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Register a new userGenerating Semi-Synthetic Validation Benchmarks for Embryomics
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Systematic validation is an essential part of algorithm development. The enormous dataset sizes and the complexity observed in many recent time-resolved 3D fluorescence microscopy imaging experiments, however, prohibit a comprehensive manual ground truth generation. Moreover, existing simulated benchmarks in this field are often too simple or too specialized to sufficiently validate the observed image analysis problems. We present a new semi-synthetic approach to generate realistic 3D+t benchmarks that combines challenging cellular movement dynamics of real embryos with simulated fluorescent nuclei and artificial image distortions including various parametrizable options like cell numbers, acquisition deficiencies or multiview simulations. We successfully applied the approach to simulate the development of a zebrafish embryo with thousands of cells over 14 hours of its early existence.
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Contemporary realistic mathematical models of single-cell cardiac electrical excitation are immensely detailed. Model complexity leads to parameter uncertainty, high computational cost and barriers to mechanistic understanding. There is a need for reduced models that are conceptually and mathematically simple but physiologically accurate. To this end, we consider an archetypal model of single-cell cardiac excitation that replicates the phase-space geometry of detailed cardiac models, but at the same time has a simple piecewise-linear form and a relatively low-dimensional configuration space. In order to make this archetypal model practically applicable, we develop and report a robust method for estimation of its parameter values from the morphology of single-stimulus action potentials derived from detailed ionic current models and from experimental myocyte measurements. The procedure is applied to five significant test cases and an excellent agreement with target biomarkers is achieved. Action potential duration restitution curves are also computed and compared to those of the target test models and data, demonstrating conservation of dynamical pacing behaviour by the fine-tuned archetypal model. An archetypal model that accurately reproduces a variety of wet-lab and synthetic electrophysiology data offers a number of specific advantages such as computational efficiency, as also demonstrated in the study. Open-source numerical code of the models and methods used is provided.
Adherent cells exert traction forces on to their environment, which allows them to migrate, to maintain tissue integrity, and to form complex multicellular structures. This traction can be measured in a perturbation-free manner with traction force microscopy (TFM). In TFM, traction is usually calculated via the solution of a linear system, which is complicated by undersampled input data, acquisition noise, and large condition numbers for some methods. Therefore, standard TFM algorithms either employ data filtering or regularization. However, these approaches require a manual selection of filter- or regularization parameters and consequently exhibit a substantial degree of subjectiveness. This shortcoming is particularly serious when cells in different conditions are to be compared because optimal noise suppression needs to be adapted for every situation, which invariably results in systematic errors. Here, we systematically test the performance of new methods from computer vision and Bayesian inference for solving the inverse problem in TFM. We compare two classical schemes, L1- and L2-regularization, with three previously untested schemes, namely Elastic Net regularization, Proximal Gradient Lasso, and Proximal Gradient Elastic Net. Overall, we find that Elastic Net regularization, which combines L1 and L2 regularization, outperforms all other methods with regard to accuracy of traction reconstruction. Next, we develop two methods, Bayesian L2 regularization and Advanced Bayesian L2 regularization, for automatic, optimal L2 regularization. Using artificial data and experimental data, we show that these methods enable robust reconstruction of traction without requiring a difficult selection of regularization parameters specifically for each data set. Thus, Bayesian methods can mitigate the considerable uncertainty inherent in comparing cellular traction forces.
Cochlear implants (CIs) are a standard treatment for patients who experience severe to profound hearing loss. Recent studies have shown that hearing outcome is correlated with intra-cochlear anatomy and electrode placement. Our group has developed image-guided CI programming (IGCIP) techniques that use image analysis methods to both segment the inner ear structures in pre- or post-implantation CT images and localize the CI electrodes in post-implantation CT images. This permits to assist audiologists with CI programming by suggesting which among the contacts should be deactivated to reduce electrode interaction that is known to affect outcomes. Clinical studies have shown that IGCIP can improve hearing outcomes for CI recipients. However, the sensitivity of IGCIP with respect to the accuracy of the two major steps: electrode localization and intra-cochlear anatomy segmentation, is unknown. In this article, we create a ground truth dataset with conventional CT and micro-CT images of 35 temporal bone specimens to both rigorously characterize the accuracy of these two steps and assess how inaccuracies in these steps affect the overall results. Our study results show that when clinical pre- and post-implantation CTs are available, IGCIP produces results that are comparable to those obtained with the corresponding ground truth in 86.7% of the subjects tested. When only post-implantation CTs are available, this number is 83.3%. These results suggest that our current method is robust to errors in segmentation and localization but also that it can be improved upon. Keywords: cochlear implant, ground truth, segmentation, validation
The cell cytoskeleton is a striking example of active medium driven out-of-equilibrium by ATP hydrolysis. Such activity has been shown recently to have a spectacular impact on the mechanical and rheological properties of the cellular medium, as well as on its transport properties : a generic tracer particle freely diffuses as in a standard equilibrium medium, but also intermittently binds with random interaction times to motor proteins, which perform active ballistic excursions along cytoskeletal filaments. Here, we propose for the first time an analytical model of transport limited reactions in active media, and show quantitatively how active transport can enhance reactivity for large enough tracers like vesicles. We derive analytically the average interaction time with motor proteins which optimizes the reaction rate, and reveal remarkable universal features of the optimal configuration. We discuss why active transport may be beneficial in various biological examples: cell cytoskeleton, membranes and lamellipodia, and tubular structures like axons.
Stem cells can precisely and robustly undergo cellular differentiation and lineage commitment, referred to as stemness. However, how the gene network underlying stemness regulation reliably specifies cell fates is not well understood. To address this question, we applied a recently developed computational method, Random Circuit Perturbation (RACIPE), to a nine-component gene regulatory network (GRN) governing stemness, from which we identified fifteen robust gene states. Among them, four out of the five most probable gene states exhibit gene expression patterns observed in single mouse embryonic cells at 32-cell and 64-cell stages. These gene states can be robustly predicted by the stemness GRN but not by randomiz
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