Noise filtering tradeoffs in spatial gradient sensing and cell polarization response

<p>Abstract</p> <p>Background</p> <p>Cells sense chemical spatial gradients and respond by polarizing internal components. This process can be disrupted by gradient noise caused by fluctuations in chemical concentration.</p> <p>Results</p> <p>We investigated how external gradient noise affects spatial sensing and response focusing on noise-filtering and the resultant tradeoffs. First, using a coarse-grained mathematical model of gradient-sensing and cell polarity, we characterized three negative consequences of noise: Inhibition of the extent of polarization, degradation of directional accuracy, and production of a noisy output polarization. Next, we explored filtering strategies and discovered that a combination of positive feedback, multiple signaling stages, and time-averaging produced good results. There was an important tradeoff, however, because filtering resulted in slower polarization. Simulations demonstrated that a two-stage filter-amplifier resulted in a balanced outcome. Then, we analyzed the effect of noise on a mechanistic model of yeast cell polarization in response to gradients of mating pheromone. This analysis showed that yeast cells likely also combine the above three filtering mechanisms into a filter-amplifier structure to achieve impressive spatial-noise tolerance, but with the consequence of a slow response time. Further investigation of the amplifier architecture revealed two positive feedback loops, a fast inner and a slow outer, both of which contributed to noise-tolerant polarization. This model also made specific predictions about how orientation performance depended upon the ratio between the gradient slope (signal) and the noise variance. To test these predictions, we performed microfluidics experiments measuring the ability of yeast cells to orient to shallow gradients of mating pheromone. The results of these experiments agreed well with the modeling predictions, demonstrating that yeast cells can sense gradients shallower than 0.1% μm^-1, approximately a single receptor-ligand molecule difference between front and back, on par with motile eukaryotic cells.</p> <p>Conclusions</p> <p>Spatial noise impedes the extent, accuracy, and smoothness of cell polarization. A combined filtering strategy implemented by a filter-amplifier architecture with slow dynamics was effective. Modeling and experimental data suggest that yeast cells employ these elaborate mechanisms to filter gradient noise resulting in a slow but relatively accurate polarization response.</p

Modeling Robustness Tradeoffs in Yeast Cell Polarization Induced by Spatial Gradients

Cells localize (polarize) internal components to specific locations in response to external signals such as spatial gradients. For example, yeast cells form a mating projection toward the source of mating pheromone. There are specific challenges associated with cell polarization including amplification of shallow external gradients of ligand to produce steep internal gradients of protein components (e.g. localized distribution), response over a broad range of ligand concentrations, and tracking of moving signal sources. In this work, we investigated the tradeoffs among these performance objectives using a generic model that captures the basic spatial dynamics of polarization in yeast cells, which are small. We varied the positive feedback, cooperativity, and diffusion coefficients in the model to explore the nature of this tradeoff. Increasing the positive feedback gain resulted in better amplification, but also produced multiple steady-states and hysteresis that prevented the tracking of directional changes of the gradient. Feedforward/feedback coincidence detection in the positive feedback loop and multi-stage amplification both improved tracking with only a modest loss of amplification. Surprisingly, we found that introducing lateral surface diffusion increased the robustness of polarization and collapsed the multiple steady-states to a single steady-state at the cost of a reduction in polarization. Finally, in a more mechanistic model of yeast cell polarization, a surface diffusion coefficient between 0.01 and 0.001 µm2/s produced the best polarization performance, and this range is close to the measured value. The model also showed good gradient-sensitivity and dynamic range. This research is significant because it provides an in-depth analysis of the performance tradeoffs that confront biological systems that sense and respond to chemical spatial gradients, proposes strategies for balancing this tradeoff, highlights the critical role of lateral diffusion of proteins in the membrane on the robustness of polarization, and furnishes a framework for future spatial models of yeast cell polarization

An Information-Theoretic Characterization of the Optimal Gradient Sensing Response of Cells

Many cellular systems rely on the ability to interpret spatial heterogeneities in chemoattractant concentration to direct cell migration. The accuracy of this process is limited by stochastic fluctuations in the concentration of the external signal and in the internal signaling components. Here we use information theory to determine the optimal scheme to detect the location of an external chemoattractant source in the presence of noise. We compute the minimum amount of mutual information needed between the chemoattractant gradient and the internal signal to achieve a prespecified chemotactic accuracy. We show that more accurate chemotaxis requires greater mutual information. We also demonstrate that a priori information can improve chemotaxis efficiency. We compare the optimal signaling schemes with existing experimental measurements and models of eukaryotic gradient sensing. Remarkably, there is good quantitative agreement between the optimal response when no a priori assumption is made about the location of the existing source, and the observed experimental response of unpolarized Dictyostelium discoideum cells. In contrast, the measured response of polarized D. discoideum cells matches closely the optimal scheme, assuming prior knowledge of the external gradient—for example, through prolonged chemotaxis in a given direction. Our results demonstrate that different observed classes of responses in cells (polarized and unpolarized) are optimal under varying information assumptions

Simulated Yeast with Mobile Polarity Sites Is More Sensitive to Pheromone Gradients

Cell polarity is the asymmetric distribution of cellular components and molecules. It is crucially important for effective cell motility and other directional functions. However, practically all types of cells were exposed in a large amount of molecular noise which interfered cell polarity, leading the cells to polarize in the wrong direction. Interestingly, though exposed in molecular noise, yeast cells can usually find and polarize in the direction of extracellular pheromone gradients during mating. This study investigated how yeast cells decoded the extracellular pheromone gradient to polarize in the right direction despite the noise. With particle-based simulations, we found that when exposed to a shallow signal gradient, the simulated yeast with mobile polarity sites interpreted the direction of the signal more accurately than the one with static polarity sites. Therefore, the highly dynamic polarity sites could help yeast cells to decode the extracellular pheromone gradient against molecular noise. Future studies will focus on adding more complex signaling pathways to the simulated yeast models to further investigate the effect of mobile polarity sites on yeast polarity establishment.Bachelor of Scienc

Broadband nonlinear modulation of incoherent light using a transparent optoelectronic neuron array

Nonlinear optical processing of ambient natural light is highly desired in computational imaging and sensing applications. A strong optical nonlinear response that can work under weak broadband incoherent light is essential for this purpose. Here we introduce an optoelectronic nonlinear filter array that can address this emerging need. By merging 2D transparent phototransistors (TPTs) with liquid crystal (LC) modulators, we create an optoelectronic neuron array that allows self-amplitude modulation of spatially incoherent light, achieving a large nonlinear contrast over a broad spectrum at orders-of-magnitude lower intensity than what is achievable in most optical nonlinear materials. For a proof-of-concept demonstration, we fabricated a 10,000-pixel array of optoelectronic neurons, each serving as a nonlinear filter, and experimentally demonstrated an intelligent imaging system that uses the nonlinear response to instantly reduce input glares while retaining the weaker-intensity objects within the field of view of a cellphone camera. This intelligent glare-reduction capability is important for various imaging applications, including autonomous driving, machine vision, and security cameras. Beyond imaging and sensing, this optoelectronic neuron array, with its rapid nonlinear modulation for processing incoherent broadband light, might also find applications in optical computing, where nonlinear activation functions that can work under ambient light conditions are highly sought.Comment: 20 Pages, 5 Figure

STOCHASTIC MODELS OF CHEMOTAXING SIGNALING PROCESSES

Stochasticity is ubiquitous in all processes. Its contribution in shaping the output response is not only restricted to systems involving entities with low copy numbers. Intrinsic fluctuations can also affect systems in which the interacting species are present in abundance. Chemotaxis, the migration of cells towards chemical cues, is one such example. Chemotaxis is a fundamental process that is behind a wide range of biological events, rang¬ing from the innate immune response of organisms to cancer metastasis. In this dissertation, we study the role that stochastic fluctuations play in the regulatory mechanism that regulates chemotaxis in the social amoeba Dictyostelium discoideum. It has been argued theoretically and shown experimentally that stochastically driven threshold crossings of an underlying excitable system lead to the protrusions that enable amoeboid cells to move. To date, how¬ ever, there has been no good computational model that accurately accounts for the effects of noise, as most models merely inject noise extraneously to deterministic models leading to stochastic differential equations. In contrast, in this study, we employ an entirely different paradigm to account for the noise effects, based on the reaction-diffusion master equation. Using a modular approach and a three-dimensional description of the cell model with specific subdomains attributed to the cell membrane and cortex, we develop a detailed model of the receptor-mediated regulation of the signal transduction excitable network (STEN), which has been shown to drive actin dynamics. Using this model, we recreate the patterns of wave propagation seen in both front- and back-side markers that are seen experimentally. Moreover, we recreate various perturbations. Our model provides further support for the biased-excitable network hypothesis that posits that directed motion occurs from a spatially biased regulation of the threshold for activation of an excitable network. Here we also consider another aspect of the chemotactic response. While front- and back-markers redistribute in response to chemoattractant gradients, over time, this spatial heterogeneity becomes established and can exist even when the external chemoattractant gradient is removed. We refer to this persistent segregation of the cell into back and front regions as polarity. In this dissertation, we study various methods by which polarity can be established. For example, we consider the role of vesicular trafficking as a means of bringing back-markers from the front to the rear of the cell. Then, we study how Bin/Amphiphysin/Rvs (BAR)¬domain proteins that are sensitive to membrane curvature, can amplify small shape heterogeneities leading to cell polarization. Finally, we develop computational models that describe a novel framework by which polarity can be established and perturbed through the alteration of the charge distribution on the inner leaf of the cell membrane