63,196 research outputs found
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
Modelling iteration in engineering design
This paper examines design iteration and its modelling in the simulation of New Product Development (NPD) processes. A framework comprising six perspectives of iteration is proposed and it is argued that the importance of each perspective depends upon domain-specific factors. Key challenges of modelling iteration in process simulation frameworks such as the Design Structure Matrix are discussed, and we argue that no single model or framework can fully capture the iterative dynamics of an NPD process. To conclude, we propose that consideration of iteration and its representation could help identify the most appropriate modelling framework for a given process and modelling objective, thereby improving the fidelity of design process simulation models and increasing their utility
Orthogonal-Array based Design Methodology for Complex, Coupled Space Systems
The process of designing a complex system, formed by many elements and sub-elements interacting between each other, is usually completed at a system level and in the preliminary phases in two major steps: design-space exploration and optimization. In a classical approach, especially in a company environment, the two steps are usually performed together, by experts of the field inferring on major phenomena, making assumptions and doing some trial-and-error runs on the available mathematical models. To support designers and decision makers during the design phases of this kind of complex systems, and to enable early discovery of emergent behaviours arising from interactions between the various elements being designed, the authors implemented a parametric methodology for the design-space exploration and optimization. The parametric technique is based on the utilization of a particular type of matrix design of experiments, the orthogonal arrays. Through successive design iterations with orthogonal arrays, the optimal solution is reached with a reduced effort if compared to more computationally-intense techniques, providing sensitivity and robustness information. The paper describes the design methodology in detail providing an application example that is the design of a human mission to support a lunar base
High-throughput Binding Affinity Calculations at Extreme Scales
Resistance to chemotherapy and molecularly targeted therapies is a major
factor in limiting the effectiveness of cancer treatment. In many cases,
resistance can be linked to genetic changes in target proteins, either
pre-existing or evolutionarily selected during treatment. Key to overcoming
this challenge is an understanding of the molecular determinants of drug
binding. Using multi-stage pipelines of molecular simulations we can gain
insights into the binding free energy and the residence time of a ligand, which
can inform both stratified and personal treatment regimes and drug development.
To support the scalable, adaptive and automated calculation of the binding free
energy on high-performance computing resources, we introduce the High-
throughput Binding Affinity Calculator (HTBAC). HTBAC uses a building block
approach in order to attain both workflow flexibility and performance. We
demonstrate close to perfect weak scaling to hundreds of concurrent multi-stage
binding affinity calculation pipelines. This permits a rapid time-to-solution
that is essentially invariant of the calculation protocol, size of candidate
ligands and number of ensemble simulations. As such, HTBAC advances the state
of the art of binding affinity calculations and protocols
Integrated Design Tools for Embedded Control Systems
Currently, computer-based control systems are still being implemented using the same techniques as 10 years ago. The purpose of this project is the development of a design framework, consisting of tools and libraries, which allows the designer to build high reliable heterogeneous real-time embedded systems in a very short time at a fraction of the present day costs. The ultimate focus of current research is on transformation control laws to efficient concurrent algorithms, with concerns about important non-functional real-time control systems demands, such as fault-tolerance, safety,\ud
reliability, etc.\ud
The approach is based on software implementation of CSP process algebra, in a modern way (pure objectoriented design in Java). Furthermore, it is intended that the tool will support the desirable system-engineering stepwise refinement design approach, relying on past research achievements Âż the mechatronics design trajectory based on the building-blocks approach, covering all complex (mechatronics) engineering phases: physical system modeling, control law design, embedded control system implementation and real-life realization. Therefore, we expect that this project will result in an\ud
adequate tool, with results applicable in a wide range of target hardware platforms, based on common (off-theshelf) distributed heterogeneous (cheap) processing units
Concurrent coupling of atomistic simulation and mesoscopic hydrodynamics for flows over soft multi-functional surfaces
We develop an efficient parallel multiscale method that bridges the atomistic
and mesoscale regimes, from nanometer to micron and beyond, via concurrent
coupling of atomistic simulation and mesoscopic dynamics. In particular, we
combine an all-atom molecular dynamics (MD) description for specific atomistic
details in the vicinity of the functional surface, with a dissipative particle
dynamics (DPD) approach that captures mesoscopic hydrodynamics in the domain
away from the functional surface. In order to achieve a seamless transition in
dynamic properties we endow the MD simulation with a DPD thermostat, which is
validated against experimental results by modeling water at different
temperatures. We then validate the MD-DPD coupling method for transient Couette
and Poiseuille flows, demonstrating that the concurrent MD-DPD coupling can
resolve accurately the continuum-based analytical solutions. Subsequently, we
simulate shear flows over polydimethylsiloxane (PDMS)-grafted surfaces (polymer
brushes) for various grafting densities, and investigate the slip flow as a
function of the shear stress. We verify that a "universal" power law exists for
the sliplength, in agreement with published results. Having validated the
MD-DPD coupling method, we simulate time-dependent flows past an endothelial
glycocalyx layer (EGL) in a microchannel. Coupled simulation results elucidate
the dynamics of EGL changing from an equilibrium state to a compressed state
under shear by aligning the molecular structures along the shear direction.
MD-DPD simulation results agree well with results of a single MD simulation,
but with the former more than two orders of magnitude faster than the latter
for system sizes above one micron.Comment: 11 pages, 12 figure
A Methodology to Engineer and Validate Dynamic Multi-level Multi-agent Based Simulations
This article proposes a methodology to model and simulate complex systems,
based on IRM4MLS, a generic agent-based meta-model able to deal with
multi-level systems. This methodology permits the engineering of dynamic
multi-level agent-based models, to represent complex systems over several
scales and domains of interest. Its goal is to simulate a phenomenon using
dynamically the lightest representation to save computer resources without loss
of information. This methodology is based on two mechanisms: (1) the activation
or deactivation of agents representing different domain parts of the same
phenomenon and (2) the aggregation or disaggregation of agents representing the
same phenomenon at different scales.Comment: Presented at 3th International Workshop on Multi-Agent Based
Simulation, Valencia, Spain, 5th June 201
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