12,963 research outputs found

    Computational and Mathematical Modelling of the EGF Receptor System

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    This chapter gives an overview of computational and mathematical modelling of the EGF receptor system. It begins with a survey of motivations for producing such models, then describes the main approaches that are taken to carrying out such modelling, viz. differential equations and individual-based modelling. Finally, a number of projects that applying modelling and simulation techniques to various aspects of the EGF receptor system are described

    Transfer Functions for Protein Signal Transduction: Application to a Model of Striatal Neural Plasticity

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    We present a novel formulation for biochemical reaction networks in the context of signal transduction. The model consists of input-output transfer functions, which are derived from differential equations, using stable equilibria. We select a set of 'source' species, which receive input signals. Signals are transmitted to all other species in the system (the 'target' species) with a specific delay and transmission strength. The delay is computed as the maximal reaction time until a stable equilibrium for the target species is reached, in the context of all other reactions in the system. The transmission strength is the concentration change of the target species. The computed input-output transfer functions can be stored in a matrix, fitted with parameters, and recalled to build discrete dynamical models. By separating reaction time and concentration we can greatly simplify the model, circumventing typical problems of complex dynamical systems. The transfer function transformation can be applied to mass-action kinetic models of signal transduction. The paper shows that this approach yields significant insight, while remaining an executable dynamical model for signal transduction. In particular we can deconstruct the complex system into local transfer functions between individual species. As an example, we examine modularity and signal integration using a published model of striatal neural plasticity. The modules that emerge correspond to a known biological distinction between calcium-dependent and cAMP-dependent pathways. We also found that overall interconnectedness depends on the magnitude of input, with high connectivity at low input and less connectivity at moderate to high input. This general result, which directly follows from the properties of individual transfer functions, contradicts notions of ubiquitous complexity by showing input-dependent signal transmission inactivation.Comment: 13 pages, 5 tables, 15 figure

    Engineering simulations for cancer systems biology

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    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

    ODE parameter inference using adaptive gradient matching with Gaussian processes

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    Parameter inference in mechanistic models based on systems of coupled differential equa- tions is a topical yet computationally chal- lenging problem, due to the need to fol- low each parameter adaptation with a nu- merical integration of the differential equa- tions. Techniques based on gradient match- ing, which aim to minimize the discrepancy between the slope of a data interpolant and the derivatives predicted from the differen- tial equations, offer a computationally ap- pealing shortcut to the inference problem. The present paper discusses a method based on nonparametric Bayesian statistics with Gaussian processes due to Calderhead et al. (2008), and shows how inference in this model can be substantially improved by consistently inferring all parameters from the joint dis- tribution. We demonstrate the efficiency of our adaptive gradient matching technique on three benchmark systems, and perform a de- tailed comparison with the method in Calder- head et al. (2008) and the explicit ODE inte- gration approach, both in terms of parameter inference accuracy and in terms of computa- tional efficiency

    Data-driven modelling of biological multi-scale processes

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    Biological processes involve a variety of spatial and temporal scales. A holistic understanding of many biological processes therefore requires multi-scale models which capture the relevant properties on all these scales. In this manuscript we review mathematical modelling approaches used to describe the individual spatial scales and how they are integrated into holistic models. We discuss the relation between spatial and temporal scales and the implication of that on multi-scale modelling. Based upon this overview over state-of-the-art modelling approaches, we formulate key challenges in mathematical and computational modelling of biological multi-scale and multi-physics processes. In particular, we considered the availability of analysis tools for multi-scale models and model-based multi-scale data integration. We provide a compact review of methods for model-based data integration and model-based hypothesis testing. Furthermore, novel approaches and recent trends are discussed, including computation time reduction using reduced order and surrogate models, which contribute to the solution of inference problems. We conclude the manuscript by providing a few ideas for the development of tailored multi-scale inference methods.Comment: This manuscript will appear in the Journal of Coupled Systems and Multiscale Dynamics (American Scientific Publishers

    When kinases meet mathematics: the systems biology of MAPK signalling

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    The mitogen activated protein kinase/extracellular signal regulated kinase pathway regulates fundamental cellular function such as cell proliferation, survival, differentiation and motility, raising the question how these diverse functions are specified and coordinated. They are encoded through the activation kinetics of the pathway, a multitude of feedback loops, scaffold proteins, subcellular compartmentalisation, and crosstalk with other pathways. These regulatory motifs alone or in combination can generate a multitude of complex behaviour. Systems biology tries to decode this complexity through mathematical modelling and prediction in order to gain a deeper insight into the inner works of signalling networks

    The rational development of molecularly imprinted polymer-based sensors for protein detection.

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    The detection of specific proteins as biomarkers of disease, health status, environmental monitoring, food quality, control of fermenters and civil defence purposes means that biosensors for these targets will become increasingly more important. Among the technologies used for building specific recognition properties, molecularly imprinted polymers (MIPs) are attracting much attention. In this critical review we describe many methods used for imprinting recognition for protein targets in polymers and their incorporation with a number of transducer platforms with the aim of identifying the most promising approaches for the preparation of MIP-based protein sensors (277 references)

    A multiscale model for collagen alignment in wound healing

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    It is thought that collagen alignment plays a significant part in scar tissue formation during dermal wound healing. We present a multiscale model for collagen deposition and alignment during this process. We consider fibroblasts as discrete units moving within an extracellular matrix of collagen and fibrin modelled as continua. Our model includes flux induced alignment of collagen by fibroblasts, and contact guidance of fibroblasts by collagen fibres. We can use the model to predict the effects of certain manipulations, such as varying fibroblast speed, or placing an aligned piece of tissue in the wound. We also simulate experiments which alter the TGF-β concentrations in a healing dermal wound and use the model to offer an explanation of the observed influence of this growth factor on scarring

    Simulation of cell movement through evolving environment: a fictitious domain approach

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    A numerical method for simulating the movement of unicellular organisms which respond to chemical signals is presented. Cells are modelled as objects of finite size while the extracellular space is described by reaction-diffusion partial differential equations. This modular simulation allows the implementation of different models at the different scales encountered in cell biology and couples them in one single framework. The global computational cost is contained thanks to the use of the fictitious domain method for finite elements, allowing the efficient solve of partial differential equations in moving domains. Finally, a mixed formulation is adopted in order to better monitor the flux of chemicals, specifically at the interface between the cells and the extracellular domain

    An integrative, multi-scale, genome-wide model reveals the phenotypic landscape of Escherichia coli.

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    Given the vast behavioral repertoire and biological complexity of even the simplest organisms, accurately predicting phenotypes in novel environments and unveiling their biological organization is a challenging endeavor. Here, we present an integrative modeling methodology that unifies under a common framework the various biological processes and their interactions across multiple layers. We trained this methodology on an extensive normalized compendium for the gram-negative bacterium Escherichia coli, which incorporates gene expression data for genetic and environmental perturbations, transcriptional regulation, signal transduction, and metabolic pathways, as well as growth measurements. Comparison with measured growth and high-throughput data demonstrates the enhanced ability of the integrative model to predict phenotypic outcomes in various environmental and genetic conditions, even in cases where their underlying functions are under-represented in the training set. This work paves the way toward integrative techniques that extract knowledge from a variety of biological data to achieve more than the sum of their parts in the context of prediction, analysis, and redesign of biological systems
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