Biology subjects

Kurata, Y.

Publications and source records attributed to Kurata, Y..

4 recordsLinked to original sources

bioRxiv2026

REN-former prioritizes candidate regulators of kidney disease-state transitions through single-cell foundation modeling and human genetics

Background Acute kidney injury (AKI)-to-chronic kidney disease (CKD) transition is associated with dynamic changes in tubular cell state. However, conventional single-cell transcriptomic analyses primarily identify genes differentially expressed between disease states and do not directly evaluate genes associated with directional transitions between cellular states. Methods We developed REN-former by fine-tuning Geneformer using the GSE183276 single-cell RNA-sequencing dataset from 45 participants representing Normal Reference, AKI, and CKD states. In silico gene deletion and overexpression analyses were used to estimate directional transcriptomic shifts, with a focus on proximal tubular cells. Selected genes were evaluated using summary-data-based Mendelian randomization (SMR), colocalization and expression analysis in additional KPMP participants not included in GSE183276. Results REN-former achieved recall values of 0.99, 0.80, and 0.79 for Normal Reference, AKI, and CKD, respectively. In silico perturbation analyses identified distinct gene programs associated with transitions from Normal Reference to AKI, from Normal Reference to CKD, from AKI to CKD, and from CKD to Normal Reference. Conventional analysis showed metabolic suppression and increased inflammatory and stress-response activation. SMR identified IFITM3, CALR, TTR, CALM1, MUC13, and RPL13, and colocalization supported IFITM3, CALR, TTR, and CALM1. In additional KPMP data, IFITM3 was higher, whereas TTR and CALM1 were lower, in CKD proximal tubules; CALR did not differ significantly. The observed expression changes were concordant with the REN-former-predicted directions for TTR and CALM1 but discordant for IFITM3. Conclusion REN-former provides a framework for prioritizing candidate regulators of kidney disease-associated cell states by integrating predicted perturbation effects with human genetic and transcriptomic evidence.

bioinformatics↗

bioRxiv2025

Octopamine signaling from clock neurons plays dual roles in Drosophila long-term memory

Circadian clock genes are best known for regulating circadian rhythms, but they also play crucial roles in memory processes. This suggests that memory is modulated by neural networks containing clock neurons, although the underlying mechanisms remain unclear. In Drosophila melanogaster, approximately 240 clock neurons are grouped into at least eight distinct clusters. Among them, the dorsal-lateral neurons (LNds) are required for maintaining long-term memory (LTM). In contrast, the neuropeptide Pigment-dispersing factor (Pdf), expressed in both small and large ventral-lateral neurons (s-LNvs and l-LNvs, respectively), functions as a circadian output signal and is also essential for maintaining LTM. In addition, Pdf-expressing neurons (hereafter, Pdf neurons) release neurotransmitters other than Pdf, which are involved in LTM consolidation. However, the specific transmitters used by LNds and Pdf neurons in LTM processing have remained unknown. Here, we show that octopamine signaling from LNds is essential for LTM maintenance, whereas octopamine in Pdf neurons is essential for LTM consolidation. Temporally restricted knockdown of Tyramine {beta} hydroxylase (Tbh), the gene encoding the enzyme required for octopamine synthesis, disrupted LTM maintenance when targeted in LNds, whereas it impaired LTM consolidation when targeted in Pdf neurons. Notably, Tbh knockdown in LNds or Pdf neurons had minimal effects on circadian behavioral rhythms or sleep. These findings reveal that octopamine released from specific subtypes of clock neurons independently regulates distinct phases of LTM in Drosophila. Author SummaryAnimal memory formed through learning is stabilized by a process called consolidation and becomes long-term memory (LTM), which can persist for extended periods. The fruit fly Drosophila melanogaster is widely used in memory research, enabling the discovery of key genes and signaling pathways. In addition, Drosophila has contributed significantly to circadian rhythm research through studies of clock neurons and clock genes. Notably, clock neurons have been implicated in LTM regulation, suggesting a potential link between circadian clock neurons and memory function. However, the neural network connecting these processes remains poorly understood. Identifying the neurotransmitters released from clock neurons is critical to clarifying how these neurons affect memory function. In this study, we show that octopamine, the fly equivalent of the vertebrate neurotransmitter norepinephrine, released from two distinct groups of clock neurons regulates different phases of LTM in Drosophila: one group supports consolidation, whereas the other supports maintenance. Our findings demonstrate that clock neurons play an active role in memory regulation, and they provide new insights into the neural circuitry that controls LTM.

neuroscience↗

bioRxiv2019

Specific decreasing of Na+ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome

One phenotypic feature of Brugada syndrome (BrS) is slowed conduction due to the reduction (loss-of-function) of Na+ channels. In contrast, recent clinical observations in BrS patients highlighted the poor correlation between the phenotype (typical ECG change or lethal arrhythmia) and the genotype (SCN5A mutation). Inspired by our previous theoretical study which showed that reduced Na+ channels in the lateral membrane (LM) of ventricular myocytes caused the slowing of conduction under myocardial ischemia, we hypothesized that a loss-of-function of Na+ channels caused by the decreases in Na+ channel expression within myocytes leads to phase-2 reentry (P2R), the major triggering mechanism of lethal arrhythmias in BrS. We constructed an in silico human ventricular myocardial strand and ring models, and investigated the relationship between the subcellular Na+ channel distribution and P2R. Reducing Na+ channel expression in the LM of each myocyte caused not only the notch-and-dome but also loss-of-dome type action potentials and slowed conduction, both of which are typically observed in BrS patients. Furthermore, we showed that both the reduction in Na+ channels on the LM of each myocyte and tissue-level heterogeneity of Na+ channel expression were essential for P2R as well as P2R-mediated reentrant excitation. Our data suggest that the alteration in subcellular Na+ channel distribution together with a tissue-level heterogeneity of Na+ channels can cause arrhythmogenesis in BrS.

biophysics↗

bioRxiv2019

Multiple Dynamical Mechanisms of Phase-2 Early Afterdepolarizations in a Human Ventricular Myocyte Model: Involvement of spontaneous SR Ca2+ release

Early afterdepolarization (EAD) is known to cause lethal ventricular arrhythmias in long QT syndrome (LQTS). In this study, dynamical mechanisms of EAD formation in human ventricular myocytes (HVMs) were investigated using the mathematical model developed by ten Tusscher & Panfilov (Am J Physiol Heart Circ Physiol, 2006). We explored how the rapid (IKr) and slow (IKs) components of delayed-rectifier K+ channel currents, L-type Ca2+ channel current (ICaL), Na+/Ca2+ exchanger current (INCX), and intracellular Ca2+ handling via the sarcoplasmic reticulum (SR) contribute to initiation, termination and modulation of phase-2 EADs during pacing in relation to bifurcation phenomena in non-paced model cells. Dynamical behaviors of the non-paced model cell were determined by calculating stabilities of equilibrium points (EPs) and limit cycles, and bifurcation points. EADs during pacing were reproduced by numerical simulations. Results are summarized as follows: 1) A modified version of the ten Tusscher-Panfilov model with accelerated ICaL inactivation could reproduce bradycardia-related EADs and {beta}-adrenergic stimulation-induced EADs in LQTS. 2) Two types of EADs with different initiation mechanisms, ICaL reactivation-dependent and spontaneous SR Ca2+ release-mediated EADs, were detected. 3) Spontaneous SR Ca2+ releases occurred at higher Ca2+ uptake rates, attributable to the instability of steady-state intracellular Ca2+ concentrations. Dynamical mechanisms of EAD formation and termination in the paced model cell are closely related to stability changes (bifurcations) in dynamical behaviors of the non-paced model cell, but they are model-dependent. Nevertheless, the modified ten Tusscher-Panfilov model would be useful for systematically investigating possible dynamical mechanisms of EAD-related arrhythmias in LQTS.\n\nKey pointsO_LIWe investigated dynamical mechanisms of phase-2 early afterdepolarization (EAD) by bifurcation analyses of the human ventricular myocyte model developed by ten Tusscher and Panfilov.\nC_LIO_LIA modified version of ten Tusscher-Panfilov model with accelerated inactivation of the L-type Ca2+ channel current could reproduce phase-2 EADs in long QT syndrome type 1 and 2 cardiomyocytes.\nC_LIO_LIDynamical mechanisms of EAD formation in the paced model cell are closely related to stability and bifurcations of the non-paced model cell.\nC_LIO_LIEAD mechanisms in the modified ten Tusscher-Panfilov model are different from those in other human ventricular myocyte models in the following respects: 1) EAD formation is partially attributable to spontaneous sarcoplasmic reticulum Ca2+ releases; and 2) EAD termination (action potential repolarization) during pacing requires the slowly-activating delayed-rectifier K+ channel current.\nC_LIO_LIThe modified ten Tusscher-Panfilov model would be useful for systematically investigating possible dynamical mechanisms of initiation and termination of EAD-related arrhythmias in LQTS.\nC_LI

physiology↗