Biology subjects

Yokoyama, S.

Publications and source records attributed to Yokoyama, S..

14 recordsLinked to original sources

bioRxiv2026

Loss of NKX2-1 predisposes thyroid to neoplasm development through regulation of oxidative stress

Many factors including ionizing radiation and iodine deficiency are known to increase thyroid carcinogenesis risk. Our dataset analysis of The Cancer Genome Atlas (TCGA) showed that lower mRNA expression of NK2 homeobox 1 (NKX2-1) transcription factor, a master regulator of genesis, homeostasis, and function of thyroid, is linked to poor prognosis of papillary thyroid cancer patients. Here we provide the findings that thyroid-specific Nkx2-1 conditional knockout (Nkx2-1{Delta}T) mice develop thyroid adenoma and carcinoma in higher frequency with combined exposure to radiation and iodine deficiency than control Nkx2-1fl/fl mice. Iodine deficiency caused oxidative stress, which subsequently resulted in DNA damage, leading to transformation of thyroid follicular cells. RNA-seq gene set enrichment analysis indicated higher production of reactive oxygen species (ROS) in the thyroids of Nkx2-1{Delta}T as compared to Nkx2-1fl/fl mice with combined exposure to radiation and iodine deficiency. This was accompanied by a feedback induction of SOD3 (superoxide dismutase 3) and GPX2 (glutathione peroxidase 2). These antioxidants were naturally expressed at higher levels in the thyroids of Nkx2-1{Delta}T than Nkx2-1fl/fl mice without iodine deficiency or radiation. Nkx2-1{Delta}T thyroids exhibited abnormal follicle architecture and up-regulation of Acox2 (encoding acyl-CoA oxidase 2), which produces hydrogen peroxide. These results suggest that loss of NKX2-1 may contribute to excess ROS production, which elevates basal oxidative stress resulting in the promotion of ROS-induced carcinogenesis. We propose a role for NKX2-1 as a regulator of ROS production homeostasis in the thyroid. Its disturbance would dispose thyroid follicular cells more vulnerable to the ROS-producing carcinogens.

cancer biology↗

bioRxiv2025

A bifunctional optical reporter for tracking estrogen response dynamics in neurons

Estrogens are inherently dynamic signaling molecules whose fluctuations induce profound shifts in physiology and behavior. However, methods for tracking the dynamics of estrogen action in vivo are limited and not tissue-specific, making it difficult to directly relate dynamics to ongoing physiological, behavioral, and neural changes. Traditionally, estrogen sensitive cells have been identified by metrics such as receptor expression or radioactive ligand binding, but these measures do not capture the dynamic nature of hormone response. In addition, current methods for assessing the dynamics of estrogens in an individual, including microdialysis and vaginal cytology, lack temporal and spatial resolution.To address this need we developed a bifunctional reporter called neuro-seeER (neuronal see Estrogen Response) that can be used to track changes in exogenous and endogenous estrogen dynamics in vitro and in vivo, including longitudinally in behaving animals. We confirmed that the fluorescent response requires estrogen receptor expression, is specific to activation with estradiol, and is consistent with the timescale of transcriptional induction. Neuro-seeER expression in the hypothalamus of Esr1-Cre mice revealed dynamic labeling of estrogen-responsive cells following treatment with exogenous estradiol, and fluorescence-aided cell sorting followed by RNA-sequencing confirmed that high neuro-seeER response is associated with enriched expression of genes associated with endogenous estrogen responses. Using a novel "snapshot" photometry method to track the dynamics longitudinally in vivo, we demonstrate that we can robustly detect exogenous estrogen response across multiple hypothalamic sites simultaneously. Finally, we demonstrate that this tool is uniquely suited to capturing endogenous estrogen response dynamics in vivo across the long timescale of the estrous cycle, revealing individual differences in neural estrogen dynamics. Together, these findings reveal unexpected cellular and temporal heterogeneity of the transcriptional response and demonstrate the feasibility of tracking the dynamics of hormonal response alongside additional neural, cell signaling, or behavioral measures.

neuroscience↗

bioRxiv2025

Immune-induced TCR-like antibodies regulate specific T cell response

Antigen-specific regulation of T cell response is crucial for limiting hyperimmune response. In this study, we discovered that antibodies specific to the antigen peptide-MHC class II complex are produced during helper T cell responses to various antigens. These antibodies specifically inhibited T cell receptor (TCR) recognition of MHC class II molecules presenting specific antigen peptide. We have termed these antibodies immuneinduced TCR-like antibodies (iTabs). Immunization with peptides containing flanking residues induced iTabs, whereas immunization with peptides lacking flanking residues did not. Furthermore, immunization of iTab-inducible peptide as well as iTab treatment suppressed autoimmune disease development. Our findings provide a strategy for suppressing antigen-specific helper T cell responses using specific peptides, potentially controlling autoimmune diseases.

immunology↗

bioRxiv2024

Comprehensive evaluation of pipelines for diagnostic biomarkers of major depressive disorder using multi-site resting-state fMRI datasets

The objective diagnostic and stratification biomarkers developed with resting-state functional magnetic resonance imaging (rs-fMRI) data are expected to contribute to more effective treatment for mental disorders. Unfortunately, there are currently no widely accepted biomarkers, partially due to the large variety of analysis pipelines for developing them. In this study we comprehensively evaluated analysis pipelines using a large-scale, multi-site fMRI dataset for major depressive disorder (MDD) (1162 participants from eight imaging sites). We explored the combinations of options in four subprocesses of analysis pipelines: six types of brain parcellation, four types of estimations of functional connectivity (FC), three types of site difference harmonization, and five types of machine learning methods. 360 different MDD diagnostic biomarkers were constructed using the SRPBS dataset acquired with unified protocols (713 participants from four imaging sites) as a discovery dataset and evaluated with datasets from other projects acquired with heterogeneous protocols (449 participants from four imaging sites) for independent validation. To identify the optimal options regardless of the discovery dataset, we repeated the same procedure after swapping the roles of the two datasets. We found pipelines that included Glassers parcellation, tangent-covariance, no harmonization, and non-sparse machine learning methods tended to result in high classification performance. The diagnosis results of the top 10 biomarkers showed high similarity, and weight similarity was also observed between eight of the biomarkers, except two that used both data-driven parcellation and FC computation. We applied the top 10 pipelines to the datasets of other mental disorders (autism spectral disorder: ASD and schizophrenia: SCZ) and eight of the ten biomarkers showed sufficient classification performances for both disorders, except two pipelines that included Pearson correlation, ComBat harmonization and random forest classifier combination. HighlightsO_LIWe evaluated the analysis pipelines of rsFC biomarker development. C_LIO_LIFour subprocesses in them were investigated with two multi-site datasets. C_LIO_LIGlassers parcellation, tangent covariance, and non-sparse methods were preferred. C_LIO_LIThe weight patterns of eight of the top 10 biomarkers showed high commonality. C_LIO_LIEight of the top 10 pipelines were successful for developing SCZ/ASD biomarkers. C_LI

neuroscience↗

bioRxiv2024

ABCA1 deficiency causes tissue-specific dysregulation of the SREBP2 pathway in mice

The ATP-binding cassette transporter ABCA1 plays an essential role in the formation of high-density lipoprotein (HDL) by mediating phospholipid and cholesterol efflux to apolipoprotein A-I. In humans, loss-of-function mutations in the ABCA1 gene cause Tangier disease (TD), a familial HDL deficiency. In addition to the disappearance of HDL, TD patients and Abca1-/- mice exhibit the cholesterol deposition in peripheral tissues through a mechanism poorly understood, which may contribute to the development of premature atherosclerosis. We and others have shown that ABCA1 deficiency causes hyperactivation of the sterol regulatory element-binding protein 2 (SREBP2) pathway in vitro. In this work, we investigate whether ABCA1 deficiency affects SREBP2-dependent cholesterol homeostatic responses in vivo. We show that SREBP2 response gene expression is partly downregulated in the liver of Abca1-/- mice compared to wild-type mouse livers in the steady-state condition. In contrast, we find that in fasted or refed condition, the expression of SREBP2 target genes is upregulated in multiple tissues of Abca1-/- mice. Correspondently, SREBP2 processing is also increased in select tissues of these mice. Altogether, our results suggest that ABCA1 deficiency is associated with the tissue-specific dysregulation of the SREBP2 pathway in a manner dependent on nutritional status. Lack of ABCA1 thus causes not only HDL deficiency but also dysregulation of the SREBP2 pathway in multiple tissues, which may underlie the pathophysiology of TD.

physiology↗

bioRxiv2023

CD38 assigns physiological function to soluble uric acid

Excessive elevation or reduction of soluble uric acid (sUA) levels has been linked to some of pathological states, raising another subject that sUA at physiological levels may be essential for the maintenance of health. Yet, the fundamental physiological functions and molecular targets of sUA remain largely unknown. Using enzyme assays and in vitro and in vivo metabolic assays, we demonstrate that sUA directly inhibits the hydrolase and cyclase activities of CD38 via a reversible non-competitive mechanism, thereby limiting nicotinamide adenine dinucleotide (NAD+) degradation. CD38 inhibition is restricted to sUA in purine metabolism, and a structural comparison using methyl analogs of sUA such as caffeine metabolites shows that 1,3-dihydroimidazol-2-one is the main functional group. Moreover, sUA at physiological levels prevents crude lipopolysaccharide (cLPS)-induced systemic inflammation and monosodium urate (MSU) crystal-induced peritonitis in mice by interacting with CD38. Together, this study unveils an unexpected physiological role for sUA in controlling NAD+ availability and innate immunity through CD38 inhibition, providing a new perspective on sUA homeostasis and purine metabolism.

physiology↗

bioRxiv2022

Dopamine Activates Astrocytes in Prefrontal Cortex via α1-Adrenergic Receptors

The prefrontal cortex (PFC) is a hub for cognitive control, and dopamine profoundly influences its functions. In other brain regions, astrocytes sense diverse neurotransmitters and neuromodulators and, in turn, orchestrate regulation of neuroactive substances. However, basic physiology of PFC astrocytes, including which neuromodulatory signals they respond to and how they contribute to PFC function, is lacking. Here, we characterize divergent signaling signatures in astrocytes of PFC and primary sensory cortex in mice, which are linked to differential responsivity to locomotion. We find that PFC astrocytes express receptors for dopamine, but are unresponsive through the Gs/Gi-cAMP pathway. Instead, fast calcium signals in PFC astrocytes are time-locked to dopamine release, and are mediated by 1-adrenergic receptors both ex vivo and in vivo. Further, we describe dopamine-triggered regulation of extracellular ATP at PFC astrocyte territories. Thus, we identify astrocytes as active players in dopaminergic signaling in PFC, contributing to PFC function though neuromodulator receptor crosstalk. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/500710v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@e71858org.highwire.dtl.DTLVardef@1ef506forg.highwire.dtl.DTLVardef@89e4edorg.highwire.dtl.DTLVardef@11483e1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Mechanosensitive Ion Channel Piezo1 Regulates Myocyte Fusion during Skeletal Myogenesis

Mechanical stimuli such as stretch and resistance training are essential to regulate growth and function of skeletal muscle. However, the molecular mechanisms involved in sensing mechanical stress during muscle formation remain unclear. Here, we investigate the role of the mechano-sensitive ion channel Piezo1 during myogenic progression. Direct manipulation of Piezo1 in muscle stem cells alters their myogenic progression. Indeed, Piezo1 knockdown suppresses myoblast fusion leading to smaller myotubes. Such event is accompanied by significant downregulation of the fusogenic protein Myomaker. In parallel, while Piezo1 knockdown also lowers Ca2+ influx in response to stretch, Piezo1 activation increases Ca2+ influx in response to stretch and enhances myoblasts fusion. We believe these findings may help understand molecular defects present in some muscle diseases. Altogether our study shows that Piezo1 is essential for terminal muscle differentiation acting on myoblast fusion, suggesting that Piezo1 deregulation may have implications in muscle aging and degenerative diseases including muscular dystrophies.

molecular biology↗

bioRxiv2020

Extra-hypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance

Oxytocin increases the salience of both positive and negative social contexts and it is thought that these diverse actions on behavior are mediated in part through circuit-specific action. This hypothesis is based primarily on manipulations of oxytocin receptor function, leaving open the question of whether different populations of oxytocin neurons mediate different effects on behavior. Here we inhibited oxytocin synthesis in a social stress-sensitive population of oxytocin neurons specifically within the medioventral bed nucleus of the stria terminalis (BNSTmv). Oxytocin knock-down prevented stress-induced increases in social vigilance and decreases in social approach. Viral tracing of BNSTmv oxytocin neurons revealed fibers in regions controlling defensive behaviors including lateral hypothalamus, anterior hypothalamus, and anteromedial BNST (BNSTam). Oxytocin infusion into BNSTam in stress naive mice increased social vigilance and reduced social approach. These results show that a population of extra-hypothalamic oxytocin neurons play a key role in controlling stress-induced social anxiety behaviors.

neuroscience↗

bioRxiv2019

Lin28a/let-7 Pathway Modulates the Hox Code via Polycomb Regulation during Axial Patterning in Vertebrates

The body plan along the anteroposterior axis and regional identities are specified by the spatiotemporal expression of Hox genes. Multistep controls are required for their unique expression patterns; however, the molecular mechanisms behind the tight control of Hox genes are not fully understood. In this study, we demonstrated that the Lin28a/let-7 reciprocal regulatory pathway is critical for vertebral specification. Lin28a-/- mice exhibited homeotic transformations of vertebrae which were caused by the global dysregulation of posterior Hox genes. The accumulation of let-7-family microRNAs in Lin28a-/- mice resulted in the reduction of PRC1 occupancy at the Hox cluster loci by targeting Cbx2. Consistently, Lin28a loss in embryonic stem-like cells led to aberrant induction of posterior Hox genes, which was rescued by the knockdown of let-7-family microRNAs. These results suggest that Lin28/let-7 pathway is possibly involved in the modulation of the "Hox code" via Polycomb regulation during axial patterning in vertebrates.

developmental biology↗

bioRxiv2019

Deformable mirror-based two-photon microscopy for axial mammalian brain imaging

This work presents the design and implementation of an enhanced version of a traditional two-photon (2P) microscope with the addition of high-speed axial scanning for live mammalian brain imaging. Our implementation utilizes a deformable mirror (DM) that can rapidly apply different defocus shapes to manipulate the laser beam divergence and consequently control the axial position of the beam focus in the sample. We provide a mathematical model describing the DM curvature, then experimentally characterize the radius of curvature as well as the Zernike terms of the DM surface for a given set of defocuses. A description of the optical setup of the 2P microscope is detailed. We conduct a thorough calibration of the system, determining the point spread function, the total scanning range, the axial step size, and the intensity curvature as a function of depth. Finally, the instrument is used for imaging different neurobiological samples, including fixed brain slices and in vivo mouse cerebral cortex.

neuroscience↗

bioRxiv2019

Characteristics of University Students Supported by Counseling Services: Analysis of psychological tests and pulse rate variability

ObjectiveThe number of students who use counseling services is increasing in universities. We clarified the characteristics of the students who access counseling services using both psychological tests and pulse rate variability (PRV).\n\nMethodsWe recruited the participants for this study from the students who had counseling sessions at Kanazawa University (Group S). As a control group, we also recruited students who had no experience in counseling sessions (Group H). We obtained health information from the database of annual health check-ups. Participants received the Wechsler Adult Intelligence Scale (WAIS) III, Autism-Spectrum Quotient (AQ), Sukemune-Hiew (S-H) Resilience Test, and State-Trait Anxiety Inventory-JYZ (STAI). We also studied the SF-12v2 Health Survey. We examined the spectral analyses of pulse rate variability (PRV) by accelerating plethysmography. We performed linear analysis of PRV for LF, HF, and LF/HF as indexes of autonomic nervous function. We also performed non-linear analysis of PRV for the largest Lyapunov exponent (LLE). We examined participants blood for autoantibodies against glutamate decarboxylase (GAD) 65.\n\nResultsA total of 105 students participated in this study. Group S had 37 participants (Male: 26, Female: 11) and Group H had 68 participants (Male: 27, Female 41). There were 12 males and two females who had been diagnosed with autism spectrum disorder (ASD) in Group S. Group S had 1) lower Working Memory Index (WMI) despite relatively high Full-Scale IQ, 2) higher AQ scores, 3) lower resilience scores, 4) higher anxiety scores, 5)lower QOL in social health, and 6) shifting of autonomic nervous balance toward higher sympathetic activity. There were only two participants who had the anti-GAD65 antibody in Group S, and one participant had the anti-GAD65 antibody in Group H.\n\nConclusionThe results of our study revealed valuable information about the students who seek mental support in our university. Our results provide information that can be used in interventions for the university students who need counseling services.

neuroscience↗

bioRxiv2018

Ciliary and rhabdomeric photoreceptor-cell circuits form a spectral depth gauge in marine zooplankton

Ciliary and rhabdomeric photoreceptor cells represent two main lines of photoreceptor evolution in animals. The two photoreceptor-cell types coexist in some animals, however how they functionally integrate is unknown. We used connectomics to map synaptic paths between ciliary and rhabdomeric photoreceptors in the planktonic larva of the annelid Platynereis and found that ciliary photoreceptors are presynaptic to the rhabdomeric circuit. The behaviors mediated by the ciliary and rhabdomeric cells also interact hierarchically. The ciliary photoreceptors are UV-sensitive and mediate downward swimming to non-directional UV light, a behavior absent in ciliary-opsin knockouts. UV avoidance antagonizes positive phototaxis mediated by the rhabdomeric eyes so that vertical swimming direction is determined by the ratio of blue/UV light. Since this ratio increases with depth, Platynereis larvae may use it as a depth gauge during planktonic migration. Our results revealed a functional integration of ciliary and rhabdomeric photoreceptors with implications for eye and photoreceptor evolution.

neuroscience↗

bioRxiv2017

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Interestingly, although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed. In addition, a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and independent manner.

molecular biology↗