24 research outputs found

    Critical irradiation doses as a function of Wip1 (<i>s</i><sub>1</sub>) and PTEN (<i>s</i><sub>2</sub>) mRNA synthesis rates.

    No full text
    <p>(A) Active PI3K level is decreased 2-fold from the nominal value. (B) The nominal value of active PI3K. (C) Active PI3K level is twice the nominal value. Color lines show the critical irradiation doses in the (<i>s</i><sub>1</sub>, <i>s</i><sub>2</sub>)-parameter space. Dashed line corresponds to the persistent (irreparable) DNA damage equal 100 DSBs. For each dose, the line separates the apoptotic region (above the line) and the survival region (below the line) in the (<i>s</i><sub>1</sub>, <i>s</i><sub>2</sub>)-parameter space. The black dot in (B) corresponds to nominal values of Wip1 and PTEN mRNA synthesis rates.</p

    Deterministic simulation trajectories of the system with the suppressed DNA repair and either nominal or perturbed mRNA synthesis rates in response to 2-Gy irradiation.

    No full text
    <p>(A) Nominal Wip1 and PTEN mRNA synthesis rates (<i>s</i><sub>1</sub> = 0.1, <i>s</i><sub>2</sub> = 0.03). (B) Decreased PTEN mRNA synthesis rate (<i>s</i><sub>2</sub> = 0.005). (C) Decreased PTEN mRNA synthesis rate (<i>s</i><sub>2</sub> = 0.005) and zero Wip1 synthesis rate (<i>s</i><sub>1</sub> = 0). The simulation started at Time = 0 h from the steady state corresponding to the resting (unstimulated) cell. At Time = 10 h the irradiation phase started and lasted for 10 min. The faded line visualizes the trajectory after the initiation of apoptosis, and thus must be interpreted with caution.</p

    Analysis of the cell fate decision-making process.

    No full text
    <p>(A) PTEN levels in subpopulations of surviving (blue) and apoptotic (red) cells after 4-Gy irradiation. 10 000 cells are simulated in total. (B) Kolmogorov—Smirnov statistics between distributions of six variables which characterize surviving and apoptotic cells.</p

    Simplified scheme of the model.

    No full text
    <p>Arrow-headed dashed lines indicate positive transcriptional regulation, arrow-headed solid lines—protein transformation, circle-headed solid lines—positive influence or activation, hammer-headed solid lines—inhibitory regulation. Pro-survival and cell cycle-promoting proteins are represented with blue boxes, pro-apoptotic proteins with yellow boxes, proteins involved in cell cycle arrest with green boxes. Details of the cell cycle arrest module and the apoptotic module are shown in Figs <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004787#pcbi.1004787.g002" target="_blank">2</a> and <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004787#pcbi.1004787.g003" target="_blank">3</a> respectively.</p

    Two-dimensional bifurcation diagram showing various types of bifurcation lines and points in the (Wip1 synthesis rate, PTEN synthesis rate)-plane.

    No full text
    <p>The black dot indicates nominal values of parameters <i>s</i><sub>1</sub> and <i>s</i><sub>2</sub>. The bifurcation lines divide the parameter domain into seven subdomains <i>D</i><sub>1</sub>,
,<i>D</i><sub>7</sub>. The recurrent solutions in each of these domains are given in main text. Bifurcation diagrams in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004787#pcbi.1004787.g005" target="_blank">Fig 5A and 5B</a> show the recurrent solutions obtained for <i>s</i><sub>1</sub> = 0.2 and <i>s</i><sub>1</sub> = 0.4, as indicated by black arrows, and varied <i>s</i><sub>2</sub>.</p

    Scheme and the bifurcation diagrams for the apoptotic module.

    No full text
    <p>(A) Scheme: pro-survival proteins are in blue boxes, pro-apoptotic proteins are in yellow boxes, other proteins or protein complexes are in gray boxes. The arrow notation is same as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004787#pcbi.1004787.g001" target="_blank">Fig 1</a>. (B) Saddle—node bifurcations line in the (p53<sub>KILLER</sub>, Akt<sub>p</sub>)-plane (2-D bifurcation diagram) separates the region of parameters for which apoptotic and survival states coexist from the region for which only the apoptotic state exists. (C) Bifurcation diagram for Casp vs. p53<sub>KILLER</sub> (bifurcation parameter) for Akt<sub>p</sub>; the saddle-node bifurcation point SN is (p53<sub>KILLER</sub>, Casp<sub>bif</sub>) ≅ (0.95×10<sup>5</sup>, 1.5×10<sup>3</sup>). (D) Bifurcation diagram for Casp vs. Akt<sub>p</sub> (bifurcation parameter) for p53<sub>KILLER</sub> ≅ 5×10<sup>5</sup>; the saddle-node bifurcation point SN is (Akt<sub>p</sub>, Casp<sub>bif</sub>) ≅ (4.4×10<sup>4</sup>, 1.5×10<sup>3</sup>). The solid and dashed lines correspond respectively to the stable and unstable steady states. The number of eigenvalues with positive real parts is either one (1<sup>+</sup>) for the unstable steady state or zero (0<sup>+</sup>) for stable steady states. Notice the logarithmic scale on vertical axes in (C) and (D).</p

    Fraction of apoptotic cells as a function of irradiation dose for two types of stochastic simulations.

    No full text
    <p>For each of analyzed doses the fraction and corresponding error was calculated based on 5000 stochastic single-cell simulations. The state of the cell was checked at 72. hour after irradiation which, as shown in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004787#pcbi.1004787.g011" target="_blank">Fig 11</a>, is sufficient for unanimous cell fate decision.</p

    Deterministic simulation trajectories of the intact system in response to 2-Gy and 10-Gy irradiation.

    No full text
    <p>(A) 2-Gy irradiation is insufficient to trigger apoptosis and after several oscillations system recovers to the survival steady state. (B) 10-Gy irradiation is sufficient to trigger apoptosis: after two oscillations p53<sub>KILLER</sub> stabilizes at a high level triggering apoptosis.</p

    Bifurcation diagram of p53<sub>KILLER</sub> vs. PTEN mRNA synthesis rate (<i>s</i><sub>2</sub>).

    No full text
    <p>(A) Wip1 synthesis rate <i>s</i><sub>1</sub> = 0.2, (B) <i>s</i><sub>1</sub> = 0.4. The stable and unstable steady states are indicated by solid and dashed lines, respectively. Ranges of stable and unstable limit cycles are indicated by dark and light blue lines, respectively; dots and open circles are the maxima and minima of the stable and unstable limit cycles, respectively. Green vertical line in (A) shows Neimark—Sacker bifurcation (N—S). Red dots mark saddle-node bifurcations (SN<sub>1</sub>, SN<sub>2</sub>), orange dots mark supercritical Hopf (H<sub>super</sub>) and subcritical Hopf (H<sub>sub</sub>) bifurcations. The numbers in format <i>n</i><sup>+</sup> adjacent to the steady state lines denote the number of eigenvalues with the positive real parts. Notice the logarithmic scale on vertical axes.</p
    corecore