Biology subjects

Ochiai, T.

Publications and source records attributed to Ochiai, T..

3 recordsLinked to original sources

bioRxiv2026

A reversible GNAS-PKA-RUNX2 checkpoint governs skeletal stem cell fate in fibrous dysplasia

Fibrous dysplasia (FD) arises from activating GNAS mutations that increase cAMP signaling in skeletal stem/progenitor cells (SSPCs), but the underlying mechanisms and whether the resulting fate imbalance can be reversed remain unclear. Using controlled GNAS induction with transcriptomic, pharmacologic, and cell-fate analyses, we identify a PKA-dependent checkpoint governing SSPC lineage commitment. GNASR201C redirects SSPCs toward osteoclastogenesis while suppressing osteoblast maturation; genetic or pharmacologic PKA inhibition reverses both effects, revealing this fate decision is dynamically reversible. Mechanistically, PKA phosphorylates RUNX2, the master regulator of osteogenesis, enforcing its cytoplasmic retention and blocking osteogenic transcription; a non-phosphorylatable RUNX2 mutant restores nuclear localization and osteoblast differentiation, defining RUNX2 phosphorylation as a disease-initiating molecular switch. Critically, PKA inhibition in vivo reduces fibrosis and osteoclast burden in established bone lesions, demonstrating reversibility even in advanced FD. These findings define a druggable GNAS-PKA-RUNX2 checkpoint and identify PKA inhibition as a strategy to reverse existing disease in FD.

cell biology↗

bioRxiv2025

Genetic basis of R-phase H:z27 antigen expression and phylogenetic relationships of Salmonella enterica serovar Senftenberg

Salmonella enterica serovar Senftenberg (S. Senftenberg) is one of the most prevalent Salmonella serovars and can be isolated from various animals and humans. According to the White-Kauffmann-Le Minor (WKL) scheme, the antigenic formula of S. Senftenberg is defined as 1,3,19:g,[s],t:-. Although the antigenic formula 1,3,19:z27:- was formerly designated as serovar Simsbury, this name was later removed from the WKL scheme due to reports of interconvertibility between serovars Senftenberg and Simsbury. The H:z27 antigen is currently recognized as one of the R-phase H antigens of S. Senftenberg. To elucidate the genetic basis of H:z27 antigen expression in S. Senftenberg, we determined the whole-genome sequences of isolates expressing the H:z27 antigen. These isolates belonged to sequence type (ST) 185 and harbored a horizontally acquired chromosomal region containing the fljA, fljB, and pinR genes, which are predicted to encode a translational repressor of fliC mRNA, a phase 2 flagellin, and an invertase, respectively. A deletion mutant lacking this region expressed the H:g,s,t antigen instead of H:z27, as confirmed by serotyping and Western blot analysis. Phylogenetic analysis based on S. Senftenberg genome archives, together with the sequences obtained in this study, suggested that the S. Senftenberg ST185 lineage acquired the fljAB-pinR locus around 1867. In contrast, our broader phylogenetic analysis of Salmonella serovars indicated that S. Senftenberg ST14 is genetically closer to certain other serovars than to ST185, while ST185 shows a closer relationship to a different serovar than to ST14. These findings suggest that S. Senftenberg comprises at least two distinct genomic lineages. IMPORTANCELimited information is available on the genetic basis of R-phase H antigen expression in S. enterica. In this study, we first demonstrated that the R-phase H:z27 antigen of S. Senftenberg is determined by a horizontally acquired chromosomal region. The ST 185 lineage of S. Senftenberg appears to have acquired this chromosomal region around 1867 and subsequently disseminated worldwide. We also demonstrated that S. Senftenberg comprises at least two distinct genomic lineages. The combined use of serotyping and multilocus sequence typing may provide a typing framework that better reflects the disease potential of Salmonella.

microbiology↗

bioRxiv2020

Synergistic anticancer effect of plasma-activated infusion and salinomycin by targeting autophagy and mitochondrial morphology

Non-thermal atmospheric plasma (NTAP)-activated liquids have emerged as new promising anticancer agents because they preferentially injure malignant cells. Here, we report plasma-activated infusion (PAI) as a novel NTAP-based anti-neoplastic agent. PAI was prepared by irradiating helium NTAP to form a clinically approved infusion fluid. PAI dose-dependently killed malignant melanoma and osteosarcoma cell lines showed much lower cytotoxic effects on dermal and lung fibroblasts. We found that PAI and salinomycin (Sal), an emerging anti-cancer stem cell agent, mutually operated as adjuvants. Combined administration of PAI and Sal was much more effective than single agent application in reducing the growth and lung metastasis of osteosarcoma allografts with minimal adverse effects. Mechanistically, PAI explicitly induced necroptosis and increased the phosphorylation of receptor-interacting protein 1/3 in a rapid and transient manner. PAI also suppressed the ambient autophagic flux by activating the mammalian target of rapamycin pathway. PAI increased the phosphorylation of Raptor, Rictor, and p70-S6 kinase, along with decreased LC3-I/II expression. In contrast, Sal promoted autophagy. Moreover, Sal exacerbated the mitochondrial network collapse caused by PAI, resulting in aberrant clustering of fragmented mitochondrial in a tumor-specific manner. Our findings suggest that combined administration of PAI and Sal is a promising approach for treating these apoptosis-resistant cancers.

cancer biology↗