1,721,060 research outputs found
Resolving the Mechanism of Subdiffusion in Cells
No full textSubdiffusion, a diffusion process characterized by a slower-than-linear increase
of the mean squared displacement over time, is widely observed inside cells.
However, its mechanism and origin are not well understood. To close the gap
between theory and experiment, we attempt to infer the microscopic origin
of subdiffusion in this thesis by simulating two biologically relevant models
(a patchy-colloid network with transient interactions and a polymer network)
and by analyzing the trajectories of protein condensates in chromatin networks in the human nucleus. We highlight the viscoelasticity of the chromatin
networks as the primary origin of the subdiffusion but found that neither the
transient networks nor the polymer networks generate sufficient viscoelasticity
so that other purely-repulsive particles moving within the networks would exhibit subdiffusive behaviors in the simulation. Viscoelasticity was also shown
to be connected to the confined motion of the droplets and the droplet sizes,
suggesting an interplay between the droplet coarsening, the chromatin network
viscoelasticity, and the subdiffusion motion
Bridging the Gap - from Simple Competition Models to the Statistical Analysis of Immune Repertoires
No full textSimple ecological models of T-cell expansion have had some success in capturing key quantitative features of experimentally observed
T-cell dynamics. We considered a model in which T-cell clone expansion is determined by competition for binding with time-dependent
antigen levels. We developed numerical methods for simulating T-cell
dynamics under such a model as well as statistical methods to bridge
the gap between these ecological models and longitudinal repertoire
sequencing data. We were able to characterize immune repertoire sequencing noise, which allows us to make testable predictions about
how underlying T-cell distributions and dynamics would manifest in
repertoire sequencing data
Bridging the Gap - from Simple Competition Models to the Statistical Analysis of Immune Repertoires
No full textSimple ecological models of T-cell expansion have had some success in capturing key quantitative features of experimentally observed
T-cell dynamics. We considered a model in which T-cell clone expansion is determined by competition for binding with time-dependent
antigen levels. We developed numerical methods for simulating T-cell
dynamics under such a model as well as statistical methods to bridge
the gap between these ecological models and longitudinal repertoire
sequencing data. We were able to characterize immune repertoire sequencing noise, which allows us to make testable predictions about
how underlying T-cell distributions and dynamics would manifest in
repertoire sequencing data
Quorum Sensing in Bacterial Biofilms: Regulating Matrix Production through Communication
No full textBacteria grow on surfaces in complex communities known as biofilms. Biofilms are composed of cells embedded in extracellular matrix. Within biofilms, bacteria often communicate, cooperate, and compete within their own species and with other species using Quorum Sensing (QS). QS refers to the process by which bacteria produce, secrete, and subsequently detect small molecules called autoinducers (AIs) to assess the local population density of their species, or of other species. QS is known to regulate the production of extracellular matrix. We investigated the benefit of QS in regulating matrix production to gain access to a nutrient that diffuses from a source far from the biofilm. We employed Agent-Based Modeling (ABM), a simulation framework that allows cells to modify their behavior based on local inputs, e.g. nutrient and AI concentrations. We first determined the optimal fixed strategies (that do not use QS) for simulated pairwise competitions between strains, and identified the conditions that favor matrix production. To understand if QS can provide a competitive advantage, we modified our model to include QS with constitutive AI production. We demonstrated that simple QS-based strategies can be superior to any fixed strategy. However, we found that if AI production is not constitutive but rather depends on nutrient intake, then QS-based strategies fail to provide an advantage. We explain this failure of QS using analytic methods. We derive an expression for the biophysically limited dynamic range of AI concentration detection in nutrient limited environments. This expression implies that for QS to provide an advantage in biofilms, production of AI should be privileged and not limited by overall metabolic rates
Rock-paper-scissors games in expanding populations: the effects of cyclic dominance and domain growth on diversity
No full textDiscovering mechanisms for the maintenance of species diversity is central in
ecology. Conditions of cyclic dominance arise frequently in nature and are
thought to be a major promoter of diversity. Rock-paper-scissors (RPS) games
can be used to characterize conditions of cyclic dominance involving three competing
strategies: rock crushes scissors, scissors cuts paper, and paper wraps
rock. The role of RPS in maintaining diversity among competing strategies
has been detailed in spatially explicit models of fixed-size microbial populations.
However, we find that RPS does not necessarily contribute to diversity
in growing populations. To explore the effects of population growth, we use
agent-based modeling (ABM). We consider two regimes: surface-only growth
and bulk growth. In the case of surface-only growth, RPS increases the rate
of interface diffusion, thereby accelerating the formation of sectors at the expanding
front and decreasing diversity. In the case of bulk growth, we observe
both regions characterized by RPS attacks that keep domain sizes in check and
regions dominated by domain growth. When domains of sufficient size become
established early on and attack rates are sufficiently low, growth in the bulk
of these domains outweighs attacks at the interface; coexistence of these established
domains can result. Therefore, while RPS games can promote diversity
in expanding populations, the growth of domains can lead to an entirely different
mechanism for the maintenance of diversity. We conclude that diversity in
growing microbial populations can stem not only from the dynamics associated
with RPS games but also from the formation of domains that become too big to fail
Bridging the Gap - from Simple Competition Models to the Statistical Analysis of Immune Repertoires
No full textSimple ecological models of T-cell expansion have had some success in capturing key quantitative features of experimentally observed
T-cell dynamics. We considered a model in which T-cell clone expansion is determined by competition for binding with time-dependent
antigen levels. We developed numerical methods for simulating T-cell
dynamics under such a model as well as statistical methods to bridge
the gap between these ecological models and longitudinal repertoire
sequencing data. We were able to characterize immune repertoire sequencing noise, which allows us to make testable predictions about
how underlying T-cell distributions and dynamics would manifest in
repertoire sequencing data
Protein Phase Separation In and Out of Cells
No full textEukaryotic cells form organelles to achieve specific local chemical concentrations and conditions. In addition to membrane-bound organelles, cells possess non-membrane-bound bodies, which are now understood as phase-separated condensates. Typically, the components of these condensates have a high turnover rate and the condensates themselves are dynamic, assembling and disassembling in response to specific stimuli. We focus on a class of condensates composed of two species of polymers, where each polymer consists of repeated domains that interact in a one-to-one fashion with the domains of the other polymer. Condensates of this class are observed in living cells and in some in vitro experiments. Through analytical and numerical studies, we determined a phase diagram for such two-component polymer systems. Strikingly, the formation and dissolution of the condensates sensitively depends on the valencies of the two components, exhibiting a "magic-number" behavior. This magic-number effect provides a possible mechanism to explain the rapid dissolution and reorganization of the pyrenoid, a non-membrane-bound carbon-fixation organelle in algal cells. We examined the robustness and generality of the magic-number effect, including the importance of the rigidity and shape of the polymers, the dependence on valency, the influence of the relative concentrations of the two species, and the role that non-specific interactions play in condensate formation. To more closely relate to experimental systems, we built an off-lattice model that includes the effect of molecular sizes, molecular non-specific interactions, and bond affinities. The modeling of the algal pyrenoid provides important insights into the structure, regulation, and inheritance of this non-membrane-bound organelle. More broadly, our findings give insights into fundamental principles of the architecture and inheritance of such liquid-phase organelles
Mechanoperception and morphogenesis of living architectures
No full textIn this thesis, we elucidate how living systems form and maintain their architectures by studying two systems that exemplify, respectively, the statical and dynamical properties of cellular assemblies. We first introduce the concept of living architectures as a unit of organization that generalizes the notion of biological tissue (Chapter 1). We begin our study of living architectures by considering how cells in connective tissue can sense the mechanical properties of biopolymer networks, which serve as scaffolds upon which cells live inside and move through (Chapters 2 and 3). In Chapter 2, we investigate the linear response of these biopolymer scaffolds and show how their intrinsic structural disorder gives rise to extreme mechanical heterogeneity that limits mechanosensing. In Chapter 3, we generalize our results to the nonlinear response regime and uncover a mechanical focusing effect, in which mechanical heterogeneity decreases as the applied force is increased. We explain how geometrical nonlinearities produce mechanical focusing by developing a novel Disordered Effective Medium approach. Then, in Chapter 4, we turn to bacterial biofilms to explore the biophysical principles underlying the self-assembly of living architectures. We show how the presence of cell-to-surface adhesion allows biofilms to grow from a two-dimensional layer of founder cells into a three-dimensional structure with a vertically-aligned core. The interplay between cell growth and cell verticalization gives rise to an exotic mechanical state in which the effective surface pressure becomes constant throughout the growing core of the biofilm surface layer. This dynamical isobaricity determines the expansion speed of a biofilm cluster and thereby governs how cells access the third dimension. We conclude by discussing general biophysical principles of living architectures that emerge from our case studies (Chapter 5)
The Physics of Spatial Differentiation in Living Systems
No full textLiving systems exhibit spatial differentiation at every scale, from the functional compartments within cells to the biogeography of multi-species communities. In this dissertation, we investigate the emergence and consequences of spatial differentiation in two contexts: biomolecular condensates in eukaryotic cells (Chapter 1) and resource competition between territorial communities (Chapter 2). We begin at the intracellular level, where eukaryotes are able to organize important biomolecules and tasks into condensates which lack a membrane. Many such condensates are liquid droplets which phase separate due to interactions between their component molecules, but it remains difficult to bridge spatial scales and determine how molecular properties shape condensate properties. In Chapter 1, we study two important aspects of condensates' molecular architecture: 1) the role of specific interactions which are one-to-one and saturating, and 2) the sequence of interaction motifs, which is under the control of evolution and regulation. Using Monte Carlo simulations and mean-field theory, we show that the motif sequence has a dramatic effect on the thermodynamic and material properties of biomolecular condensates. Sequences with larger domains of repeated motifs phase separate under a much wider range of conditions, and the resulting condensates are much more viscous and solid-like. We find that the sequence primarily acts through the entropy of intramolecular interactions, a new mechanism for the biological control of phase separation. Having shown how spatial differentiation emerges at the intracellular level, we zoom out to the ecological level to understand how spatial structure shapes biodiversity and population dynamics. Many important ecosystems are comprised of populations which compete for both territory and diffusing resources (e.g. bacterial biofilms, terrestrial plants, coral and mussels). How diverse will such an ecosystem be, compared to a well-mixed system with the same competitors but no spatial organization? Using a model that couples mechanistic interactions to biophysical constraints, we unexpectedly find that space reduces biodiversity but renders it more robust to differences in intrinsic metabolic capacity. Finally, we conclude by asking whether these two disparate case studies offer any general lessons for theorists grappling with space and difference in biology
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