A long-term vision of evolutionary robotics is a technology enabling the evolution of entire auto... more A long-term vision of evolutionary robotics is a technology enabling the evolution of entire autonomous robotic ecosystems that live and work for long periods in challenging and dynamic environments without the need for direct human oversight. Evolutionary robotics has been widely used due to its capability of creating unique robot designs in simulation. Recent work has shown that it is possible to autonomously construct evolved designs in the physical domain; however, this brings new challenges: the autonomous manufacture and assembly process introduces new constraints that are not apparent in simulation. To tackle this, we introduce a new method for producing a repertoire of diverse but manufacturable robots. This repertoire is used to seed an evolutionary loop that subsequently evolves robot designs and controllers capable of solving a maze-navigation task. We show that compared to random initialisation, seeding with a diverse and manufacturable population speeds up convergence a...
Background: Human visceral leishmaniasis, caused by infection with Leishmania donovani or L. infa... more Background: Human visceral leishmaniasis, caused by infection with Leishmania donovani or L. infantum, is a potentially fatal disease affecting 50,000-90,000 people yearly in 75 disease endemic countries, with more than 20,000 deaths reported. Experimental models of infection play a major role in understanding parasite biology, host-pathogen interaction, disease pathogenesis, and parasite transmission. In addition, they have an essential role in the identification and pre-clinical evaluation of new drugs and vaccines. However, our understanding of these models remains fragmentary. Although the immune response to Leishmania donovani infection in mice has been extensively characterized, transcriptomic analysis capturing the tissue-specific evolution of disease has yet to be reported. Methods: We provide an analysis of the transcriptome of spleen, liver and peripheral blood of BALB/c mice infected with L. donovani. Where possible, we compare our data in murine experimental visceral lei...
Cellular activation by interferons, cytokines, and chemokines is a commonly recognized mechanism ... more Cellular activation by interferons, cytokines, and chemokines is a commonly recognized mechanism to amplify immune effector function and limit pathogen spread. However, an optimal host response also requires that collateral damage associated with inflammation is limited. This may be particularly so in the case of granulomatous inflammation, where an excessive number and/or excessively florid granulomas can have significant pathological consequences. Here, we have combined transcriptomics, agent-based modeling, and experimental approaches to study constraints on hepatic granuloma formation in a murine model of experimental leishmaniasis. We demonstrate that chemokine production by non-infected Kupffer cells in the -infected liver promotes competition with infected KCs for available iNKT cells, ultimately inhibiting the extent of granulomatous inflammation. We propose trans-activation for chemokine production as a novel broadly applicable mechanism that may operate early in infection ...
This tutorial promotes good practice for exploring the rationale of systems pharmacology models. ... more This tutorial promotes good practice for exploring the rationale of systems pharmacology models. A safety systems engineering inspired notation approach provides much needed rigour and transparency in development and 1 application of models for therapeutic discovery and design of intervention strategies. Structured arguments over a models development, underpinning biological knowledge, and analyses of model behaviours, are constructed to determine the confidence that a model is fit for the purpose for which it will be applied.
Journal of the Royal Society, Interface, Sep 1, 2016
Computational agent-based simulation (ABS) is increasingly used to complement laboratory techniqu... more Computational agent-based simulation (ABS) is increasingly used to complement laboratory techniques in advancing our understanding of biological systems. Calibration, the identification of parameter values that align simulation with biological behaviours, becomes challenging as increasingly complex biological domains are simulated. Complex domains cannot be characterized by single metrics alone, rendering simulation calibration a fundamentally multi-metric optimization problem that typical calibration techniques cannot handle. Yet calibration is an essential activity in simulation-based science; the baseline calibration forms a control for subsequent experimentation and hence is fundamental in the interpretation of results. Here, we develop and showcase a method, built around multi-objective optimization, for calibrating ABSs against complex target behaviours requiring several metrics (termed objectives) to characterize. Multi-objective calibration (MOC) delivers those sets of param...
The advent of two-photon microscopy now reveals unprecedented, detailed spatio-temporal data on c... more The advent of two-photon microscopy now reveals unprecedented, detailed spatio-temporal data on cellular motility and interactions in vivo. Understanding cellular motility patterns is key to gaining insight into the development and possible manipulation of the immune response. Computational simulation has become an established technique for understanding immune processes and evaluating hypotheses in the context of experimental data, and there is clear scope to integrate microscopy-informed motility dynamics. However, determining which motility model best reflects in vivo motility is non-trivial: 3D motility is an intricate process requiring several metrics to characterize. This complicates model selection and parameterization, which must be performed against several metrics simultaneously. Here we evaluate Brownian motion, Lévy walk and several correlated random walks (CRWs) against the motility dynamics of neutrophils and lymph node T cells under inflammatory conditions by simultan...
Computational modelling and simulation is increasingly being used to complement traditional wet-l... more Computational modelling and simulation is increasingly being used to complement traditional wet-lab techniques when investigating the mechanistic behaviours of complex biological systems. In order to ensure computational models are fit for purpose, it is essential that the abstracted view of biology captured in the computational model, is clearly and unambiguously defined within a conceptual model of the biological domain (a domain model), that acts to accurately represent the biological system and to document the functional requirements for the resultant computational model. We present a domain model of the IL-1 stimulated NF-κB signalling pathway, which unambiguously defines the spatial, temporal and stochastic requirements for our future computational model. Through the development of this model, we observe that, in isolation, UML is not sufficient for the purpose of creating a domain model, and that a number of descriptive and multivariate statistical techniques provide compleme...
The ornamental plant trade has been identified as a key introduction pathway for plant pathogens.... more The ornamental plant trade has been identified as a key introduction pathway for plant pathogens. Establishing effective biosecurity measures to reduce the risk of plant pathogen outbreaks in the live plant trade is therefore important. Management of invasive pathogens has been identified as a weakest link public good, and thus is reliant on the actions of individual private agents. This paper therefore provides an analysis of the impact of the private agents' biosecurity decisions on pathogen prevention and control within the plant trade. We model the impact that an infectious disease has on a plant nursery under a constant pressure of potentially infected input plant materials, like seeds and saplings, where the spread of the disease reduces the value of mature plants. We explore six scenarios to understand the influence of three key bioeconomic parameters; the disease's basic reproductive number, the loss in value of a mature plant from acquiring an infection and the cost-effectiveness of restriction. The results characterise the disease dynamics within the nursery and explore the trade-offs and synergies between the optimal level of efforts on restriction strategies (actions to prevent buying infected inputs), and on removal of infected plants in the nursery. For diseases that can be easily controlled, restriction and removal are substitutable strategies. In contrast, for highly infectious diseases, restriction and removal are often found to be complementary, provided that restriction is cost-effective and the optimal level of removal is non-zero.
A tracking infrastructure is a useful tool for swarm robotics research, and has many potential ap... more A tracking infrastructure is a useful tool for swarm robotics research, and has many potential applications. Unfortunately, for many research laboratories, constructing one may be prohibitively expensive. In this paper we present a low-cost tracking infrastructure that was built at the York Robotics Laboratory for tracking ground-based robot swarms in real-time. We highlight the considerations that were taken when building and configuring the system, using a swarm of e-puck robots as a case study. Potential applications of the system are discussed, the cost of the equipment is documented, and its known limitations are addressed. This paper aims to serve as a resource for other swarm robotics researchers interested in implementing a similar low-cost tracking solution.
CPT: Pharmacometrics & Systems Pharmacology, 2015
Modeling and simulation (M&S) techniques provide a platform for knowledge integration and hypothe... more Modeling and simulation (M&S) techniques provide a platform for knowledge integration and hypothesis testing to gain insights into biological systems that would not be possible a priori. Agent-based modeling (ABM) is an M&S technique that focuses on describing individual components rather than homogenous populations. This tutorial introduces ABM to systems pharmacologists, using relevant case studies to highlight how ABM-specific strengths have yielded success in the area of preclinical mechanistic modeling.
A study by Cheng et al. in this issue of Science Signaling highlights the distinct single-cell si... more A study by Cheng et al. in this issue of Science Signaling highlights the distinct single-cell signaling characteristics conferred by pathways mediated by the adaptor proteins MyD88 and TRIF in the TLR4-dependent activation of the transcription factor nuclear factor κB (NF-κB).
Journal of the Royal Society, Interface / the Royal Society, Jan 6, 2015
The application of computational and mathematical modelling to explore the mechanics of biologica... more The application of computational and mathematical modelling to explore the mechanics of biological systems is becoming prevalent. To significantly impact biological research, notably in developing novel therapeutics, it is critical that the model adequately represents the captured system. Confidence in adopting in silico approaches can be improved by applying a structured argumentation approach, alongside model development and results analysis. We propose an approach based on argumentation from safety-critical systems engineering, where a system is subjected to a stringent analysis of compliance against identified criteria. We show its use in examining the biological information upon which a model is based, identifying model strengths, highlighting areas requiring additional biological experimentation and providing documentation to support model publication. We demonstrate our use of structured argumentation in the development of a model of lymphoid tissue formation, specifically Pe...
We present a novel Neuro-Immune inspired real-time tracking system that is capable of tracking mo... more We present a novel Neuro-Immune inspired real-time tracking system that is capable of tracking morphing moving targets over nonbenign backgrounds. We have employed ideas from antigen-presenting cells, T-cell interaction, together with cytokine interaction with neural systems. Our experiments show that the neuro-immune tracking system has the ability to maintain tracking a target even if the target changes shape, or is covered for periods of time by other objects.
A long-term vision of evolutionary robotics is a technology enabling the evolution of entire auto... more A long-term vision of evolutionary robotics is a technology enabling the evolution of entire autonomous robotic ecosystems that live and work for long periods in challenging and dynamic environments without the need for direct human oversight. Evolutionary robotics has been widely used due to its capability of creating unique robot designs in simulation. Recent work has shown that it is possible to autonomously construct evolved designs in the physical domain; however, this brings new challenges: the autonomous manufacture and assembly process introduces new constraints that are not apparent in simulation. To tackle this, we introduce a new method for producing a repertoire of diverse but manufacturable robots. This repertoire is used to seed an evolutionary loop that subsequently evolves robot designs and controllers capable of solving a maze-navigation task. We show that compared to random initialisation, seeding with a diverse and manufacturable population speeds up convergence a...
Background: Human visceral leishmaniasis, caused by infection with Leishmania donovani or L. infa... more Background: Human visceral leishmaniasis, caused by infection with Leishmania donovani or L. infantum, is a potentially fatal disease affecting 50,000-90,000 people yearly in 75 disease endemic countries, with more than 20,000 deaths reported. Experimental models of infection play a major role in understanding parasite biology, host-pathogen interaction, disease pathogenesis, and parasite transmission. In addition, they have an essential role in the identification and pre-clinical evaluation of new drugs and vaccines. However, our understanding of these models remains fragmentary. Although the immune response to Leishmania donovani infection in mice has been extensively characterized, transcriptomic analysis capturing the tissue-specific evolution of disease has yet to be reported. Methods: We provide an analysis of the transcriptome of spleen, liver and peripheral blood of BALB/c mice infected with L. donovani. Where possible, we compare our data in murine experimental visceral lei...
Cellular activation by interferons, cytokines, and chemokines is a commonly recognized mechanism ... more Cellular activation by interferons, cytokines, and chemokines is a commonly recognized mechanism to amplify immune effector function and limit pathogen spread. However, an optimal host response also requires that collateral damage associated with inflammation is limited. This may be particularly so in the case of granulomatous inflammation, where an excessive number and/or excessively florid granulomas can have significant pathological consequences. Here, we have combined transcriptomics, agent-based modeling, and experimental approaches to study constraints on hepatic granuloma formation in a murine model of experimental leishmaniasis. We demonstrate that chemokine production by non-infected Kupffer cells in the -infected liver promotes competition with infected KCs for available iNKT cells, ultimately inhibiting the extent of granulomatous inflammation. We propose trans-activation for chemokine production as a novel broadly applicable mechanism that may operate early in infection ...
This tutorial promotes good practice for exploring the rationale of systems pharmacology models. ... more This tutorial promotes good practice for exploring the rationale of systems pharmacology models. A safety systems engineering inspired notation approach provides much needed rigour and transparency in development and 1 application of models for therapeutic discovery and design of intervention strategies. Structured arguments over a models development, underpinning biological knowledge, and analyses of model behaviours, are constructed to determine the confidence that a model is fit for the purpose for which it will be applied.
Journal of the Royal Society, Interface, Sep 1, 2016
Computational agent-based simulation (ABS) is increasingly used to complement laboratory techniqu... more Computational agent-based simulation (ABS) is increasingly used to complement laboratory techniques in advancing our understanding of biological systems. Calibration, the identification of parameter values that align simulation with biological behaviours, becomes challenging as increasingly complex biological domains are simulated. Complex domains cannot be characterized by single metrics alone, rendering simulation calibration a fundamentally multi-metric optimization problem that typical calibration techniques cannot handle. Yet calibration is an essential activity in simulation-based science; the baseline calibration forms a control for subsequent experimentation and hence is fundamental in the interpretation of results. Here, we develop and showcase a method, built around multi-objective optimization, for calibrating ABSs against complex target behaviours requiring several metrics (termed objectives) to characterize. Multi-objective calibration (MOC) delivers those sets of param...
The advent of two-photon microscopy now reveals unprecedented, detailed spatio-temporal data on c... more The advent of two-photon microscopy now reveals unprecedented, detailed spatio-temporal data on cellular motility and interactions in vivo. Understanding cellular motility patterns is key to gaining insight into the development and possible manipulation of the immune response. Computational simulation has become an established technique for understanding immune processes and evaluating hypotheses in the context of experimental data, and there is clear scope to integrate microscopy-informed motility dynamics. However, determining which motility model best reflects in vivo motility is non-trivial: 3D motility is an intricate process requiring several metrics to characterize. This complicates model selection and parameterization, which must be performed against several metrics simultaneously. Here we evaluate Brownian motion, Lévy walk and several correlated random walks (CRWs) against the motility dynamics of neutrophils and lymph node T cells under inflammatory conditions by simultan...
Computational modelling and simulation is increasingly being used to complement traditional wet-l... more Computational modelling and simulation is increasingly being used to complement traditional wet-lab techniques when investigating the mechanistic behaviours of complex biological systems. In order to ensure computational models are fit for purpose, it is essential that the abstracted view of biology captured in the computational model, is clearly and unambiguously defined within a conceptual model of the biological domain (a domain model), that acts to accurately represent the biological system and to document the functional requirements for the resultant computational model. We present a domain model of the IL-1 stimulated NF-κB signalling pathway, which unambiguously defines the spatial, temporal and stochastic requirements for our future computational model. Through the development of this model, we observe that, in isolation, UML is not sufficient for the purpose of creating a domain model, and that a number of descriptive and multivariate statistical techniques provide compleme...
The ornamental plant trade has been identified as a key introduction pathway for plant pathogens.... more The ornamental plant trade has been identified as a key introduction pathway for plant pathogens. Establishing effective biosecurity measures to reduce the risk of plant pathogen outbreaks in the live plant trade is therefore important. Management of invasive pathogens has been identified as a weakest link public good, and thus is reliant on the actions of individual private agents. This paper therefore provides an analysis of the impact of the private agents' biosecurity decisions on pathogen prevention and control within the plant trade. We model the impact that an infectious disease has on a plant nursery under a constant pressure of potentially infected input plant materials, like seeds and saplings, where the spread of the disease reduces the value of mature plants. We explore six scenarios to understand the influence of three key bioeconomic parameters; the disease's basic reproductive number, the loss in value of a mature plant from acquiring an infection and the cost-effectiveness of restriction. The results characterise the disease dynamics within the nursery and explore the trade-offs and synergies between the optimal level of efforts on restriction strategies (actions to prevent buying infected inputs), and on removal of infected plants in the nursery. For diseases that can be easily controlled, restriction and removal are substitutable strategies. In contrast, for highly infectious diseases, restriction and removal are often found to be complementary, provided that restriction is cost-effective and the optimal level of removal is non-zero.
A tracking infrastructure is a useful tool for swarm robotics research, and has many potential ap... more A tracking infrastructure is a useful tool for swarm robotics research, and has many potential applications. Unfortunately, for many research laboratories, constructing one may be prohibitively expensive. In this paper we present a low-cost tracking infrastructure that was built at the York Robotics Laboratory for tracking ground-based robot swarms in real-time. We highlight the considerations that were taken when building and configuring the system, using a swarm of e-puck robots as a case study. Potential applications of the system are discussed, the cost of the equipment is documented, and its known limitations are addressed. This paper aims to serve as a resource for other swarm robotics researchers interested in implementing a similar low-cost tracking solution.
CPT: Pharmacometrics & Systems Pharmacology, 2015
Modeling and simulation (M&S) techniques provide a platform for knowledge integration and hypothe... more Modeling and simulation (M&S) techniques provide a platform for knowledge integration and hypothesis testing to gain insights into biological systems that would not be possible a priori. Agent-based modeling (ABM) is an M&S technique that focuses on describing individual components rather than homogenous populations. This tutorial introduces ABM to systems pharmacologists, using relevant case studies to highlight how ABM-specific strengths have yielded success in the area of preclinical mechanistic modeling.
A study by Cheng et al. in this issue of Science Signaling highlights the distinct single-cell si... more A study by Cheng et al. in this issue of Science Signaling highlights the distinct single-cell signaling characteristics conferred by pathways mediated by the adaptor proteins MyD88 and TRIF in the TLR4-dependent activation of the transcription factor nuclear factor κB (NF-κB).
Journal of the Royal Society, Interface / the Royal Society, Jan 6, 2015
The application of computational and mathematical modelling to explore the mechanics of biologica... more The application of computational and mathematical modelling to explore the mechanics of biological systems is becoming prevalent. To significantly impact biological research, notably in developing novel therapeutics, it is critical that the model adequately represents the captured system. Confidence in adopting in silico approaches can be improved by applying a structured argumentation approach, alongside model development and results analysis. We propose an approach based on argumentation from safety-critical systems engineering, where a system is subjected to a stringent analysis of compliance against identified criteria. We show its use in examining the biological information upon which a model is based, identifying model strengths, highlighting areas requiring additional biological experimentation and providing documentation to support model publication. We demonstrate our use of structured argumentation in the development of a model of lymphoid tissue formation, specifically Pe...
We present a novel Neuro-Immune inspired real-time tracking system that is capable of tracking mo... more We present a novel Neuro-Immune inspired real-time tracking system that is capable of tracking morphing moving targets over nonbenign backgrounds. We have employed ideas from antigen-presenting cells, T-cell interaction, together with cytokine interaction with neural systems. Our experiments show that the neuro-immune tracking system has the ability to maintain tracking a target even if the target changes shape, or is covered for periods of time by other objects.
In this paper, we propose an algorithm for cluster analysis inspired by the lymphocyte-cytokine n... more In this paper, we propose an algorithm for cluster analysis inspired by the lymphocyte-cytokine network in the immune system. Our algorithm attempts to optimally represent a large data set by its principle subset whilst maximising the data kernel density distribution. Experiments show that the output data set created by our algorithm effectively represents the original input data set, according to
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