In order for the memory model (2) to reproduce the radioadaptive response, the probability for a cell to become permanently altered by radiation exposure, <i>p</i>, must increase sufficiently at the higher radiation dose, <i>α</i>.

<p>In other words, the radioadaptive response is not observed in the model if the increase in the parameter <i>p</i> at the higher value of <i>α</i> lies below a threshold. The graph plots the number of permanently altered cells in the presence of priming divided by the number of altered cells generated in the absence of priming, as a function of <i>n</i>-fold increase in the value of <i>p</i> at high <i>α</i>. If the value of <i>p</i> for high α is not increased sufficiently, more permanently altered cells are generated in the presence of priming. In contrast, if the value of <i>p</i> is increased by a threshold amount at high <i>α</i>, then priming lowers the total number of altered cells relative to the scenario where no low-dose priming is given. The horizontal line represents the ratio of one, where priming makes no difference. Base parameters are given as follows: <i>α = 0.1</i> for priming low dose radiation, and <i>α = 100</i> for higher dose radiation, <i>c = 1</i>, <i>η = 0.01</i>, <i>x₀ = 100</i>, <i>y₀ = 0</i>, <i>z₀ = 0</i>, <i>w₀ = 0</i>. For low-dose priming, <i>p = 0.05</i>. For high dose challenge, the value of <i>p</i> is increased <i>n</i>-fold, the horizontal axis of the graph.</p

Variability of the parameter estimates across the different experimental setups and cell lines.

<p>Parameters have been estimated by fitting model (2) independently to eight experimental data sets, see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003513#pcbi-1003513-g002" target="_blank">Figure 2</a> of Supporting <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003513#pcbi.1003513.s001" target="_blank">Text S1</a> and references therein. Box-and-whiskers diagrams for parameters are presented. The dimensionless quantities <i>p₀</i> and <i>p₁</i> parameterize the saturating function , as defined in the caption for <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003513#pcbi-1003513-g004" target="_blank">figure 4(ii)</a>. A box-and-whiskers plot consists of a box that spans the distance between two quantiles surrounding the median, with lines (“whiskers”) that extend to span the full range.</p

Hybrid Highway Landscape: Integrating highway into urban context

Urban highway, as a product of modern city, is one of the most important influencing factors that shape the contemporary urban landscape. It was built to ease the urban traffic pressure. However, the negative impacts on the urban space and the surrounding environment cannot be ignored. In the most cases, highway is widely regarded and treated as an only functional infrastructure. In my point of view, it also has potentials to be a public facility instead of strictly utilitarian by being contextualized, integrated and interacted with urban environment and urban life. Therefore, I have developed a concept of ‘hybrid highway landscape’ as a new phase of urban highway. In order to explore the potential of hybrid highway landscape, highway A40 in the centre of Duisburg, a highly urban context, and its right-of-way is regarded as an interesting experimental field for the research project

Dynamics of Cellular Responses to Radiation

<div><p>Understanding the consequences of exposure to low dose ionizing radiation is an important public health concern. While the risk of low dose radiation has been estimated by extrapolation from data at higher doses according to the linear non-threshold model, it has become clear that cellular responses can be very different at low compared to high radiation doses. Important phenomena in this respect include radioadaptive responses as well as low-dose hyper-radiosensitivity (HRS) and increased radioresistance (IRR). With radioadaptive responses, low dose exposure can protect against subsequent challenges, and two mechanisms have been suggested: an intracellular mechanism, inducing cellular changes as a result of the priming radiation, and induction of a protected state by inter-cellular communication. We use mathematical models to examine the effect of these mechanisms on cellular responses to low dose radiation. We find that the intracellular mechanism can account for the occurrence of radioadaptive responses. Interestingly, the same mechanism can also explain the existence of the HRS and IRR phenomena, and successfully describe experimentally observed dose-response relationships for a variety of cell types. This indicates that different, seemingly unrelated, low dose phenomena might be connected and driven by common core processes. With respect to the inter-cellular communication mechanism, we find that it can also account for the occurrence of radioadaptive responses, indicating redundancy in this respect. The model, however, also suggests that the communication mechanism can be vital for the long term survival of cell populations that are continuously exposed to relatively low levels of radiation, which cannot be achieved with the intracellular mechanism in our model. Experimental tests to address our model predictions are proposed.</p></div

Effect of continuous radiation on the cell population (a) in the memory model (equation 2) and (b) the communication model (equation 3).

<p>Note that the long time-spans considered are important to demonstrate the quasi-equilibrium behavior in the communication model, and the absence of this behavior in the memory model. Parameters were chosen as follows (a) <i>α = 0.1</i>, <i>p = 0.05</i>, <i>c = 1</i>, <i>η = 0.01</i>, <i>x₀ = 100</i>, <i>y₀ = 0</i>, <i>z₀ = 0</i>, <i>w₀ = 0</i>. (b) <i>α = 0.1</i>, <i>p = 0.05</i>, <i>c = 1</i>, <i>η = 0.01</i>, β<i>₀ = 10</i>, β<i>₁ = 0</i>, <i>x₀ = 100</i>, <i>y₀ = 0</i>, <i>z₀ = 0</i>, <i>w₀ = 0</i>.</p

Dose-response curve predicted by the memory model (equation 2).

<p>(i) General picture. The fraction of cells surviving after a defined radiation time is plotted against the radiation dose. The model can reproduce experimentally observed patterns, including the phenomena of HRS and IRR at lower doses. Parameters are given by: <i>p = 0.4+0.55α</i>, <i>c = 1</i>, <i>η = 0.01</i>, <i>x₀ = 100</i>, <i>y₀ = 0</i>, <i>z₀ = 0</i>, <i>w₀ = 0</i>. Radiation was applied for a duration of 150 time steps. (ii). Fits of the model to previously published dose-response curves for different cell lines and radiation regimes. The fitting procedures and the estimated parameters are found in the Supporting <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003513#pcbi.1003513.s001" target="_blank">Text S1</a>. A two-parametric saturating function was used for <i>p</i>: where . The data were taken from the following sources: (a) p53 mutant T98G cells from reference <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003513#pcbi.1003513-Krueger1" target="_blank">[41]</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003513#pcbi-1003513-g001" target="_blank">figure 1</a>; (b) T98G cells from reference <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003513#pcbi.1003513-Short2" target="_blank">[42]</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003513#pcbi-1003513-g001" target="_blank">figure 1</a>; (c) HGL21 cells from reference <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003513#pcbi.1003513-Short3" target="_blank">[43]</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003513#pcbi-1003513-g001" target="_blank">figure 1</a>; (d) U138 cells from reference <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003513#pcbi.1003513-Short3" target="_blank">[43]</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003513#pcbi-1003513-g001" target="_blank">figure 1</a>.</p