Biology subjects

Sugimoto, M.

Publications and source records attributed to Sugimoto, M..

12 recordsLinked to original sources

bioRxiv2026

Mouse suppressyn-like 1 is an endogenous retrovirus-derived inhibitor of membrane fusion through direct association with envelope glycoproteins

Cell-cell fusion is essential for placental development and is mediated by endogenous retrovirus (ERV)-derived fusogens known as syncytins. However, how ERV-derived proteins negatively regulate membrane fusion remains largely unknown. Here, we identify a previously uncharacterized murine ERV envelope-derived protein, mouse suppressyn-like 1 (mSUPYNL1), that suppresses syncytin-mediated membrane fusion through a mechanism distinct from that of placental human suppressyn (hSUPYN). Unlike hSUPYN, which acts through receptor interference, mSUPYNL1 inhibits both murine and human syncytin-mediated fusion independently of receptor usage by associating with the surface (SU) subunits of multiple syncytin envelope glycoproteins, revealing a receptor-independent mechanism of fusion suppression. This mechanism extends beyond endogenous fusogens. mSUPYNL1 also associates with the SU glycoprotein (gp46) of Human T-cell Leukemia Virus type 1 (HTLV-1) and suppresses Env-dependent syncytium formation, whereas hSUPYN showed no detectable antiviral activity in this assay. These findings identify mSUPYNL1 as a broad-spectrum inhibitor of envelope glycoprotein-mediated membrane fusion. Analysis of mSUPYNL1 knockout mice revealed that, in contrast to the placenta-restricted expression of hSUPYN, mSUPYNL1 was broadly expressed, with its most prominent localization in decidual stromal and vascular endothelial cells of the pregnant uterus, as well as in hematopoietic tissues such as the spleen and thymus. Together, our findings uncover an evolutionarily distinct class of ERV-derived fusion suppressors that function through envelope glycoprotein recognition instead of receptor interference. Our study expands current models of ERV domestication by demonstrating that retroviral envelope proteins have been independently co-opted not only to promote membrane fusion but also to restrain it, thereby linking placental biology, antiviral defense, and host evolution. HIGHLIGHTSO_LImSUPYNL1 is an endogenous retrovirus-derived membrane fusion inhibitor C_LIO_LImSUPYNL1 binds the SU domains of murine and human syncytins C_LIO_LImSUPYNL1 suppresses HTLV-1 Env-mediated syncytium formation C_LIO_LIDirect envelope recognition enables receptor-independent fusion inhibition C_LI

developmental biology↗

bioRxiv2026

Identification of a pharmacokinetic interaction between teicoplanin and sulfo-butyl ether-β-cyclodextrin, an excipient in the intravenous posaconazole formulation

Patients undergoing hematopoietic stem cell transplantation (HSCT) often receive multiple antibiotics and antifungals concurrently, making it crucial to understand their potential pharmacokinetic interactions of these agents. We report here an interaction between the glycopeptide antibiotic teicoplanin (TEIC) and sulfo-butyl ether-{beta}-cyclodextrin (SBECD), a solubilizing excipient in the intravenous formulation of posaconazole (PSCZ). We performed a single-center retrospective analysis of patients who underwent HSCT and received oral and intravenous PSCZ during TEIC therapy. The associations between PSCZ administration and TEIC concentration-to-dose (C/D) ratios were evaluated using linear mixed-effects models. We also examined the effects of intravenous PSCZ and SBECD on TEIC pharmacokinetics in rats by assessing the area under the concentration-time curve (AUC) and urinary excretion of total TEIC and its components. In addition, molecular docking and in vitro protein-binding assays were conducted to investigate the interaction between TEIC and SBECD. In patients who underwent HSCT, TEIC C/D ratio was significantly lower following intravenous PSCZ administration than without administration. In contrast, the effect of oral PSCZ administration relative to non-administration was not statistically significant. In rats, intravenous PSCZ and SBECD decreased the AUC of TEIC and increased urinary excretion, particularly in the A2 group. Docking simulations indicated that the hydrophobic side chain of TEIC A2-2 fit within the SBECD cavity, and in vitro assays confirmed SBECD concentration-dependent increases in TEIC unbound fractions. The co-administration of intravenous PSCZ containing SBECD may reduce TEIC protein binding, thereby enhancing renal excretion.

pharmacology and toxicology↗

bioRxiv2025

Transcranial Static Magnetic Stimulation Dissociates the Causal Roles of the Parietal Cortex in Spatial and Temporal Processing

Accurate time estimation is essential for optimizing our perception and actions. Previous neuroimaging and transcranial magnetic stimulation (TMS) studies have suggested that the right inferior parietal lobule (IPL) and supplementary motor area (SMA) are involved in time perception. However, it remains inconclusive whether the activity in these regions is crucial for time perception, partly due to the possible spread of TMS effects across anatomically connected brain regions. Such a remote effect is less likely to happen with transcranial static magnetic stimulation (tSMS), as the static magnetic field is expected to modulate the firing threshold of neurons rather than directly triggering an action potential. In this study, we aimed to determine the causal relevance of local activities in the right IPL and the SMA for temporal processing using tSMS. 48 human volunteers (26 males and 22 females) participated in the study. We measured duration discrimination thresholds, along with orientation discrimination thresholds, using staircase methods before and during the administration of tSMS over the IPL/SMA. Our results indicated no significant changes in duration discrimination thresholds in either the IPL or SMA conditions. In contrast, we observed an improvement in orientation discrimination thresholds in the IPL condition. This improvement correlated with individual differences in the distance between the scalp and the IPL. Overall, our findings demonstrate a causal involvement of the IPL in orientation processing. The correlation between the effects of tSMS and the scalp-to-target distance suggests that the efficacy of tSMS may be sensitive to the magnetic field strength. Significance StatementAccurate time estimation is essential for optimizing our perception and actions. While prior studies using transcranial magnetic stimulation (TMS) investigated a role of inferior parietal lobule (IPL) and supplementary motor area in spatiotemporal processing, the results have been inconclusive because TMS can affect anatomically connected areas. Here, using transcranial static magnetic stimulation (tSMS), we examined the causal relevance of local activities in these areas. Our findings showed that tSMS over the IPL did not alter duration discrimination but, unexpectedly, significantly enhanced orientation discrimination, with the degree of improvement correlating with individual anatomical differences. These results provide new insights into the neural basis of spatial and temporal processing and emphasize the potential of tSMS as a localized neuromodulation technique of interest.

neuroscience↗

bioRxiv2024

Serine chirality guides metabolic flow between one-carbon metabolism and neuromodulator synthesis

O_SCPLOWLC_SCPLOW-serine serves as a central metabolic node that integrates glycolytic flux, lipid metabolism, and one-carbon metabolism. In the mature central nervous system, O_SCPLOWLC_SCPLOW-serine is actively stereo-converted to O_SCPLOWDC_SCPLOW-serine, which functions as a neurotransmitter. However, the role of O_SCPLOWDC_SCPLOW-serine in cellular metabolism remains unclear. Here, we show that O_SCPLOWDC_SCPLOW-serine competes with mitochondrial O_SCPLOWLC_SCPLOW-serine transport, thereby suppressing one-carbon metabolism. Metabolomic analysis revealed that O_SCPLOWDC_SCPLOW-serine reduces intracellular glycine and formate levels, indicating inhibition of the initial step of the one-carbon pathway. Molecular dynamics simulations and enzymatic assays revealed that O_SCPLOWDC_SCPLOW-serine has low affinity for serine hydroxymethyltransferase 2 (Shmt2), which catalyzes the first step in mitochondrial one-carbon metabolism, and does not directly inhibit its activity. Instead, membrane transport assays demonstrated that O_SCPLOWDC_SCPLOW-serine competes with mitochondrial O_SCPLOWLC_SCPLOW-serine transport, depleting the substrate of Shmt2. Functionally, under O_SCPLOWLC_SCPLOW-serine poor conditions in vitro and ex vivo, O_SCPLOWDC_SCPLOW-serine inhibited the proliferation of immature and undifferentiated neural cells including glioblastoma stem cells, which depend highly on one-carbon metabolism. Notably, endogenous O_SCPLOWDC_SCPLOW-serine levels were low during early neurodevelopment, but increased with maturation, coinciding with a shift in the transcriptional profiles of serine metabolic enzymes at the cellular level. Given that O_SCPLOWLC_SCPLOW-serine supports neurodevelopment and O_SCPLOWDC_SCPLOW-serine modulates neurotransmission, this developmental shift in serine enantiomer metabolism appears to align with the functional transitions of the maturing nervous system. Thus, our findings reveal that serine chirality can influence mitochondrial substrate availability and one-carbon flux, offering previously unappreciated insight into the stereoselective regulation of cellular metabolism.

developmental biology↗

bioRxiv2023

Comparison of classification accuracy and feature selection between sparse and non-sparse modeling of metabolomics data

Machine learnings such as multivariate analyses and clustering have been frequently used for metabolomics data analyses. In metabolomics data analyses, how much difference there is between the results calculated by supervised and unsupervised learning models is an interesting topic. Since metabolomics data include hundreds to thousands of metabolites greater than the sample numbers, only a small fraction of metabolites is relevant to the phenotype of interest. For this reason, sparse mechanisms have been introduced into many machine learning models. However, its explanatory power decreases when the number of explanatory variables is reduced to an extreme level. In this paper, serum lipidomic data of breast cancer patients (1) pre/post-menopause and (2) before/after neoadjuvant chemotherapy was chosen as one of metabolomics data. Here, this data was analyzed by partial least squares (PLS) for regression and K-means and hierarchical clustering for clustering. Results were also compare with the sparse modeling. Between the non-sparse and sparse modeling accuracy, there is no significant difference. Metabolite subsets selected by sparse modeling were almost identical to the PLS-selected features. At the same time, several metabolites were consistently selected regardless of the algorithm used. These results contribute to exploring biomarkers in high-dimensional metabolomics datasets.

bioinformatics↗

bioRxiv2022

The usefulness of sparse k-means in metabolomics data: Anexample from breast cancer data

In processing metabolomics data, multidimensional quantitative data from thousands of metabolites are often sparse, that is, only a small fraction of metabolites are relevant to the phenotype of interest. Clustering is therefore used to discover subtypes from omics data. Sparse processing, which selects important metabolites from the total omics data, is an effective clustering technique. This study investigated the effectiveness of sparse k-means for metabolomics data. Specifically, sparse k-means was used to cluster blood lipid metabolite data of breast cancer patients in two studies: (1) before and after menopause, and (2) pre- and postoperative chemotherapy. In both cases, sparse k-means showed comparable discrimination accuracy with fewer metabolites than k-means. Furthermore, when the L1 norm values were varied, no significant changes were observed. The mean silhouette coefficients of sparse k-means and k-means were (1) 0.38 {+/-} 0.14 (S.D.) and 0.17 {+/-} 0.01, (2) 0.38 {+/-} 0.07 and 0.17 {+/-} 0.01, indicating that feature selection using sparse k-means can improve clustering results. In addition, metabolite selection using sparse k-means was consistent regardless of the test data or the constrained value of the L1 norm, indicating robustness.

bioinformatics↗

bioRxiv2022

Embodiment of Supernumerary Robotic Limbs in Virtual Reality

The supernumerary robotic limb system expands the motor function of human users by adding extra artificially designed limbs. It is important for us to embody the system as if it is a part of ones own body and to maintain cognitive transparency in which the cognitive load is suppressed. Embodiment studies have been conducted with an expansion of bodily functions through a "substitution" and "extension." However, there have been few studies on the "addition" of supernumerary body parts. In this study, we developed a supernumerary robotic limb system that operates in a virtual environment, and then evaluated whether the extra limb can be regarded as a part of ones own body using a questionnaire and whether the perception of peripersonal space changes with a visuotactile crossmodal congruency task. We found that the participants can embody the extra-limbs after using the supernumerary robotic limb system. We also found a positive correlation between the perceptual change in the crossmodal congruency task and the subjective feeling that the number of ones arms had increased (supernumerary limb sensation). These results suggest that the addition of an extra body part may cause the participants to feel that they had acquired a new body part that differs from their original body part through a functional expansion.

neuroscience↗

bioRxiv2020

Circumstances and factors of sleep-related sudden infant deaths in Japan

Background Sudden unexpected death in infancy (SUDI) comprises both natural and unnatural causes of death. However, a few epidemiological surveys have investigated SUDI in Japan.Objective This retrospective study was conducted to investigate the recent trends of circumstances and risk factors of sleep-related SUDI cases.Methods Forensic pathology sections from eight universities participated in the selection of subjects from 2013 to 2018. Data obtained from the checklist form were analyzed based on information at postmortem.Results There were 259 SUDI cases consisting of 145 male infants and 114 female infants with a mean birth weight of 2888 ± 553 and 2750 ± 370 g, respectively. Deaths most frequently occurred among infants at 1 month of age (18%). According to population-based analyses, the odds ratio (95% confidence interval) of mother’s age ≤19 years was 11.1 (6.9–17.7) compared with ages 30–39. The odds ratio for the fourth- and later born infants was 5.2 (3.4–7.9) compared with the frequency of first-born infants. The most frequent time of day for discovery was between 7 and 8 o’clock. Co-sleeping was recorded for 61%, and the prone position was found for 40% of cases at discovery. Mother’s smoking habit exhibited an adds ratio of 4.5 (2.9–5.8).Conclusion This study confirmed the trends that have been observed for sudden infant death syndrome; particularly, very high odds ratios were evident for teenage mothers and later birth order in comparison with those in other developed countries. The child of a young mother tended to die within 2 months of age. To our knowledge, this is the first report of an extensive survey of sleep-related SUDI in Japan.View Full Text

pathology↗

bioRxiv2020

A meiosis-specific factor MRM/C19orf57 modulates localization of RAD51 and DMC1 recombinases to DSBs in mouse meiotic recombination

Meiotic recombination is critical for genetic exchange and generation of chiasmata that ensures faithful chromosome segregation during meiosis I. Meiotic recombination is initiated by DNA double-strand break (DSB) followed by multiple processes of DNA repair. The exact mechanisms how recombinases localize to DSB remained elusive. Here we show that C19orf57/4930432K21Rik/BRME1 is a new player for meiotic recombination in mice. C19orf57/4930432K21Rik/BRME1 associates with ssDNA binding proteins, BRCA2 and MEILB2/HSF2BP, critical recruiters of recombinases onto DSB sites. Disruption of C19orf57/4930432K21Rik/BRME1 shows severe impact on DSB repair and male fertility. Remarkably, removal of single stranded DNA (ssDNA) binding proteins from DSB sites is delayed, and reciprocally the loading of RAD51 and DMC1 onto resected ssDNA is impaired in Brme1 KO spermatocytes. We propose that C19orf57/4930432K21Rik/BRME1 modulates localization of recombinases to meiotic DSB sites through the interaction with the BRCA2-MEILB2/HSF2BP complex during meiotic recombination.

molecular biology↗

bioRxiv2019

Transcriptomic analysis of developing seeds in a wheat mutant RSD32 with reduced seed dormancy

Seed dormancy, a major factor regulating pre-harvest sprouting, can severely hinder wheat cultivation. Abscisic acid biosynthesis and sensitivity play important roles in the regulation of seed dormancy. Reduced Seed Dormancy 32 (RSD32), a wheat mutant with reduced seed dormancy, is derived from the pre-harvest sprouting tolerant cultivar, Norin61. RSD32 is regulated by a single recessive gene and mutant phenotype expressed in a seed-specific manner. Results of this study show that Norin61 has a low germination index (GI) of whole seeds at 50 days after pollination (DAP) and earlier developmental stages. In RSD32, higher GI of whole seeds was found on DAP40. Dormancy was released by DAP50. Gene expressions in embryos of Norin61 and RSD32 were compared using RNA-seq analysis at the different developmental stages of DAP20, DAP30, and DAP40. Numbers of up-regulated gene in RSD32 are similar in all developmental stages. However, down-regulated genes in RSD32 are more numerous on DAP20 and DAP30 than on DAP40. Homologous genes related to circadian clock regulation and Ca2+ signaling pathway, which have fundamental functions for plant growth and development, are involved in down-regulated genes in RSD32 on DAP20. For central components affecting the circadian clock, genes homologous to CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY), which act as morning expressed genes, are expressed at lower levels in RSD32. However, higher expressions of TIMING OF CAB EXPRESSION 1 (TOC1) and PHYTOCLOCK 1 homologues, acting as evening expressed genes, are observed in RSD32. Homologues of Ca2+ signaling pathway related genes are found to be specifically expressed on DAP20 in Norin61. Lower expression is shown in RSD32. These results suggest that RSD32 mutation expresses on DAP20 and earlier seed developmental stages and suggest that circadian clock regulation and Ca2+ signaling pathway are involved in regulating wheat seed dormancy.

plant biology↗

bioRxiv2019

Ablation of Arf-expressing cells ameliorates cigarette smoke-induced lung dysfunction in mice.

Senescent cells accumulate in tissues during aging or pathological settings. The semi-genetic or pharmacological targeting of senescent cells revealed that cellular senescence underlies many aspects of the aging-associated phenotype and diseases. We previously reported that cellular senescence contributes to aging- and disease-associated pulmonary dysfunction. We herein report that the elimination of Arf-expressing senescent cells ameliorates cigarette smoke-induced lung pathologies in mice. Cigarette smoke induced the expression of Ink4a and Arf in lung tissue with concomitant increases in lung tissue compliance and alveolar airspace. The elimination of Arf-expressing senescent cells prior to cigarette smoke exposure protected against these changes. Furthermore, the administration of cigarette smoke extract lead to pulmonary dysfunction, which was ameliorated by subsequent senescent cell elimination. Collectively, these results suggest that senescent cells are a potential therapeutic target for cigarette smoking-associated lung disease.

physiology↗

bioRxiv2019

Decreased Activity of the Ghrhr and Gh Promoters Causes Dominantly Inherited GH Deficiency

Isolated growth hormone deficiency type II (IGHD2) is mainly caused by heterozygous splice-site mutations in intron 3 of the GH1 gene. A dominant negative effect of the mutant growth hormone (GH) lacking exon 3 on wild-type GH secretion has been proposed; however, the molecular mechanisms involved are elusive. To uncover the molecular systems underlying GH deficiency in IGHD2, we established IGHD2 model mice, which carry both wild-type and mutant copies of the human GH1 gene, replacing each of the endogenous mouse Gh loci. Our IGHD2 model mice exhibited growth retardation associated with intact cellular architecture and mildly activated ER stress in the pituitary gland, caused by decreases in the growth hormone releasing hormone receptor (Ghrhr) and Gh gene promoter activities. Decreases in Ghrhr and Gh promoter activities were likely caused by reduced levels of nuclear CREB3L2, which was demonstrated to stimulate the activity of the Ghrhr and Gh promoters. This is the first in vivo study revealing a novel molecular mechanism of GH deficiency in IGHD2, representing a new paradigm, differing from widely accepted models.

genetics↗