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Flip-sort is a natural sorting procedure which raises fascinating combinatorial questions. It finds its roots in the seminal work of Knuth on stack-based sorting algorithms and leads to many links with permutation patterns. We present several structural, enumerative, and algorithmic results on permutations that need few (resp. many) iterations of this procedure to be sorted. In particular, we give the shape of the permutations after one iteration, and characterize several families of permutations related to the best and worst cases of flip-sort. En passant, we also give some links between pop-stack sorting, automata, and lattice paths, and introduce several tactics of bijective proofs which have their own interest.

Current treatments for anxiety and depression show limited efficacy in many patients, indicating the need for further research into the underlying mechanisms. JNK1 has been shown to regulate anxiety- and depressive-like behaviours in mice, however the effectors downstream of JNK1 are not known. Here we compare the phosphoproteomes from wild-type and Jnk1-/- mouse brains and identify JNK1-regulated signalling hubs. We next employ a zebrafish ( Danio rerio ) larvae behavioural assay to identify an antidepressant- and anxiolytic-like (AA) phenotype based on 2759 measured stereotypic responses to clinically proven antidepressant and anxiolytic (AA) drugs. Employing machine learning, we classify an AA phenotype from extracted features measured during and after a startle battery in fish exposed to AA drugs. Using this classifier, we demonstrate that structurally independent JNK inhibitors replicate the AA phenotype with high accuracy, consistent with findings in mice. Furthermore, pharmacological targeting of JNK1-regulated signalling hubs identifies AKT, GSK-3, 14–3-3 ζ/ε and PKCε as downstream hubs that phenocopy clinically proven AA drugs. This study identifies AKT and related signalling molecules as mediators of JNK1-regulated antidepressant- and anxiolytic-like behaviours. Moreover, the assay shows promise for early phase screening of compounds with anti-stress-axis properties and for mode of action analysis.

The number of down-steps between pairs of up-steps in$k_t$ -Dyck paths, a generalization of Dyck paths consisting of steps$\\{(1, k), (1, -1)\\}$such that the path stays (weakly) above the line$y=-t$ , is studied. Results are proved bijectively and by means of generating functions, and lead to several interesting identities as well as links to other combinatorial structures. In particular, there is a connection between$k_t$ -Dyck paths and perforation patterns for punctured convolutional codes (binary matrices) used in coding theory. Surprisingly, upon restriction to usual Dyck paths this yields a new combinatorial interpretation of Catalan numbers.

Duchenne muscular dystrophy (DMD), a severe muscle disease caused by mutations in the gene encoding for the intracellular protein dystrophin, is associated with impaired cardiac function and arrhythmias. A causative factor for complications in the dystrophic heart is abnormal calcium (Ca) handling in ventricular cardiomyocytes, and restoration of normal Ca homeostasis has emerged as therapeutic strategy. Here, we used a rodent model of DMD, the dystrophin-deficient DMD mdx rat, to test the following hypothesis: chronic administration of ivabradine (IVA), a drug clinically approved for the treatment of heart failure, improves Ca handling in dystrophic ventricular cardiomyocytes and thereby enhances contractile performance in the dystrophic heart. Intracellular Ca measurements revealed that 4-months administration of IVA to DMD mdx rats significantly improves Ca handling properties in dystrophic ventricular cardiomyocytes. In particular, IVA treatment increased electrically-evoked Ca transients and speeded their decay. This suggested enhanced sarcoplasmic reticulum Ca release and faster removal of Ca from the cytosol. Chronic IVA administration also enhanced the sarcoplasmic reticulum Ca load. Transthoracic echocardiography revealed a significant improvement of cardiac systolic function in IVA-treated DMD mdx rats. Thus, left ventricular ejection fraction and fractional shortening were enhanced, and end-systolic as well as end-diastolic diameters were diminished by the drug. Finally, chronic IVA administration neither significantly attenuated cardiac fibrosis and apoptosis, nor was vascular function improved by the drug. Collectively our findings suggest that long-term IVA administration enhances contractile function in the dystrophic heart by improvement of Ca handling in ventricular cardiomyocytes. Chronic IVA administration may be beneficial for DMD patients.

Background and purpose: Ivabradine is clinically administered to lower the heart rate, proposedly by inhibiting hyperpolarization-activated cyclic nucleotide-gated cation channels in the sinoatrial node. Recent evidence suggests that voltage-gated sodium channels (VGSC) are inhibited within the same concentration range. VGSCs are expressed within the sinoatrial node and throughout the conduction system of the heart. A block of these channels thus likely contributes to the established and newly raised clinical indications of ivabradine. We, therefore, investigated the pharmacological action of ivabradine on VGSCs in sufficient detail in order to gain a better understanding of the pro- and anti-arrhythmic effects associated with the administration of this drug. Experimental Approach: Ivabradine was tested on VGSCs in native cardiomyocytes isolated from mouse ventricles and the His-Purkinje system and on human Na v 1.5 in a heterologous expression system. We investigated the mechanism of channel inhibition by determining its voltage-, frequency-, state-, and temperature-dependence, complemented by a molecular drug docking to the recent Na v 1.5 cryoEM structure. Automated patch-clamp experiments were used to investigate ivabradine-mediated changes in Na v 1.5 inactivation parameters and inhibition of different VGSC isoforms. Key results: Ivabradine inhibited VGSCs in a voltage- and frequency-dependent manner, but did not alter voltage-dependence of activation and fast inactivation, nor recovery from fast inactivation. Cardiac (Na v 1.5), neuronal (Na v 1.2), and skeletal muscle (Na v 1.4) VGSC isoforms were inhibited by ivabradine within the same concentration range, as were sodium currents in native cardiomyocytes isolated from the ventricles and the His-Purkinje system. Molecular drug docking suggested an interaction of ivabradine with the classical local anesthetic binding site. Conclusion and Implications: Ivabradine acts as an atypical inhibitor of VGSCs. Inhibition of VGSCs likely contributes to the heart rate lowering effect of ivabradine, in particular at higher stimulation frequencies and depolarized membrane potentials, and to the observed slowing of intra-cardiac conduction. Inhibition of VGSCs in native cardiomyocytes and across channel isoforms may provide a potential basis for the anti-arrhythmic potential as observed upon administration of ivabradine.

Stanley lists the class of Dyck paths where all returns to the axis are of odd length as one of the many objects enumerated by (shifted) Catalan numbers. By the standard bijection in this context, these special Dyck paths correspond to a class of rooted plane trees, so-called Catalan-Stanley trees. This paper investigates a deterministic growth procedure for these trees by which any Catalan-Stanley tree can be grown from the tree of size one after some number of rounds; a parameter that will be referred to as the age of the tree. Asymptotic analyses are carried out for the age of a random Catalan-Stanley tree of given size as well as for the \"speed\" of the growth process by comparing the size of a given tree to the size of its ancestors.

The muscular dystrophies caused by dystrophin deficiency, the so‐called dystrophinopathies, are associated with impaired cardiac contractility and arrhythmias, which considerably contribute to disease morbidity and mortality. Impaired Ca handling in ventricular cardiomyocytes has been identified as a causative factor for complications in the dystrophic heart, and restoration of normal Ca handling in myocytes has emerged as a promising new therapeutic strategy. In the present study, we explored the hypothesis that ivabradine, a drug clinically approved for the treatment of heart failure and stable angina pectoris, improves Ca handling in dystrophic cardiomyocytes and thereby enhances contractile performance in the dystrophic heart. Therefore, ventricular cardiomyocytes were isolated from the hearts of adult dystrophin‐deficient DMDmdx rats, and the effects of acutely applied ivabradine on intracellular Ca transients were tested. In addition, the drug's acute impact on cardiac function in DMDmdx rats was assessed by transthoracic echocardiography. We found that administration of ivabradine to DMDmdx rats significantly improved cardiac function. Moreover, the amplitude of electrically induced intracellular Ca transients in ventricular cardiomyocytes isolated from DMDmdx rats was increased by the drug. We conclude that ivabradine enhances Ca release from the sarcoplasmic reticulum in dystrophic cardiomyocytes and thereby improves contractile performance in the dystrophic heart. We have investigated the acute effects of the heart rate‐ lowering drug ivabradine on cardiac Ca handling and function in a rat model of Duchenne muscular dystrophy. Our findings suggest that the drug improves Ca handling in dystrophic cardiomyocytes and thereby enhances contractile performance in the dystrophic heart.

T-type Ca channels are strongly expressed and important in the developing heart. In the adult heart, these channels play a significant role in pacemaker tissues, but there is uncertainty about their presence and physiological relevance in the working myocardium. Here, we show that the T-type Ca channel isoforms Cav3.1 and Cav3.2 are expressed at a protein level in ventricular cardiomyocytes from healthy adult C57/BL6 mice. Myocytes isolated from adult wild-type and Cav3.2 KO mice showed considerable whole cell T-type Ca currents under beta-adrenergic stimulation with isoprenaline. We further show that the detectability of basal T-type Ca currents in murine wild-type cardiomyocytes depends on the applied experimental conditions. Together, these findings reveal the presence of functional T-type Ca channels in the membrane of ventricular myocytes. In addition, electrically evoked Ca release from the sarcoplasmic reticulum was significantly impaired in Cav3.2 KO compared to wild-type cardiomyocytes. Our work implies a physiological role of T-type Ca channels in the healthy adult murine ventricular working myocardium.

Abstract Psilocybin, a hallucinogen contained in “magic” mushrooms, holds great promise for the treatment of various psychiatric disorders, and early clinical trials are encouraging. Adverse cardiac events after intake of high doses of psilocybin and a trial reporting QT interval prolongation in the electrocardiogram attributed to the drug’s main metabolite, psilocin, gave rise to safety concerns. Here we show that clinical concentrations of psilocin do not cause significant human ether-a-go-go-related gene (hERG) potassium channel inhibition, a major risk factor for adverse cardiac events. We conclude that hERG channel blockage by psilocin is not liable for psilocybin- associated cardiotoxic effects.

Flip-sort is a natural sorting procedure which raises fascinating combinatorial questions. It finds its roots in the seminal work of Knuth on stack-based sorting algorithms and leads to many links with permutation patterns. We present several structural, enumerative, and algorithmic results on permutations that need few (resp. many) iterations of this procedure to be sorted. In particular, we give the shape of the permutations after one iteration, and characterize several families of permutations related to the best and worst cases of flip-sort. En passant, we also give some links between pop-stack sorting, automata, and lattice paths, and introduce several tactics of bijective proofs which have their own interest.