Physical modelling of epithelia: reverse engineering cell competition in silico

Cell competition is a phenomenon in which less fit cells are removed from a tissue for optimal survival of the host. Competition has been observed in many physiological and pathophysiological conditions, especially in the prevention of tumor development. While there have been extensive population-scale experimental studies of competition, the competitive strategies and their underlying mechanisms in single cells are poorly understood. To date, two main mechanisms of cell competition have been described. Mechanical competition arises when the two competing cell types have different sensitivities to crowding. In contrast, during biochemical competition, signaling occurs at the interface between cell types leading to apoptosis of the loser cells. However, rigorously testing these hypotheses remains challenging due to the difficulty of obtaining sufficient single cell level information to bridge scales to the whole tissue. In this thesis, I present metrics aimed at characterising competition at the single cell level. Then, I demonstrate the development of a multi-layered, cell-scale computational model that I use to gain understanding on the single cell mechanisms that govern mechanical competition and decipher the "rules of the cellular game". After benchmarking cell growth and homeostasis in pure populations, I show that competition emerges when both cell types are included in simulations. I then investigate the impact of each computational parameter on the outcome of cell competition. Intriguingly, the outcome of biochemical competition is controlled by topological entropy between cell types, whereas the outcome of mechanical cell competition is exclusively controlled by differences in energetic potential between cell types. As 90% of cancers arise from epithelia and a number of genetic diseases present symptoms of epithelial fragility, I anticipate that my model of realistic implementation of epithelia will be of use to the biophysics and computational modelling community

Flexible high performance agent based modelling on graphics card hardware

Agent Based Modelling is a technique for computational simulation of complex interacting systems, through the specification of the behaviour of a number of autonomous individuals acting simultaneously. This is a bottom up approach, in contrast with the top down one of modelling the behaviour of the whole system through dynamic mathematical equations. The focus on individuals is considerably more computationally demanding, but provides a natural and flexible environment for studying systems demonstrating emergent behaviour. Despite the obvious parallelism, traditionally frameworks for Agent Based Modelling fail to exploit this and are often based on highly serialised mobile discrete agents. Such an approach has serious implications, placing stringent limitations on both the scale of models and the speed at which they may be simulated. Serial simulation frameworks are also unable to exploit multiple processor architectures which have become essential in improving overall processing speed. This thesis demonstrates that it is possible to use the parallelism of graphics card hardware as a mechanism for high performance Agent Based Modelling. Such an approach is in contrast with alternative high performance architectures, such as distributed grids and specialist computing clusters, and is considerably more cost effective. The use of consumer hardware makes the techniques described available to a wide range of users, and the use of automatically generated simulation code abstracts the process of mapping algorithms to the specialist hardware. This approach avoids the steep learning curve associated with the graphics card hardware's data parallel architecture, which has previously limited the uptake of this emerging technology. The performance and flexibility of this approach are considered through the use of benchmarking and case studies. The resulting speedup and locality of agent data within the graphics processor also allow real time visualisation of computationally and demanding high population models

Cellular automata and dynamical systems

In this thesis we investigate the theoretical nature of the mathematical structures termed cellular automata. Chapter 1: Reviews the origin and history of cellular automata in order to place the current work into context. Chapter 2: Develops a cellular automata framework which contains the main aspects of cellular automata structure which have appeared in the literature. We present a scheme for specifying the cellular automata rules for this general model and present six examples of cellular automata within the model. Chapter 3: Here we develop a statistical mechanical model of cellular automata behaviour. We consider the relationship between variations within the model and their relationship to dynamical systems. We obtain results on the variance of the state changes, scaling of the cellular automata lattice, the equivalence of noise, spatial mixing of the lattice states and entropy, synchronous and asynchronous cellular automata and the equivalence of the rule probability and the time step of a discrete approximation to a dynamical system. Chapter 4: This contains an empirical comparison of cellular automata within our general framework and the statistical mechanical model. We obtain results on the transition from limit cycle to limit point behaviour as the rule probabilities are decreased. We also discuss failures of the statistical mechanical model due to failure of the assumptions behind it. Chapter 5: Here a practical application of the preceding work to population genetics is presented. We study this in the context of some established population models and show it may be most useful in the field of epidemiology. Further generalisations of the statistical mechanical and cellular automata models allow the modelling of more complex population models and mobile populations of organisms. Chapter 6: Reviews the results obtained in the context of the open questions introduced in Chapter 1. We also consider further questions this work raises and make some general comments on how these may apply to related fields

Using MapReduce Streaming for Distributed Life Simulation on the Cloud

Distributed software simulations are indispensable in the study of large-scale life models but often require the use of technically complex lower-level distributed computing frameworks, such as MPI. We propose to overcome the complexity challenge by applying the emerging MapReduce (MR) model to distributed life simulations and by running such simulations on the cloud. Technically, we design optimized MR streaming algorithms for discrete and continuous versions of Conway’s life according to a general MR streaming pattern. We chose life because it is simple enough as a testbed for MR’s applicability to a-life simulations and general enough to make our results applicable to various lattice-based a-life models. We implement and empirically evaluate our algorithms’ performance on Amazon’s Elastic MR cloud. Our experiments demonstrate that a single MR optimization technique called strip partitioning can reduce the execution time of continuous life simulations by 64%. To the best of our knowledge, we are the first to propose and evaluate MR streaming algorithms for lattice-based simulations. Our algorithms can serve as prototypes in the development of novel MR simulation algorithms for large-scale lattice-based a-life models.https://digitalcommons.chapman.edu/scs_books/1014/thumbnail.jp

The role of groups in smart camera networks

Thesis (Ph. D.)--Massachusetts Institute of Technology, School of Architecture and Planning, Program in Media Arts and Sciences, 2006.Includes bibliographical references (p. 103-111).Recent research in sensor networks has made it possible to deploy networks of sensors with significant local processing. These sensor networks are revolutionising information collection and processing in many different environments. Often the amount of local data produced by these devices, and their sheer number, makes centralised data processing infeasible. Smart camera networks represent a particular challenge in this regard, partly because of the amount of data produced by each camera, but also because many high level vision algorithms require data from more than one camera. Many distributed algorithms exist that work locally to produce results from a collection of nodes, but as this number grows the algorithm's performance is quickly crippled by the resulting exponential increase in communication overhead. This thesis examines the limits this puts on peer-to-peer cooperation between nodes, and demonstrates how for large networks these can only be circumvented by locally formed organisations of nodes. A local group forming protocol is described that provides a method for nodes to create a bottom-up organisation based purely on local conditions. This allows the formation of a dynamic information network of cooperating nodes, in which a distributed algorithm can organise the communications of its nodes using purely local knowledge to maintain its global network performance.(cont.) Building on recent work using SIFT feature detection, this protocol is demonstrated in a network of smart cameras. Local groups with shared views are established, which allow each camera to locally determine their relative position with others in the network. The result partitions the network into groups of cameras with known visual relationships, which can then be used for further analysis.by Jacky Mallett.Ph.D

Emergent structure formation of the actin cytoskeleton

Anders als menschengemachte Maschinen verfügen Zellen über keinen festgeschriebenen Bauplan und die Positionen einzelner Elemente sind häufig nicht genau festgelegt, da die Moleküle diffusiven Zufallsbewegungen unterworfen sind. Darüber hinaus sind einzelne Bauteile auch nicht auf eine einzelne Funktion festgelegt, sondern können parallel in verschiedene Prozesse einbezogen sein. Basierend auf Selbstorganisation und Selbstassemblierung muß die Organisation von Anordnung und Funktion einer lebenden Zelle also bereits in ihren einzelnen Komponenten inhärent enthalten sein. Die intrazelluläre Organisation wird zum großen Teil durch ein internes Biopolymergerüst reguliert, das Zytoskelett. Biopolymer-Netzwerke und –Fasern durchdringen die gesamte Zelle und sind verantworlich für mechanische Integrität und die funktionale Architektur. Unzählige essentielle biologische Prozesse hängen direkt von einem funktionierenden Zytoskelett ab. Die vorliegende Arbeit zielt auf ein besser Verständnis und den Nachbau zweier verschiedener funktionaler Module lebender Zellen anhand stark reduzierter Modellsysteme. Als zentrales Element wurde Aktin gewählt, da dieses Biopolymer eine herausragende Rolle in nahezu allen eukaryotischen Zellen spielt. Mit dem ersten Modellsystem wird der bewegliche Aktin-Polymerfilm an der Vorderkante migrierender Zellen betrachtet. Die wichtigsten Elemente dieser hochdynamischen Netzwerke sind bereits bekannt und wurden in dieser Arbeit benutzt um ein experimentelles Modellsystem zu etablieren. Vor allem aber lieferten detailierte Computersimulationen und ein mathematisches Modell neue Erkenntnisse über grundlegende Organisationsprinzipien dieser Aktinnetzwerke. Damit war es nicht nur möglich, experimentelle Daten erfolgreich zu reproduzieren, sondern das Entstehen von Substrukturen und deren Charakteristika auf proteinunabhängige, generelle Mechanismen zurückzuführen. Das zweite studierte System betrachtet die Selbstassemblierung von Aktinnetzwerken durch entropische Kräfte. Aktinfilamente aggregieren hierbei durch Kondensation multivalenter Ionen oder durch Volumenausschluss hochkonzentrierter inerter Polymere. Ein neu entwickelter Experimentalaufbau bietet die Möglichkeit in gut definierten zellähnlichen Volumina, Konvektionseinflüsse zu umgehen und Aggregationseffekte gezielt einzuschalten. Hierbei wurden neuartige, regelmäßige Netzwerkstrukturen entdeckt, die bislang nur im Zusammenhang mit molekularen Motoren bekannt waren. Es konnte ferner gezeigt werden, dass die Physik der Flüssigkristalle entscheidend zu weiteren Variationen dieser Netzwerke beiträgt. Dabei wird ersichtlich, dass entstehende Netzwerke in ihrer Architektur direkt die zuvor herrschenden Anisotropien der Filamentlösung widerspiegeln.:1 Introduction 1 2 General background 7 2.1 General concepts 7 2.1.1 Coarse-graining as hierarchical reduction 8 2.1.2 Functional modules and redundancies 10 2.1.3 Emergence 11 2.1.4 Self-organization and self-assembly 13 2.1.5 Bottom-up and top-down 13 2.2 The cytoskeleton 15 2.2.1 From actin monomers to filaments 16 2.2.2 Accessory proteins and actin networks 21 2.3 Biopolymer pattern formation 25 2.3.1 Random networks and nematic phases 25 2.3.2 Linker and motor induced networks 28 3 Lamellipodial actin network formation 33 3.1 Background: crawling cell migration 33 3.1.1 Leading edge actin structures 35 3.1.2 Lamellipodial self-organization into oriented branches? 40 3.1.3 Lamellipodial modeling 41 3.1.4 Beyond the lamellipodium: adhesion and network contraction 42 3.2 Methods: lamellar treadmilling model 45 3.2.1 Assumptions 45 3.2.2 Choice of model parameters 51 3.2.3 Computer simulation (implementation) 52 3.2.4 Mathematical modeling 56 3.3 Modeling results 63 3.3.1 Reproduction of motile cell characteristics 64 3.3.2 Self-organization into lamellipodium and lamellum 65 3.3.3 Filament severing and annealing influence network properties 70 3.3.4 Unconfined network growth 74 3.4 Feasible model extensions 76 3.4.1 Alternative nucleation mechanisms 77 3.4.2 Convergence zone through myosin-driven network contraction 80 3.5 Experimental bottom-up approach 82 3.6 Discussion: Arp2/3 induced actin networks 87 4 Actin network patterns in confined systems 91 4.1 Background: counterion condensation and depletion forces 91 4.1.1 Actin, a polyelectrolyte: counterion condensation 92 4.1.2 Actin and molecular crowding: depletion forces 95 4.2 Methods: Experimental design and data analysis 97 4.2.1 Protein purification and handling 98 4.2.2 Droplet formation 98 4.2.3 Volume monitoring and pattern analysis 100 4.3 Actin pattern formation 105 4.3.1 Counterion-induced network formation 105 4.3.2 Depletion force induced network formation 111 4.4 First modeling attempts: bundling simulation 116 4.4.1 Model concept and assumptions 116 4.5 Discussion: Counterion and depletion-based network assembly 119 5 Discussion & Outlook 125 Appendix 129 A. Variation of filament orientation 129 B. Analytical solution of the mathematical model 131 C. Pre-alignment of filaments 132 D. Protocols 134 d1. Acetone Powder Prep 134 d2. Actin prep 135 d3. Actin labling with rhodamine dye 137 Bibliography 141 Acknowledgements 15

Pushing the Boundaries of Consciousness and Cognition

This thesis synthesises material from contemporary cognitive science, analytic philosophy of mind continental phenomenology to defend a view of the mind as embodied and extended. The first three chapters focus primarily on embodiment, while the last two chapters focus more on factors external to the body. In chapter I, I introduce Merleau-Ponty's concept of the body schema and argue that we should resist reducing the body schema to an internal representation of the body, and also that it does not always coincide with the boundaries of the biological body. In chapter II, I explicate and defend the sensorimotor approach to visual perception, further invoking Merleau-Ponty's phenomenology to support the arguments therein and to address certain worries internal to the sensorimotor approach. Chapter III builds on the conclusions of chapters I and II to explore one way in which technological extensions of the body can lead to novel perceptual experiences, and tentatively suggests a limited sense in which these experience may still be said to be visual in character. In chapter IV, I move beyond the body to explicate and defend the extended mind thesis, according to which cognition can and often does take place partly outside of brain and body via the active use of external aids and props. Finally, in chapter V, I consider the question of whether, given the perceptual phenomenology described in chapter II and the case for cognitive extension presented in chapter IV, consciousness might also be said to be extended, and argue that if certain assumptions are granted, it can

Origin of the Moon

edited by W.K. Hartmann, R.J. Phillips, G.J. TaylorHistory--Dynamical Constraints--Geochemical Constraints--Geophysical Constraints--Theories and Processes of Origin 1, Lunar Formation Involving Capture or Fission--Theories and Processes of Origin 2, Considerations Involving Large Bodies in the Environment of Primordial Earth, and Chances for Close Approaches or Impacts--Theories and Processes of Origin 3, Lunar Formation Triggered by Large Impact--Theories and Processes of Origin 4, Models Emphasizing Coaccretion or Evolution of a Circumterrestrial Swarm, of Whatever Origin