Fluctuations and Oscillatory Instabilities of Intracellular Fiber networks

Biological systems with their complex biochemical networks are known to be intrinsically noisy. The interplay between noise and dynamical behavior is particularly relevant in the case of chemotactic amoeboid cells as their cytoskeleton operates close to an oscillatory instability. Here, we investigate the oscillatory dynamics in the actin system of chemotactic amoeboid cells. We show that the large phenotypic variability in the polymerization dynamics can be accurately captured by a generic nonlinear oscillator model, in the presence of noise. The relative role of the noise is fully determined by a single dimensionless parameter, experimentally measurable, and whose distribution completely characterizes the possible cellular behavior. We find that cells operate either below or above the threshold of self-oscillation, always in a regime where noise plays a very substantial role. To test the limits of this phenomenological description, we perturbed experimentally the cytoskeletal dynamics by a short chemoattractant pulse and measured the spatio-temporal response of filamentous actin reporter, LimE, and depolymerization regulators Coronin1 and Aip1. After pulsing, we observed self oscillating cells to relax back to their oscillatory state after a noisy transient. Particularly long transients were observed for cells initially displaying highly correlated oscillations. The observation of a slow recovery time of the actin polymerizing network provides a link to the long times scales, characteristic of chemotactic cell motility. In the second part of this work, we have characterized the response of LimE, Aip1, and Coronin to cAMP in non oscillating cells. We have used a proposed method that transforms the observed time series into symbolic dynamics, that gives partial information on the interactions between these proteins. We tested the predictions by studying the LimE response in mutant cells that either lacked Aip1 or Coronin. Finally, a model is proposed where Aip1 and Coronin synergizes to control actin polymerization

Cells in Space

Discussions and presentations addressed three aspects of cell research in space: the suitability of the cell as a subject in microgravity experiments, the requirements for generic flight hardware to support cell research, and the potential for collaboration between academia, industry, and government to develop these studies in space. Synopses are given for the presentations and follow-on discussions at the conference and papers are presented from which the presentations were based. An Executive Summary outlines the recommendations and conclusions generated at the conference

Models of self-organization in biological development

Bibliography: p. 297-320.In this thesis we thus wish to consider the concept of self-organization as an overall paradigm within which various theoretical approaches to the study of development may be described and evaluated. In the process, an attempt is made to give a fair and reasonably comprehensive overview of leading modelling approaches in developmental biology, with particular reference to self-organization. The work proceeds from a physical or mathematical perspective, but not unduly so - the major mathematical derivations and results are relegated to appendices - and attempts to fill a perceived gap in the extant review literature, in its breadth and attempted impartiality of scope. A characteristic of the present account is its markedly interdisciplinary approach: it seeks to place self-organization models that have been proposed for biological pattern formation and morphogenesis both within the necessary experimentally-derived biological framework, and in the wider physical context of self-organization and the mathematical techniques that may be employed in its study. Hence the thesis begins with appropriate introductory chapters to provide the necessary background, before proceeding to a discussion of the models themselves. It should be noted that the work is structured so as to be read sequentially, from beginning to end; and that the chapters in the main text were designed to be understood essentially independently of the appendices, although frequent references to the latter are given. In view of the vastness of the available information and literature on developmental biology, a working knowledge of embryological principles must be assumed. Consequently, rather than attempting a comprehensive introduction to experimental embryology, chapter 2 presents just a few biological preliminaries, to 'set the scene', outlining some of the major issues that we are dealing with, and sketching an indication of the current status of knowledge and research on development. The chapter is aimed at furnishing the necessary biological, experimental background, in the light of which the rest of the thesis should be read, and which should indeed underpin and motivate any theoretical discussions. We encounter the different hierarchical levels of description in this chapter, as well as some of the model systems whose experimental study has proved most fruitful, some of the concepts of experimental embryology, and a brief reference to some questions that will not be addressed in this work. With chapter 3, we temporarily move away from developmental biology, and consider the wider physical and mathematical concepts related to the study of self-organization. Here we encounter physical and chemical examples of spontaneous structure formation, thermodynamic considerations, and different approaches to the description of complexity. Mathematical approaches to the dynamical study of self-organization are also introduced, with specific reference to reaction-diffusion equations, and we consider some possible chemical and biochemical realizations of self-organizing kinetics. The chapter may be read in conjunction with appendix A, which gives a somewhat more in-depth study of reaction-diffusion equations, their analysis and properties, as an example of the approach to the analysis of self-organizing dynamical systems and mathematically-formulated models. Appendix B contains a more detailed discussion of the Belousov-Zhabotinskii reaction, which provides a vivid chemical paradigm for the concepts of symmetry-breaking and self-organization. Chapter 3 concludes with a brief discussion of a model biological system, the cellular slime mould, which displays rudimentary development and has thus proved amenable to detailed study and modelling. The following two chapters form the core of the thesis, as they contain discussions of the detailed application of theoretical concepts and models, largely based on self-organization, to various developmental situations. We encounter a diversity of models which has arisen largely in the last quarter century, each of which attempts to account for some aspect of biological pattern formation and morphogenesis; an aim of the discussion is to assess the extent of the underlying unity of these models in terms of the self-organization paradigm. In chapter 4 chemical pre-patterns and positional information are considered, without the overt involvement of cells in the patterning. In chapter 5, on the other hand, cellular interactions and activities are explicitly taken into account; this chapter should be read together with appendix C, which contains a brief introduction to the mathematical formulation and analysis of some of the models discussed. The penultimate chapter, 6, considers two other approaches to the study of development; one of these has faded away, while the other is still apparently in the ascendant. The assumptions underlying catastrophe theory, the value of its applications to developmental biology and the reasons for its decline in popularity, are considered. Lastly, discrete approaches, including the recently fashionable cellular automata, are dealt with, and the possible roles of rule-based interactions, such as of the so-called L-systems, and of fractals and chaos are evaluated. Chapter 7 then concludes the thesis with a brief assessment of the value of the self-organization concept to the study of biological development

Partial Differential Equations in Ecology

Partial differential equations (PDEs) have been used in theoretical ecology research for more than eighty years. Nowadays, along with a variety of different mathematical techniques, they remain as an efficient, widely used modelling framework; as a matter of fact, the range of PDE applications has even become broader. This volume presents a collection of case studies where applications range from bacterial systems to population dynamics of human riots

Complexity in Developmental Systems: Toward an Integrated Understanding of Organ Formation

During animal development, embryonic cells assemble into intricately structured organs by working together in organized groups capable of implementing tightly coordinated collective behaviors, including patterning, morphogenesis and migration. Although many of the molecular components and basic mechanisms underlying such collective phenomena are known, the complexity emerging from their interplay still represents a major challenge for developmental biology. Here, we first clarify the nature of this challenge and outline three key strategies for addressing it: precision perturbation, synthetic developmental biology, and data-driven inference. We then present the results of our effort to develop a set of tools rooted in two of these strategies and to apply them to uncover new mechanisms and principles underlying the coordination of collective cell behaviors during organogenesis, using the zebrafish posterior lateral line primordium as a model system. To enable precision perturbation of migration and morphogenesis, we sought to adapt optogenetic tools to control chemokine and actin signaling. This endeavor proved far from trivial and we were ultimately unable to derive functional optogenetic constructs. However, our work toward this goal led to a useful new way of perturbing cortical contractility, which in turn revealed a potential role for cell surface tension in lateral line organogenesis. Independently, we hypothesized that the lateral line primordium might employ plithotaxis to coordinate organ formation with collective migration. We tested this hypothesis using a novel optical tool that allows targeted arrest of cell migration, finding that contrary to previous assumptions plithotaxis does not substantially contribute to primordium guidance. Finally, we developed a computational framework for automated single-cell segmentation, latent feature extraction and quantitative analysis of cellular architecture. We identified the key factors defining shape heterogeneity across primordium cells and went on to use this shape space as a reference for mapping the results of multiple experiments into a quantitative atlas of primordium cell architecture. We also propose a number of data-driven approaches to help bridge the gap from big data to mechanistic models. Overall, this study presents several conceptual and methodological advances toward an integrated understanding of complex multi-cellular systems

Universal properties of self-organized localized structures

Ziel dieser Arbeit ist es, einen Beitrag zur Aufklärung der universellen teilchenartigen Eigenschaften von selbstorganisierten lokalisierten Strukturen in unterschiedlichen räumlich ausgedehnten Systemen zu leisten. Untersucht werden zunächst Mechanismen der Bildung, Dynamik und Wechselwirkung in Prototyp-Modellsystemen wie Reaktions-Diffusions-, Ginzburg-Landau- und Swift-Hohenberg-Gleichungen. Mittels adiabatischer Eliminationsmethoden kann die Feldbeschreibung in vielen Fällen auf gewöhnliche Differentialgleichungen von einheitlicher Form reduziert werden. So kann auch das Verhalten großer Ensembles lokalisierter Strukturen analytisch und numerisch analysiert werden. Hier ergeben sich zahlreiche neue Phänomene ohne klassisches Analogon. Zuletzt ist die Dynamik von biologischen teilchenartigen Strukturen in Form von Dictyostelium-Zellen von Interesse, die experimentell in mikrofluidischen Aufbauten erforscht wird. This work tries to contribute to explaining the universal particle-like behavior of self-organized localized structures in different spatially extended systems. First, mechanisms of generation, dynamics and interaction in prototype systems like reaction-diffusion, Ginzburg-Landau or Swift-Hohenberg equations are investigated. Using methods of adiabatic elimination, in many cases the field description can be reduced to ordinary differential equations of uniform structure. In this way, one may also explore the behavior of large particle ensembles analytically and numerically. Here, many new phenomena without classical analogue arise. Finally, an experimental analysis of biological particle-like structures in the form of Dictyostelium cells is carried out using microfluidic devices

Investigating homeostatic disruption by constitutive signals during biological ageing

PhD ThesisAgeing and disease can be understood in terms of a loss in biological homeostasis. This will often manifest as a constitutive elevation in the basal levels of biological entities. Examples include chronic inflammation, hormonal imbalances and oxidative stress. The ability of reactive oxygen species (ROS) to cause molecular damage has meant that chronic oxidative stress has been mostly studied from the point of view of being a source of toxicity to the cell. However, the known duality of ROS molecules as both damaging agents and cellular redox signals implies another perspective in the study of sustained oxidative stress. This is a perspective of studying oxidative stress as a constitutive signal within the cell. In this work a computational modelling approach is undertaken to examine how chronic oxidative stress can interfere with signal processing by redox signalling pathways in the cell. A primary outcome of this study is that constitutive signals can give rise to a ‘molecular habituation’ effect that can prime for a gradual loss of biological function. Experimental results obtained highlight the difficulties in testing for this effect in cell lines exposed to oxidative stress. However, further analysis suggests this phenomenon is likely to occur in different signalling pathways exposed to persistent signals and potentially at different levels of biological organisation.Centre for Integrated Research into Musculoskeletal Ageing (CIMA) and through them, Arthritis Research UK and the Medical Research Counc