Complex computational models are often designed to simulate real-world physical phenomena in many scientific disciplines. However, these simulation models tend to be computationally very expensive and involve a large number of simulation input parameters, which need to be analyzed and properly calibrated before the models can be applied for real scientific studies. We propose a visual analysis system to facilitate interactive exploratory analysis of high-dimensional input parameter space for a complex yeast cell polarization simulation. The proposed system can assist the computational biologists, who designed the simulation model, to visually calibrate the input parameters by modifying the parameter values and immediately visualizing the predicted simulation outcome without having the need to run the original expensive simulation for every instance. Our proposed visual analysis system is driven by a trained neural network-based surrogate model as the backend analysis framework. In this work, we demonstrate the advantage of using neural networks as surrogate models for visual analysis by incorporating some of the recent advances in the field of uncertainty quantification, interpretability and explainability of neural network-based models. We utilize the trained network to perform interactive parameter sensitivity analysis of the original simulation as well as recommend optimal parameter configurations using the activation maximization framework of neural networks. We also facilitate detail analysis of the trained network to extract useful insights about the simulation model, learned by the network, during the training process. We performed two case studies, and discovered multiple new parameter configurations, which can trigger high cell polarization results in the original simulation model. We evaluated our results by comparing with the original simulation model outcomes as well as the findings from previous parameter analysis performed by our experts.

Soft errors or bit flips have recently become an important challenge in high performance computing. In this paper, we focus on soft errors in a particular algorithm: conjugate gradients (CG). We present a series of techniques to detect soft errors in CG. We first derive a mathematical quantity that is monotonically decreasing. Next, we add a set of heuristics and combine our approach with previously established methods. We have extensively evaluated our method considering three distinct dimensions. First, we show that the F-score of our detection is significantly better than two other methods. Second, we show that for soft errors that are not detected by our method, the resulting inaccuracy in the final results are small, and better than those with other methods. Finally, we show that the runtime overheads of our method are lower than for other methods.

Intracellular polarization, where a cell specifies a spatial axis by segregation of specific factors, is a fundamental biological process. In the early embryo of the nematode worm Caenorhabditis elegans (C. elegans), polarization is often accompanied by deformations of the cortex, a highly contractile structure consisting of actin filaments cross-linked by the motor protein myosin (actomyosin). It has been suggested that the eggshell surrounding the early embryo plays a role in polarization although its function is not understood. Here we develop a mathematical model which couples a reaction-diffusion model of actomyosin dynamics with a phase field model of the cell cortex to implicitly track cell shape changes in the early C. elegans embryo. We investigate the potential rigidity effect of the geometric constraint imposed by the presence and size of the eggshell on polarization dynamics. Our model suggests that the geometric constraint of the eggshell is essential for proper polarization and the size of the eggshell also affects the dynamics of polarization. Therefore, we conclude that geometric constraint on a cell might affect the dynamics of a biochemical process.

A common challenge in systems biology is quantifying the effects of unknown parameters and estimating parameter values from data. For many systems, this task is computationally intractable due to expensive model evaluations and large numbers of parameters. In this work, we investigate a new method for performing sensitivity analysis and parameter estimation of complex biological models using techniques from uncertainty quantification. The primary advance is a significant improvement in computational efficiency from the replacement of model simulation by evaluation of a polynomial surrogate model. We demonstrate the method on two models of mating in budding yeast: a smaller ODE model of the heterotrimeric G-protein cycle, and a larger spatial model of pheromone-induced cell polarization. A small number of model simulations are used to fit the polynomial surrogates, which are then used to calculate global parameter sensitivities. The surrogate models also allow rapid Bayesian inference of the parameters via Markov chain Monte Carlo (MCMC) by eliminating model simulations at each step. Application to the ODE model shows results consistent with published single-point estimates for the model and data, with the added benefit of calculating the correlations between pairs of parameters. On the larger PDE model, the surrogate models allowed convergence for the distribution of 15 parameters, which otherwise would have been computationally prohibitive using simulations at each MCMC step. We inferred parameter distributions that in certain cases peaked at values different from published values, and showed that a wide range of parameters would permit polarization in the model. Strikingly our results suggested different diffusion constants for active versus inactive Cdc42 to achieve good polarization, which is consistent with experimental observations in another yeast species S. pombe.

Budding yeast, which undergoes polarized growth during budding and mating, has been a useful model system to study cell polarization. Bud sites are selected differently in haploid and diploid yeast cells: haploid cells bud in an axial manner, while diploid cells bud in a bipolar manner. While previous studies have been focused on the molecular details of the bud site selection and polarity establishment, not much is known about how different budding patterns give rise to different functions at the population level. In this paper, we develop a two-dimensional agent-based model to study budding yeast colonies with cell-type specific biological processes, such as budding, mating, mating type switch, consumption of nutrients, and cell death. The model demonstrates that the axial budding pattern enhances mating probability at an early stage and the bipolar budding pattern improves colony development under nutrient limitation. Our results suggest that the frequency of mating type switch might control the trade-off between diploidization and inbreeding. The effect of cellular aging is also studied through our model. Based on the simulations, colonies initiated by an aged haploid cell show declined mating probability at an early stage and recover as the rejuvenated offsprings become the majority. Colonies initiated with aged diploid cells do not show disadvantage in colony expansion possibly due to the fact that young cells contribute the most to colony expansion.

Mating of budding yeast cells is a model system for studying cell-cell interactions. Haploid yeast cells secrete mating pheromones that are sensed by the partner which responds by growing a mating projection toward the source. The two projections meet and fuse to form the diploid. Successful mating relies on precise coordination of dynamic extracellular signals, signaling pathways, and cell shape changes in a noisy background. It remains elusive how cells mate accurately and efficiently in a natural multi-cell environment. Here we present the first stochastic model of multiple mating cells whose morphologies are driven by pheromone gradients and intracellular signals. Our novel computational framework encompassed a moving boundary method for modeling both a-cells and α-cells and their cell shape changes, the extracellular diffusion of mating pheromones dynamically coupled with cell polarization, and both external and internal noise. Quantification of mating efficiency was developed and tested for different model parameters. Computer simulations revealed important robustness strategies for mating in the presence of noise. These strategies included the polarized secretion of pheromone, the presence of the α-factor protease Bar1, and the regulation of sensing sensitivity; all were consistent with data in the literature. In addition, we investigated mating discrimination, the ability of an a-cell to distinguish between α-cells either making or not making α-factor, and mating competition, in which multiple a-cells compete to mate with one α-cell. Our simulations were consistent with previous experimental results. Moreover, we performed a combination of simulations and experiments to estimate the diffusion rate of the pheromone a-factor. In summary, we constructed a framework for simulating yeast mating with multiple cells in a noisy environment, and used this framework to reproduce mating behaviors and to identify strategies for robust cell-cell interactions.