Engineering simulations for cancer systems biology

Computer simulation can be used to inform in vivo and in vitro experimentation, enabling rapid, low-cost hypothesis generation and directing experimental design in order to test those hypotheses. In this way, in silico models become a scientific instrument for investigation, and so should be developed to high standards, be carefully calibrated and their findings presented in such that they may be reproduced. Here, we outline a framework that supports developing simulations as scientific instruments, and we select cancer systems biology as an exemplar domain, with a particular focus on cellular signalling models. We consider the challenges of lack of data, incomplete knowledge and modelling in the context of a rapidly changing knowledge base. Our framework comprises a process to clearly separate scientific and engineering concerns in model and simulation development, and an argumentation approach to documenting models for rigorous way of recording assumptions and knowledge gaps. We propose interactive, dynamic visualisation tools to enable the biological community to interact with cellular signalling models directly for experimental design. There is a mismatch in scale between these cellular models and tissue structures that are affected by tumours, and bridging this gap requires substantial computational resource. We present concurrent programming as a technology to link scales without losing important details through model simplification. We discuss the value of combining this technology, interactive visualisation, argumentation and model separation to support development of multi-scale models that represent biologically plausible cells arranged in biologically plausible structures that model cell behaviour, interactions and response to therapeutic interventions

Calibrated Stochastic Dynamic Models for Resource Management

In this paper we develop a positive calibrated approach to stochastic dynamic programming. Risk aversion, discount rate, and intertemporal substitution preferences of the decision-maker are calibrated by a procedure that minimizes the mean squared error from data on past decisions. We apply this framework to managing stochastic water supplies from Oroville Reservoir, located in Northern California. The calibrated positive SDP closely reproduces the historical storage and releases from the dam and shows sensitivity of optimal decisions to a decision-maker's risk aversion and intertemporal preferences. The calibrated model has average prediction errors that are substantially lower than those from the model with an expected net present value objective.Resource /Energy Economics and Policy,

On green routing and scheduling problem

The vehicle routing and scheduling problem has been studied with much interest within the last four decades. In this paper, some of the existing literature dealing with routing and scheduling problems with environmental issues is reviewed, and a description is provided of the problems that have been investigated and how they are treated using combinatorial optimization tools

The inference of gene trees with species trees

Molecular phylogeny has focused mainly on improving models for the reconstruction of gene trees based on sequence alignments. Yet, most phylogeneticists seek to reveal the history of species. Although the histories of genes and species are tightly linked, they are seldom identical, because genes duplicate, are lost or horizontally transferred, and because alleles can co-exist in populations for periods that may span several speciation events. Building models describing the relationship between gene and species trees can thus improve the reconstruction of gene trees when a species tree is known, and vice-versa. Several approaches have been proposed to solve the problem in one direction or the other, but in general neither gene trees nor species trees are known. Only a few studies have attempted to jointly infer gene trees and species trees. In this article we review the various models that have been used to describe the relationship between gene trees and species trees. These models account for gene duplication and loss, transfer or incomplete lineage sorting. Some of them consider several types of events together, but none exists currently that considers the full repertoire of processes that generate gene trees along the species tree. Simulations as well as empirical studies on genomic data show that combining gene tree-species tree models with models of sequence evolution improves gene tree reconstruction. In turn, these better gene trees provide a better basis for studying genome evolution or reconstructing ancestral chromosomes and ancestral gene sequences. We predict that gene tree-species tree methods that can deal with genomic data sets will be instrumental to advancing our understanding of genomic evolution.Comment: Review article in relation to the "Mathematical and Computational Evolutionary Biology" conference, Montpellier, 201

A novel haptic model and environment for maxillofacial surgical operation planning and manipulation

This paper presents a practical method and a new haptic model to support manipulations of bones and their segments during the planning of a surgical operation in a virtual environment using a haptic interface. To perform an effective dental surgery it is important to have all the operation related information of the patient available beforehand in order to plan the operation and avoid any complications. A haptic interface with a virtual and accurate patient model to support the planning of bone cuts is therefore critical, useful and necessary for the surgeons. The system proposed uses DICOM images taken from a digital tomography scanner and creates a mesh model of the filtered skull, from which the jaw bone can be isolated for further use. A novel solution for cutting the bones has been developed and it uses the haptic tool to determine and define the bone-cutting plane in the bone, and this new approach creates three new meshes of the original model. Using this approach the computational power is optimized and a real time feedback can be achieved during all bone manipulations. During the movement of the mesh cutting, a novel friction profile is predefined in the haptical system to simulate the force feedback feel of different densities in the bone

Detailed analysis of the lattice Boltzmann method on unstructured grids

The lattice Boltzmann method has become a standard for efficiently solving problems in fluid dynamics. While unstructured grids allow for a more efficient geometrical representation of complex boundaries, the lattice Boltzmann methods is often implemented using regular grids. Here we analyze two implementations of the lattice Boltzmann method on unstructured grids, the standard forward Euler method and the operator splitting method. We derive the evolution of the macroscopic variables by means of the Chapman-Enskog expansion, and we prove that it yields the Navier-Stokes equation and is first order accurate in terms of the temporal discretization and second order in terms of the spatial discretization. Relations between the kinetic viscosity and the integration time step are derived for both the Euler method and the operator splitting method. Finally we suggest an improved version of the bounce-back boundary condition. We test our implementations in both standard benchmark geometries and in the pore network of a real sample of a porous rock.Comment: 42 page