747 research outputs found
Bistability: Requirements on Cell-Volume, Protein Diffusion, and Thermodynamics
Bistability is considered wide-spread among bacteria and eukaryotic cells,
useful e.g. for enzyme induction, bet hedging, and epigenetic switching.
However, this phenomenon has mostly been described with deterministic dynamic
or well-mixed stochastic models. Here, we map known biological bistable systems
onto the well-characterized biochemical Schloegl model, using analytical
calculations and stochastic spatio-temporal simulations. In addition to network
architecture and strong thermodynamic driving away from equilibrium, we show
that bistability requires fine-tuning towards small cell volumes (or
compartments) and fast protein diffusion (well mixing). Bistability is thus
fragile and hence may be restricted to small bacteria and eukaryotic nuclei,
with switching triggered by volume changes during the cell cycle. For large
volumes, single cells generally loose their ability for bistable switching and
instead undergo a first-order phase transition.Comment: 23 pages, 8 figure
Entropy production selects nonequilibrium states in multistable systems
Far-from-equilibrium thermodynamics underpins the emergence of life, but how
has been a long-outstanding puzzle. Best candidate theories based on the
maximum entropy production principle could not be unequivocally proven, in part
due to complicated physics, unintuitive stochastic thermodynamics, and the
existence of alternative theories such as the minimum entropy production
principle. Here, we use a simple, analytically solvable, one-dimensional
bistable chemical system to demonstrate the validity of the maximum entropy
production principle. To generalize to multistable stochastic system, we use
the stochastic least-action principle to derive the entropy production and its
role in the stability of nonequilibrium steady states. This shows that in a
multistable system, all else being equal, the steady state with the highest
entropy production is favored, with a number of implications for the evolution
of biological, physical, and geological systems.Comment: 15 pages, 4 figure
Noise characteristics of the Escherichia coli rotary motor
The chemotaxis pathway in the bacterium Escherichia coli allows cells to
detect changes in external ligand concentration (e.g. nutrients). The pathway
regulates the flagellated rotary motors and hence the cells' swimming
behaviour, steering them towards more favourable environments. While the
molecular components are well characterised, the motor behaviour measured by
tethered cell experiments has been difficult to interpret. Here, we study the
effects of sensing and signalling noise on the motor behaviour. Specifically,
we consider fluctuations stemming from ligand concentration, receptor switching
between their signalling states, adaptation, modification of proteins by
phosphorylation, and motor switching between its two rotational states. We
develop a model which includes all signalling steps in the pathway, and discuss
a simplified version, which captures the essential features of the full model.
We find that the noise characteristics of the motor contain signatures from all
these processes, albeit with varying magnitudes. This allows us to address how
cell-to-cell variation affects motor behaviour and the question of optimal
pathway design. A similar comprehensive analysis can be applied to other
two-component signalling pathways.Comment: 22 pages, 7 figures, 3 tutorials, supplementary information;
submitted manuscrip
Target shape dependence in a simple model of receptor-mediated endocytosis and phagocytosis
Phagocytosis and receptor-mediated endocytosis are vitally important particle
uptake mechanisms in many cell types, ranging from single-cell organisms to
immune cells. In both processes, engulfment by the cell depends critically on
both particle shape and orientation. However, most previous theoretical work
has focused only on spherical particles and hence disregards the wide-ranging
particle shapes occurring in nature, such as those of bacteria. Here, by
implementing a simple model in one and two dimensions, we compare and contrast
receptor-mediated endocytosis and phagocytosis for a range of biologically
relevant shapes, including spheres, ellipsoids, capped cylinders, and
hourglasses. We find a whole range of different engulfment behaviors with some
ellipsoids engulfing faster than spheres, and that phagocytosis is able to
engulf a greater range of target shapes than other types of endocytosis.
Further, the 2D model can explain why some nonspherical particles engulf
fastest (not at all) when presented to the membrane tip-first (lying flat). Our
work reveals how some bacteria may avoid being internalized simply because of
their shape, and suggests shapes for optimal drug delivery.Comment: 18 pages, 5 figure
Unraveling Adaptation in Eukaryotic Pathways: Lessons from Protocells
Eukaryotic adaptation pathways operate within wide-ranging environmental
conditions without stimulus saturation. Despite numerous differences in the
adaptation mechanisms employed by bacteria and eukaryotes, all require energy
consumption. Here, we present two minimal models showing that expenditure of
energy by the cell is not essential for adaptation. Both models share important
features with large eukaryotic cells: they employ small diffusible molecules
and involve receptor subunits resembling highly conserved G-protein cascades.
Analyzing the drawbacks of these models helps us understand the benefits of
energy consumption, in terms of adjustability of response and adaptation times
as well as separation of cell-external sensing and cell-internal signaling. Our
work thus sheds new light on the evolution of adaptation mechanisms in complex
systems.Comment: accepted for publication in PLoS Computational Biology; 19 pages, 8
figure
Bistable forespore engulfment in Bacillus subtilis by a zipper mechanism in absence of the cell wall
To survive starvation, the bacterium Bacillus subtilis forms durable spores.
The initial step of sporulation is asymmetric cell division, leading to a large
mother-cell and a small forespore compartment. After division is completed and
the dividing septum is thinned, the mother cell engulfs the forespore in a slow
process based on cell-wall degradation and synthesis. However, recently a new
cell-wall independent mechanism was shown to significantly contribute, which
can even lead to fast engulfment in 60 of the cases when the cell
wall is completely removed. In this backup mechanism, strong ligand-receptor
binding between mother-cell protein SpoIIIAH and forespore-protein SpoIIQ leads
to zipper-like engulfment, but quantitative understanding is missing. In our
work, we combined fluorescence image analysis and stochastic Langevin
simulations of the fluctuating membrane to investigate the origin of fast
bistable engulfment in absence of the cell wall. Our cell morphologies compare
favorably with experimental time-lapse microscopy, with engulfment sensitive to
the number of SpoIIQ-SpoIIIAH bonds in a threshold-like manner. By systematic
exploration of model parameters, we predict regions of osmotic pressure and
membrane-surface tension that produce successful engulfment. Indeed, decreasing
the medium osmolarity in experiments prevents engulfment in line with our
predictions. Forespore engulfment may thus not only be an ideal model system to
study decision-making in single cells, but its biophysical principles are
likely applicable to engulfment in other cell types, e.g. during phagocytosis
in eukaryotes
The zipper mechanism in phagocytosis: energetic requirements and variability in phagocytic cup shape
Phagocytosis is the fundamental cellular process by which eukaryotic cells
bind and engulf particles by their cell membrane. Particle engulfment involves
particle recognition by cell-surface receptors, signaling and remodeling of the
actin cytoskeleton to guide the membrane around the particle in a zipper-like
fashion. Despite the signaling complexity, phagocytosis also depends strongly
on biophysical parameters, such as particle shape, and the need for
actin-driven force generation remains poorly understood. Here, we propose a
novel, three-dimensional and stochastic biophysical model of phagocytosis, and
study the engulfment of particles of various sizes and shapes, including spiral
and rod-shaped particles reminiscent of bacteria. Highly curved shapes are not
taken up, in line with recent experimental results. Furthermore, we
surprisingly find that even without actin-driven force generation, engulfment
proceeds in a large regime of parameter values, albeit more slowly and with
highly variable phagocytic cups. We experimentally confirm these predictions
using fibroblasts, transfected with immunoreceptor FcyRIIa for engulfment of
immunoglobulin G-opsonized particles. Specifically, we compare the wild-type
receptor with a mutant receptor, unable to signal to the actin cytoskeleton.
Based on the reconstruction of phagocytic cups from imaging data, we indeed
show that cells are able to engulf small particles even without support from
biological actin-driven processes. This suggests that biochemical pathways
render the evolutionary ancient process of phagocytic highly robust, allowing
cells to engulf even very large particles. The particle-shape dependence of
phagocytosis makes a systematic investigation of host-pathogen interactions and
an efficient design of a vehicle for drug delivery possible.Comment: Accepted for publication in BMC Systems Biology. 17 pages, 6 Figures,
+ supplementary informatio
Predicting chemical environments of bacteria from receptor signaling
Sensory systems have evolved to respond to input stimuli of certain
statistical properties, and to reliably transmit this information through
biochemical pathways. Hence, for an experimentally well-characterized sensory
system, one ought to be able to extract valuable information about the
statistics of the stimuli. Based on dose-response curves from in vivo
fluorescence resonance energy transfer (FRET) experiments of the bacterial
chemotaxis sensory system, we predict the chemical gradients chemotactic
Escherichia coli cells typically encounter in their natural environment. To
predict average gradients cells experience, we revaluate the phenomenological
Weber's law and its generalizations to the Weber-Fechner law and fold-change
detection. To obtain full distributions of gradients we use information theory
and simulations, considering limitations of information transmission from both
cell-external and internal noise. We identify broad distributions of
exponential gradients, which lead to log-normal stimuli and maximal drift
velocity. Our results thus provide a first step towards deciphering the
chemical nature of complex, experimentally inaccessible cellular
microenvironments, such as the human intestine.Comment: DG and GM contributed equally to this wor
Upper limits on the robustness of Turing models and other multiparametric dynamical systems
Traditional linear stability analysis based on matrix diagonalization is a
computationally intensive process for -dimensional systems of
differential equations, posing substantial limitations for the exploration of
Turing systems of pattern formation where an additional wave-number parameter
needs to be investigated. In this study, we introduce an efficient
technique that leverages Gershgorin's theorem to determine upper limits on
regions of parameter space and the wave number beyond which Turing
instabilities cannot occur. This method offers a streamlined avenue for
exploring the phase diagrams of other complex multiparametric models, such as
those found in systems biology
The mechanism of phagocytosis: two stages of engulfment
Despite being of vital importance to the immune system, the mechanism by
which cells engulf relatively large solid particles during phagocytosis is
still poorly understood. From movies of neutrophil phagocytosis of polystyrene
beads, we measure the fractional engulfment as a function of time and
demonstrate that phagocytosis occurs in two distinct stages. During the first
stage, engulfment is relatively slow and progressively slows down as
phagocytosis proceeds. However, at approximately half-engulfment, the rate of
engulfment increases dramatically, with complete engulfment attained soon
afterwards. By studying simple mathematical models of phagocytosis, we suggest
that the first stage is due to a passive mechanism, determined by receptor
diffusion and capture, whereas the second stage is more actively controlled,
perhaps with receptors being driven towards the site of engulfment. We then
consider a more advanced model that includes signaling and captures both stages
of engulfment. This model predicts that there is an optimum ligand density for
quick engulfment. Further, we show how this model explains why non-spherical
particles engulf quickest when presented tip-first. Our findings suggest that
active regulation may be a later evolutionary innovation, allowing fast and
robust engulfment even for large particles.Comment: 21 pages, 7 figure
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