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  1. Abstract Intercellular electrical coupling is an essential means of communication between cells. It is important to obtain quantitative knowledge of such coupling between cardiomyocytes and non-excitable cells when, for example, pathological electrical coupling between myofibroblasts and cardiomyocytes yields increased arrhythmia risk or during the integration of donor (e.g., cardiac progenitor) cells with native cardiomyocytes in cell-therapy approaches. Currently, there is no direct method for assessing heterocellular coupling within multicellular tissue. Here we demonstrate experimentally and computationally a new contactless assay for electrical coupling, OptoGap, based on selective illumination of inexcitable cells that express optogenetic actuators and optical sensing of the response of coupled excitable cells (e.g., cardiomyocytes) that are light-insensitive. Cell–cell coupling is quantified by the energy required to elicit an action potential via junctional current from the light-stimulated cell(s). The proposed technique is experimentally validated against the standard indirect approach, GapFRAP, using light-sensitive cardiac fibroblasts and non-transformed cardiomyocytes in a two-dimensional setting. Its potential applicability to the complex three-dimensional setting of the native heart is corroborated by computational modelling and proper calibration. Lastly, the sensitivity of OptoGap to intrinsic cell-scale excitability is robustly characterized via computational analysis.
  2. Free, publicly-accessible full text available January 13, 2024
  3. null (Ed.)
  4. Lyons, Kathleen (Ed.)
  5. null (Ed.)
  6. Bellingham, Peter (Ed.)
  7. Abstract

    We test several quantitative algorithms as palaeoclimate reconstruction tools for North American and European fossil pollen data, using both classical methods and newer machine-learning approaches based on regression tree ensembles and artificial neural networks. We focus on the reconstruction of secondary climate variables (here, January temperature and annual water balance), as their comparatively small ecological influence compared to the primary variable (July temperature) presents special challenges to palaeo-reconstructions. We test the pollen–climate models using a novel and comprehensive cross-validation approach, running a series ofh-block cross-validations usinghvalues of 100–1500 km. Our study illustrates major benefits of this variableh-block cross-validation scheme, as the effect of spatial autocorrelation is minimized, while the cross-validations with increasinghvalues can reveal instabilities in the calibration model and approximate challenges faced in palaeo-reconstructions with poor modern analogues. We achieve well-performing calibration models for both primary and secondary climate variables, with boosted regression trees providing the overall most robust performance, while the palaeoclimate reconstructions from fossil datasets show major independent features for the primary and secondary variables. Our results suggest that with careful variable selection and consideration of ecological processes, robust reconstruction of both primary and secondary climate variables is possible.