Biology subjects

Murata, H.

Publications and source records attributed to Murata, H..

5 recordsLinked to original sources

bioRxiv2026

ACKR1-expressing venous endothelial cells establish a pro-fibrotic niche in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by excessive extracellular matrix deposition and irreversible architectural distortion of the lung. Fibrotic remodeling is driven by dynamic interactions among endothelial, fibroblast, epithelial and immune cells. Although pulmonary endothelial cells (ECs) are increasingly recognized as important contributors to IPF pathogenesis, the molecular and cellular events underlying endothelial dysfunction remains poorly understood. Using integrative multi-omics analyses of human IPF lungs combined with functional in vitro assays, we identify ACKR1-expressing venous endothelial cells (ACKR1+ VECs) as critical regulators of a pathogenic niche that promotes lung fibrosis. Single-cell RNA sequencing and spatial transcriptomics analyses reveal that ACKR1+ VECs exhibit a distinct pro-fibrotic and pro-inflammatory transcriptional program enriched for hypoxia responses, extracellular matrix remodeling, and immune cell recruitment. In both mouse and human fibrotic lungs, ACKR1+ VECs localize adjacent to fibroblastic foci and are surrounded by pro-fibrotic CD68+/CCR5+/SPP1+ macrophages-monocytes, suggesting a spatial organized cellular crosstalk supporting fibrotic remodeling. Consistent with these findings, in vitro co-culture assays using ACKR1+ VECs isolated from IPF lungs demonstrate that these cells drive myeloid recruitment and fibroblast activation through ACKR1 dependent mechanisms. Silencing of ACKR1 in IPF-derived VECs suppressed inflammatory and fibrotic transcriptional programs, and pharmacological inhibition of ACKR1 attenuated stromal and immune remodeling and reduced bleomycin-induced lung fibrosis in vivo. Together, these findings identify ACKR1+ VECs as key orchestrators of fibrosis progression and establish ACKR1 and the pathogenic vasculature as promising therapeutic targets for IPF. Clinical RelevanceIdiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited treatment options. We identify ACKR1-expressing venous endothelial cells as key drivers of inflammatory and fibrotic remodeling and show that pharmacologic inhibition of ACKR1 attenuates experimental lung fibrosis. These findings establish endothelial ACKR1 as a promising therapeutic target and highlight the pulmonary vasculature as a novel avenue for disease-modifying therapies in IPF.

molecular biology↗

bioRxiv2024

Protein superfolds are characterised as frustration-free topologies: A case study of pure parallel beta-sheet topologies

A protein superfold is a type of protein fold that is observed in at least three distinct, non-homologous protein families. Structural classification studies have revealed a limited number of prevalent superfolds alongside several infrequent occurring folds, and in /{beta} type superfolds, the C-terminal {beta}-strand tends to favor the edge of the {beta}-sheet, while the N-terminal {beta}-strand is often found in the middle. The reasons behind these observations, whether they are due to evolutionary sampling bias or physical interactions, remain unclear. This article offers a physics-based explanation for these observations, specifically for pure parallel {beta}-sheet topologies. Our investigation is grounded in three established structural rules that are based on physical interactions. We have identified "frustration-free topologies" which are topologies that can satisfy all three rules simultaneously. In contrast, topologies that cannot are termed "frustrated topologies." Our findings reveal that frustration-free topologies represent only a fraction of all theoretically possible patterns, these topologies strongly favor positioning the C-terminal {beta}-strand at the edge of the {beta}-sheet and the N-terminal {beta}-strand in the middle, and there is significant overlap between frustration-free topologies and superfolds. We also used a lattice protein model to thoroughly investigate sequence-structure relationships. Our results show that frustration-free structures are highly designable, while frustrated structures are poorly designable. These findings suggest that superfolds are highly designable due to their lack of frustration, and the preference for positioning C-terminal {beta}-strands at the edge of the {beta}-sheet is a direct result of frustration-free topologies. These insights not only enhance our understanding of sequence-structure relationships but also have significant implications for de novo protein design. Author summaryA protein superfold is a protein fold that appears in at least three different non-homologous protein families. Superfolds are unique in their ability to accommodate multiple functions within a single fold, a feature not typically seen in other folds. Studies in structural classification have led to two notable observations: the existence of a limited number of common superfolds contrasted with a larger variety of less frequent folds, and a recurring pattern in /{beta} type superfolds where the C-terminal {beta}-strand often occupies the edge of the {beta}-sheet, while the N-terminal {beta}-strand is usually found in the middle. The origins of these patterns, whether they stem from evolutionary sampling bias or physical interaction mechanisms, remain unclear. This article provides a physics-oriented explanation for these observations, specifically concentrating on pure parallel {beta}-sheet topologies. The insights gained from this research are crucial in enhancing our understanding of the relationship between protein sequences and structures, and are expected to contribute significantly to the de novo design of new proteins.

bioinformatics↗

bioRxiv2023

Complete de novo assembly of Tricholoma bakamatsutake chromosomes revealed the structural divergence and differentiation of Tricholoma genomes

Tricholoma bakamatsutake, which is an edible ectomycorrhizal fungus associated with Fagaceae trees, may have diverged before the other species in Tricholoma section Caligata. We generated a highly contiguous whole-genome sequence for T. bakamatsutake SF-Tf05 isolated in an oak (Quercus salicina) forest in Japan. The assembly of high-fidelity long reads, with a median read length of 12.3 kb, resulted in 13 chromosome-sized contigs comprising 142,068,211 bases with an average GC content of 43.94%. The 13 chromosomes were predicted to encode 11,060 genes. A contig (122,566 bases) presumably containing the whole circular mitochondrial genome was also recovered. The chromosome-wide comparison of T. bakamatsutake and T. matsutake (TMA_r1.0) indicated that the basic number of chromosomes (13) was conserved, but the structures of the corresponding chromosomes diverged, with multiple inversions and translocations. Gene conservation and cluster analyses revealed at least three groups in Tricholoma. Specifically, all T. bakamatsutake strains belonged to the "bakamatsutake" clade, which is most proximal to the "caligatum" clade consisting of T. caligatum and T. fulvocastaneum. The constructed highly contiguous telomere-to-telomere genome sequence of a T. bakamatsutake isolate will serve as a fundamental resource for future research on the evolution and differentiation of Tricholoma species.

genomics↗

bioRxiv2021

Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma

Myasthenia gravis (MG) is a neurological disease caused by autoantibodies against neuromuscular-associated proteins. While MG is frequently developed in thymoma patients, the etiologic factors for MG are not well understood. Here, by constructing a comprehensive atlas of thymoma using bulk and single-cell RNA-seq, we identified ectopic expression of neuromuscular molecules in MG-associated thymoma (MG-thymoma). These molecules were originated from a distinct subpopulation of medullary thymic epithelial cells (mTECs), which we named neuromuscular mTECs (nmTECs). MG-thymoma also exhibited microenvironments dedicated to autoantibody production, including ectopic germinal center formation, T follicular helper cell accumulation, and type 2 conventional dendritic cell migration. Cell-cell interaction analysis also predicted the interaction between nmTECs and T/B cells via CXCL12-CXCR4. The enrichment of nmTECs presenting neuromuscular molecules within MG-thymoma was further confirmed by immunohistochemically and by cellular composition estimation from MG-thymoma transcriptome. Altogether, this study suggests that nmTECs play a significant role in MG pathogenesis via ectopic expression of neuromuscular molecules.

immunology↗

bioRxiv2019

Human recombinant erythropoietin improves motor function in rats with spinal cord compression myelopathy

OBJECTIVEErythropoietin (EPO) is a clinically available hematopoietic cytokine. The aim of this study was to evaluate the effect of EPO on a rat model of cervical cord compression myelopathy and to explore the possibility of its use as a pharmacological treatment.\n\nMETHODSTo produce the chronic cervical cord compression model, thin polyurethane sheets were implanted under the C5-C6 laminae of rats and gradually expanded due to water absorption. In this model, motor functions significantly declined from 7 weeks after surgery. Based on the result, EPO administration was started 8 weeks after surgery. Motor function as seen with rotarod performance and grip strength was measured 16 weeks after surgery, and then motor neurons were stained with H-E and NeuN staining, and counted. Apoptotic cell death was assessed with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) staining. To assess transfer of EPO into spinal cord tissue, the EPO level in spinal cord tissue was measured with an enzyme-linked immunosorbent assay for each group after subcutaneous injection of EPO.\n\nRESULTSHigh-dose EPO (5000 IU/kg) administered from 8 weeks after surgery markedly restored and maintained motor function in the Compression groups (P < 0.01). EPO significantly prevented loss of motor neurons in the anterior horn (P < 0.05) and significantly decreased the number of TUNEL-positive apoptotic cells (P < 0.05). The EPO level in spinal cord tissue was significantly higher in the High-dose EPO group than other groups.\n\nCONCLUSIONSEPO improves motor function in rats with progressive chronic compression myelopathy. EPO protects anterior horn motor neurons and inhibits neuronal cell apoptosis in spinal cord compression. The neuroprotective effects can be produced through transfer of EPO into spinal cord tissue. These findings suggest that EPO has high potential as a treatment for developing compression myelopathy.

neuroscience↗