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Male contraceptive options and infertility treatments are limited. To help overcome these limitations we established a small molecule library as a toolbox for assay development and screening campaigns using human spermatozoa. We have profiled all compounds in our automated high-throughput screening platform and provide the dataset, which allows direct side-by-side comparisons of compound effects and assays using live human spermatozoa.

Current understanding of arrhythmia mechanisms and design of anti-arrhythmic drug therapies hinges on the assumption that myocytes from the same region of a single heart have similar, if not identical, action potential waveforms and drug responses. On the contrary, recent experiments reveal significant heterogeneity in uncoupled healthy myocytes both from different hearts as well as from identical regions within a single heart. In this work, a methodology is developed for quantifying the individual electrophysiological properties of large numbers of uncoupled cardiomyocytes under ion channel block in terms of the parameters values of a conceptual fast-slow model of electrical excitability. The approach is applied to a population of nearly 500 rabbit ventricular myocytes for which action potential duration (APD) before and after the application of the drug nifedipine was experimentally measured (Lachaud et al., 2022, Cardiovasc. Res.). To this end, drug action is represented by a multiplicative factor to an effective ion conductance, a closed form asymptotic expression for APD is derived and inverted to determine model parameters as functions of APD and dAPD (drug-induced change in APD) for each myocyte. Two free protocol-related quantities are calibrated to experiment using an adaptive-domain procedure based on an original assumption of optimal excitability. The explicit APD expression and the resulting set of model parameter values allow (a) direct evaluation of conditions necessary to maintain fixed APD or dAPD, (b) predictions of the proportion of cells remaining excitable after drug application, (c) predictions of stimulus period dependency and (d) predictions of dose-response curves, the latter being in agreement with additional experimental data., Accepted for publication in Mathematical Medicine and Biology: A Journal of the IMA (ISSN (Online):1477-8602) on 2023-01-15

Heart failure is a heterogeneous clinical syndrome which is accompanied by a variety of phenotypic changes, many of which have been linked to abnormalities in the intracellular calcium (Ca2+) signal. These range from mechanical dysfunction, usually characterized by reduced systolic contractile function, to electrophysiological dysfunction including QT interval prolongation, increased incidence of ventricular premature beats, and arrhythmic sudden cardiac death. In ventricular myocardial cells, intracellular Ca2+ ion fluxes govern the translation of the depolarizing signal into mechanical contraction, a process termed excitation–contraction (E–C) coupling. Abnormalities of intracellular Ca2+ handling are thought to underlie both mechanical and electrophysiological dysfunction in failing myocardium. This chapter summarizes the events involved in normal E–C coupling and describes the changes observed in heart failure, with particular focus on the changes reported in remodelled ventricular myocardium. Changes in intracellular Ca2+ signalling in other cardiac cell types, such as atrial cardiomyocytes and Purkinje fibre cells, may also be crucial to the final heart failure phenotype, but less is known about pathological changes in these tissues, and therefore these are only mentioned briefly.