182,766 research outputs found
Deterministic characterization of stochastic genetic circuits
For cellular biochemical reaction systems where the numbers of molecules is
small, significant noise is associated with chemical reaction events. This
molecular noise can give rise to behavior that is very different from the
predictions of deterministic rate equation models. Unfortunately, there are few
analytic methods for examining the qualitative behavior of stochastic systems.
Here we describe such a method that extends deterministic analysis to include
leading-order corrections due to the molecular noise. The method allows the
steady-state behavior of the stochastic model to be easily computed,
facilitates the mapping of stability phase diagrams that include stochastic
effects and reveals how model parameters affect noise susceptibility, in a
manner not accessible to numerical simulation. By way of illustration we
consider two genetic circuits: a bistable positive-feedback loop and a
negative-feedback oscillator. We find in the positive feedback circuit that
translational activation leads to a far more stable system than transcriptional
control. Conversely, in a negative-feedback loop triggered by a
positive-feedback switch, the stochasticity of transcriptional control is
harnessed to generate reproducible oscillations.Comment: 6 pages (Supplementary Information is appended
Bistability of cell-matrix adhesions resulting from non-linear receptor-ligand dynamics
Bistability is a major mechanism for cellular decision making and usually
results from positive feedback in biochemical control systems. Here we show
theoretically that bistability between unbound and bound states of adhesion
clusters results from positive feedback mediated by structural rather than
biochemical processes, namely by receptor-ligand dissociation and association
dynamics which depend non-linearly on mechanical force and receptor-ligand
separation. For small cell-matrix adhesions, we find rapid switching between
unbound and bound states, which in the initial stages of adhesion allows the
cell to explore its environment through many transient adhesions.Comment: Revtex, 3 pages, 3 postscript figures included, to appear in
Biophysical Journal as Biophysical Lette
Coupling between feedback loops in autoregulatory networks affects bistability range, open-loop gain and switching times
Biochemical regulatory networks governing diverse cellular processes such as stress-response,
differentiation and cell cycle often contain coupled feedback loops. We aim at understanding
how features of feedback architecture, such as the number of loops, the sign of the loops and
the type of their coupling, affect network dynamical performance. Specifically, we investigate
how bistability range, maximum open-loop gain and switching times of a network with
transcriptional positive feedback are affected by additive or multiplicative coupling with
another positive- or negative-feedback loop. We show that a network's bistability range is
positively correlated with its maximum open-loop gain and that both quantities depend on the
sign of the feedback loops and the type of feedback coupling. Moreover, we find that the
addition of positive feedback could decrease the bistability range if we control the basal level
in the signal-response curves of the two systems. Furthermore, the addition of negative
feedback has the capacity to increase the bistability range if its dissociation constant is much
lower than that of the positive feedback. We also find that the addition of a positive feedback to
a bistable network increases the robustness of its bistability range, whereas the addition of a
negative feedback decreases it. Finally, we show that the switching time for a transition from a
high to a low steady state increases with the effective fold change in gene regulation. In
summary, we show that the effect of coupled feedback loops on the bistability range and
switching times depends on the underlying mechanistic details
Integral Feedback Control Is at the Core of Task Allocation and Resilience of Insect Societies
Homeostatic self-regulation is a fundamental aspect of open dissipative systems. Integral feedback has been found to be important for homeostatic control on both the cellular and molecular levels of biological organization and in engineered systems. Analyzing the task allocation mechanisms of three insect societies, we identified a model of integral control residing at colony level. We characterized a general functional core mechanism, called the “common stomach,” where a crucial shared substance for colony function self-regulates its own quantity via reallocating the colony’s workforce, which collects and uses this substance. The central component in a redundant feedback network is the saturation level of this substance in the colony. An interaction network of positive and negative feedback loops ensures the homeostatic state of this substance and the workforce involved in processing this substance. Extensive sensitivity and stability analyses of the core model revealed that the system is very resilient against perturbations and compensates for specific types of stress that real colonies face in their ecosystems. The core regulation system is highly scalable, and due to its buffer function, it can filter noise and find a new equilibrium quickly after environmental (supply) or colony-state (demand) changes. The common stomach regulation system is an example of convergent evolution among the three different societies, and we predict that similar integral control regulation mechanisms have evolved frequently within natural complex systems
Understanding Control of Metabolite Dynamics and Heterogeneity
Microbes live in complex and continually changing environments. Rapid shifts in nutrient availability are a common challenge for microbes, and cause changes in intracellular metabolite levels. Microbial response to dynamic environments requires coordination of multiple levels of cellular machinery including gene expression and metabolite concentrations. This coordination is achieved through metabolic control systems, which sense metabolite concentrations and direct cellular activity in response. Several reoccurring control architectures are found throughout diverse metabolic systems, which suggests underlying evolutionary advantages for using these control systems to coordinate metabolism. One common, yet understudied, control architecture is the positive feedback metabolite uptake loop, which features a metabolite responsive-transcription factor (MRTF) that activates genes necessary to uptake its cognate metabolite. Understanding the design principles behind these complex metabolic control systems is a fundamental issue across many biological sub-disciplines since metabolism is a central feature of cellular behavior.The goal of this dissertation is to elucidate how the architecture and parameters of a MRTF-based control system shape metabolite dynamics and heterogenous metabolic response to changing nutrient environments. This dissertation focuses on the Escherichia coli fatty acid degradation system, which employs the positive feedback uptake loop architecture. The function and performance of these control systems to three common metabolic tasks was evaluated. First, after a nutrient depletion, microbes must rapidly turn off metabolic pathways to conserve resources. Second, microbes must maintain sensing ability in the face of metabolic conditions which impact cellular growth rate. Finally, upon abrupt shifts between nutrients, microbes must shift metabolic resources to uptake the new nutrient or otherwise cease growth. This shifting process can be heterogenous, with a sub-population which maintains a non-growing state that confers tolerance to antimicrobial compounds. Taken together, this work provides deeper understanding of the design principles for the control of metabolite dynamics and heterogeneity for applications in metabolic engineering and synthetic biology
Noise control and utility: From regulatory network to spatial patterning
Stochasticity (or noise) at cellular and molecular levels has been observed
extensively as a universal feature for living systems. However, how living
systems deal with noise while performing desirable biological functions remains
a major mystery. Regulatory network configurations, such as their topology and
timescale, are shown to be critical in attenuating noise, and noise is also
found to facilitate cell fate decision. Here we review major recent findings on
noise attenuation through regulatory control, the benefit of noise via
noise-induced cellular plasticity during developmental patterning, and
summarize key principles underlying noise control
Pulsed Feedback Defers Cellular Differentiation
Environmental signals induce diverse cellular differentiation programs. In certain systems, cells defer differentiation for extended time periods after the signal appears, proliferating through multiple rounds of cell division before committing to a new fate. How can cells set a deferral time much longer than the cell cycle? Here we study Bacillus subtilis cells that respond to sudden nutrient limitation with multiple rounds of growth and division before differentiating into spores. A well-characterized genetic circuit controls the concentration and phosphorylation of the master regulator Spo0A, which rises to a critical concentration to initiate sporulation. However, it remains unclear how this circuit enables cells to defer sporulation for multiple cell cycles. Using quantitative time-lapse fluorescence microscopy of Spo0A dynamics in individual cells, we observed pulses of Spo0A phosphorylation at a characteristic cell cycle phase. Pulse amplitudes grew systematically and cell-autonomously over multiple cell cycles leading up to sporulation. This pulse growth required a key positive feedback loop involving the sporulation kinases, without which the deferral of sporulation became ultrasensitive to kinase expression. Thus, deferral is controlled by a pulsed positive feedback loop in which kinase expression is activated by pulses of Spo0A phosphorylation. This pulsed positive feedback architecture provides a more robust mechanism for setting deferral times than constitutive kinase expression. Finally, using mathematical modeling, we show how pulsing and time delays together enable “polyphasic” positive feedback, in which different parts of a feedback loop are active at different times. Polyphasic feedback can enable more accurate tuning of long deferral times. Together, these results suggest that Bacillus subtilis uses a pulsed positive feedback loop to implement a “timer” that operates over timescales much longer than a cell cycle
Collective oscillation period of inter-coupled biological negative cyclic feedback oscillators
A number of biological rhythms originate from networks comprised of multiple
cellular oscillators. But analytical results are still lacking on the
collective oscillation period of inter-coupled gene regulatory oscillators,
which, as has been reported, may be different from that of an autonomous
oscillator. Based on cyclic feedback oscillators, we analyze the collective
oscillation pattern of coupled cellular oscillators. First we give a condition
under which the oscillator network exhibits oscillatory and synchronized
behavior. Then we estimate the collective oscillation period based on a novel
multivariable harmonic balance technique. Analytical results are derived in
terms of biochemical parameters, thus giving insight into the basic mechanism
of biological oscillation and providing guidance in synthetic biology design.Comment: arXiv admin note: substantial text overlap with arXiv:1203.125
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