Network motifs exhibiting a differential response to spaced and massed inputs.

One characteristic of long-term memory is the existence of an inverted U-shaped response to increasing intervals between training sessions, and consequently, an optimal spacing that maximizes memory formation. Current models of this spacing effect focus on specific molecular components and their interactions. Here, we computationally study the underlying network architecture, in particular, the potential of motif dynamics in qualitatively capturing the spacing effect in a manner that is independent of the animal model, biomolecular components, and the timescales involved. We define a common training and test protocol, and computationally identify network topologies that can qualitatively replicate the experimentally observed characteristics of the spacing effect. For 41 motifs derived from fundamental network architectures such as autoregulation, feedback, and feedforward motifs, we tested their capacity to manifest the spacing effect in terms of an inverted U-shaped response curve, using different combinations of stimulation protocols, response metrics, and kinetic parameters. Our findings indicate that positive feedback motifs where the stimulus enhances conversion reaction in the loop replicate the spacing effect across all response metrics, while feedforward motifs exhibit a metric-specific spacing effect. For some parameter combinations, linear cascades of activation and conversion reactions were found sufficient to qualitatively exhibit spacing effect characteristics.

A novel ryanodine receptor 2 inhibitor, M201-A, enhances natriuresis, renal function and lusi-inotropic actions: Preclinical and phase I study.

BACKGROUND AND PURPOSE: The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca2+ homeostasis in cells in these organs. This study aimed to investigate the impact of M201-A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies. EXPERIMENTAL APPROACH: Following the administration of M201-A (1,4-benzothiazepine-1-oxide derivative), we monitored diastolic Ca2+ leak via RyR2 and intracellular Ca2+ concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201-A was administered intravenously at doses of 0.2 and 0.4 mg·kg-1 once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses. KEY RESULTS: In rat heart cells, M201-A effectively inhibited spontaneous diastolic Ca2+ leakage through RyR2 and exhibited positive lusi-inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201-A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability. CONCLUSIONS AND IMPLICATIONS: The novel drug M201-A inhibited diastolic Ca2+ leak via RyR2, improved cardiac lusi-inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.