TOPAS-Tissue: A Framework for the Simulation of the Biological Response to Ionizing Radiation at the Multi-Cellular Level.

This work aims to develop and validate a framework for the multiscale simulation of the biological response to ionizing radiation in a population of cells forming a tissue. We present TOPAS-Tissue, a framework to allow coupling two Monte Carlo (MC) codes: TOPAS with the TOPAS-nBio extension, capable of handling the track-structure simulation and subsequent chemistry, and CompuCell3D, an agent-based model simulator for biological and environmental behavior of a population of cells. We verified the implementation by simulating the experimental conditions for a clonogenic survival assay of a 2-D PC-3 cell culture model (10 cells in 10,000 µm2) irradiated by MV X-rays at several absorbed dose values from 0-8 Gy. The simulation considered cell growth and division, irradiation, DSB induction, DNA repair, and cellular response. The survival was obtained by counting the number of colonies, defined as a surviving primary (or seeded) cell with progeny, at 2.7 simulated days after irradiation. DNA repair was simulated with an MC implementation of the two-lesion kinetic model and the cell response with a p53 protein-pulse model. The simulated survival curve followed the theoretical linear-quadratic response with dose. The fitted coefficients α = 0.280 ± 0.025/Gy and ß = 0.042 ± 0.006/Gy2 agreed with published experimental data within two standard deviations. TOPAS-Tissue extends previous works by simulating in an end-to-end way the effects of radiation in a cell population, from irradiation and DNA damage leading to the cell fate. In conclusion, TOPAS-Tissue offers an extensible all-in-one simulation framework that successfully couples Compucell3D and TOPAS for multiscale simulation of the biological response to radiation.

Multiscale simulations suggest a protective role of neo-adventitia in abdominal aortic aneurysms.

Abdominal aortic aneurysms (AAAs) are a dangerous cardiovascular disease, the pathogenesis of which is not yet fully understood. In the present work a recent mechanopathological theory, which correlates AAA progression with microstructural and mechanical alterations in the tissue, is investigated using multiscale models. The goal is to combine these changes, within the framework of mechanobiology, with possible mechanical cues that are sensed by vascular cells along the AAA pathogenesis. Particular attention is paid to the formation of a 'neo-adventitia' on the abluminal side of the aortic wall, which is characterized by a highly random (isotropic) distribution of collagen fibers. Macro- and micro-scale results suggest that the formation of an AAA, as expected, perturbs the micromechanical state of the aortic tissue and triggers a growth and remodeling (G&R) reaction by mechanosensing cells such as fibroblasts. This G&R then leads to the formation of a thick neo-adventitia that appears to bring the micromechanical state of the tissue closer to the original homeostatic level. In this context, this new layer could act like a protective sheath, similar to the tunica adventitia in healthy aortas. This potential 'attempt at healing' by vascular cells would have important implications on the stability of the AAA wall and thus on the risk of rupture. STATEMENT OF SIGNIFICANCE: Current clinical criteria for risk assessment in AAAs are still empirical, as the causes and mechanisms of the disease are not yet fully understood. The strength of the arterial tissue is closely related to its microstructure, which in turn is remodeled by mechanosensing cells in the course of the disease. In this study, multiscale simulations show a possible connection between mechanical cues at the microscopic level and collagen G&R in AAA tissue. It should be emphasized that these micromechanical cues cannot be visualized in vivo. Therefore, the results presented here will help to advance our current understanding of the disease and motivate future experimental studies, with important implications for AAA risk assessment.

Membrane signalosome: where biophysics meets systems biology.

We opine on the recent advances in experiments and modeling of modular signaling complexes assembled on mammalian cell membranes (membrane signalosomes) in the context of several applications including intracellular trafficking, cell migration, and immune response. Characterizing the individual components of the membrane assemblies at the nanoscale, ranging from protein-lipid and protein-protein interactions, to membrane morphology, and the energetics of emergent assemblies at the subcellular to cellular scales pose significant challenges. Overcoming these challenges through the iterative coupling of multiscale modeling and experiment can be transformative in terms of addressing the gaps between structural biology and super-resolution microscopy, as it holds the key to the discovery of fundamental mechanisms behind the emergence of function in the membrane signalosome.

Surface-Atmosphere Coupling Scale, the Fate of Water, and Ecophysiological Function in a Brazilian Forest.

Tropical South America plays a central role in global climate. Bowen ratio teleconnects to circulation and precipitation processes far afield, and the global CO2 growth rate is strongly influenced by carbon cycle processes in South America. However, quantification of basin-wide seasonality of flux partitioning between latent and sensible heat, the response to anomalies around climatic norms, and understanding of the processes and mechanisms that control the carbon cycle remains elusive. Here, we investigate simulated surface-atmosphere interaction at a single site in Brazil, using models with different representations of precipitation and cloud processes, as well as differences in scale of coupling between the surface and atmosphere. We find that the model with parameterized clouds/precipitation has a tendency toward unrealistic perpetual light precipitation, while models with explicit treatment of clouds produce more intense and less frequent rain. Models that couple the surface to the atmosphere on the scale of kilometers, as opposed to tens or hundreds of kilometers, produce even more realistic distributions of rainfall. Rainfall intensity has direct consequences for the "fate of water," or the pathway that a hydrometeor follows once it interacts with the surface. We find that the model with explicit treatment of cloud processes, coupled to the surface at small scales, is the most realistic when compared to observations. These results have implications for simulations of global climate, as the use of models with explicit (as opposed to parameterized) cloud representations becomes more widespread.

Development of cell differentiation in the transition to multicellularity: a dynamical modeling approach.

Multicellularity has emerged and continues to emerge in a variety of lineages and under diverse environmental conditions. In order to attain individuality and integration, multicellular organisms must exhibit spatial cell differentiation, which in turn allows cell aggregates to robustly generate traits and behaviors at the multicellular level. Nevertheless, the mechanisms that may lead to the development of cellular differentiation and patterning in emerging multicellular organisms remain unclear. We briefly review two conceptual frameworks that have addressed this issue: the cooperation-defection framework and the dynamical patterning modules (DPMs) framework. Then, situating ourselves in the DPM formalism first put forward by S. A. Newman and collaborators, we state a hypothesis for cell differentiation and arrangement in cellular masses of emerging multicellular organisms. Our hypothesis is based on the role of the generic cell-to-cell communication and adhesion patterning mechanisms, which are two fundamental mechanisms for the evolution of multicellularity, and whose molecules seem to be well-conserved in extant multicellular organisms and their unicellular relatives. We review some fundamental ideas underlying this hypothesis and contrast them with empirical and theoretical evidence currently available. Next, we use a mathematical model to illustrate how the mechanisms and assumptions considered in the hypothesis we postulate may render stereotypical arrangements of differentiated cells in an emerging cellular aggregate and may contribute to the variation and recreation of multicellular phenotypes. Finally, we discuss the potential implications of our approach and compare them to those entailed by the cooperation-defection framework in the study of cell differentiation in the transition to multicellularity.