Biology subjects

Kodama, M.

Publications and source records attributed to Kodama, M..

10 recordsLinked to original sources

bioRxiv2025

Successive failure triggered by motor exploration in a reinforcement-based reaching task

Motor exploration, a key process in reinforcement-based motor learning, is triggered by suboptimal performance and leads to increased movement variability. Consequently, failure in one trial may increase the likelihood of failure in subsequent trials. If this pattern emerges, successive failures (SFs) are not merely events to be avoided but part of the trial-and-error process of identifying optimal movements, which can facilitate motor learning. This study investigated whether and how SFs occur above chance levels during a motor learning task with binary success/failure feedback and explored the relationship between SFs and motor learning outcomes. Thirty-three healthy young adults participated in the study, performing a reaching task to pass through a target without visual feedback of their hand position. Binary feedback was provided after each trial, indicating whether the hand trajectory overlapped with the target. The results showed that the probability of two SFs was significantly higher than the square of the overall failure probability, indicating that failure streaks occurred above chance levels. A computational model, in which motor variability comprised constant motor noise and exploratory variability regulated by recent reward history (where variability increased following failure), successfully explained SF emergence. However, the learning index, defined as the difference in failure probability between the first and latter halves of the experiment, was unrelated to SF emergence. Additionally, failure streaks disappeared when participants were asked to reach one of seven randomly selected targets in each trial, suggesting that introducing environmental variability can help alleviate SFs.

neuroscience↗

bioRxiv2024

A novel RyR2-selective stabilizer prevents and ameliorates severe arrhythmias in stress-induced ventricular tachycardia

Background and PurposeAberrant activation of the type 2 ryanodine receptor (RyR2) causes lethal arrhythmias, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). Developing drugs that suppress RyR2 hyperactivation may be key to novel arrhythmia treatments. This study evaluated the antiarrhythmic potential of Ryanozole, a recently developed novel RyR2 modulator with high affinity and selectivity, using CPVT mouse models harboring mutant RyR2s. Experimental approachIn vitro effects of Ryanozole were evaluated by ER Ca2+-based assay and [3H]Ryanodine binding assay using RyR2-expressing HEK293 cells. Two lines of mice with different arrhythmia severity, RyR2-R420W and -K4750Q, were employed for in vivo assessments. Intracellular Ca2+ signals were analyzed in isolated cardiomyocytes using Cal520. Antiarrhythmic effects were evaluated by ECG under catecholaminergic challenge in anesthetized mice and during spontaneous arrhythmias in conscious mice. ECG and echocardiographic parameters were evaluated before and after drug administration. Key resultsRyanozole inhibited both wild type and mutant RyR2s with similar IC50 of 15-40 nM. The inhibition was more potent at lower cytosolic Ca2+ concentrations. It suppressed Ca2+ waves and Ca2+ sparks without affecting action potential-evoked Ca2+ transients. Ryanozole effectively prevented adrenaline-induced arrhythmias and rapidly terminated spontaneous arrhythmias during daily activity. Importantly, Ryanozole did not impair cardiac conduction or contractility, unlike conventional antiarrhythmic drugs. Conclusions and implicationsRyanozole strongly suppresses RyR2 under diastolic Ca2+ conditions, thereby preventing the arrhythmogenic trigger of aberrant Ca2+ release. This mechanism likely provides potent antiarrhythmic effects while preserving cardiac function. Ryanozole is a promising therapeutic candidate treating RyR2-mediated arrhythmias, such as CPVT.

pharmacology and toxicology↗

bioRxiv2024

Tertiary lymphoid structure as a therapeutic target of Crohns disease: modulation by TNFα blockade

Inflammatory diseases, such as Crohns disease (CD), are primarily treated with therapies aimed at alleviating inflammation. Notably, biological agents like TNF inhibitors have transformed the management of these conditions. Previous research has indicated that TNF inhibitors affect the cells in the lamina propria. However, this study demonstrates that infliximab, a type of TNF inhibitor, reduces the presence of tertiary lymphoid structures (TLS) and alleviates inflammation of CD by targeting follicular dendritic cells and macrophages within these structures. TLS could also be a potential target for various biological agents used to treat inflammatory diseases beyond CD. Furthermore, our study suggests that the status of TLS may serve as a predictor for the response to TNF inhibitor treatment. Our research could pave the way for new treatment strategies and the advancement of personalized medicine for inflammatory diseases.

immunology↗

bioRxiv2024

The need for high-resolution gut microbiome characterization to design efficient strategies for sustainable aquaculture production

Microbiome-directed dietary interventions such as microbiota-directed fibers (MDFs) have a proven track record in eliciting responses in beneficial gut microbes and are increasingly being promoted as an effective strategy to improve animal production systems. Here we used initial metataxonomic data on fish gut microbiomes as well as a wealth of a priori mammalian microbiome knowledge on -MOS and {beta}-mannan-derived MDFs to study effects of such feed supplements in Atlantic salmon (Salmo salar) and their hitherto poorly characterized gut microbiomes. Our multi-omic analysis revealed that the investigated MDFs (two -mannans and an acetylated {beta}-galactoglucomannan), at a dose of 0.2%, had negligible effects on both host gene expression, and gut microbiome structure and function under studied conditions. While a subsequent trial using a higher (4%) dietary inclusion of {beta}-mannan significantly shifted the gut microbiome composition, there were still no biologically relevant effects on salmon metabolism and physiology. Only a single Burkholderia-Caballeronia-Paraburkholderia (BCP) population demonstrated consistent and significant abundance shifts across both feeding trials, although with no evidence of {beta}-mannan utilization capabilities or changes in gene transcripts for producing metabolites beneficial to the host. In light of these findings, we revisited our omics data to predict and outline novel and potentially beneficial endogenous lactic acid bacteria that should be targeted with future, conceivably more suitable, MDF strategies for salmon. IMPORTANCEThis study focuses on the potential of MDFs to improve aquaculture production. Despite preliminary 16S rRNA amplicon data suggested that populations in the salmon gut microbiome could utilize structurally complex mannans, our findings indicates that endogenous microbes could not metabolize it, nor the host responds to its dietary inclusion, at least not under the trial conditions investigated in this study. We highlight that high-resolution and host-specific microbiome characterization can greatly improve trial design and selection of candidate MDFs for future nutritional interventions. Understanding the intricate interplay between host and its gut microbiome is paramount in studies seeking to leverage endogenous microbial communities to benefit the host. While each new condition, whether it is a disease onset or a nutritional stressor, has the potential to profoundly reshape the microbial diversity, composition and outputs, the functional microbiome information gained under healthy conditions represent a pivotal step towards designing more effective trials involving microbiome-reprogramming feed additives. Overall, we envisage that these results will lead to improved focus on coupling fundamental microbiome characterization to the design of next-generation feeds for salmon aquaculture.

microbiology↗

bioRxiv2023

Screening for novel RyR2 inhibitors by ER Ca2+ monitoring

Type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic/sarcoplasmic reticulum (ER/SR) that plays a central role in the excitation-contraction coupling in the heart. Hyperactivity of RyR2 has been linked to ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) and heart failure, where spontaneous Ca2+ release via hyperactivated RyR2 depolarizes diastolic membrane potential to induce triggered activity. In such cases, drugs that suppress RyR2 activity are expected to prevent the arrhythmias, but there is no clinically available RyR2 inhibitors at present. In this study, we searched for RyR2 inhibitors from a well-characterized compound library using a recently developed ER Ca2+-based assay, where the inhibition of RyR2 activity was detected by the increase in ER Ca2+ signals from R-CEPIA1er, a genetically encoded ER Ca2+ indicator, in RyR2-expressing HEK293 cells. By screening 1535 compounds in the library, we identified three compounds (chloroxylenol, methyl orsellinate and riluzole) that greatly increased the ER Ca2+ signal. All of the three compounds suppressed spontaneous Ca2+ oscillations in RyR2-expressing HEK293 cells and correspondingly reduced the Ca2+-dependent [3H]ryanodine binding activity. In cardiomyocytes from RyR2-mutant mice, the three compounds effectively suppressed abnormal Ca2+ waves without substantial effects on the action-potential-induced Ca2+ transients. These results confirm that ER Ca2+-based screening is useful for identifying modulators of ER Ca2+ release channels and suggest that RyR2 inhibitors have potential to be developed as a new category of antiarrhythmic drugs. Significance statementWe successfully identified three compounds having RyR2 inhibitory action from a well-characterized compound library using an ER Ca2+-based assay, and demonstrated that these compounds suppressed arrhythmogenic Ca2+ wave generation without substantially affecting physiological action-potential induced Ca2+ transients in cardiomyocytes. This study will facilitate the development of RyR2 specific inhibitors as a potential new class of drugs for life-threatening arrhythmias induced by hyperactivation of RyR2.

pharmacology and toxicology↗

bioRxiv2023

Host-gut microbiota interactions shape parasite infections in farmed Atlantic salmon

Animals and their associated microbiota share long evolutionary histories. Both host genotype and associated microbiota influence phenotypes such as growth and disease resilience. We applied a hologenomic approach to explore the relationship between host and microbiota in shaping lifetime growth and parasitic cestode infection in farmed Atlantic salmon. Genomes, transcriptomes, metabolomes and metagenomes were generated from the guts of 460 harvest-aged salmon, 82% of which were naturally infected with an intestinal cestode. One salmonid-specific Mycoplasma dominated the gut microbiota of uninfected salmon. However, the microbiota was perturbed in smaller, parasitised fish, with increased abundance of Vibrionaceae and other Mycoplasma species previously linked to the cestode microbiota. The cestode-associated Mycoplasma carry more virulence-associated genes than the salmonid Mycoplasma. Colonisation by one cestode-associated Mycoplasma was associated with a region of the salmon genome encoding several long noncoding RNA genes previously associated with host control of intestinal microbiota. Integrating the multiple omic datasets revealed coordinated changes in the salmon gut transcriptome and metabolome that correlated with shifts in the microbiota of smaller, parasitised fish. Our results suggest that cestode infections introduce new microbes and trigger host responses, altering the gut microbiota with increases in potentially pathogenic microbes. Establishment of these microbes is partially shaped by the genetic background of the host. Our study highlights the value of a hologenomic approach for gaining an in-depth understanding of trilateral interactions among host, microbiota and parasite.

systems biology↗

bioRxiv2021

LIGHTHOUSE illuminates therapeutics for a variety of diseases including COVID-19

One of the bottlenecks in the application of basic research findings to patients is the enormous cost, time, and effort required for high-throughput screening of potential drugs for given therapeutic targets. Here we have developed LIGHTHOUSE, a graph-based deep learning approach for discovery of the hidden principles underlying the association of small-molecule compounds with target proteins. Without any 3D structural information for proteins or chemicals, LIGHTHOUSE estimates protein-compound scores that incorporate known evolutionary relations and available experimental data. It identified novel therapeutics for cancer, lifestyle-related disease, and bacterial infection. Moreover, LIGHTHOUSE predicted ethoxzolamide as a therapeutic for coronavirus disease 2019 (COVID-19), and this agent was indeed effective against alpha, beta, gamma, and delta variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that are rampant worldwide. We envision that LIGHTHOUSE will bring about a paradigm shift in translational medicine, providing a bridge from bench side to bedside.

systems biology↗

bioRxiv2021

Genome-wide association study of gastric cancer- and duodenal ulcer-derived Helicobacter pylori strains reveals discriminatory amino acid differences and novel oncoprotein candidates

Genome-wide association studies (GWASs) can reveal genetic variations associated with a phenotype in the absence of any hypothesis of candidate genes. The problem of false-positive sites linked with the responsible site might be bypassed in bacteria with a high homologous recombination rate, such as Helicobacter pylori, which causes gastric cancer (GC). We conducted a GWAS followed by regression-based prediction of GC and duodenal ulcer H. pylori strains. We identified 14 single nucleotide polymorphisms (11 amino acid changes) that, combined, allowed effective disease discrimination. They were often informative of the underlying molecular mechanisms, such as electric charge alteration at the ligand-binding pocket, alteration in subunit interaction, and mode-switching of DNA methylation. We also identified three novel virulence factors/oncoprotein candidates. These results provide both defined targets for further informatic and experimental analyses to gain insights into GC pathogenesis and a basis for identifying a set of biomarkers for application in clinical settings.

physiology↗

bioRxiv2020

Gating mechanism of cardiac ryanodine receptor 2 upon calcium ion binding

Cardiac ryanodine receptor (RyR2) is a large Ca2+ release channel in the sarcoplasmic reticulum and indispensable for excitation-contraction coupling in the heart. RyR2 is activated by Ca2+ and RyR2 mutations are implicated in severe arrhythmogenic diseases. Yet, the structural basis underlying channel opening and how mutations affect the channel remain unknown. Here, we addressed gating mechanism of RyR2 by combining high-resolution structures determined by cryo-electron microscopy with quantitative functional analysis of channels carrying various mutations in specific residues. We demonstrated two fundamental mechanisms for channel gating: interactions close to the channel pore stabilize the channel to prevent hyperactivity and a series of interactions in the surrounding regions is necessary for channel opening upon Ca2+ binding. Mutations at the residues involved in the former and the latter mechanisms cause gain-of-function and loss-of-function, respectively. Our results reveal gating mechanisms of the RyR2 channel and alterations by pathogenic mutations at the atomic level.

biochemistry↗

bioRxiv2020

Genome sequence of Hydrangea macrophylla and its application in analysis of the double flower phenotype

Owing to its high ornamental value, the double flower phenotype of hydrangea (Hydrangea macrophylla) is one of its most important traits. In this study, genome sequence information was obtained to explore effective DNA markers and the causative genes for double flower production in hydrangea. Single molecule real-time sequencing data followed by a HiC analysis was employed. The resultant haplotype-phased sequences consisted of 3,779 sequences (2.256 Gb in length and N50 of 1.5 Mb), and 18 pseudomolecules comprising 1.08 Gb scaffold sequences along with a high-density SNP genetic linkage map. Using the genome sequence data obtained from two breeding populations, the SNPs linked to double flower loci (Djo and Dsu), were discovered for each breeding population. DNA markers J01 linked to Djo and S01 linked to Dsu were developed, and these could be used successfully to distinguish the recessive double flower allele for each locus respectively. The LEAFY gene was suggested as the causative gene for Dsu, since frameshift was specifically observed in double flower accession with dsu. The genome information obtained in this study will facilitate a wide range of genomic studies on hydrangea in the future.

genomics↗