximum duration. Moreover, 5FU exposure has led to an increase in constitutive p53 protein expression, which may be associated with an increase in basal apoptosis cell fraction. Given the existing correlation between radiosensitivity and the percentage of basal apoptosis. the constitutive p53 protein expression may be related to intrinsic radiosensitivity in our cellular model. (author)

  16. Cell cycle delays induced by heavy ion irradiation of synchronous mammalian cells

    International Nuclear Information System (INIS)

    Scholz, M.; Kraft-Weyrather, W.; Ritter, S.; Kraft, G.

    1994-01-01

    Cell cycle delays in V79 Chinese hamster cells induced by heavy ion exposure have been investigated using flow cytometry. Synchronous cell populations in G 1 -, S- and late-S/G 2 M-phase were used. Cells were irradiated with particles from Z = 10 (neon) up to Z = 96 (uranium) in the energy range from 2.4 to 17.4 MeV/u and the LET range from 415 to 16225 keV/μm at the UNILAC at GSI, Darmstadt. For comparison, experiments with 250 kV X-rays were performed. For light particles like neon, cell cycle perturbations comparable to those after X-ray irradiation were found, and with increasing LET an increasing delay per particle traversal was observed. For the highest LET-values, extended delays in G 1 -, S- and G 2 M-phase were detected immediately after irradiation. A large fraction of the cells remained in S-phase or G 2 M-phase up to 48 h or longer after irradiation. No significant cell age dependence of cycle delays was detected for the very high LET values. In addition to cell cycle delays, two effects related to the DNA-content as determined by flow cytometry were found after irradiation with very high LET particles, which were attributed to cell fusion and to drastic morphological changes of the cells. Estimations based on the dose deposited by a single particle hit in the cell nucleus and the actual number of hits show, that the basic trend of the experimental results can be explained by the stochastic properties of particle radiation. (orig.)

  17. Mechanisms involved in alternariol-induced cell cycle arrest

    Energy Technology Data Exchange (ETDEWEB)

    Solhaug, A., E-mail: Anita.Solhaug@vetinst.no [Norwegian Veterinary Institute, Oslo (Norway); Vines, L.L. [Michigan State University, Department of Food Science and Human Nutrition, East Lansing, MI (United States); Ivanova, L.; Spilsberg, B. [Norwegian Veterinary Institute, Oslo (Norway); Holme, J.A. [Norwegian Institute of Public Health, Division of Environmental Medicine, Oslo (Norway); Pestka, J. [Michigan State University, Department of Food Science and Human Nutrition, East Lansing, MI (United States); Collins, A. [University of Oslo, Department of Nutrition, Faculty of Medicine, Oslo (Norway); Eriksen, G.S. [Norwegian Veterinary Institute, Oslo (Norway)

    2012-10-15

    Alternariol (AOH), a mycotoxin produced by Alternaria sp, is often found as a contaminant in fruit and cereal products. Here we employed the murine macrophage cell line RAW 264.7 to test the hypothesis that AOH causes toxicity as a response to DNA damage. AOH at concentrations of 15-30 {mu}M almost completely blocked cell proliferation. Within 30 min treatment, AOH (30 {mu}M) significantly increased the level of reactive oxygen species (ROS). Furthermore, DNA base oxidations as well as DNA strand breaks and/or alkaline labile sites were detected by the comet assay after 2 h exposure of AOH. Cell death (mostly necrosis) was observed after prolonged exposure to the highest concentration of AOH (60 {mu}M for 24 and 48 h) in our study. The DNA damage response involved phosphorylation (activation) of histone H2AX and check point kinase-1- and 2 (Chk-1/2). Moreover, AOH activated p53 and increased the expression of p21, Cyclin B, MDM2, and Sestrin 2; likewise the level of several miRNA was affected. AOH-induced Sestrin 2 expression was regulated by p53 and could at least partly be inhibited by antioxidants, suggesting a role of ROS in the response. Interestingly, the addition of antioxidants did not inhibit cell cycle arrest. Although the formation of ROS by itself was not directly linked cell proliferation, AOH-induced DNA damage and resulting transcriptional changes in p21, MDM2, and Cyclin B likely contribute to the reduced cell proliferation; while Sestrin 2 would contribute to the oxidant defense.

  18. Mechanisms involved in alternariol-induced cell cycle arrest

    International Nuclear Information System (INIS)

    Solhaug, A.; Vines, L.L.; Ivanova, L.; Spilsberg, B.; Holme, J.A.; Pestka, J.; Collins, A.; Eriksen, G.S.

    2012-01-01

    Alternariol (AOH), a mycotoxin produced by Alternaria sp, is often found as a contaminant in fruit and cereal products. Here we employed the murine macrophage cell line RAW 264.7 to test the hypothesis that AOH causes toxicity as a response to DNA damage. AOH at concentrations of 15–30 μM almost completely blocked cell proliferation. Within 30 min treatment, AOH (30 μM) significantly increased the level of reactive oxygen species (ROS). Furthermore, DNA base oxidations as well as DNA strand breaks and/or alkaline labile sites were detected by the comet assay after 2 h exposure of AOH. Cell death (mostly necrosis) was observed after prolonged exposure to the highest concentration of AOH (60 μM for 24 and 48 h) in our study. The DNA damage response involved phosphorylation (activation) of histone H2AX and check point kinase-1- and 2 (Chk-1/2). Moreover, AOH activated p53 and increased the expression of p21, Cyclin B, MDM2, and Sestrin 2; likewise the level of several miRNA was affected. AOH-induced Sestrin 2 expression was regulated by p53 and could at least partly be inhibited by antioxidants, suggesting a role of ROS in the response. Interestingly, the addition of antioxidants did not inhibit cell cycle arrest. Although the formation of ROS by itself was not directly linked cell proliferation, AOH-induced DNA damage and resulting transcriptional changes in p21, MDM2, and Cyclin B likely contribute to the reduced cell proliferation; while Sestrin 2 would contribute to the oxidant defense.

  19. Boron neutron capture therapy induces cell cycle arrest and cell apoptosis of glioma stem/progenitor cells in vitro

    International Nuclear Information System (INIS)

    Sun, Ting; Zhang, Zizhu; Li, Bin; Chen, Guilin; Xie, Xueshun; Wei, Yongxin; Wu, Jie; Zhou, Youxin; Du, Ziwei

    2013-01-01

    Glioma stem cells in the quiescent state are resistant to clinical radiation therapy. An almost inevitable glioma recurrence is due to the persistence of these cells. The high linear energy transfer associated with boron neutron capture therapy (BNCT) could kill quiescent and proliferative cells. The present study aimed to evaluate the effects of BNCT on glioma stem/progenitor cells in vitro. The damage induced by BNCT was assessed using cell cycle progression, apoptotic cell ratio and apoptosis-associated proteins expression. The surviving fraction and cell viability of glioma stem/progenitor cells were decreased compared with differentiated glioma cells using the same boronophenylalanine pretreatment and the same dose of neutron flux. BNCT induced cell cycle arrest in the G2/M phase and cell apoptosis via the mitochondrial pathway, with changes in the expression of associated proteins. Glioma stem/progenitor cells, which are resistant to current clinical radiotherapy, could be effectively killed by BNCT in vitro via cell cycle arrest and apoptosis using a prolonged neutron irradiation, although radiosensitivity of glioma stem/progenitor cells was decreased compared with differentiated glioma cells when using the same dose of thermal neutron exposure and boronophenylalanine pretreatment. Thus, BNCT could offer an appreciable therapeutic advantage to prevent tumor recurrence, and may become a promising treatment in recurrent glioma

  20. Rho-associated kinase (ROCK) function is essential for cell cycle progression, senescence and tumorigenesis.

    Science.gov (United States)

    Kümper, Sandra; Mardakheh, Faraz K; McCarthy, Afshan; Yeo, Maggie; Stamp, Gordon W; Paul, Angela; Worboys, Jonathan; Sadok, Amine; Jørgensen, Claus; Guichard, Sabrina; Marshall, Christopher J

    2016-01-14

    Rho-associated kinases 1 and 2 (ROCK1/2) are Rho-GTPase effectors that control key aspects of the actin cytoskeleton, but their role in proliferation and cancer initiation or progression is not known. Here, we provide evidence that ROCK1 and ROCK2 act redundantly to maintain actomyosin contractility and cell proliferation and that their loss leads to cell-cycle arrest and cellular senescence. This phenotype arises from down-regulation of the essential cell-cycle proteins CyclinA, CKS1 and CDK1. Accordingly, while the loss of either Rock1 or Rock2 had no negative impact on tumorigenesis in mouse models of non-small cell lung cancer and melanoma, loss of both blocked tumor formation, as no tumors arise in which both Rock1 and Rock2 have been genetically deleted. Our results reveal an indispensable role for ROCK, yet redundant role for isoforms 1 and 2, in cell cycle progression and tumorigenesis, possibly through the maintenance of cellular contractility.

  1. A model for a knowledge-based system's life cycle

    Science.gov (United States)

    Kiss, Peter A.

    1990-01-01

    The American Institute of Aeronautics and Astronautics has initiated a Committee on Standards for Artificial Intelligence. Presented here are the initial efforts of one of the working groups of that committee. The purpose here is to present a candidate model for the development life cycle of Knowledge Based Systems (KBS). The intent is for the model to be used by the Aerospace Community and eventually be evolved into a standard. The model is rooted in the evolutionary model, borrows from the spiral model, and is embedded in the standard Waterfall model for software development. Its intent is to satisfy the development of both stand-alone and embedded KBSs. The phases of the life cycle are detailed as are and the review points that constitute the key milestones throughout the development process. The applicability and strengths of the model are discussed along with areas needing further development and refinement by the aerospace community.

  2. Glucose-ABL1-TOR Signaling Modulates Cell Cycle Tuning to Control Terminal Appressorial Cell Differentiation.

    Science.gov (United States)

    Marroquin-Guzman, Margarita; Sun, Guangchao; Wilson, Richard A

    2017-01-01

    The conserved target of rapamycin (TOR) pathway integrates growth and development with available nutrients, but how cellular glucose controls TOR function and signaling is poorly understood. Here, we provide functional evidence from the devastating rice blast fungus Magnaporthe oryzae that glucose can mediate TOR activity via the product of a novel carbon-responsive gene, ABL1, in order to tune cell cycle progression during infection-related development. Under nutrient-free conditions, wild type (WT) M. oryzae strains form terminal plant-infecting cells (appressoria) at the tips of germ tubes emerging from three-celled spores (conidia). WT appressorial development is accompanied by one round of mitosis followed by autophagic cell death of the conidium. In contrast, Δabl1 mutant strains undergo multiple rounds of accelerated mitosis in elongated germ tubes, produce few appressoria, and are abolished for autophagy. Treating WT spores with glucose or 2-deoxyglucose phenocopied Δabl1. Inactivating TOR in Δabl1 mutants or glucose-treated WT strains restored appressorium formation by promoting mitotic arrest at G1/G0 via an appressorium- and autophagy-inducing cell cycle delay at G2/M. Collectively, this work uncovers a novel glucose-ABL1-TOR signaling axis and shows it engages two metabolic checkpoints in order to modulate cell cycle tuning and mediate terminal appressorial cell differentiation. We thus provide new molecular insights into TOR regulation and cell development in response to glucose.

  3. Prognostic value of cell cycle regulatory proteins in muscle-infiltrating bladder cancer.

    Science.gov (United States)

    Galmozzi, Fabia; Rubagotti, Alessandra; Romagnoli, Andrea; Carmignani, Giorgio; Perdelli, Luisa; Gatteschi, Beatrice; Boccardo, Francesco

    2006-12-01

    The aims of this study were to investigate the expression levels of proteins involved in cell cycle regulation in specimens of bladder cancer and to correlate them with the clinicopathological characteristics, proliferative activity and survival. Eighty-two specimens obtained from patients affected by muscle-invasive bladder cancer were evaluated immunohistochemically for p53, p21 and cyclin D1 expression, as well as for the tumour proliferation index, Ki-67. The statistical analysis included Kaplan-Meier curves with log-rank test and Cox proportional hazards models. In univariate analyses, low Ki-67 proliferation index (P = 0.045) and negative p21 immunoreactivity (P = 0.04) were associated to patient's overall survival (OS), but in multivariate models p21 did not reach statistical significance. When the combinations of the variables were assessed in two separate multivariate models that included tumour stage, grading, lymph node status, vascular invasion and perineural invasion, the combined variables p21/Ki-67 or p21/cyclin D1 expression were independent predictors for OS; in particular, patients with positive p21/high Ki-67 (P = 0.015) or positive p21/negative cyclin D1 (P = 0.04) showed the worst survival outcome. Important alterations in the cell cycle regulatory pathways occur in muscle-invasive bladder cancer and the combined use of cell cycle regulators appears to provide significant prognostic information that could be used to select the patients most suitable for multimodal therapeutic approaches.

  4. Measuring cell cycle progression kinetics with metabolic labeling and flow cytometry.

    Science.gov (United States)

    Fleisig, Helen; Wong, Judy

    2012-05-22

    Precise control of the initiation and subsequent progression through the various phases of the cell cycle are of paramount importance in proliferating cells. Cell cycle division is an integral part of growth and reproduction and deregulation of key cell cycle components have been implicated in the precipitating events of carcinogenesis. Molecular agents in anti-cancer therapies frequently target biological pathways responsible for the regulation and coordination of cell cycle division. Although cell cycle kinetics tend to vary according to cell type, the distribution of cells amongst the four stages of the cell cycle is rather consistent within a particular cell line due to the consistent pattern of mitogen and growth factor expression. Genotoxic events and other cellular stressors can result in a temporary block of cell cycle progression, resulting in arrest or a temporary pause in a particular cell cycle phase to allow for instigation of the appropriate response mechanism. The ability to experimentally observe the behavior of a cell population with reference to their cell cycle progression stage is an important advance in cell biology. Common procedures such as mitotic shake off, differential centrifugation or flow cytometry-based sorting are used to isolate cells at specific stages of the cell cycle. These fractionated, cell cycle phase-enriched populations are then subjected to experimental treatments. Yield, purity and viability of the separated fractions can often be compromised using these physical separation methods. As well, the time lapse between separation of the cell populations and the start of experimental treatment, whereby the fractionated cells can progress from the selected cell cycle stage, can pose significant challenges in the successful implementation and interpretation of these experiments. Other approaches to study cell cycle stages include the use of chemicals to synchronize cells. Treatment of cells with chemical inhibitors of key

  5. A CASKCOM: A cask life cycle cost model

    International Nuclear Information System (INIS)

    Anon.

    1989-01-01

    CASKCOM (cask cost model) is a computerized model which calculates the life cycle costs (LCC) associated with specific transportation cask designs and discounts those costs, if the user so chooses, to a net present value. The model has been used to help analyze and compare the life cycle economics of burnup credit and nonburnup credit cask designs being considered as conditions for a new generation of spent fuel transportation casks. CASKCOM is parametric in the sense that its input data can be easily changed in order to analyze and compare the life cycle cost implications arising from alternative assumptions. The input data themselves are organized into two main groupings. The first grouping comprises a set of data which is independent of cask design. This first grouping does not change from the analysis of one cask design to another. The second grouping of data is specific to each individual cask design. This second grouping thus changes each time a new cask design is analyzed

  6. EASEWASTE-life cycle modeling capabilities for waste management technologies

    DEFF Research Database (Denmark)

    Bhander, Gurbakhash Singh; Christensen, Thomas Højlund; Hauschild, Michael Zwicky

    2010-01-01

    Background, Aims and Scope The management of municipal solid waste and the associated environmental impacts are subject of growing attention in industrialized countries. EU has recently strongly emphasized the role of LCA in its waste and resource strategies. The development of sustainable solid...... waste management systems applying a life-cycle perspective requires readily understandable tools for modelling the life cycle impacts of waste management systems. The aim of the paper is to demonstrate the structure, functionalities and LCA modelling capabilities of the PC-based life cycle oriented...... waste management model EASEWASTE, developed at the Technical University of Denmark specifically to meet the needs of the waste system developer with the objective to evaluate the environmental performance of the various elements of existing or proposed solid waste management systems. Materials...

  7. Combined Turbine and Cycle Optimization for Organic Rankine Cycle Power Systems—Part A: Turbine Model

    Directory of Open Access Journals (Sweden)

    Andrea Meroni

    2016-04-01

    Full Text Available Axial-flow turbines represent a well-established technology for a wide variety of power generation systems. Compactness, flexibility, reliability and high efficiency have been key factors for the extensive use of axial turbines in conventional power plants and, in the last decades, in organic Rankine cycle power systems. In this two-part paper, an overall cycle model and a model of an axial turbine were combined in order to provide a comprehensive preliminary design of the organic Rankine cycle unit, taking into account both cycle and turbine optimal designs. Part A presents the preliminary turbine design model, the details of the validation and a sensitivity analysis on the main parameters, in order to minimize the number of decision variables in the subsequent turbine design optimization. Part B analyzes the application of the combined turbine and cycle designs on a selected case study, which was performed in order to show the advantages of the adopted methodology. Part A presents a one-dimensional turbine model and the results of the validation using two experimental test cases from literature. The first case is a subsonic turbine operated with air and investigated at the University of Hannover. The second case is a small, supersonic turbine operated with an organic fluid and investigated by Verneau. In the first case, the results of the turbine model are also compared to those obtained using computational fluid dynamics simulations. The results of the validation suggest that the model can predict values of efficiency within ± 1.3%-points, which is in agreement with the reliability of classic turbine loss models such as the Craig and Cox correlations used in the present study. Values similar to computational fluid dynamics simulations at the midspan were obtained in the first case of validation. Discrepancy below 12 % was obtained in the estimation of the flow velocities and turbine geometry. The values are considered to be within a

  8. Nuclear fuel cycle optimization - methods and modelling techniques

    International Nuclear Information System (INIS)

    Silvennoinen, P.

    1982-01-01

    This book is aimed at presenting methods applicable in the analysis of fuel cycle logistics and optimization as well as in evaluating the economics of different reactor strategies. After a succinct introduction to the phases of a fuel cycle, uranium cost trends are assessed in a global perspective and subsequent chapters deal with the fuel cycle problems faced by a power utility. A fundamental material flow model is introduced first in the context of light water reactor fuel cycles. Besides the minimum cost criterion, the text also deals with other objectives providing for a treatment of cost uncertainties and of the risk of proliferation of nuclear weapons. Methods to assess mixed reactor strategies, comprising also other reactor types than the light water reactor, are confined to cost minimization. In the final Chapter, the integration of nuclear capacity within a generating system is examined. (author)

  9. Abnormal mitosis triggers p53-dependent cell cycle arrest in human tetraploid cells.

    Science.gov (United States)

    Kuffer, Christian; Kuznetsova, Anastasia Yurievna; Storchová, Zuzana

    2013-08-01

    Erroneously arising tetraploid mammalian cells are chromosomally instable and may facilitate cell transformation. An increasing body of evidence shows that the propagation of mammalian tetraploid cells is limited by a p53-dependent arrest. The trigger of this arrest has not been identified so far. Here we show by live cell imaging of tetraploid cells generated by an induced cytokinesis failure that most tetraploids arrest and die in a p53-dependent manner after the first tetraploid mitosis. Furthermore, we found that the main trigger is a mitotic defect, in particular, chromosome missegregation during bipolar mitosis or spindle multipolarity. Both a transient multipolar spindle followed by efficient clustering in anaphase as well as a multipolar spindle followed by multipolar mitosis inhibited subsequent proliferation to a similar degree. We found that the tetraploid cells did not accumulate double-strand breaks that could cause the cell cycle arrest after tetraploid mitosis. In contrast, tetraploid cells showed increased levels of oxidative DNA damage coinciding with the p53 activation. To further elucidate the pathways involved in the proliferation control of tetraploid cells, we knocked down specific kinases that had been previously linked to the cell cycle arrest and p53 phosphorylation. Our results suggest that the checkpoint kinase ATM phosphorylates p53 in tetraploid cells after abnormal mitosis and thus contributes to proliferation control of human aberrantly arising tetraploids.

  10. Cell cycle variation in x-ray survival for cells from spheroids measured by volume cell sorting

    International Nuclear Information System (INIS)

    Freyer, J.P.; Wilder, M.E.; Raju, M.R.

    1984-01-01

    Considerable work has been done studying the variation in cell survival as a function of cell cycle position for monolayers or single cells exposed to radiation. Little is known about the effects of multicellular growth on the relative radiation sensitivity of cells in different cell cycle stages. The authors have developed a new technique for measuring the response of cells, using volume cell sorting, which is rapid, non-toxic, and does not require cell synchronization. By combining this technique with selective spheroid dissociation,they have measured the age response of cells located at various depths in EMT6 and Colon 26 spheroids. Although cells in the inner region had mostly G1-phase DNA contents, 15-20% had S- and G2-phase DNA contents. Analysis of these cells using BrdU labeling and flow cytometric analysis with a monoclonal antibody to BrdU indicated that the inner region cells were not synthesizing DNA. Thus, the authors were able to measure the radiation response of cells arrested in G1, S and G2 cell cycle phases. Comparison of inner and outer spheroid regions, and monolayer cultures, indicates that it is improper to extrapolate age response data in standard culture conditions to the situation in spheroids

  11. Flow cytometric analysis of mitotic cycle perturbation by chemical carcinogens in cultured epithelial cells. [Effects of benzo(a)pyrene-diol-epoxide on mitotic cycle of cultural mouse liver epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Pearlman, Andrew Leonard [Univ. of California, Berkeley, CA (United States)

    1978-08-01

    A system for kinetic analysis of mitotic cycle perturbation by various agents was developed and applied to the study of the mitotic cycle effects and dependency of the chemical carcinogen benzo(a)pyrene-diolepoxide, DE, upon a mouse lever epithelial cell line, NMuLi. The study suggests that the targets of DE action are not confined to DNA alone but may include cytoplasmic structures as well. DE was found to affect cells located in virtually every phase of the mitotic cycle, with cells that were actively synthesizing DNA showing the strongest response. However, the resulting perturbations were not confined to S-phase alone. DE slowed traversal through S-phase by about 40% regardless of the cycle phase of the cells exposed to it, and slowed traversal through G2M by about 50%. When added to G1 cells, DE delayed recruitment of apparently quiescent (G0) cells by 2 hours, and reduced the synchrony of the cohort of cells recruited into active proliferation. The kinetic analysis system consists of four elements: tissue culture methods for propagating and harvesting cell populations; an elutriation centrifugation system for bulk synchronization of cells in various phases of the mitotic cycle; a flow cytometer (FCM), coupled with appropriate staining protocols, to enable rapid analysis of the DNA distribution of any given cell population; and data reduction and analysis methods for extracting information from the DNA histograms produced by the FCM. The elements of the system are discussed. A mathematical analysis of DNA histograms obtained by FCM is presented. The analysis leads to the detailed implementation of a new modeling approach. The new modeling approach is applied to the estimation of cell cycle kinetic parameters from time series of DNA histograms, and methods for the reduction and interpretation of such series are suggested.

  12. Chloroplast Dysfunction Causes Multiple Defects in Cell Cycle Progression in the Arabidopsis crumpled leaf Mutant

    KAUST Repository

    Hudik, Elodie; Yoshioka, Yasushi; Domenichini, Sé Verine; Bourge, Mickaë l; Soubigout-Taconnat, Ludivine; Mazubert, Christelle; Yi, Dalong; Bujaldon, Sandrine; Hayashi, Hiroyuki; De Veylder, Lieven; Bergounioux, Catherine; Benhamed, Moussa; Raynaud, Cé cile

    2014-01-01

    The majority of research on cell cycle regulation is focused on the nuclear events that govern the replication and segregation of the genome between the two daughter cells. However, eukaryotic cells contain several compartmentalized organelles

  13. Nutrient cycle benchmarks for earth system land model

    Science.gov (United States)

    Zhu, Q.; Riley, W. J.; Tang, J.; Zhao, L.

    2017-12-01

    Projecting future biosphere-climate feedbacks using Earth system models (ESMs) relies heavily on robust modeling of land surface carbon dynamics. More importantly, soil nutrient (particularly, nitrogen (N) and phosphorus (P)) dynamics strongly modulate carbon dynamics, such as plant sequestration of atmospheric CO2. Prevailing ESM land models all consider nitrogen as a potentially limiting nutrient, and several consider phosphorus. However, including nutrient cycle processes in ESM land models potentially introduces large uncertainties that could be identified and addressed by improved observational constraints. We describe the development of two nutrient cycle benchmarks for ESM land models: (1) nutrient partitioning between plants and soil microbes inferred from 15N and 33P tracers studies and (2) nutrient limitation effects on carbon cycle informed by long-term fertilization experiments. We used these benchmarks to evaluate critical hypotheses regarding nutrient cycling and their representation in ESMs. We found that a mechanistic representation of plant-microbe nutrient competition based on relevant functional traits best reproduced observed plant-microbe nutrient partitioning. We also found that for multiple-nutrient models (i.e., N and P), application of Liebig's law of the minimum is often inaccurate. Rather, the Multiple Nutrient Limitation (MNL) concept better reproduces observed carbon-nutrient interactions.

  14. Exploring the Underlying Mechanisms of the Xenopus laevis Embryonic Cell Cycle.

    Science.gov (United States)

    Zhang, Kun; Wang, Jin

    2018-05-31

    The cell cycle is an indispensable process in proliferation and development. Despite significant efforts, global quantification and physical understanding are still challenging. In this study, we explored the mechanisms of the Xenopus laevis embryonic cell cycle by quantifying the underlying landscape and flux. We uncovered the Mexican hat landscape of the Xenopus laevis embryonic cell cycle with several local basins and barriers on the oscillation path. The local basins characterize the different phases of the Xenopus laevis embryonic cell cycle, and the local barriers represent the checkpoints. The checkpoint mechanism of the cell cycle is revealed by the landscape basins and barriers. While landscape shape determines the stabilities of the states on the oscillation path, the curl flux force determines the stability of the cell cycle flow. Replication is fundamental for biology of living cells. We quantify the input energy (through the entropy production) as the thermodynamic requirement for initiation and sustainability of single cell life (cell cycle). Furthermore, we also quantify curl flux originated from the input energy as the dynamical requirement for the emergence of a new stable phase (cell cycle). This can provide a new quantitative insight for the origin of single cell life. In fact, the curl flux originated from the energy input or nutrition supply determines the speed and guarantees the progression of the cell cycle. The speed of the cell cycle is a hallmark of cancer. We characterized the quality of the cell cycle by the coherence time and found it is supported by the flux and energy cost. We are also able to quantify the degree of time irreversibility by the cross correlation function forward and backward in time from the stochastic traces in the simulation or experiments, providing a way for the quantification of the time irreversibility and the flux. Through global sensitivity analysis upon landscape and flux, we can identify the key elements for

  15. Life cycle analysis of photovoltaic cell and wind power plants

    International Nuclear Information System (INIS)

    Uchiyama, Yohji

    1997-01-01

    The paper presents life cycle analyses of net energy and CO 2 emissions on photovoltaic cell and wind power generation plants. Energy requirements associated with a plant are estimated for producing materials, manufacturing equipment, constructing facilities, acid operating plants. Energy ratio and net supplied energy are calculated by the process energy analysis that examines the entire energy inventory of input and output during life time of a plant. Life cycle CO 2 emission can also be calculated from the energy requirements obtained by the net energy analysis. The emission also includes greenhouse effect equivalent to CO 2 emission of methane gas leakage at a mining as well as CO 2 emissions from fossil fuel combustion during generating electricity, natural gas treatment at an extracting well and cement production in industry. The commercially available and future-commercial technologies are dealt with in the study. Regarding PV technologies, two different kinds of installation are investigated; roof-top typed installation of residential houses and ground installation of electric utilities. (author)

  16. A balance of FGF and BMP signals regulates cell cycle exit and Equarin expression in lens cells

    Science.gov (United States)

    Jarrin, Miguel; Pandit, Tanushree; Gunhaga, Lena

    2012-01-01

    In embryonic and adult lenses, a balance of cell proliferation, cell cycle exit, and differentiation is necessary to maintain physical function. The molecular mechanisms regulating the transition of proliferating lens epithelial cells to differentiated primary lens fiber cells are poorly characterized. To investigate this question, we used gain- and loss-of-function analyses to modulate fibroblast growth factor (FGF) and/or bone morphogenetic protein (BMP) signals in chick lens/retina explants. Here we show that FGF activity plays a key role for proliferation independent of BMP signals. Moreover, a balance of FGF and BMP signals regulates cell cycle exit and the expression of Ccdc80 (also called Equarin), which is expressed at sites where differentiation of lens fiber cells occurs. BMP activity promotes cell cycle exit and induces Equarin expression in an FGF-dependent manner. In contrast, FGF activity is required but not sufficient to induce cell cycle exit or Equarin expression. Furthermore, our results show that in the absence of BMP activity, lens cells have increased cell cycle length or are arrested in the cell cycle, which leads to decreased cell cycle exit. Taken together, these findings suggest that proliferation, cell cycle exit, and early differentiation of primary lens fiber cells are regulated by counterbalancing BMP and FGF signals. PMID:22718906

  17. Cell cycle arrest and cell survival induce reverse trends of cardiolipin remodeling.

    Directory of Open Access Journals (Sweden)

    Yu-Jen Chao

    Full Text Available Cell survival from the arrested state can be a cause of the cancer recurrence. Transition from the arrest state to the growth state is highly regulated by mitochondrial activity, which is related to the lipid compositions of the mitochondrial membrane. Cardiolipin is a critical phospholipid for the mitochondrial integrity and functions. We examined the changes of cardiolipin species by LC-MS in the transition between cell cycle arrest and cell reviving in HT1080 fibrosarcoma cells. We have identified 41 cardiolipin species by MS/MS and semi-quantitated them to analyze the detailed changes of cardiolipin species. The mass spectra of cardiolipin with the same carbon number form an envelope, and the C64, C66, C68, C70 C72 and C74 envelopes in HT1080 cells show a normal distribution in the full scan mass spectrum. The cardiolipin quantity in a cell decreases while entering the cell cycle arrest, but maintains at a similar level through cell survival. While cells awakening from the arrested state and preparing itself for replication, the groups with short acyl chains, such as C64, C66 and C68 show a decrease of cardiolipin percentage, but the groups with long acyl chains, such as C70 and C72 display an increase of cardiolipin percentage. Interestingly, the trends of the cardiolipin species changes during the arresting state are completely opposite to cell growing state. Our results indicate that the cardiolipin species shift from the short chain to long chain cardiolipin during the transition from cell cycle arrest to cell progression.

  18. Restrictions in cell cycle progression of adult vestibular supporting cells in response to ectopic cyclin D1 expression.

    Directory of Open Access Journals (Sweden)

    Heidi Loponen

    Full Text Available Sensory hair cells and supporting cells of the mammalian inner ear are quiescent cells, which do not regenerate. In contrast, non-mammalian supporting cells have the ability to re-enter the cell cycle and produce replacement hair cells. Earlier studies have demonstrated cyclin D1 expression in the developing mouse supporting cells and its downregulation along maturation. In explant cultures of the mouse utricle, we have here focused on the cell cycle control mechanisms and proliferative potential of adult supporting cells. These cells were forced into the cell cycle through adenoviral-mediated cyclin D1 overexpression. Ectopic cyclin D1 triggered robust cell cycle re-entry of supporting cells, accompanied by changes in p27(Kip1 and p21(Cip1 expressions. Main part of cell cycle reactivated supporting cells were DNA damaged and arrested at the G2/M boundary. Only small numbers of mitotic supporting cells and rare cells with signs of two successive replications were found. Ectopic cyclin D1-triggered cell cycle reactivation did not lead to hyperplasia of the sensory epithelium. In addition, a part of ectopic cyclin D1 was sequestered in the cytoplasm, reflecting its ineffective nuclear import. Combined, our data reveal intrinsic barriers that limit proliferative capacity of utricular supporting cells.

  19. Restrictions in cell cycle progression of adult vestibular supporting cells in response to ectopic cyclin D1 expression.

    Science.gov (United States)

    Loponen, Heidi; Ylikoski, Jukka; Albrecht, Jeffrey H; Pirvola, Ulla

    2011-01-01

    Sensory hair cells and supporting cells of the mammalian inner ear are quiescent cells, which do not regenerate. In contrast, non-mammalian supporting cells have the ability to re-enter the cell cycle and produce replacement hair cells. Earlier studies have demonstrated cyclin D1 expression in the developing mouse supporting cells and its downregulation along maturation. In explant cultures of the mouse utricle, we have here focused on the cell cycle control mechanisms and proliferative potential of adult supporting cells. These cells were forced into the cell cycle through adenoviral-mediated cyclin D1 overexpression. Ectopic cyclin D1 triggered robust cell cycle re-entry of supporting cells, accompanied by changes in p27(Kip1) and p21(Cip1) expressions. Main part of cell cycle reactivated supporting cells were DNA damaged and arrested at the G2/M boundary. Only small numbers of mitotic supporting cells and rare cells with signs of two successive replications were found. Ectopic cyclin D1-triggered cell cycle reactivation did not lead to hyperplasia of the sensory epithelium. In addition, a part of ectopic cyclin D1 was sequestered in the cytoplasm, reflecting its ineffective nuclear import. Combined, our data reveal intrinsic barriers that limit proliferative capacity of utricular supporting cells.

  20. Fanconi anemia and the cell cycle: new perspectives on aneuploidy

    Science.gov (United States)

    2014-01-01

    Fanconi anemia (FA) is a complex heterogenic disorder of genomic instability, bone marrow failure, cancer predisposition, and congenital malformations. The FA signaling network orchestrates the DNA damage recognition and repair in interphase as well as proper execution of mitosis. Loss of FA signaling causes chromosome instability by weakening the spindle assembly checkpoint, disrupting centrosome maintenance, disturbing resolution of ultrafine anaphase bridges, and dysregulating cytokinesis. Thus, the FA genes function as guardians of genome stability throughout the cell cycle. This review discusses recent advances in diagnosis and clinical management of Fanconi anemia and presents the new insights into the origins of genomic instability in FA. These new discoveries may facilitate the development of rational therapeutic strategies for FA and for FA-deficient malignancies in the general population. PMID:24765528

  1. UV-induced changes in cell cycle and gene expression within rabbit lens epithelial cells

    International Nuclear Information System (INIS)

    Sidjanin, D.; Grdina, D.; Woloschak, G.E.

    1996-01-01

    Damage to lens epithelial cells is a probable initiation process in cataract formation mediated by UV radiation. In these experiments, we investigated the effects of exposure to 254 nm radiation on cell cycle progression in the rabbit lens epithelial cell line N/N1003A. The RNA was harvested at various times following exposure to UV (254 nm) radiation and analyzed by dot-blot and northern blot hybridizations. These results revealed that during the first 6 h following exposure of the cells to UV, there was, associated with decreasing dose, a decrease in accumulation of transcripts specific for histones H3 and H4 and an increase in the mRNA encoding protein kinase C and β- and γ-actin. Using flow cytometry, we detected an accumulation of cells in G1/S phase of the cell cycle 1 h following exposure to 254 nm radiation. The observed changes in gene expression, especially the decreased accumulation of histone transcripts reported here, may play a role in UV-induced inhibition of cell cycle progression. (Author)

  2. Effects on proliferation and cell cycle of irradiated KG-1 cells stimulated by CM-CSF

    International Nuclear Information System (INIS)

    Guo Dehuang; Dong Bo; Wen Gengyun; Luo Qingliang; Mao Bingzhi

    2000-01-01

    In order to explore the variety of cell proliferation and cell cycle after exposure to ionizing radiation, the responses of irradiated KG-1 cells of the human myeloid leukemia stimulated by GM-CSF, the most common used cytokine in clinic, were investigated. The results showed that GM-CSF enhance KG-1 cells proliferation, reduce G0/G1 block, increase S phase and G2/M phase. The stimulation effects of the GM-CSF are more effective in irradiated group than in control group

  3. Performance analysis of hybrid solid oxide fuel cell and gas turbine cycle: Application of alternative fuels

    International Nuclear Information System (INIS)

    Zabihian, Farshid; Fung, Alan S.

    2013-01-01

    Highlights: • Variation of the stream properties in the syngas-fueled hybrid SOFC–GT cycle. • Detailed analysis of the operation of the methane-fueled SOFC–GT cycle. • Investigate effects of inlet fuel type and composition on performance of cycle. • Comparison of system operation when operated with and without anode recirculation. - Abstract: In this paper, the hybrid solid oxide fuel cell (SOFC) and gas turbine (GT) model was applied to investigate the effects of the inlet fuel type and composition on the performance of the cycle. This type of analysis is vital for the real world utilization of manufactured fuels in the hybrid SOFC–GT system due to the fact that these fuel compositions depends on the type of material that is processed, the fuel production process, and process control parameters. In the first part of this paper, it is shown that the results of a limited number of studies on the utilization of non-conventional fuels have been published in the open literature. However, further studies are required in this area to investigate all aspects of the issue for different configurations and assumptions. Then, the results of the simulation of the syngas-fueled hybrid SOFC–GT cycle are employed to explain the variation of the stream properties throughout the cycle. This analysis can be very helpful in understanding cycle internal working and can provide some interesting insights to the system operation. Then, the detailed information of the operation of the methane-fueled SOFC–GT cycle is presented. For both syngas- and methane-fueled cycles, the operating conditions of the equipment are presented and compared. Moreover, the comparison of the characteristics of the system when it is operated with two different schemes to provide the required steam for the cycle, with anode recirculation and with an external source of water, provides some interesting insights to the system operation. For instance, it was shown that although the physical

  4. Quantitative proteomic analysis of cell cycle of the dinoflagellate Prorocentrum donghaiense (Dinophyceae.

    Directory of Open Access Journals (Sweden)

    Da-Zhi Wang

    Full Text Available Dinoflagellates are the major causative agents of harmful algal blooms in the coastal zone, which has resulted in adverse effects on the marine ecosystem and public health, and has become a global concern. Knowledge of cell cycle regulation in proliferating cells is essential for understanding bloom dynamics, and so this study compared the protein profiles of Prorocentrum donghaiense at different cell cycle phases and identified differentially expressed proteins using 2-D fluorescence difference gel electrophoresis combined with MALDI-TOF-TOF mass spectrometry. The results showed that the synchronized cells of P. donghaiense completed a cell cycle within 24 hours and cell division was phased with the diurnal cycle. Comparison of the protein profiles at four cell cycle phases (G1, S, early and late G2/M showed that 53 protein spots altered significantly in abundance. Among them, 41 were identified to be involved in a variety of biological processes, e.g. cell cycle and division, RNA metabolism, protein and amino acid metabolism, energy and carbon metabolism, oxidation-reduction processes, and ABC transport. The periodic expression of these proteins was critical to maintain the proper order and function of the cell cycle. This study, to our knowledge, for the first time revealed the major biological processes occurring at different cell cycle phases which provided new insights into the mechanisms regulating the cell cycle and growth of dinoflagellates.

  5. Chloroplast Dysfunction Causes Multiple Defects in Cell Cycle Progression in the Arabidopsis crumpled leaf Mutant

    KAUST Repository

    Hudik, Elodie

    2014-07-18

    The majority of research on cell cycle regulation is focused on the nuclear events that govern the replication and segregation of the genome between the two daughter cells. However, eukaryotic cells contain several compartmentalized organelles with specialized functions, and coordination among these organelles is required for proper cell cycle progression, as evidenced by the isolation of several mutants in which both organelle function and overall plant development were affected. To investigate how chloroplast dysfunction affects the cell cycle, we analyzed the crumpled leaf (crl) mutant of Arabidopsis (Arabidopsis thaliana), which is deficient for a chloroplastic protein and displays particularly severe developmental defects. In the crl mutant, we reveal that cell cycle regulation is altered drastically and that meristematic cells prematurely enter differentiation, leading to reduced plant stature and early endoreduplication in the leaves. This response is due to the repression of several key cell cycle regulators as well as constitutive activation of stress-response genes, among them the cell cycle inhibitor SIAMESE-RELATED5. One unique feature of the crl mutant is that it produces aplastidic cells in several organs, including the root tip. By investigating the consequence of the absence of plastids on cell cycle progression, we showed that nuclear DNA replication occurs in aplastidic cells in the root tip, which opens future research prospects regarding the dialogue between plastids and the nucleus during cell cycle regulation in higher plants.

  6. Modeling of the global carbon cycle - isotopic data requirements

    International Nuclear Information System (INIS)

    Ciais, P.

    1994-01-01

    Isotopes are powerful tools to constrain carbon cycle models. For example, the combinations of the CO 2 and the 13 C budget allows to calculate the net-carbon fluxes between atmosphere, ocean, and biosphere. Observations of natural and bomb-produced radiocarbon allow to estimate gross carbon exchange fluxes between different reservoirs and to deduce time scales of carbon overturning in important reservoirs. 18 O in CO 2 is potentially a tool to make the deconvolution of C fluxes within the land biosphere (assimilation vs respirations). The scope of this article is to identify gaps in our present knowledge about isotopes in the light of their use as constraint for the global carbon cycle. In the following we will present a list of some future data requirements for carbon cycle models. (authors)

  7. Endo- and exocytic rate constants for spontaneous and protein kinase C-activated T cell receptor cycling

    DEFF Research Database (Denmark)

    Menné, Charlotte; Møller Sørensen, Tine; Siersma, Volkert

    2002-01-01

    To determine the rate constants of spontaneous and activated TCR cycling, we examined TCR endo- and exocytosis in the human T cell line Jurkat by three different methods. Using a simple kinetic model for TCR cycling and non-linear regression analyses, we found that the spontaneous endocytic rate...... constant of the TCR was low (approximately 0.012 min(-1)) whereas the spontaneous exocytic rate constant was similar to that of other cycling receptors (approximately 0.055 min(-1)). Following protein kinase C activation (PKC) the endocytic rate constant was increased tenfold (to approximately 0.128 min(-1......)) whereas the exocytic rate constant was unaffected. Thus, the TCR becomes a rapidly cycling receptor with kinetics similar to classical cycling receptors subsequent to PKC activation. This results in a reduction of the half-life of cell surface expressed TCR from approximately 58 to 6 min and allows rapid...

  8. Absorption Cycle Heat Pump Model for Control Design

    DEFF Research Database (Denmark)

    Vinther, Kasper; Just Nielsen, Rene; Nielsen, Kirsten Mølgaard

    2015-01-01

    Heat pumps have recently received increasing interest due to green energy initiatives and increasing energy prices. In this paper, a nonlinear dynamic model of a single-effect LiBr-water absorption cycle heat pump is derived for simulation and control design purposes. The model is based on an act......Heat pumps have recently received increasing interest due to green energy initiatives and increasing energy prices. In this paper, a nonlinear dynamic model of a single-effect LiBr-water absorption cycle heat pump is derived for simulation and control design purposes. The model is based...... to operational data and different scenarios are simulated to investigate the operational stability of the heat pump. Finally, this paper provides suggestions and examples of derivation of lower order linear models for control design. © Copyright IEEE - All rights reserved....

  9. Synchronization ability of coupled cell-cycle oscillators in changing environments

    Science.gov (United States)

    2012-01-01

    Background The biochemical oscillator that controls periodic events during the Xenopus embryonic cell cycle is centered on the activity of CDKs, and the cell cycle is driven by a protein circuit that is centered on the cyclin-dependent protein kinase CDK1 and the anaphase-promoting complex (APC). Many studies have been conducted to confirm that the interactions in the cell cycle can produce oscillations and predict behaviors such as synchronization, but much less is known about how the various elaborations and collective behavior of the basic oscillators can affect the robustness of the system. Therefore, in this study, we investigate and model a multi-cell system of the Xenopus embryonic cell cycle oscillators that are coupled through a common complex protein, and then analyze their synchronization ability under four different external stimuli, including a constant input signal, a square-wave periodic signal, a sinusoidal signal and a noise signal. Results Through bifurcation analysis and numerical simulations, we obtain synchronization intervals of the sensitive parameters in the individual oscillator and the coupling parameters in the coupled oscillators. Then, we analyze the effects of these parameters on the synchronization period and amplitude, and find interesting phenomena, e.g., there are two synchronization intervals with activation coefficient in the Hill function of the activated CDK1 that activates the Plk1, and different synchronization intervals have distinct influences on the synchronization period and amplitude. To quantify the speediness and robustness of the synchronization, we use two quantities, the synchronization time and the robustness index, to evaluate the synchronization ability. More interestingly, we find that the coupled system has an optimal signal strength that maximizes the synchronization index under different external stimuli. Simulation results also show that the ability and robustness of the synchronization for the square

  10. Influence of cell cycle on responses of MCF-7 cells to benzo[a]pyrene

    Directory of Open Access Journals (Sweden)

    Giddings Ian

    2011-06-01

    Full Text Available Abstract Background Benzo[a]pyrene (BaP is a widespread environmental genotoxic carcinogen that damages DNA by forming adducts. This damage along with activation of the aryl hydrocarbon receptor (AHR induces complex transcriptional responses in cells. To investigate whether human cells are more susceptible to BaP in a particular phase of the cell cycle, synchronised breast carcinoma MCF-7 cells were exposed to BaP. Cell cycle progression was analysed by flow cytometry, DNA adduct formation was assessed by 32P-postlabeling analysis, microarrays of 44K human genome-wide oligos and RT-PCR were used to detect gene expression (mRNA changes and Western blotting was performed to determine the expression of some proteins, including cytochrome P450 (CYP 1A1 and CYP1B1, which are involved in BaP metabolism. Results Following BaP exposure, cells evaded G1 arrest and accumulated in S-phase. Higher levels of DNA damage occurred in S- and G2/M- compared with G0/G1-enriched cultures. Genes that were found to have altered expression included those involved in xenobiotic metabolism, apoptosis, cell cycle regulation and DNA repair. Gene ontology and pathway analysis showed the involvement of various signalling pathways in response to BaP exposure, such as the Catenin/Wnt pathway in G1, the ERK pathway in G1 and S, the Nrf2 pathway in S and G2/M and the Akt pathway in G2/M. An important finding was that higher levels of DNA damage in S- and G2/M-enriched cultures correlated with higher levels of CYP1A1 and CYP1B1 mRNA and proteins. Moreover, exposure of synchronised MCF-7 cells to BaP-7,8-diol-9,10-epoxide (BPDE, the ultimate carcinogenic metabolite of BaP, did not result in significant changes in DNA adduct levels at different phases of the cell cycle. Conclusions This study characterised the complex gene response to BaP in MCF-7 cells and revealed a strong correlation between the varying efficiency of BaP metabolism and DNA damage in different phases of the cell

  11. Arctigenin induces cell cycle arrest by blocking the phosphorylation of Rb via the modulation of cell cycle regulatory proteins in human gastric cancer cells.

    Science.gov (United States)

    Jeong, Jin Boo; Hong, Se Chul; Jeong, Hyung Jin; Koo, Jin Suk

    2011-10-01

    Gastric cancer is a leading cause of cancer-related deaths, worldwide being second only to lung cancer as a cause of death. Arctigenin, a representative dibenzylbutyrolactone lignan, occurs in a variety of plants. However, the molecular mechanisms of arctigenin for anti-tumor effect on gastric cancer have not been examined. This study examined the biological effects of arctigenin on the human gastric cancer cell line SNU-1 and AGS. Cell proliferation was determined by MTT assay. In MTT assay, the proliferation of SNU-1 and AGS cells was significantly inhibited by arctigenin in a time and dose dependent manner, as compared with SNU-1 and AGS cells cultured in the absence of arctigenin. Inhibition of cell proliferation by arctigenin was in part associated with apoptotic cell death, as shown by changes in the expression ratio of Bcl-2 to Bax by arctigenin. Also, arctigenin blocked cell cycle arrest from G(1) to S phase by regulating the expression of cell cycle regulatory proteins such as Rb, cyclin D1, cyclin E, CDK4, CDK2, p21Waf1/Cip1 and p15 INK4b. The antiproliferative effect of arctigenin on SNU-1 and AGS gastric cancer cells revealed in this study suggests that arctigenin has intriguing potential as a chemopreventive or chemotherapeutic agent. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

  12. Manipulation of Cell Cycle and Chromatin Configuration by Means of Cell-Penetrating Geminin.

    Directory of Open Access Journals (Sweden)

    Yoshinori Ohno

    Full Text Available Geminin regulates chromatin remodeling and DNA replication licensing which play an important role in regulating cellular proliferation and differentiation. Transcription of the Geminin gene is regulated via an E2F-responsive region, while the protein is being closely regulated by the ubiquitin-proteasome system. Our objective was to directly transduce Geminin protein into cells. Recombinant cell-penetrating Geminin (CP-Geminin was generated by fusing Geminin with a membrane translocating motif from FGF4 and was efficiently incorporated into NIH 3T3 cells and mouse embryonic fibroblasts. The withdrawal study indicated that incorporated CP-Geminin was quickly reduced after removal from medium. We confirmed CP-Geminin was imported into the nucleus after incorporation and also that the incorporated CP-Geminin directly interacted with Cdt1 or Brahma/Brg1 as the same manner as Geminin. We further demonstrated that incorporated CP-Geminin suppressed S-phase progression of the cell cycle and reduced nuclease accessibility in the chromatin, probably through suppression of chromatin remodeling, indicating that CP-Geminin constitutes a novel tool for controlling chromatin configuration and the cell cycle. Since Geminin has been shown to be involved in regulation of stem cells and cancer cells, CP-Geminin is expected to be useful for elucidating the role of Geminin in stem cells and cancer cells, and for manipulating their activity.

  13. Endothelial nitric oxide synthase deficiency influences normal cell cycle progression and apoptosis in trabecular meshwork cells

    Directory of Open Access Journals (Sweden)

    Qiong Liao

    2016-06-01

    Full Text Available AIM: To clarify how the endothelial nitric oxide synthase (eNOS, NOS3 make effect on outflow facility through the trabecular meshwork (TM. METHODS: Inhibition of NOS3 gene expression in human TM cells were conducted by three siRNAs. Then the mRNA and protein levels of NOS3 in siRNA-treated and negative control (NC cells were determined, still were the collagen, type IV, alpha 1 (COL4A1 and fibronectin 1 by real-time PCR and Western blot analysis. In addition, NOS3 concentrations in culture supernatant fluids of TM cells were measured. Cell cycle and cell apoptosis analysis were performed using flow cytometry. RESULTS: The mRNA level of NOS3 was decreased by three different siRNA interference, similar results were obtained not only of the relative levels of NOS3 protein, but also the expression levels of COL4A1 and fibronectin 1. The number of cells in S phase was decreased, while contrary result was obtained in G2 phase. The number of apoptotic cells in siRNA-treated groups were significant increased compared to the NC samples. CONCLUSION: Abnormal NOS3 expression can make effects on the proteins levels of extracellular matrix component (e.g. fibronectin 1 and COL4A1. Reduced NOS3 restrains the TM cell cycle progression at the G2/M-phase transition and induced cell apoptosis.

  14. The cell cycle inhibitor p27Kip¹ controls self-renewal and pluripotency of human embryonic stem cells by regulating the cell cycle, Brachyury and Twist.

    Science.gov (United States)

    Menchón, Cristina; Edel, Michael J; Izpisua Belmonte, Juan Carlos

    2011-05-01

    The continued turn over of human embryonic stem cells (hESC) while maintaining an undifferentiated state is dependent on the regulation of the cell cycle. Here we asked the question if a single cell cycle gene could regulate the self-renewal or pluripotency properties of hESC. We identified that the protein expression of the p27(Kip)¹ cell cycle inhibitor is low in hESC cells and increased with differentiation. By adopting a gain and loss of function strategy we forced or reduced its expression in undifferentiating conditions to define its functional role in self-renewal and pluripotency. Using undifferentiation conditions, overexpression of p27(Kip)¹ in hESC lead to a G₁phase arrest with an enlarged and flattened hESC morphology and consequent loss of self-renewal ability. Loss of p27(Kip)¹ caused an elongated/scatter cell-like phenotype involving up-regulation of Brachyury and Twist gene expression. We demonstrate the novel finding that p27(Kip)¹ protein occupies the Twist1 gene promoter and manipulation of p27(Kip)¹ by gain and loss of function is associated with Twist gene expression changes. These results define p27(Kip)¹ expression levels as critical for self-renewal and pluripotency in hESC and suggest a role for p27(Kip)¹ in controlling an epithelial to mesenchymal transition (EMT) in hESC.

  15. Fuel cycle modelling of open cycle thorium-fuelled nuclear energy systems

    International Nuclear Information System (INIS)

    Ashley, S.F.; Lindley, B.A.; Parks, G.T.; Nuttall, W.J.; Gregg, R.; Hesketh, K.W.; Kannan, U.; Krishnani, P.D.; Singh, B.; Thakur, A.; Cowper, M.; Talamo, A.

    2014-01-01

    Highlights: • We study three open cycle Th–U-fuelled nuclear energy systems. • Comparison of these systems is made to a reference U-fuelled EPR. • Fuel cycle modelling is performed with UK NNL code “ORION”. • U-fuelled system is economically favourable and needs least separative work per kWh. • Th–U-fuelled systems offer negligible waste and proliferation resistance advantages. - Abstract: In this study, we have sought to determine the advantages, disadvantages, and viability of open cycle thorium–uranium-fuelled (Th–U-fuelled) nuclear energy systems. This has been done by assessing three such systems, each of which requires uranium enriched to ∼20% 235 U, in comparison to a reference uranium-fuelled (U-fuelled) system over various performance indicators, spanning material flows, waste composition, economics, and proliferation resistance. The values of these indicators were determined using the UK National Nuclear Laboratory’s fuel cycle modelling code ORION. This code required the results of lattice-physics calculations to model the neutronics of each nuclear energy system, and these were obtained using various nuclear reactor physics codes and burn-up routines. In summary, all three Th–U-fuelled nuclear energy systems required more separative work capacity than the equivalent benchmark U-fuelled system, with larger levelised fuel cycle costs and larger levelised cost of electricity. Although a reduction of ∼6% in the required uranium ore per kWh was seen for one of the Th–U-fuelled systems compared to the reference U-fuelled system, the other two Th–U-fuelled systems required more uranium ore per kWh than the reference. Negligible advantages and disadvantages were observed for the amount and the properties of the spent nuclear fuel (SNF) generated by the systems considered. Two of the Th–U-fuelled systems showed some benefit in terms of proliferation resistance of the SNF generated. Overall, it appears that there is little

  16. Function of trehalose and glycogen in cell cycle progression and cell viability in Saccharomyces cerevisiae

    NARCIS (Netherlands)

    Silljé, H H; Paalman, J W; ter Schure, E G; Olsthoorn, S Q; Verkleij, A J; Boonstra, Johannes; Verrips, C T

    Trehalose and glycogen accumulate in Saccharomyces cerevisiae when growth conditions deteriorate. It has been suggested that aside from functioning as storage factors and stress protectants, these carbohydrates may be required for cell cycle progression at low growth rates under carbon limitation.

  17. Polyamine metabolism during the cell cycle of synchronized tobacco BY-2 cell line

    Czech Academy of Sciences Publication Activity Database

    Gemperlová, Lenka; Cvikrová, Milena; Fischerová, Lucie; Binarová, Pavla; Fischer, L.; Eder, Josef

    2009-01-01

    Roč. 47, č. 7 (2009), s. 584-591 ISSN 0981-9428 R&D Projects: GA AV ČR IAA500200719 Institutional research plan: CEZ:AV0Z50380511; CEZ:AV0Z50200510 Keywords : ADC * Cell cycle * DAO Subject RIV: EF - Botanics Impact factor: 2.485, year: 2009

  18. Cell cycle perturbations induced by Cisplatin in normal and tumor transformed cells

    Czech Academy of Sciences Publication Activity Database

    Mareš, Vladislav; Mazzini, G.; Lisá, Věra; Ferrari, C.; Malík, Radek; Šedo, A.

    2001-01-01

    Roč. 5, - (2001), s. 23-29 ISSN 1212-3137 Grant - others:GA UK(XC) 58/1999/C; LF UK(XC) 206019-2-"Oncology" Institutional research plan: CEZ:AV0Z5011922 Keywords : cell cycle * cisplatin * DNA content Subject RIV: FD - Oncology ; Hematology

  19. Backup pathways of NHEJ in cells of higher eukaryotes: Cell cycle dependence

    International Nuclear Information System (INIS)

    Iliakis, George

    2009-01-01

    DNA double-strand breaks (DSBs) induced by ionizing radiation (IR) in cells of higher eukaryotes are predominantly repaired by a pathway of non-homologous end joining (NHEJ) utilizing Ku, DNA-PKcs, DNA ligase IV, XRCC4 and XLF/Cernunnos (D-NHEJ) as central components. Work carried out in our laboratory and elsewhere shows that when this pathway is chemically or genetically compromised, cells do not shunt DSBs to homologous recombination repair (HRR) but instead use another form of NHEJ operating as a backup (B-NHEJ). Here I review our efforts to characterize this repair pathway and discuss its dependence on the cell cycle as well as on the growth conditions. I present evidence that B-NHEJ utilizes ligase III, PARP-1 and histone H1. When B-NHEJ is examined throughout the cell cycle, significantly higher activity is observed in G2 phase that cannot be attributed to HRR. Furthermore, the activity of B-NHEJ is compromised when cells enter the plateau phase of growth. Together, these observations uncover a repair pathway with unexpected biochemical constitution and interesting cell cycle and growth factor regulation. They generate a framework for investigating the mechanistic basis of HRR contribution to DSB repair.

  20. PENGARUH MODEL PEMBELAJARAN LEARNING CYCLE TERHADAP KETERAMPILAN BERPIKIR KRITIS SISWA

    Directory of Open Access Journals (Sweden)

    Aryani Novianti

    2015-03-01

    Full Text Available Tujuan dari penelitian ini adalah untuk mengetahui pengaruh model pembelajaran Learning Cycle pada konsep Sistem Pencernaan pada Manusia terhadap keterampilan berpikir kritis siswa. Adapun model pembelajaran Learning Cycle yang diterapkan adalah jenis 5E (Engangement, Exploration, Explanation, Elaboration dan Evaluation. Populasi dari penelitian ini adalah seluruh siswa kelas VIII SMP N 9 Kota Tangerang Selatan sedangkan sampelnya adalah seluruh siswa di kelas VIII 7 (38 orang dan VIII 8 (38 orang SMP N 9 Kota Tangsel. Teknik pengambilan sampel dalam penelitian ini dilakukan dengan teknik Sampling Purposive. Metode penelitian yang digunakan dalam penelitian ini adalah metode penelitian Quasi-eksperimental design dengan desain penelitian berupa nonequivalent control group design. Instrumen yang digunakan berupa tes tertulis berupa pilihan ganda dan esai yang ditujukan untuk mengukur keterampilan berpikir kritis. Sedangkan lembar observasi digunakan untuk mengamati keterlaksanaan model pembelajaran Learning Cycle oleh guru dan keterampilan berpikir kritis yang tergali oleh siswa. Analisis data menggunakan uji-t diperoleh hasil thitung 3,703 dan ttabel pada taraf signifikansi 5 % sebesar 2, maka thitung > ttabel. Hal ini dapat disimpulkan bahwa penerapan model pembelajaran Learning Cycle pada konsep Sistem Pencernaan pada Manusia berpengaruh terhadap keterampilan berpikir kritis siswa.

  1. Spectral analysis and markov switching model of Indonesia business cycle

    Science.gov (United States)

    Fajar, Muhammad; Darwis, Sutawanir; Darmawan, Gumgum

    2017-03-01

    This study aims to investigate the Indonesia business cycle encompassing the determination of smoothing parameter (λ) on Hodrick-Prescott filter. Subsequently, the components of the filter output cycles were analyzed using a spectral method useful to know its characteristics, and Markov switching regime modeling is made to forecast the probability recession and expansion regimes. The data used in the study is real GDP (1983Q1 - 2016Q2). The results of the study are: a) Hodrick-Prescott filter on real GDP of Indonesia to be optimal when the value of the smoothing parameter is 988.474, b) Indonesia business cycle has amplitude varies between±0.0071 to±0.01024, and the duration is between 4 to 22 quarters, c) the business cycle can be modelled by MSIV-AR (2) but regime periodization is generated this model not perfect exactly with real regime periodzation, and d) Based on the model MSIV-AR (2) obtained long-term probabilities in the expansion regime: 0.4858 and in the recession regime: 0.5142.

  2. Anticipated growth and business cycles in matching models

    NARCIS (Netherlands)

    den Haan, W.J.; Kaltenbrunner, G.

    2009-01-01

    In a business cycle model that incorporates a standard matching framework, employment increases in response to news shocks, even though the wealth effect associated with the increase in expected productivity reduces labor force participation. The reason is that the matching friction induces

  3. Nuclear weapons data for use in carbon cycle modelling

    International Nuclear Information System (INIS)

    Enting, I.G.

    1982-01-01

    This report contains tables of atmospheric explosions for use in carbon cycle modelling studies. Descriptions of the sources of the data and the manner in which it can be used are given. The essential requirement is for a specification of the amount of 14 C injected into the atmosphere as a function of time, height, latitude and longitude

  4. Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle

    NARCIS (Netherlands)

    C. Feillet (Céline); C.A. Krusche; F. Tamanini (Filippo); R. Janssens (Roel); R.A. Downey (Roger); P. Martin (Patrick); J.L. Teboul (Jean Louis); S. Saito (Seiji); F.A. Lévi (Francis); T. Bretschneider (Till); G.T.J. van der Horst (Gijsbertus); F. Delaunay (Franck); D.A. Rand (David)

    2014-01-01

    textabstractDaily synchronous rhythms of cell division at the tissue or organism level are observed in many species and suggest that the circadian clock and cell cycle oscillators are coupled. For mammals, despite known mechanistic interactions, the effect of such coupling on clock and cell cycle

  5. DNA Damage and Cell Cycle Arrest Induced by Protoporphyrin IX in Sarcoma 180 Cells

    Directory of Open Access Journals (Sweden)

    Qing Li

    2013-09-01

    Full Text Available Background: Porphyrin derivatives have been widely used in photodynamic therapy as effective sensitizers. Protoporphyrin IX (PpIX, a well-known hematoporphyrin derivative component, shows great potential to enhance light induced tumor cell damage. However, PpIX alone could also exert anti-tumor effects. The mechanisms underlying those direct effects are incompletely understood. This study thus investigated the putative mechanisms underlying the anti-tumor effects of PpIX on sarcoma 180 (S180 cells. Methods: S180 cells were treated with different concentrations of PpIX. Following the treatment, cell viability was evaluated by the 3-(4, 5- dimethylthiazol-2-yl-2, 5-diphenyltetrazoliumbromide (MTT assay; Disruption of mitochondrial membrane potential was measured by flow cytometry; The trans-location of apoptosis inducer factor (AIF from mitochondria to nucleus was visualized by confocal laser scanning microscopy; DNA damage was detected by single cell gel electrophoresis; Cell cycle distribution was analyzed by DNA content with flow cytometry; Cell cycle associated proteins were detected by western blotting. Results: PpIX (≥ 1 µg/ml significantly inhibited proliferation and reduced viability of S180 cells in a dose-dependent manner. PpIX rapidly and significantly triggered mitochondrial membrane depolarization, AIF (apoptosis inducer factor translocation from mitochondria to nucleus and DNA damage, effects partially relieved by the specific inhibitor of MPTP (mitochondrial permeability transition pore. Furthermore, S phase arrest and upregulation of the related proteins of P53 and P21 were observed following 12 and 24 h PpIX exposure. Conclusion: PpIX could inhibit tumor cell proliferation by induction of DNA damage and cell cycle arrest in the S phase.

  6. ALG-2 knockdown in HeLa cells results in G2/M cell cycle phase accumulation and cell death

    DEFF Research Database (Denmark)

    Høj, Berit Rahbek; la Cour, Peter Jonas Marstrand; Mollerup, Jens

    2009-01-01

    downregulation induces accumulation of HeLa cells in the G2/M cell cycle phase and increases the amount of early apoptotic and dead cells. Caspase inhibition by the pan-caspase inhibitor zVAD-fmk attenuated the increase in the amount of dead cells following ALG-2 downregulation. Thus, our results indicate...... that ALG-2 has an anti-apoptotic function in HeLa cells by facilitating the passage through checkpoints in the G2/M cell cycle phase.......ALG-2 (apoptosis-linked gene-2 encoded protein) has been shown to be upregulated in a variety of human tumors questioning its previously assumed pro-apoptotic function. The aim of the present study was to obtain insights into the role of ALG-2 in human cancer cells. We show that ALG-2...

  7. Simulation of E. coli gene regulation including overlapping cell cycles, growth, division, time delays and noise.

    Directory of Open Access Journals (Sweden)

    Ruoyu Luo

    Full Text Available Due to the complexity of biological systems, simulation of biological networks is necessary but sometimes complicated. The classic stochastic simulation algorithm (SSA by Gillespie and its modified versions are widely used to simulate the stochastic dynamics of biochemical reaction systems. However, it has remained a challenge to implement accurate and efficient simulation algorithms for general reaction schemes in growing cells. Here, we present a modeling and simulation tool, called 'GeneCircuits', which is specifically developed to simulate gene-regulation in exponentially growing bacterial cells (such as E. coli with overlapping cell cycles. Our tool integrates three specific features of these cells that are not generally included in SSA tools: 1 the time delay between the regulation and synthesis of proteins that is due to transcription and translation processes; 2 cell cycle-dependent periodic changes of gene dosage; and 3 variations in the propensities of chemical reactions that have time-dependent reaction rates as a consequence of volume expansion and cell division. We give three biologically relevant examples to illustrate the use of our simulation tool in quantitative studies of systems biology and synthetic biology.

  8. Slow-cycling stem cells in hydra contribute to head regeneration

    Directory of Open Access Journals (Sweden)

    Niraimathi Govindasamy

    2014-11-01

    Full Text Available Adult stem cells face the challenge of maintaining tissue homeostasis by self-renewal while maintaining their proliferation potential over the lifetime of an organism. Continuous proliferation can cause genotoxic/metabolic stress that can compromise the genomic integrity of stem cells. To prevent stem cell exhaustion, highly proliferative adult tissues maintain a pool of quiescent stem cells that divide only in response to injury and thus remain protected from genotoxic stress. Hydra is a remarkable organism with highly proliferative stem cells and ability to regenerate at whole animal level. Intriguingly, hydra does not display consequences of high proliferation, such as senescence or tumour formation. In this study, we investigate if hydra harbours a pool of slow-cycling stem cells that could help prevent undesirable consequences of continuous proliferation. Hydra were pulsed with the thymidine analogue 5-ethynyl-2′-deoxyuridine (EdU and then chased in the absence of EdU to monitor the presence of EdU-retaining cells. A significant number of undifferentiated cells of all three lineages in hydra retained EdU for about 8–10 cell cycles, indicating that these cells did not enter cell cycle. These label-retaining cells were resistant to hydroxyurea treatment and were predominantly in the G2 phase of cell cycle. Most significantly, similar to mammalian quiescent stem cells, these cells rapidly entered cell division during head regeneration. This study shows for the first time that, contrary to current beliefs, cells in hydra display heterogeneity in their cell cycle potential and the slow-cycling cells in this population enter cell cycle during head regeneration. These results suggest an early evolution of slow-cycling stem cells in multicellular animals.

  9. Molecular machinery of signal transduction and cell cycle regulation in Plasmodium

    OpenAIRE

    Koyama, Fernanda C.; Chakrabarti, Debopam; Garcia, Célia R.S.

    2009-01-01

    The regulation of the Plasmodium cell cycle is not understood. Although the Plasmodium falciparum genome is completely sequenced, about 60% of the predicted proteins share little or no sequence similarity with other eukaryotes. This feature impairs the identification of important proteins participating in the regulation of the cell cycle. There are several open questions that concern cell cycle progression in malaria parasites, including the mechanism by which multiple nuclear divisions is co...

  10. Identification of transcription factors linked to cell cycle regulation in Arabidopsis

    OpenAIRE

    Dehghan Nayeri, Fatemeh

    2014-01-01

    Cell cycle is an essential process in growth and development of living organisms consists of the replication and mitotic phases separated by 2 gap phases; G1 and G2. It is tightly controlled at the molecular level and especially at the level of transcription. Precise regulation of the cell cycle is of central significance for plant growth and development and transcription factors are global regulators of gene expression playing essential roles in cell cycle regulation. This study has uncovere...

  11. Feedback loops and reciprocal regulation: recurring motifs in the systems biology of the cell cycle

    OpenAIRE

    Ferrell, James E.

    2013-01-01

    The study of eukaryotic cell cycle regulation over the last several decades has led to a remarkably detailed understanding of the complex regulatory system that drives this fundamental process. This allows us to now look for recurring motifs in the regulatory system. Among these are negative feedback loops, which underpin checkpoints and generate cell cycle oscillations; positive feedback loops, which promote oscillations and make cell cycle transitions switch-like and unidirectional; and rec...

  12. Design and Modelling of Small Scale Low Temperature Power Cycles

    DEFF Research Database (Denmark)

    Wronski, Jorrit

    he work presented in this report contributes to the state of the art within design and modelling of small scale low temperature power cycles. The study is divided into three main parts: (i) fluid property evaluation, (ii) expansion device investigations and (iii) heat exchanger performance......-oriented Modelica code and was included in the thermo Cycle framework for small scale ORC systems. Special attention was paid to the valve system and a control method for variable expansion ratios was introduced based on a cogeneration scenario. Admission control based on evaporator and condenser conditions...

  13. A Simulation Model for the Waterfall Software Development Life Cycle

    OpenAIRE

    Bassil, Youssef

    2012-01-01

    Software development life cycle or SDLC for short is a methodology for designing, building, and maintaining information and industrial systems. So far, there exist many SDLC models, one of which is the Waterfall model which comprises five phases to be completed sequentially in order to develop a software solution. However, SDLC of software systems has always encountered problems and limitations that resulted in significant budget overruns, late or suspended deliveries, and dissatisfied client...

  14. Hopf bifurcation of the stochastic model on business cycle

    International Nuclear Information System (INIS)

    Xu, J; Wang, H; Ge, G

    2008-01-01

    A stochastic model on business cycle was presented in thas paper. Simplifying the model through the quasi Hamiltonian theory, the Ito diffusion process was obtained. According to Oseledec multiplicative ergodic theory and singular boundary theory, the conditions of local and global stability were acquired. Solving the stationary FPK equation and analyzing the stationary probability density, the stochastic Hopf bifurcation was explained. The result indicated that the change of parameter awas the key factor to the appearance of the stochastic Hopf bifurcation

  15. Fluctuations in a mixed IS-LM business cycle model

    Directory of Open Access Journals (Sweden)

    Hamad Talibi Alaoui

    2008-09-01

    Full Text Available In the present paper, we extend a delayed IS-LM business cycle model by introducing an additional advance (anticipated capital stock in the investment function. The resulting model is represented in terms of mixed differential equations. For the deviating argument $au$ (advance and delay being a bifurcation parameter we investigate the local stability and the local Hopf bifurcation. Also some numerical simulations are given to support the theoretical analysis.

  16. High-dose irradiation induces cell cycle arrest, apoptosis, and developmental defects during Drosophila oogenesis.

    Directory of Open Access Journals (Sweden)

    Hee Jin Shim

    Full Text Available Ionizing radiation (IR treatment induces a DNA damage response, including cell cycle arrest, DNA repair, and apoptosis in metazoan somatic cells. Because little has been reported in germline cells, we performed a temporal analysis of the DNA damage response utilizing Drosophila oogenesis as a model system. Oogenesis in the adult Drosophila female begins with the generation of 16-cell cyst by four mitotic divisions of a cystoblast derived from the germline stem cells. We found that high-dose irradiation induced S and G2 arrests in these mitotically dividing germline cells in a grp/Chk1- and mnk/Chk2-dependent manner. However, the upstream kinase mei-41, Drosophila ATR ortholog, was required for the S-phase checkpoint but not for the G2 arrest. As in somatic cells, mnk/Chk2 and dp53 were required for the major cell death observed in early oogenesis when oocyte selection and meiotic recombination occurs. Similar to the unscheduled DNA double-strand breaks (DSBs generated from defective repair during meiotic recombination, IR-induced DSBs produced developmental defects affecting the spherical morphology of meiotic chromosomes and dorsal-ventral patterning. Moreover, various morphological abnormalities in the ovary were detected after irradiation. Most of the IR-induced defects observed in oogenesis were reversible and were restored between 24 and 96 h after irradiation. These defects in oogenesis severely reduced daily egg production and the hatch rate of the embryos of irradiated female. In summary, irradiated germline cells induced DSBs, cell cycle arrest, apoptosis, and developmental defects resulting in reduction of egg production and defective embryogenesis.

  17. Microsporidia infection impacts the host cell's cycle and reduces host cell apoptosis

    Science.gov (United States)

    Higes, Mariano; Sagastume, Soledad; Juarranz, Ángeles; Dias-Almeida, Joyce; Budge, Giles E.; Meana, Aránzazu; Boonham, Neil

    2017-01-01

    Intracellular parasites can alter the cellular machinery of host cells to create a safe haven for their survival. In this regard, microsporidia are obligate intracellular fungal parasites with extremely reduced genomes and hence, they are strongly dependent on their host for energy and resources. To date, there are few studies into host cell manipulation by microsporidia, most of which have focused on morphological aspects. The microsporidia Nosema apis and Nosema ceranae are worldwide parasites of honey bees, infecting their ventricular epithelial cells. In this work, quantitative gene expression and histology were studied to investigate how these two parasites manipulate their host’s cells at the molecular level. Both these microsporidia provoke infection-induced regulation of genes involved in apoptosis and the cell cycle. The up-regulation of buffy (which encodes a pro-survival protein) and BIRC5 (belonging to the Inhibitor Apoptosis protein family) was observed after infection, shedding light on the pathways that these pathogens use to inhibit host cell apoptosis. Curiously, different routes related to cell cycle were modified after infection by each microsporidia. In the case of N. apis, cyclin B1, dacapo and E2F2 were up-regulated, whereas only cyclin E was up-regulated by N. ceranae, in both cases promoting the G1/S phase transition. This is the first report describing molecular pathways related to parasite-host interactions that are probably intended to ensure the parasite’s survival within the cell. PMID:28152065

  18. Lithium iron phosphate based battery – Assessment of the aging parameters and development of cycle life model

    International Nuclear Information System (INIS)

    Omar, Noshin; Monem, Mohamed Abdel; Firouz, Yousef; Salminen, Justin; Smekens, Jelle; Hegazy, Omar; Gaulous, Hamid; Mulder, Grietus; Van den Bossche, Peter; Coosemans, Thierry; Van Mierlo, Joeri

    2014-01-01

    Highlights: • Extended life cycle tests. • Investigation of the battery life cycle at different working conditions. • Investigation of the impact fast charging on the battery performances. • Extraction all required relationship for development of a cycle life model. • Development of a new life cycle model. - Abstract: This paper represents the evaluation of ageing parameters in lithium iron phosphate based batteries, through investigating different current rates, working temperatures and depths of discharge. From these analyses, one can derive the impact of the working temperature on the battery performances over its lifetime. At elevated temperature (40 °C), the performances are less compared to at 25 °C. The obtained mathematical expression of the cycle life as function of the operating temperature reveals that the well-known Arrhenius law cannot be applied to derive the battery lifetime from one temperature to another. Moreover, a number of cycle life tests have been performed to illustrate the long-term capabilities of the proposed battery cells at different discharge constant current rates. The results reveal the harmful impact of high current rates on battery characteristics. On the other hand, the cycle life test at different depth of discharge levels indicates that the battery is able to perform 3221 cycles (till 80% DoD) compared to 34,957 shallow cycles (till 20% DoD). To investigate the cycle life capabilities of lithium iron phosphate based battery cells during fast charging, cycle life tests have been carried out at different constant charge current rates. The experimental analysis indicates that the cycle life of the battery degrades the more the charge current rate increases. From this analysis, one can conclude that the studied lithium iron based battery cells are not recommended to be charged at high current rates. This phenomenon affects the viability of ultra-fast charging systems. Finally, a cycle life model has been developed, which

  19. Cell Cycle Control in the Early Embryonic Development of Aquatic Animal Species

    Science.gov (United States)

    Siefert, Joseph C.; Clowdus, Emily A.; Sansam, Christopher L.

    2016-01-01

    The cell cycle is integrated with many aspects of embryonic development. Not only is proper control over the pace of cell proliferation important, but also the timing of cell cycle progression is coordinated with transcription, cell migration, and cell differentiation. Due to the ease with which the embryos of aquatic organisms can be observed and manipulated, they have been a popular choice for embryologists throughout history. In the cell cycle field, aquatic organisms have been extremely important because they have played a major role in the discovery and analysis of key regulators of the cell cycle. In particular, the frog Xenopus laevis has been instrumental for understanding how the basic embryonic cell cycle is regulated. More recently, the zebrafish has been used to understand how the cell cycle is remodeled during vertebrate development and how it is regulated during morphogenesis. This review describes how some of the unique strengths of aquatic species have been leveraged for cell cycle research and suggests how species such as Xenopus and zebrafish will continue to reveal the roles of the cell cycle in human biology and disease. PMID:26475527

  20. Cell cycle regulation by feed-forward loops coupling transcription and phosphorylation

    DEFF Research Database (Denmark)

    Csikász-Nagy, Attila; Kapuy, Orsolya; Tóth, Attila

    2009-01-01

    of these EPs. From genome-scale data sets of budding yeast, we identify 126 EPs that are regulated by Cdk1 both through direct phosphorylation of the EP and through phosphorylation of the transcription factors that control expression of the EP, so that each of these EPs is regulated by a feed-forward loop (FFL......) from Cdk1. By mathematical modelling, we show that such FFLs can activate EPs at different phases of the cell cycle depending of the effective signs (+ or -) of the regulatory steps of the FFL. We provide several case studies of EPs that are controlled by FFLs exactly as our models predict. The signal...

  1. Redox Changes During the Cell Cycle in the Embryonic Root Meristem of Arabidopsis thaliana.

    Science.gov (United States)

    de Simone, Ambra; Hubbard, Rachel; de la Torre, Natanael Viñegra; Velappan, Yazhini; Wilson, Michael; Considine, Michael J; Soppe, Wim J J; Foyer, Christine H

    2017-12-20

    The aim of this study was to characterize redox changes in the nuclei and cytosol occurring during the mitotic cell cycle in the embryonic roots of germinating Arabidopsis seedlings, and to determine how redox cycling was modified in mutants with a decreased capacity for ascorbate synthesis. Using an in vivo reduction-oxidation (redox) reporter (roGFP2), we show that transient oxidation of the cytosol and the nuclei occurred at G1 in the synchronized dividing cells of the Arabidopsis root apical meristem, with reduction at G2 and mitosis. This redox cycle was absent from low ascorbate mutants in which nuclei were significantly more oxidized than controls. The cell cycle-dependent increase in nuclear size was impaired in the ascorbate-deficient mutants, which had fewer cells per unit area in the root proliferation zone. The transcript profile of the dry seeds and size of the imbibed seeds was strongly influenced by low ascorbate but germination, dormancy release and seed aging characteristics were unaffected. These data demonstrate the presence of a redox cycle within the plant cell cycle and that the redox state of the nuclei is an important factor in cell cycle progression. Controlled oxidation is a key feature of the early stages of the plant cell cycle. However, sustained mild oxidation restricts nuclear functions and impairs progression through the cell cycle leading to fewer cells in the root apical meristem. Antioxid. Redox Signal. 27, 1505-1519.

  2. Cell cycle arrest in the jewel wasp Nasonia vitripennis in larval diapause.

    Science.gov (United States)

    Shimizu, Yuta; Mukai, Ayumu; Goto, Shin G

    2018-04-01

    Insects enter diapause to synchronise their life cycle with biotic and abiotic environmental conditions favourable for their development, reproduction, and survival. One of the most noticeable characteristics of diapause is the blockage of ontogeny. Although this blockage should occur with the cessation of cellular proliferation, i.e. cell cycle arrest, it was confirmed only in a few insect species and information on the molecular pathways involved in cell cycle arrest is limited. In the present study, we investigated developmental and cell cycle arrest in diapause larvae of the jewel wasp Nasonia vitripennis. Developmental and cell cycle arrest occur in the early fourth instar larval stage of N. vitripennis under short days. By entering diapause, the S fraction of the cell cycle disappears and approximately 80% and 20% of cells arrest their cell cycle in the G0/G1 and G2 phases, respectively. We further investigated expression of cell cycle regulatory genes and some housekeeping genes to dissect molecular mechanisms underlying the cell cycle arrest. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Cytoplasmic sequestration of cyclin D1 associated with cell cycle withdrawal of neuroblastoma cells

    International Nuclear Information System (INIS)

    Sumrejkanchanakij, Piyamas; Eto, Kazuhiro; Ikeda, Masa-Aki

    2006-01-01

    The regulation of D-type cyclin-dependent kinase activity is critical for neuronal differentiation and apoptosis. We recently showed that cyclin D1 is sequestered in the cytoplasm and that its nuclear localization induces apoptosis in postmitotic primary neurons. Here, we further investigated the role of the subcellular localization of cyclin D1 in cell cycle withdrawal during the differentiation of N1E-115 neuroblastoma cells. We show that cyclin D1 became predominantly cytoplasmic after differentiation. Targeting cyclin D1 expression to the nucleus induced phosphorylation of Rb and cdk2 kinase activity. Furthermore, cyclin D1 nuclear localization promoted differentiated N1E-115 cells to reenter the cell cycle, a process that was inhibited by p16 INK4a , a specific inhibitor of D-type cyclin activity. These results indicate that cytoplasmic sequestration of cyclin D1 plays a role in neuronal cell cycle withdrawal, and suggests that the abrogation of machinery involved in monitoring aberrant nuclear cyclin D1 activity contributes to neuronal tumorigenesis

  4. Cell cycle and anti-estrogen effects synergize to regulate cell proliferation and ER target gene expression.

    Directory of Open Access Journals (Sweden)

    Mathieu Dalvai

    Full Text Available Antiestrogens are designed to antagonize hormone induced proliferation and ERalpha target gene expression in mammary tumor cells. Commonly used drugs such as OH-Tamoxifen and ICI 182780 (Fulvestrant block cell cycle progression in G0/G1. Inversely, the effect of cell cycle stage on ER regulated gene expression has not been tested directly. We show that in ERalpha-positive breast cancer cells (MCF-7 the estrogen receptor gene and downstream target genes are cell cycle regulated with expression levels varying as much as three-fold between phases of the cell cycle. Steroid free culture conditions commonly used to assess the effect of hormones or antiestrogens on gene expression also block MCF-7 cells in G1-phase when several ERalpha target genes are overexpressed. Thus, cell cycle effects have to be taken into account when analyzing the impact of hormonal treatments on gene transcription. We found that antiestrogens repress transcription of several ERalpha target genes specifically in S phase. This observation corroborates the more rapid and strong impact of antiestrogen treatments on cell proliferation in thymidine, hydroxyurea or aphidicolin arrested cells and correlates with an increase of apoptosis compared to similar treatments in lovastatin or nocodazol treated cells. Hence, cell cycle effects synergize with the action of antiestrogens. An interesting therapeutic perspective could be to enhance the action of anti-estrogens by associating hormone-therapy with specific cell cycle drugs.

  5. Cycle length maximization in PWRs using empirical core models

    International Nuclear Information System (INIS)

    Okafor, K.C.; Aldemir, T.

    1987-01-01

    The problem of maximizing cycle length in nuclear reactors through optimal fuel and poison management has been addressed by many investigators. An often-used neutronic modeling technique is to find correlations between the state and control variables to describe the response of the core to changes in the control variables. In this study, a set of linear correlations, generated by two-dimensional diffusion-depletion calculations, is used to find the enrichment distribution that maximizes cycle length for the initial core of a pressurized water reactor (PWR). These correlations (a) incorporate the effect of composition changes in all the control zones on a given fuel assembly and (b) are valid for a given range of control variables. The advantage of using such correlations is that the cycle length maximization problem can be reduced to a linear programming problem

  6. Forecasting Macedonian Business Cycle Turning Points Using Qual Var Model

    Directory of Open Access Journals (Sweden)

    Petrovska Magdalena

    2016-09-01

    Full Text Available This paper aims at assessing the usefulness of leading indicators in business cycle research and forecast. Initially we test the predictive power of the economic sentiment indicator (ESI within a static probit model as a leading indicator, commonly perceived to be able to provide a reliable summary of the current economic conditions. We further proceed analyzing how well an extended set of indicators performs in forecasting turning points of the Macedonian business cycle by employing the Qual VAR approach of Dueker (2005. In continuation, we evaluate the quality of the selected indicators in pseudo-out-of-sample context. The results show that the use of survey-based indicators as a complement to macroeconomic data work satisfactory well in capturing the business cycle developments in Macedonia.

  7. The circadian molecular clock regulates adult hippocampal neurogenesis by controlling the timing of cell-cycle entry and exit.

    Science.gov (United States)

    Bouchard-Cannon, Pascale; Mendoza-Viveros, Lucia; Yuen, Andrew; Kærn, Mads; Cheng, Hai-Ying M

    2013-11-27

    The subgranular zone (SGZ) of the adult hippocampus contains a pool of quiescent neural progenitor cells (QNPs) that are capable of entering the cell cycle and producing newborn neurons. The mechanisms that control the timing and extent of adult neurogenesis are not well understood. Here, we show that QNPs of the adult SGZ express molecular-clock components and proliferate in a rhythmic fashion. The clock proteins PERIOD2 and BMAL1 are critical for proper control of neurogenesis. The absence of PERIOD2 abolishes the gating of cell-cycle entrance of QNPs, whereas genetic ablation of bmal1 results in constitutively high levels of proliferation and delayed cell-cycle exit. We use mathematical model simulations to show that these observations may arise from clock-driven expression of a cell-cycle inhibitor that targets the cyclin D/Cdk4-6 complex. Our findings may have broad implications for the circadian clock in timing cell-cycle events of other stem cell populations throughout the body. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  8. The Circadian Molecular Clock Regulates Adult Hippocampal Neurogenesis by Controlling the Timing of Cell-Cycle Entry and Exit

    Directory of Open Access Journals (Sweden)

    Pascale Bouchard-Cannon

    2013-11-01

    Full Text Available The subgranular zone (SGZ of the adult hippocampus contains a pool of quiescent neural progenitor cells (QNPs that are capable of entering the cell cycle and producing newborn neurons. The mechanisms that control the timing and extent of adult neurogenesis are not well understood. Here, we show that QNPs of the adult SGZ express molecular-clock components and proliferate in a rhythmic fashion. The clock proteins PERIOD2 and BMAL1 are critical for proper control of neurogenesis. The absence of PERIOD2 abolishes the gating of cell-cycle entrance of QNPs, whereas genetic ablation of bmal1 results in constitutively high levels of proliferation and delayed cell-cycle exit. We use mathematical model simulations to show that these observations may arise from clock-driven expression of a cell-cycle inhibitor that targets the cyclin D/Cdk4-6 complex. Our findings may have broad implications for the circadian clock in timing cell-cycle events of other stem cell populations throughout the body.

  9. Cell Cycle Deregulation in the Neurons of Alzheimer’s Disease

    Science.gov (United States)

    Moh, Calvin; Kubiak, Jacek Z.; Bajic, Vladan P.; Zhu, Xiongwei; Smith, Mark A.

    2018-01-01

    The cell cycle consists of four main phases: G1, S, G2, and M. Most cells undergo these cycles up to 40–60 times in their life. However, neurons remain in a nondividing, nonreplicating phase, G0. Neurons initiate but do not complete cell division, eventually entering apoptosis. Research has suggested that like cancer, Alzheimer’s disease (AD) involves dysfunction in neuronal cell cycle reentry, leading to the development of the two-hit hypothesis of AD. The first hit is abnormal cell cycle reentry, which typically results in neuronal apoptosis and prevention of AD. However, with the second hit of chronic oxidative damage preventing apoptosis, neurons gain “immortality” analogous to tumor cells. Once both of these hits are activated, AD can develop and produce senile plaques and neurofibrillary tangles throughout brain tissue. In this review, we propose a mechanism for neuronal cell cycle reentry and the development of AD. PMID:21630160

  10. Variable cycle control model for intersection based on multi-source information

    Science.gov (United States)

    Sun, Zhi-Yuan; Li, Yue; Qu, Wen-Cong; Chen, Yan-Yan

    2018-05-01

    In order to improve the efficiency of traffic control system in the era of big data, a new variable cycle control model based on multi-source information is presented for intersection in this paper. Firstly, with consideration of multi-source information, a unified framework based on cyber-physical system is proposed. Secondly, taking into account the variable length of cell, hysteresis phenomenon of traffic flow and the characteristics of lane group, a Lane group-based Cell Transmission Model is established to describe the physical properties of traffic flow under different traffic signal control schemes. Thirdly, the variable cycle control problem is abstracted into a bi-level programming model. The upper level model is put forward for cycle length optimization considering traffic capacity and delay. The lower level model is a dynamic signal control decision model based on fairness analysis. Then, a Hybrid Intelligent Optimization Algorithm is raised to solve the proposed model. Finally, a case study shows the efficiency and applicability of the proposed model and algorithm.

  11. Physical model of the nuclear fuel cycle simulation code SITON

    International Nuclear Information System (INIS)

    Brolly, Á.; Halász, M.; Szieberth, M.; Nagy, L.; Fehér, S.

    2017-01-01

    Finding answers to main challenges of nuclear energy, like resource utilisation or waste minimisation, calls for transient fuel cycle modelling. This motivation led to the development of SITON v2.0 a dynamic, discrete facilities/discrete materials and also discrete events fuel cycle simulation code. The physical model of the code includes the most important fuel cycle facilities. Facilities can be connected flexibly; their number is not limited. Material transfer between facilities is tracked by taking into account 52 nuclides. Composition of discharged fuel is determined using burnup tables except for the 2400 MW thermal power design of the Gas-Cooled Fast Reactor (GFR2400). For the GFR2400 the FITXS method is used, which fits one-group microscopic cross-sections as polynomial functions of the fuel composition. This method is accurate and fast enough to be used in fuel cycle simulations. Operation of the fuel cycle, i.e. material requests and transfers, is described by discrete events. In advance of the simulation reactors and plants formulate their requests as events; triggered requests are tracked. After that, the events are simulated, i.e. the requests are fulfilled and composition of the material flow between facilities is calculated. To demonstrate capabilities of SITON v2.0, a hypothetical transient fuel cycle is presented in which a 4-unit VVER-440 reactor park was replaced by one GFR2400 that recycled its own spent fuel. It is found that the GFR2400 can be started if the cooling time of its spent fuel is 2 years. However, if the cooling time is 5 years it needs an additional plutonium feed, which can be covered from the spent fuel of a Generation III light water reactor.

  12. KOH concentration effect on cycle life of nickel-hydrogen cells

    Science.gov (United States)

    Lim, Hong S.; Verzwyvelt, S. A.

    1987-01-01

    A cycle life test of Ni/H2 cells containing electrolytes of various KOH concentrations and a sintered type nickel electrode was carried out at 23 C using a 45 min accelerated low Earth orbit (LEO) cycle regime at 80 percent depth of discharge. One of three cells containing 26 percent KOH has achieved over 28,000 cycles, and the other two 19,000 cycles, without a sign of failure. Two other cells containing 31 percent KOH electrolyte, which is the concentration presently used in aerospace cells, failed after 2,979 and 3,620 cycles. This result indicates that the cycle life of the present type of Ni/H2 cells may be extended by a factor of 5 to 10 simply by lowering the KOH concentration. Long cycle life of a Ni/H2 battery at high depth-of-discharge operation is desired, particularly for an LEO spacecraft application. Typically, battery life of about 30,000 cycles is required for a five year mission in an LEO. Such a cycle life with presently available cells can be assured only at a very low depth-of-discharge operation. Results of testing already show that the cycle life of an Ni/H2 cell is tremendously improved by simply using an electrolyte of low KOH concentration.

  13. The cytotoxic effect of oxybuprocaine on human corneal epithelial cells by inducing cell cycle arrest and mitochondria-dependent apoptosis.

    Science.gov (United States)

    Fan, W-Y; Wang, D-P; Wen, Q; Fan, T-J

    2017-08-01

    Oxybuprocaine (OBPC) is a widely used topical anesthetic in eye clinic, and prolonged and repeated usage of OBPC might be cytotoxic to the cornea, especially to the outmost corneal epithelium. In this study, we characterized the cytotoxic effect of OBPC on human corneal epithelial (HCEP) cells and investigated its possible cellular and molecular mechanisms using an in vitro model of non-transfected HCEP cells. Our results showed that OBPC at concentrations ranging from 0.025% to 0.4% had a dose- and time-dependent cytotoxicity to HCEP cells. Moreover, OBPC arrested the cells at S phase and induced apoptosis of these cells by inducing plasma membrane permeability, phosphatidylserine externalization, DNA fragmentation, and apoptotic body formation. Furthermore, OBPC could trigger the activation of caspase-2, -3, and -9, downregulate the expression of Bcl-xL, upregulate the expression of Bax along with the cytoplasmic amount of mitochondria-released apoptosis-inducing factor, and disrupt mitochondrial transmembrane potential. Our results suggest that OBPC has a dose- and time-dependent cytotoxicity to HCEP cells by inducing cell cycle arrest and cell apoptosis via a death receptor-mediated mitochondria-dependent proapoptotic pathway, and this novel finding provides new insights into the acute cytotoxicity and its toxic mechanisms of OBPC on HCEP cells.

  14. Effects of hyaluronic acid- chitosan-gelatin complex on the apoptosis and cell cycle of L929 cells

    Institute of Scientific and Technical Information of China (English)

    MAO Jinshu; WANG Xianghui; CUI Yuanlu; YAO Kangde

    2003-01-01

    With the development in the field of tissue engineering, the interaction between biomaterials and cells has been deeply studied. Viewing the cells seeded on the surface of materials as an organic whole, cell cycle and apoptosis are analyzed to deepen the study of cell compatibility on biomaterials, while cellproliferation and differentiation are studied at the same time. In this paper, hyaluronic acid is incorporated into the chitosan-gelatin system. Propidium iodide (PI) was used in cell cycle analysis and the double-staining of cells with annexin-V and PI was applied in cell apoptosis analysis. The results show that incorporated hyaluronic acid shortens the adaptation period of cells on the material surface, and then cells enter the normal cell cycle quickly. In addition, added hyaluronic acid inhibits cell apoptosis triggered by the membranes. Therefore,hyaluronic acid improves the cell compatibility of chitosan-gelatin system and benefits the design of biomimetic materials.

  15. Modeling Women's Menstrual Cycles using PICI Gates in Bayesian Network.

    Science.gov (United States)

    Zagorecki, Adam; Łupińska-Dubicka, Anna; Voortman, Mark; Druzdzel, Marek J

    2016-03-01

    A major difficulty in building Bayesian network (BN) models is the size of conditional probability tables, which grow exponentially in the number of parents. One way of dealing with this problem is through parametric conditional probability distributions that usually require only a number of parameters that is linear in the number of parents. In this paper, we introduce a new class of parametric models, the Probabilistic Independence of Causal Influences (PICI) models, that aim at lowering the number of parameters required to specify local probability distributions, but are still capable of efficiently modeling a variety of interactions. A subset of PICI models is decomposable and this leads to significantly faster inference as compared to models that cannot be decomposed. We present an application of the proposed method to learning dynamic BNs for modeling a woman's menstrual cycle. We show that PICI models are especially useful for parameter learning from small data sets and lead to higher parameter accuracy than when learning CPTs.

  16. Externalities in a life cycle model with endogenous survival☆

    Science.gov (United States)

    Kuhn, Michael; Wrzaczek, Stefan; Prskawetz, Alexia; Feichtinger, Gustav

    2011-01-01

    We study socially vs individually optimal life cycle allocations of consumption and health, when individual health care curbs own mortality but also has a spillover effect on other persons’ survival. Such spillovers arise, for instance, when health care activity at aggregate level triggers improvements in treatment through learning-by-doing (positive externality) or a deterioration in the quality of care through congestion (negative externality). We combine an age-structured optimal control model at population level with a conventional life cycle model to derive the social and private value of life. We then examine how individual incentives deviate from social incentives and how they can be aligned by way of a transfer scheme. The age-patterns of socially and individually optimal health expenditures and the transfer rate are derived. Numerical analysis illustrates the working of our model. PMID:28298810

  17. Thermodynamic Modeling for Open Combined Regenerative Brayton and Inverse Brayton Cycles with Regeneration before the Inverse Cycle

    Directory of Open Access Journals (Sweden)

    Lingen Chen

    2012-01-01

    Full Text Available A thermodynamic model of an open combined regenerative Brayton and inverse Brayton cycles with regeneration before the inverse cycle is established in this paper by using thermodynamic optimization theory. The flow processes of the working fluid with the pressure drops and the size constraint of the real power plant are modeled. There are 13 flow resistances encountered by the working fluid stream for the cycle model. Four of these, the friction through the blades and vanes of the compressors and the turbines, are related to the isentropic efficiencies. The remaining nine flow resistances are always present because of the changes in flow cross-section at the compressor inlet of the top cycle, regenerator inlet and outlet, combustion chamber inlet and outlet, turbine outlet of the top cycle, turbine outlet of the bottom cycle, heat exchanger inlet, and compressor inlet of the bottom cycle. These resistances associated with the flow through various cross-sectional areas are derived as functions of the compressor inlet relative pressure drop of the top cycle, and control the air flow rate, the net power output and the thermal efficiency. The analytical formulae about the power output, efficiency and other coefficients are derived with 13 pressure drop losses. It is found that the combined cycle with regenerator can reach higher thermal efficiency but smaller power output than those of the base combined cycle at small compressor inlet relative pressure drop of the top cycle.

  18. VRK1 regulates Cajal body dynamics and protects coilin from proteasomal degradation in cell cycle.

    Science.gov (United States)

    Cantarero, Lara; Sanz-García, Marta; Vinograd-Byk, Hadar; Renbaum, Paul; Levy-Lahad, Ephrat; Lazo, Pedro A

    2015-06-12

    Cajal bodies (CBs) are nuclear organelles associated with ribonucleoprotein functions and RNA maturation. CBs are assembled on coilin, its main scaffold protein, in a cell cycle dependent manner. The Ser-Thr VRK1 (vaccinia-related kinase 1) kinase, whose activity is also cell cycle regulated, interacts with and phosphorylates coilin regulating assembly of CBs. Coilin phosphorylation is not necessary for its interaction with VRK1, but it occurs in mitosis and regulates coilin stability. Knockdown of VRK1 or VRK1 inactivation by serum deprivation causes a loss of coilin phosphorylation in Ser184 and of CBs formation, which are rescued with an active VRK1, but not by kinase-dead VRK1. The phosphorylation of coilin in Ser184 occurs during mitosis before assembly of CBs. Loss of coilin phosphorylation results in disintegration of CBs, and of coilin degradation that is prevented by proteasome inhibitors. After depletion of VRK1, coilin is ubiquitinated in nuclei, which is partly mediated by mdm2, but its proteasomal degradation occurs in cytosol and is prevented by blocking its nuclear export. We conclude that VRK1 is a novel regulator of CBs dynamics and stability in cell cycle by protecting coilin from ubiquitination and degradation in the proteasome, and propose a model of CB dynamics.

  19. Cell division cycle 20 overexpression predicts poor prognosis for patients with lung adenocarcinoma.

    Science.gov (United States)

    Shi, Run; Sun, Qi; Sun, Jing; Wang, Xin; Xia, Wenjie; Dong, Gaochao; Wang, Anpeng; Jiang, Feng; Xu, Lin

    2017-03-01

    The cell division cycle 20, a key component of spindle assembly checkpoint, is an essential activator of the anaphase-promoting complex. Aberrant expression of cell division cycle 20 has been detected in various human cancers. However, its clinical significance has never been deeply investigated in non-small-cell lung cancer. By analyzing The Cancer Genome Atlas database and using some certain online databases, we validated overexpression of cell division cycle 20 in both messenger RNA and protein levels, explored its clinical significance, and evaluated the prognostic role of cell division cycle 20 in non-small-cell lung cancer. Cell division cycle 20 expression was significantly correlated with sex (p = 0.003), histological classification (p overexpression of cell division cycle 20 was significantly associated with bigger primary tumor size (p = 0.0023), higher MKI67 level (r = 0.7618, p Overexpression of cell division cycle 20 is associated with poor prognosis in lung adenocarcinoma patients, and its overexpression can also be used to identify high-risk groups. In conclusion, cell division cycle 20 might serve as a potential biomarker for lung adenocarcinoma patients.

  20. Determination of cell cycle phases in live B16 melanoma cells using IRMS.

    Science.gov (United States)

    Bedolla, Diana E; Kenig, Saša; Mitri, Elisa; Ferraris, Paolo; Marcello, Alessandro; Grenci, Gianluca; Vaccari, Lisa

    2013-07-21

    The knowledge of cell cycle phase distribution is of paramount importance for understanding cellular behaviour under normal and stressed growth conditions. This task is usually assessed using Flow Cytometry (FC) or immunohistochemistry. Here we report on the use of FTIR microspectroscopy in Microfluidic Devices (MD-IRMS) as an alternative technique for studying cell cycle distribution in live cells. Asynchronous, S- and G0-synchronized B16 mouse melanoma cells were studied by running parallel experiments based on MD-IRMS and FC using Propidium Iodide (PI) staining. MD-IRMS experiments have been done using silicon-modified BaF2 devices, where the thin silicon layer prevents BaF2 dissolution without affecting the transparency of the material and therefore enabling a better assessment of the Phosphate I (PhI) and II (PhII) bands. Hierarchical Cluster Analysis (HCA) of cellular microspectra in the 1300-1000 cm(-1) region pointed out a distribution of cells among clusters, which is in good agreement with FC results among G0/G1, S and G2/M phases. The differentiation is mostly driven by the intensity of PhI and PhII bands. In particular, PhI almost doubles from the G0/G1 to G2/M phase, in agreement with the trend followed by nucleic acids during cellular progression. MD-IRMS is then proposed as a powerful method for the in situ determination of the cell cycle stage of an individual cell, without any labelling or staining, which gives the advantage of possibly monitoring specific cellular responses to several types of stimuli by clearly separating the spectral signatures related to the cellular response from those of cells that are normally progressing.

  1. Biochemical effects of veterinary antibiotics on proliferation and cell cycle arrest of human HEK293 cells.

    Science.gov (United States)

    Kim, Hyeon Young; Kim, Ki-Tae; Kim, Sang Don

    2012-08-01

    The purpose of this study was to examine the effects of veterinary antibiotics, including amoxicillin (AMX), chlortetracycline (CTC) and tylosin (TYL), on the biochemical mechanism of human embryonic kidney cells (HEK293). CTC and TYL inhibited HEK293 cell proliferation, in both time- and dose-dependent manners, and changed the cell morphology; whereas, AMX showed no cytotoxic effects. The cell cycle analysis of CTC and TYL revealed G1-arrest in HEK293 cells. Western blot analysis also showed that CTC and TYL affected the activation of DNA damage responsive proteins, as well as cell cycle regulatory proteins, such as p53, p21(Waf1/Cip1) and Rb protein, which are crucial in the G1-S transition. The activation of p21(Waf1/Cip1) was significantly up-regulated over time, but there was no change in the level of CDK2 expression. The results of this study suggest that veterinary antibiotics, even at low level concentrations on continuous exposure, can potentially risk the development of human cells.

  2. Cell cycle evaluation of granulosa cells in the {gamma}-irradiated mouse ovarian follicles

    Energy Technology Data Exchange (ETDEWEB)

    KIm, Jin Kyu; Lee, Chang Joo; Lee, Young Keun [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of); Song, Kang Won; Yoon, Yong Dal [Hanyang Univ., Seoul (Korea, Republic of)

    1999-03-01

    This study was carried out to evaluate the biochemical and morphological effects of ionizing radiation on mouse ovarian follicles. Immature mice (ICR, 3 week-old) were irradiated with a dose of LD{sub 80(30)} at KAERI. The ovaries were collected after 6 hours, 12 hours, 1 day, and 2 days post irradiation. With the morphological basis of the histological staining with hematoxylin-eosin, immunohistochemical preparation using in situ 3'-end labeling was evaluated. Flow cytometric evaluation of DNA extracted from the whole ovary was performed. The percentage of A{sub 0} (subpopulation of cells with degraded DNA and with lower DNA fluorescence than G{sub 0}/G{sub 1} cells), apoptotic, cells in the cell cycle was significantly higher in the irradiated group than in the control group. The number of in situ 3'-end labeled follicles increased at 6 hours post irradiation. All the analyses represented that the ionizing radiation-induced follicular atresia was taken place via an apoptotic degeneration. Such a degeneration underwent very fast and acutely. Therefore, it is concluded that the radiation-induced follicular degeneration is, like the spontaneous atresia, mediated by an acute apoptosis of follicular granulosa cells. Flow cytometric evaluation of cell cycles can make the role for quantifying the atretic follicles and understanding the mechanism of the radiation-induced cell death.

  3. Study of the G2/M cell cycle checkpoint in irradiated mammary epithelial cells overexpressing Cul-4A gene

    International Nuclear Information System (INIS)

    Gupta, Anu; Yang, L.-X.; Chen, L.-C.

    2002-01-01

    Purpose: Members of the cullin gene family are known to be involved in cell cycle control. One of the cullin genes, Cul-4A, is amplified and overexpressed in breast cancer cells. This study investigates the effect of Cul-4A overexpression upon G2/M cell cycle checkpoint after DNA damage induced by either ionizing or nonionizing radiation. Methods and Materials: The normal mammary epithelial cell line MCF10A was stably transfected with full-length Cul-4A cDNA. Independent clones of MCF10A cells that overexpress Cul-4A proteins were selected and treated with either 8 Gy of ionizing radiation or 7 J/M 2 of UV radiation. The profile of cell cycle progression and the accumulation of several cell cycle proteins were analyzed. Results: We found that overexpression of Cul-4A in MCF10A cells abrogated the G2/M cell cycle checkpoint in response to DNA damage induced by ionizing irradiation, but not to DNA damage induced by nonionizing radiation. Analysis of cell cycle proteins showed that after ionizing irradiation, p53 accumulated in the mock-transfected MCF10A cells, but not in the Cul-4A transfectants. Conclusion: Our results suggest a role for Cul-4A in tumorigenesis and/or tumor progression, possibly through disruption of cell cycle control

  4. Effect of hyperthermia and radiation on the cell cycle progression of HeLa cells

    International Nuclear Information System (INIS)

    Kubota, Nobuo

    1982-01-01

    The effect of hyperthermia and irradiation on cytokinetics was studied using exponentially growing HeLa cells. To determine the effect of heat and/or radiation on the cell cycle progression, the changes in the DNA distribution of the cell population after time intervals after treatment were studied. The cellular DNA content of the cell population was measured by flow cytometry. The results obtained were as follows: 1. Compared with the control, the cellular DNA content distribution of HeLa cells treated with 43 0 C for 20 min and 60 min showed cell accumulation in S and G 2 M phases 8 hours after treatment. 2. Hyperthermic treatment at 45 0 C for 20 min caused cells to accumulate in S phase in the first 4 hours and G 2 M phase after 8 to 14.5 hours, whereas heat treatment at 45 0 C for 60 min caused cells to accumulate in G 2 M phase after 24 hours. 3. Irradiation of exponentially growing cells induced a block in the progress from G 2 M to G 1 phase. 4. Dose survival curves of HeLa cells with and without postirradiation thermal treatment (43 0 C, 60 min) showed significant enhancement of radiosensitivity by hyperthermia. 5. The sequential treatment, i.e. 5 Gy irradiation followed immediately by heat treatment at 43 0 C for 60 min, caused more cells to accumulate in G 2 M phase after 24 and 48 hours, as compared with 5 Gy irradiation alone. (author)

  5. Cell-cycle-dependent regulation of cell motility and determination of the role of Rac1

    DEFF Research Database (Denmark)

    Walmod, Peter S.; Hartmann-Petersen, Rasmus; Prag, S.

    2004-01-01

    comparable to those of control cells in G1. In contrast, transfection with dominant-negative Rac1 reduced cell speed and resulted in cellular displacements, which were identical in G1 and G2. These observations indicate that migration of cultured cells is regulated in a cell-cycle-dependent manner...... for calculation of three key parameters describing cell motility: speed, persistence time and rate of diffusion. All investigated cell lines demonstrated a lower cell displacement in the G2 phase than in the G1/S phases. This was caused by a decrease in speed and/or persistence time. The decrease in motility...... was accompanied by changes in morphology reflecting the larger volume of cells in G2 than in G1. Furthermore, L-cells and HeLa-cells appeared to be less adherent in the G2 phase. Transfection of L-cells with constitutively active Rac1 led to a general increase in the speed and rate of diffusion in G2 to levels...

  6. Analysis of cell-cycle regulation following exposure of lung-derived cells to γ-rays

    Science.gov (United States)

    Trani, D.; Lucchetti, C.; Cassone, M.; D'Agostino, L.; Caputi, M.; Giordano, A.

    Acute exposure of mammalian cells to ionizing radiation results in a delay of cell-cycle progression and/or augmentation of apoptosis. Following ionizing radiation-induced DNA damage, cell-cycle arrest in the G1- or G2-phase of the cell-cycle prevents or delays DNA replication or mitosis, providing time for the DNA repair machinery to exert its function. Deregulation or failing of cell-cycle checkpoints and/or DNA repair mechanisms may lead normal cells bearing chromosome mutations to acquire neoplastic autonomy, which in turn can trigger the onset of cancer. Existing studies have focused on the impact of p53 status on the radiation response of lung cancer (LC) cell lines in terms of both cell-cycle regulation and apoptosis, while no comparative studies have been performed on the radiation response of lung derived normal and cancerous epithelial cells. To investigate the radiation response in normal and cancerous phenotypes, along with the role and impact of p53 status, and possible correlations with pRb/p105 or other proteins involved in carcinogenesis and cell-cycle regulation, we selected two lung-derived epithelial cell lines, one normal (NL20, p53 wild-type) and one non-small cell lung cancer (NSCLC), H358 (known to be p53-deficient). We compared the levels of γ-induced cell proliferation ability, cell-cycle arrest, apoptotic index, and expression levels of cell-cycle regulating and regulated proteins. The different cell sensitivity, apoptotic response and protein expression profiles resulting from our study for NL20 and H358 cells suggest that still unknown mechanisms involving p53, pRb/p105 and their target molecules might play a pivotal role in determining cell sensitivity and resistance upon exposure to ionizing radiation.

  7. Tofacitinib induces G1 cell-cycle arrest and inhibits tumor growth in Epstein-Barr virus-associated T and natural killer cell lymphoma cells.

    Science.gov (United States)

    Ando, Shotaro; Kawada, Jun-Ichi; Watanabe, Takahiro; Suzuki, Michio; Sato, Yoshitaka; Torii, Yuka; Asai, Masato; Goshima, Fumi; Murata, Takayuki; Shimizu, Norio; Ito, Yoshinori; Kimura, Hiroshi

    2016-11-22

    Epstein-Barr virus (EBV) infects not only B cells, but also T cells and natural killer (NK) cells, and is associated with T or NK cell lymphoma. These lymphoid malignancies are refractory to conventional chemotherapy. We examined the activation of the JAK3/STAT5 pathway in EBV-positive and -negative B, T and NK cell lines and in cell samples from patients with EBV-associated T cell lymphoma. We then evaluated the antitumor effects of the selective JAK3 inhibitor, tofacitinib, against these cell lines in vitro and in a murine xenograft model. We found that all EBV-positive T and NK cell lines and patient samples tested displayed activation of the JAK3/STAT5 pathway. Treatment of these cell lines with tofacitinib reduced the levels of phospho-STAT5, suppressed proliferation, induced G1 cell-cycle arrest and decreased EBV LMP1 and EBNA1 expression. An EBV-negative NK cell line was also sensitive to tofacitinib, whereas an EBV-infected NK cell line was more sensitive to tofacitinib than its parental line. Tofacitinib significantly inhibited the growth of established tumors in NOG mice. These findings suggest that tofacitinib may represent a useful therapeutic agent for patients with EBV-associated T and NK cell lymphoma.

  8. Vitisin A inhibits adipocyte differentiation through cell cycle arrest in 3T3-L1 cells

    International Nuclear Information System (INIS)

    Kim, Soon-hee; Park, Hee-Sook; Lee, Myoung-su; Cho, Yong-Jin; Kim, Young-Sup; Hwang, Jin-Taek; Sung, Mi Jeong; Kim, Myung Sunny; Kwon, Dae Young

    2008-01-01

    Inhibition of adipocyte differentiation is one approach among the anti-obesity strategies. This study demonstrates that vitisin A, a resveratrol tetramer, inhibits adipocyte differentiation most effectively of 18 stilbenes tested. Fat accumulation and PPARγ expression were decreased by vitisin A in a dose-dependent manner. Vitisin A significantly inhibited preadipocyte proliferation and consequent differentiation within the first 2 days of treatment, indicating that the anti-adipogenic effect of vitisin A was derived from anti-proliferation. Based on cell cycle analysis, vitisin A blocked the cell cycle at the G1-S phase transition, causing cells to remain in the preadipocyte state. Vitisin A increased p21 expression, while the Rb phosphorylation level was reduced. Therefore, vitisin A seems to induce G1 arrest through p21- and consequent Rb-dependent suppression of transcription. On the other hand, ERK and Akt signaling pathways were not involved in the anti-mitotic regulation by vitisin A. Taken together, these results suggest that vitisin A inhibits adipocyte differentiation through preadipocyte cell cycle arrest

  9. TGEV nucleocapsid protein induces cell cycle arrest and apoptosis through activation of p53 signaling

    International Nuclear Information System (INIS)

    Ding, Li; Huang, Yong; Du, Qian; Dong, Feng; Zhao, Xiaomin; Zhang, Wenlong; Xu, Xingang; Tong, Dewen

    2014-01-01

    Highlights: • TGEV N protein reduces cell viability by inducing cell cycle arrest and apoptosis. • TGEV N protein induces cell cycle arrest and apoptosis by regulating p53 signaling. • TGEV N protein plays important roles in TGEV-induced cell cycle arrest and apoptosis. - Abstract: Our previous studies showed that TGEV infection could induce cell cycle arrest and apoptosis via activation of p53 signaling in cultured host cells. However, it is unclear which viral gene causes these effects. In this study, we investigated the effects of TGEV nucleocapsid (N) protein on PK-15 cells. We found that TGEV N protein suppressed cell proliferation by causing cell cycle arrest at the S and G2/M phases and apoptosis. Characterization of various cellular proteins that are involved in regulating cell cycle progression demonstrated that the expression of N gene resulted in an accumulation of p53 and p21, which suppressed cyclin B1, cdc2 and cdk2 expression. Moreover, the expression of TGEV N gene promoted translocation of Bax to mitochondria, which in turn caused the release of cytochrome c, followed by activation of caspase-3, resulting in cell apoptosis in the transfected PK-15 cells following cell cycle arrest. Further studies showed that p53 inhibitor attenuated TGEV N protein induced cell cycle arrest at S and G2/M phases and apoptosis through reversing the expression changes of cdc2, cdk2 and cyclin B1 and the translocation changes of Bax and cytochrome c induced by TGEV N protein. Taken together, these results demonstrated that TGEV N protein might play an important role in TGEV infection-induced p53 activation and cell cycle arrest at the S and G2/M phases and apoptosis occurrence

  10. Cyclin D1 overexpression, cell cycle progression and radiosensitivity in MBP cells

    International Nuclear Information System (INIS)

    Wu Lijun; Yu Zengliang

    2000-11-01

    Clones that exhibited a minimum of 7-8 fold cyclin D1 level above the parent cell lines or the vector control were obtained after transfected with the entire coding sequence of human 1.1 kb cyclin D1 cDNA. Studies showed that there was no significant difference in Radiosensitivity between over-expressing cyclin D1 and control cultures from either mouse or human origin. Using flow cytometry to access cell cycle distribution in the exponentially growth cultures of MCF10F-D1-21 and MCF10F-V-3, it was found that there was a 50 percent increase in the proportion of G2/M phase cells and 5.3 percent decrease in the proportion of G0/G1 phase cells in MCF10F-D1-21 comparing with MCF10F-V-3, though they were with the same proportion of cells in S phase

  11. Drosophila cell cycle under arrest: uncapped telomeres plead guilty.

    Science.gov (United States)

    Cenci, Giovanni

    2009-04-01

    Telomeres are specialized structures that protect chromosome ends from degradation and fusion events. In most organisms, telomeres consist of short, repetitive G-rich sequences added to chromosome ends by a reverse transcriptase with an internal RNA template, called telomerase. Specific DNA-binding protein complexes associate with telomeric sequences preventing chromosome ends from being recognized as DNA double strand breaks (DSBs). Telomeres that lose their cap activate the DNA damage response (DDR) likewise DSBs and, if inappropriately repaired, generate telomeric fusions, which eventually lead to genome instability. In Drosophila there is not telomerase, and telomere length is maintained by transposition of three specialized retroelements. Howe