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

Fair decomposition of group obligations

We consider the problem of decomposing a group norm into a set of individual obligations for the agents comprising the group, such that if the individual obligations are fulfilled, the group obligation is fulfilled. Such an assignment of tasks to agents is often subject to additional social or organisational norms that specify permissible ways in which tasks can be assigned. An important role of social norms is that they can be used to impose ‘fairness constraints’, which seek to distribute individual responsibility for discharging the group norm in a ‘fair’ or ‘equitable’ way. We propose a simple language for this kind of fairness constraints and analyse the problem of computing a fair decomposition of a group obligation, both for non-repeating and for repeating group obligations

A Model-Free Sampling Method for Estimating Basins of Attraction Using Hybrid Active Learning (HAL)

Understanding the basins of attraction (BoA) is often a paramount consideration for nonlinear systems. Most existing approaches to determining a high-resolution BoA require prior knowledge of the system's dynamical model (e.g., differential equation or point mapping for continuous systems, cell mapping for discrete systems, etc.), which allows derivation of approximate analytical solutions or parallel computing on a multi-core computer to find the BoA efficiently. However, these methods are typically impractical when the BoA must be determined experimentally or when the system's model is unknown. This paper introduces a model-free sampling method for BoA. The proposed method is based upon hybrid active learning (HAL) and is designed to find and label the "informative" samples, which efficiently determine the boundary of BoA. It consists of three primary parts: 1) additional sampling on trajectories (AST) to maximize the number of samples obtained from each simulation or experiment; 2) an active learning (AL) algorithm to exploit the local boundary of BoA; and 3) a density-based sampling (DBS) method to explore the global boundary of BoA. An example of estimating the BoA for a bistable nonlinear system is presented to show the high efficiency of our HAL sampling method.Comment: Update: 1) add the schematic of the magnet-induced bistable system, 2) emphasize that the proposed method can be implemented when the system's model is unknown. 6 pages, 5 figures, 2 table

When Europe encounters urban governance: Policy Types, Actor Games and Mechanisms of cites Europeanization

This paper examines European Union (EU) causal mechanisms and policy instruments affecting the urban domain throughout the lenses of the Europeanization approach. Instead of looking at EU instruments that are formally/legally consecrated to cities, we use theoretical public policy analysis to explore the arenas and the causal mechanisms that structure the encounters between the EU and urban systems of governance. Policy instruments are related to policy arenas and in turn to different mechanisms of transmission thus originating a typology of European Policy Modes. The paper focuses on four different EU instruments in the in the macro-area of sustainable development and proposes potential game-theoretical models for each of them. In the conclusions we highlight the differences between this approach and the traditional analysis of EU urban policy, and suggest avenues for future empirical research based on typologies of policy instruments and modes of Europeanization

Matching under Preferences

Matching theory studies how agents and/or objects from different sets can be matched with each other while taking agents\u2019 preferences into account. The theory originated in 1962 with a celebrated paper by David Gale and Lloyd Shapley (1962), in which they proposed the Stable Marriage Algorithm as a solution to the problem of two-sided matching. Since then, this theory has been successfully applied to many real-world problems such as matching students to universities, doctors to hospitals, kidney transplant patients to donors, and tenants to houses. This chapter will focus on algorithmic as well as strategic issues of matching theory. Many large-scale centralized allocation processes can be modelled by matching problems where agents have preferences over one another. For example, in China, over 10 million students apply for admission to higher education annually through a centralized process. The inputs to the matching scheme include the students\u2019 preferences over universities, and vice versa, and the capacities of each university. The task is to construct a matching that is in some sense optimal with respect to these inputs. Economists have long understood the problems with decentralized matching markets, which can suffer from such undesirable properties as unravelling, congestion and exploding offers (see Roth and Xing, 1994, for details). For centralized markets, constructing allocations by hand for large problem instances is clearly infeasible. Thus centralized mechanisms are required for automating the allocation process. Given the large number of agents typically involved, the computational efficiency of a mechanism's underlying algorithm is of paramount importance. Thus we seek polynomial-time algorithms for the underlying matching problems. Equally important are considerations of strategy: an agent (or a coalition of agents) may manipulate their input to the matching scheme (e.g., by misrepresenting their true preferences or underreporting their capacity) in order to try to improve their outcome. A desirable property of a mechanism is strategyproofness, which ensures that it is in the best interests of an agent to behave truthfully

Accounting for Diffusion in Agent Based Models of Reaction-Diffusion Systems with Application to Cytoskeletal Diffusion

Diffusion plays a key role in many biochemical reaction systems seen in nature. Scenarios where diffusion behavior is critical can be seen in the cell and subcellular compartments where molecular crowding limits the interaction between particles. We investigate the application of a computational method for modeling the diffusion of molecules and macromolecules in three-dimensional solutions using agent based modeling. This method allows for realistic modeling of a system of particles with different properties such as size, diffusion coefficients, and affinity as well as the environment properties such as viscosity and geometry. Simulations using these movement probabilities yield behavior that mimics natural diffusion. Using this modeling framework, we simulate the effects of molecular crowding on effective diffusion and have validated the results of our model using Langevin dynamics simulations and note that they are in good agreement with previous experimental data. Furthermore, we investigate an extension of this framework where single discrete cells can contain multiple particles of varying size in an effort to highlight errors that can arise from discretization that lead to the unnatural behavior of particles undergoing diffusion. Subsequently, we explore various algorithms that differ in how they handle the movement of multiple particles per cell and suggest an algorithm that properly accommodates multiple particles of various sizes per cell that can replicate the natural behavior of these particles diffusing. Finally, we use the present modeling framework to investigate the effect of structural geometry on the directionality of diffusion in the cell cytoskeleton with the observation that parallel orientation in the structural geometry of actin filaments of filopodia and the branched structure of lamellipodia can give directionality to diffusion at the filopodia-lamellipodia interface

Managerial ownership and urban water utilities efficiency in Uganda

This paper assesses the impact of the early 1980s neoliberalistic reform strategies in urban water distribution in developing countries. It examines in particular, the technical efficiency of two heterogeneous urban water utility-groups in Uganda. Performance is considered in light of the key urban water sector objectives that are to universally increase qualitative water coverage and enhance utility revenue. Using a two-staged bias-corrected metafrontier based on the data envelopment analysis estimators, the public-private (than the public-public) owned utilities are found less efficient. Efficiency differences between both groups are further linked to utilities scale of operation and market capture capabilities among other factors. The paper urges policy makers to strengthen public sector capabilities as a development policy solution for inclusive quality water services access among other basic public utility services in Uganda, Africa and the developing countries in general.Efficiency, managerial ownership, non-parametric, Uganda, urban water supply, water supply, water resource management, water utilities

QoS-Aware Middleware for Web Services Composition

The paradigmatic shift from a Web of manual interactions to a Web of programmatic interactions driven by Web services is creating unprecedented opportunities for the formation of online Business-to-Business (B2B) collaborations. In particular, the creation of value-added services by composition of existing ones is gaining a significant momentum. Since many available Web services provide overlapping or identical functionality, albeit with different Quality of Service (QoS), a choice needs to be made to determine which services are to participate in a given composite service. This paper presents a middleware platform which addresses the issue of selecting Web services for the purpose of their composition in a way that maximizes user satisfaction expressed as utility functions over QoS attributes, while satisfying the constraints set by the user and by the structure of the composite service. Two selection approaches are described and compared: one based on local (task-level) selection of services and the other based on global allocation of tasks to services using integer programming