Biology subjects

Ishibashi, N.

Publications and source records attributed to Ishibashi, N..

6 recordsLinked to original sources

bioRxiv2026

Tetrahydrobiopterin restores oligodendrocyte maturation after hypoxic white matter injury by reprogramming translational output

Complex congenital heart defects (CHDs) are frequently associated with chronic cerebral hypoxemia, leading to impaired white matter maturation. One proposed mechanism involves hypoxia-induced disruption of the nitric oxide synthase cofactor tetrahydrobiopterin (BH4), resulting in oxidative stress and impaired oligodendrocyte (OL) development. While our previous studies found BH4 supplementation improves hypoxia-induced white matter dysmaturation, the molecular mechanisms remain incompletely understood. Because OL maturation requires coordinated translational control, we hypothesized that BH4 promotes white matter maturation by restoring translation programs disrupted by hypoxia.Translating Ribosome Affinity Purification sequencing (TRAP-seq) was performed on OL lineage cells isolated from transgenic ribosomal reporter mice exposed to chronic hypoxia with or without daily BH4 treatment. Differential translation, weighted gene co-expression network analysis, pathway enrichment, RNAscope, and immunohistochemistry identified translational programs associated with hypoxia and BH4-mediated rescue. Developmental hypoxia extensively altered the OL translatome, suppressing transcripts associated with OL maturation while enriching pathways related to translational regulation and cellular stress. Network analyses identified BH4-responsive gene modules enriched for OL maturation, protein metabolism, and translation-related processes. BH4 partially reversed hypoxia-induced translational changes, restored OL maturation gene expression, and normalized nuclear localization of the lineage regulator OLIG1, consistent with recovery of maturation-associated regulatory programs. Developmental hypoxia disrupts OL maturation through coordinated alterations in ribosome-associated gene expression and post-transcriptional regulatory pathways. BH4 promotes recovery of OL maturation programs, including restoration of translation-related networks and OLIG1 nuclear localization, providing mechanistic insight into BH4-supported white matter maturation under chronic hypoxic conditions.

neuroscience↗

bioRxiv2026

MARiO: predicting cancer variant pathogenicity by integrating in silico evaluation and patient-level mutational contexts

Comprehensive genomic profiling (CGP) supports precision medicine in cancer care, but accurate assessment of missense variant pathogenicity, especially for variants without established consensus, remains challenging. Various computational tools have been developed for variant functional prediction, but most current tools rely solely on variant-level features and do not capture the clinical context of individual patients. To address this limitation, we developed MARiO (Missense Alteration Risk for Oncogenicity), a machine-learning model that integrates variant-level features and patient-level clinical and genomic contexts to effectively predict the pathogenicity of missense variants in cancer. We collected a total of 10,642 missense variants from 1271 patients, and evaluated candidate features for their association with variant pathogenicity, identifying informative features including in silico functional predictions, population allele frequency, variant allele frequency, and tumor mutational burden. Using these selected features, MARiO was developed with extreme gradient boosting. The model integrates multiple in silico prediction tools and patient-specific genomic contexts while accommodating missing values frequently observed in real-world CGP datasets. MARiO outperformed existing tools, achieving an area under the receiver operating characteristic curve of 0.942. The model demonstrated strong generalizability across multiple external datasets and showed consistency with real-world molecular treatment proposals. MARiO offers a robust and clinically relevant approach for missense variant pathogenicity assessment by integrating variant- and patient-level features and serves as a valuable tool to support clinical decision-making.

bioinformatics↗

bioRxiv2025

Arabidopsis epigenetic factor AS2 attenuates nucleolar stress by camptothecin and establishes leaf polarity by repressing a CDK inhibitor

The Arabidopsis thaliana leaf, exhibiting a symmetrically extended flat morphology, consists of two distinct cellular domains: adaxial and abaxial layers. The ASYMMETRIC LEAVES2 (AS2) gene is essential for specifying the adaxial domain, and its protein forms nucleolar structures, termed AS2 bodies, at ribosomal-DNA loci. Numerous nucleolus-related genes have been reported to be cooperatively involved in leaf adaxialization together with AS2. However, the molecular relationships between AS2 and these genes remain unclear. To identify chemical modulators of AS2 function, we screened a chemical library containing natural products and identified eight molecules, including camptothecin, that induced filamentous leaves in the as2 mutant. Camptothecin is an inhibitor of topoisomerase I, which is required for transcription of ribosomal-RNA genes, and induces nucleolar stress. Treatment with 10-hydroxy-camptothecin increased KIP-RELATED-PROTEIN5/INHIBITOR-OF-CYCLIN-DEPENDENT-KINASE3 (KRP5/ICK3) transcript levels, encoding a CDK inhibitor, and caused notable changes in the number and morphology of AS2 bodies. Given its role in leaf morphogenesis, our findings suggest that AS2 is a key factor in establishing leaf adaxial-abaxial polarity by regulating cell proliferation and protecting against nucleolar stress through coordinated interactions with nucleolar proteins.

developmental biology↗

bioRxiv2025

Functionally-structured Bayesian model for localizing neural activity and information in magnetoencephalography signals

Magnetoencephalography (MEG) is a noninvasive method that can measure human brain activity with high temporal resolution. However, the spatial resolution of MEG is not sufficient to reveal neural mechanisms. Although MEG source estimation overcomes this problem to some extent, the combination of MEG source estimation and multivariate analysis results in "information spreading", where significant predictions are observed in brain areas outside the true signal source location. This paper describes a model that achieves high source estimation accuracy and suppresses information spreading simultaneously. The proposed approach is based on a Bayesian estimation model that utilizes functional structure of the human brain. We compare the performance of the proposed model with simulated data generated under various signal-to-noise ratio conditions. The results show that the functionally-structured Bayesian model achieves source estimation accuracy that is better than that of conventional source estimation models. Additionally, the comparison of information spreading among the models reveals that our model outperforms the conventional ones. These results suggest that information spreading in the MEG source estimation can be suppressed while maintaining high source estimation accuracy.

neuroscience↗

bioRxiv2024

Ciliopathy interacts with neonatal anesthesia to cause non-apoptotic caspase-mediated motor deficits

Increasing evidence suggests that anesthesia may induce developmental neurotoxicity, yet the influence of genetic predispositions associated with congenital anomalies on this toxicity remains largely unknown. Children with congenital heart disease often exhibit mutations in cilia-related genes and ciliary dysfunction, requiring sedation for their catheter or surgical interventions during the neonatal period. Here we demonstrate that briefly exposing ciliopathic neonatal mice to ketamine causes motor skill impairments, which are associated with a baseline deficit in neocortical layer V neuron apical spine density and their altered dynamics during motor learning.. These neuromorphological changes were linked to augmented non-apoptotic neuronal caspase activation. Neonatal caspase suppression rescued the spine density and motor deficits, confirming the requirement for sublethal caspase signaling in appropriate spine formation and motor learning. Our findings suggest that ciliopathy interacts with ketamine to induce motor impairments, which is reversible through caspase inhibition. Furthermore, they underscore the potential for ketamine- induced sublethal caspase responses in shaping neurodevelopmental outcomes.

neuroscience↗

bioRxiv2020

Chronic Perinatal Hypoxia Delays Cardiac Maturation in a Mouse Model for Cyanotic Congenital Heart Disease

BackgroundCompared to acyanotic congenital heart disease (CHD), cyanotic CHD has an increased risk of lifelong mortality and morbidity. These adverse outcomes may be attributed to delayed cardiomyocyte maturation, since the transition from a hypoxic fetal milieu to oxygen rich postnatal environment is disrupted. We established a rodent model to replicate hypoxic myocardial conditions spanning perinatal development, and tested the hypothesis that chronic hypoxia impairs cardiac development. MethodsMouse dams were housed in hypoxia beginning at embryonic day 16. Pups stayed in hypoxia until postnatal day (P)8 when cardiac development is nearly complete. Global gene expression was quantified at P8 and at P30, after recovering in normoxia. Phenotypic testing included electrocardiogram, echocardiogram, and ex-vivo electrophysiology study. ResultsHypoxic animals were 48% smaller than controls. Gene expression was grossly altered by hypoxia at P8 (1427 genes affected), but normalized after recovery (P30). Electrocardiograms revealed bradycardia and slowed conduction velocity in hypoxic animals at P8, which resolved after recovery (P30). Notable differences that persisted after recovery (P30) included a 65% prolongation in ventricular effective refractory period, sinus node dysfunction, and a 24% reduction in contractile function in animals exposed to hypoxia. ConclusionsWe investigated the impact of chronic hypoxia on the developing heart. Perinatal hypoxia was associated with changes in gene expression and cardiac function. Persistent changes to the electrophysiologic substrate and contractile function warrant further investigation, and may contribute to adverse outcomes observed in the cyanotic CHD population.

physiology↗