Uncovering potential interventions for pancreatic cancer patients via mathematical modeling

Pancreatic Ductal Adenocarcinoma (PDAC) is widely known for its poor prognosis because it is often diagnosed when the cancer is in a later stage. We built a model to analyze the microenvironment of pancreatic cancer in order to better understand the interplay between pancreatic cancer, stellate cells, and their signaling cytokines. Specifically, we have used our model to study the impact of inducing four common mutations: KRAS, TP53, SMAD4, and CDKN2A. After implementing the various mutation combinations, we used our stochastic simulator to derive aggressiveness scores based on simulated attractor probabilities and long-term trajectory approximations. These aggression scores were then corroborated with clinical data. Moreover, we found sets of control targets that are effective among common mutations. These control sets contain nodes within both the pancreatic cancer cell and the pancreatic stellate cell, including PIP3, RAF, PIK3 and BAX in pancreatic cancer cell as well as ERK and PIK3 pancreatic stellate cell. Many of these nodes were found to be differentially expressed among pancreatic cancer patients in the TCGA database. Furthermore, literature suggests that many of these nodes can be targeted by drugs currently in circulation. The results herein help provide a proof of concept in the path towards personalized medicine through a means of mathematical systems biology. All data and code used for running simulations, statistical analysis, and plotting is available on a GitHub repository at https://github.com/drplaugher/PCC_Mutations .

BiPSim: a flexible and generic stochastic simulator for polymerization processes

Detailed whole-cell modeling requires an integration of heterogeneous cell processes having different modeling formalisms, for which whole-cell simulation could remain tractable. Here, we introduce BiPSim, an open-source stochastic simulator of template-based polymerization processes, such as replication, transcription and translation. BiPSim combines an efficient abstract representation of reactions and a constant-time implementation of the Gillespie’s Stochastic Simulation Algorithm (SSA) with respect to reactions, which makes it highly efficient to simulate large-scale polymerization processes stochastically. Moreover, multi-level descriptions of polymerization processes can be handled simultaneously, allowing the user to tune a trade-off between simulation speed and model granularity. We evaluated the performance of BiPSim by simulating genome-wide gene expression in bacteria for multiple levels of granularity. Finally, since no cell-type specific information is hard-coded in the simulator, models can easily be adapted to other organismal species. We expect that BiPSim should open new perspectives for the genome-wide simulation of stochastic phenomena in biology.

Accelerated regression-based summary statistics for discrete stochastic systems via approximate simulators

Background Approximate Bayesian Computation (ABC) has become a key tool for calibrating the parameters of discrete stochastic biochemical models. For higher dimensional models and data, its performance is strongly dependent on having a representative set of summary statistics. While regression-based methods have been demonstrated to allow for the automatic construction of effective summary statistics, their reliance on first simulating a large training set creates a significant overhead when applying these methods to discrete stochastic models for which simulation is relatively expensive. In this τ work, we present a method to reduce this computational burden by leveraging approximate simulators of these systems, such as ordinary differential equations and τ-Leaping approximations. Results We have developed an algorithm to accelerate the construction of regression-based summary statistics for Approximate Bayesian Computation by selectively using the faster approximate algorithms for simulations. By posing the problem as one of ratio estimation, we use state-of-the-art methods in machine learning to show that, in many cases, our algorithm can significantly reduce the number of simulations from the full resolution model at a minimal cost to accuracy and little additional tuning from the user. We demonstrate the usefulness and robustness of our method with four different experiments. Conclusions We provide a novel algorithm for accelerating the construction of summary statistics for stochastic biochemical systems. Compared to the standard practice of exclusively training from exact simulator samples, our method is able to dramatically reduce the number of required calls to the stochastic simulator at a minimal loss in accuracy. This can immediately be implemented to increase the overall speed of the ABC workflow for estimating parameters in complex systems.

Pandæsim: An Epidemic Spreading Stochastic Simulator

Many methods have been used to model epidemic spreading. They include ordinary differential equation systems for globally homogeneous environments and partial differential equation systems to take into account spatial localisation and inhomogeneity. Stochastic differential equations systems have been used to model the inherent stochasticity of epidemic spreading processes. In our case study, we wanted to model the numbers of individuals in different states of the disease, and their locations in the country. Among the many existing methods we used our own variant of the well known Gillespie stochastic algorithm, along with the sub-volumes method to take into account the spatial localisation. Our algorithm allows us to easily switch from stochastic discrete simulation to continuous deterministic resolution using mean values. We applied our approaches on the study of the Covid-19 epidemic in France. The stochastic discrete version of Pandæsim showed very good correlations between the simulation results and the statistics gathered from hospitals, both on day by day and on global numbers, including the effects of the lockdown. Moreover, we have highlighted interesting differences in behaviour between the continuous and discrete methods that may arise in some particular conditions.

Geomechanical modelling of spent fluid reinjection in the Hengill geothermal field

<p align="justify"><span>Monitoring micro-seismicity during operations of a geothermal field is critical to the understanding of seismic hazard and changes in the reservoir. In the context of a geothermal project, induced earthquakes are an important tool to enhance the permeability and thus productivity of reservoirs and to image structure and processes. However, felt and/or damaging earthquakes are a major threat to societal acceptance and regulatory license to operate. With the adaptive data-driven tool ATLS (Adaptive Traffic Light System), we aim at managing and mitigating the risk posed by induced earthquakes during stimulation and operations, while at the same time ensuring and optimising the productivity.</span></p><p align="justify"><span>The demonstration site for the application of ATLS lies in the Hengill volcanic region located in the South-West of Iceland, host to two power plants (Hellisheiði and Nesjavellir) with a total production capacity of 423 MW</span><sub><span>e</span></sub><span> and 433MW</span><sub><span>th</span></sub><span>. The production of energy and heat is accompanied by reinjection of the spent geothermal water in dedicated areas, both to maintain production and to comply with legal requirements. These reinjection areas have been showing different seismic responses to drilling and injection operations. We investigate these different behaviours by performing numerical modelling for two of the reinjection regions. </span></p><p align="justify"><span>Two models are compared: TOUGH2-Seed, a full 3-dimensional stochastic simulator and an analytical model based on a cumulative density function linking maximum pressure in the reservoir and reactivation. Those two models fulfil two different aspects of the development of an ATLS, with the full 3D allowing an in-depth dive in the driving mechanisms of induced seismicity; and the analytical solution providing a robust and fast approximation of the forecast for real-time application. We show that both models can reproduce observed seismicity patterns in the Hengill geothermal field.</span></p>

Using TurbSim stochastic simulator to improve accuracy of computational modelling of wind in the built environment

Small wind turbines are often sited in more complex environments than in open terrain. These sites include locations near buildings, trees and other obstacles, and in such situations, the wind is normally highly three-dimensional, turbulent, unstable and weak. There is a need to understand the turbulent flow conditions for a small wind turbine in the built environment. This knowledge is crucial for input into the design process of a small wind turbine to accurately predict blade fatigue loads and lifetime and to ensure that it operates safely with a performance that is optimized for the environment. Computational fluid dynamics is a useful method to provide predictions of local wind flow patterns and to investigate turbulent flow conditions at small wind turbine sites, in a manner that requires less time and investment than actual measurements. This article presents the results of combining a computational fluid dynamics package (ANSYS CFX software) with a stochastic simulator (TurbSim) as an approach to investigate the turbulent flow conditions on the rooftop of a building where small wind turbines are sited. The findings of this article suggest that the combination of a computational fluid dynamics package with the TurbSim stochastic simulator is a promising tool to assess turbulent flow conditions for small wind turbines on the roof of buildings. In particular, in the prevailing wind direction, the results show a significant gain in accuracy in using TurbSim to generate wind speed and turbulence kinetic energy profiles for the inlet of the computational fluid dynamics domain rather than using a logarithmic wind-speed profile and a pre-set value of turbulence intensity in the computational fluid dynamics code. The results also show that small wind turbine installers should erect turbines in the middle of the roof of the building and avoid the edges of the roof as well as areas on the roof close to the windward and leeward walls of the building in the prevailing wind direction.