Proportion of women with BC who received adjuvant therapies.

<p>*Obtained from Mariotto <i>et al</i>. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030157#pone.0030157-Mariotto1" target="_blank">[24]</a>. In this work chemotherapy was restricted to multiagent chemotherapy and hormonotheraphy was restricted to tamoxifen.</p><p>**Obtained from the Alamo I study for years 1990–93 and the Alamo II study for 1994–97 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030157#pone.0030157-Grupo1" target="_blank">[22]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030157#pone.0030157-Grupo2" target="_blank">[23]</a>.</p><p>Positive and negative signs refer to node affectation. Stratification by BC stage groups differs between the two countries.</p

Percent decline compared to Background for the year 2008 and the period 1975–2008.

<p>“<i>All interventions</i>” includes Screening + Adjuvant treatments + Other causes.</p

BC mortality rates and different scenarios.

<p>Standardized BC mortality rates for the age group 30–69. Observed rates (dots) and estimations under different scenarios <i>Background</i> (gray), <i>Only screening</i> (green), <i>Only adjuvant treatments</i> (cyan), and <i>Both interventions</i> (magenta).</p

BC mortality rates and screening.

<p>Standardized BC mortality rates for the age groups: <b>A</b>) 30–79, <b>B</b>) 30–69. Observed rates (dots) and estimations under different scenarios <i>Background</i> (gray) and <i>Only screening</i> (green).</p

Percent decline compared to Background for the year 2008 and the period 1975–2008.

<p>Percent decline compared to Background for the year 2008 and the period 1975–2008.</p

Summary of the comparison of physiologically relevant criteria between the alternative designs for monofunctional TCS^a.

a<p>The model with the largest number of “+” signs for a given criterion is the one with the best performance with respect to that criterion.</p><p>A|B stands for Model A controlled for Model B. A|C stands for Model A controlled for Model C.</p

Experiments to analyze the effect of changes in different parameter values and protein concentrations on the range of bistability for the alternative TCS modules^a.

a<p>The steady state(s) for the three models by scanning a)k₁ (SK autophosphorylation reaction rate constant) and b)k₂ (SKP autodephosphorylation reaction rate constant) between 10⁻⁶ and 10 at different values of the parameters named in the table (see text for details).</p

Temporal responsiveness curves of Models A, B, and C.

<p>The systems are at an initial steady state and, at time zero, the signal, represented in the x axis, changes instantaneously and the time it takes for the system to get to within 90% of the new steady state is measured and plotted in the y axis. A–D: Response times of TCS with monofunctional SK. E–H: Response times of TCS with bifunctional SK. The OFF to ON plots start with the systems at an OFF steady state (low levels of RRP) corresponding to a low value of k₁ (A, C, E, G) or a high value of k₂ (B, D, F, H). The signal is then changed to increase the steady state level of RRP. The ON to OFF plots start with the systems at an ON steady state (high levels of RRP) corresponding to a high value of k₁ or a low value of k₂. The signal is then changed to decrease the steady state level of RRP. Peaks that indicate slower response times are located immediately outside the range of bistability. The lack of a peak in a curve can be due to monostability or irreversibility. The dashed lines indicate the signal value at which Models B and C exit its bistable range. Absence of a dashed line indicates irreversible turning ON or OFF of the system (Model B in panel C ) or absence of bistability (see the signal-response curves of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031095#pone-0031095-g002" target="_blank">Figure 2</a>).</p

Analyzed Two Component Systems modules.

<p>Model A represents a prototypical TCS. Model B represents a TCS with a SK-binding third component (TC_SK). Model C represents a TCS with a RR-binding third component (TC_RR). SK: sensor kinase; RR: response regulator; SKP: phosphorylated SK; RRP: phosphorylated RR; Ph: alternative phosphatase that dephosphorylates RRP; SKRR: dead-end complex, resulting from the binding of SK and RR; SKPRR: protein complex formed by the binding of SKP and RR; SKRRP: protein complex formed by the binding of SK and RRP; PhRRP: protein complex formed by the binding of Ph and RRP; SKTC and RRPTC: protein complexes formed by the binding of the third component to SK and RRP, respectively; (k₁, …, k₁₈): kinetic constants of the individual reactions. For simplicity, ATP and the release of inorganic phosphate are omitted. To analyze TCS modules with monofunctional sensors, k₈ is set to 0. To analyze TCS modules with bifunctional sensors, k₈ is set to be different from 0.</p

Percentage of parameter space where bistable responses are possible^a.

a<p>Some bidimensional sections of the multidimensional parameter space of bistability are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031095#pone.0031095.s002" target="_blank">Figure S2</a>. The results show that in TCS with a bifunctional SK, both a TC_SK and a TC_RR cause a decrease in the size of the parametric region of bistability, with one exception: Model C has a larger parametric region of bistability when the signaling target is SK autophosphorylation (k₁). However, in systems with a monofunctional SK, a TCSK causes an increase and a TCRR causes a decrease in the size of the parametric region of bistability if the environment modulates the SK dephosphorylation (k₂). A|B stands for Model A controlled for Model B. A|C stands for Model A controlled for Model C.</p