Biology subjects

Katsuki, S.

Publications and source records attributed to Katsuki, S..

7 recordsLinked to original sources

bioRxiv2026

Single-cell spatial multiomics identifies POSTN+ CAFs mediating chemoradiotherapy resistance in rectal cancer

Neoadjuvant chemoradiotherapy (CRT) is standard for locally advanced rectal cancer (LARC), yet many patients retain residual disease. To resolve CRT-associated remodeling of the tumor microenvironment, we generated a multimodal spatial atlas from serial sections of paired pretreatment and post-treatment specimens from 24 patients using Xenium single-cell spatial transcriptomics and PhenoCycler multiplex proteomics, profiling 2.8 million cells; matched Visium HD datasets were generated on adjacent serial sections. Resistance was most strongly associated with fibroblast and myeloid programs adjacent to residual tumor. We identify a periostin (POSTN)-expressing CAF subset selectively enriched around residual tumor cells in non-responders, displaying a myofibroblastic phenotype and activating extracellular matrix remodeling, noncanonical WNT signaling, and immunosuppressive pathways. Tumor cells neighboring POSTN+ CAFs show consistent epithelial-mesenchymal transition signatures. Together, this atlas enables interrogation of CRT-induced spatial remodeling and nominates POSTN+ CAFs as key mediators and targets of CRT resistance, with direct relevance to CRT-based combination strategies.

cancer biology↗

bioRxiv2026

Contrasting effects of geographic distance, environmental distance, and intraspecific diversity on the performance of a marine invertebrate in common gardens

Restoration and management of natural populations often assume that local genotypes are best suited for transplantation to their local environment. Prioritizing a single local genotype, however, contrasts with the framework of maximizing intraspecific diversity to increase population resilience to environmental change. Local populations may also become maladapted to a rapidly changing environment, motivating alternative frameworks that instead minimize environmental distance between source and transplantation sites. Here, we tested the predictive power of the local is best, maximize intraspecific diversity, and minimize environmental distance frameworks on the survival and growth of Eastern oyster (Crassostrea virginica) genotypes in field common gardens that differed in salinity and disease pressure. Although a genome scan revealed patterns of adaptation to disease, heat stress, and salinity among source populations, we did not find strong support for the local is best framework: geographically distant southern genotypes performed comparably to local selection lines and a local wild population. Higher genetic diversity within monocultures was associated with higher survival, yet highly diverse polycultures survived at lower rates than the best-performing monocultures, providing mixed support for the maximize intraspecific diversity framework. Temperature and salinity of the environments-of-origin of parents predicted the survival of their offspring in common gardens, but the relationship between survival and environmental distance was context-dependent, leading to mixed support for the minimize environmental distance framework. Together, these results demonstrate that no single framework reliably predicted transplantation success, suggesting that effective management strategies may need to integrate genomic and environmental lines of evidence to guide genotype selection.

evolutionary biology↗

bioRxiv2024

Drp1-mediated mitochondrial fission protects macrophages from mtDNA/ZBP1-mediated sterile inflammation and inhibits post-infarct cardiac remodeling

BackgroundIschemic heart disease is a leading cause of death worldwide, and heart failure after myocardial infarction (MI) is a growing issue in this aging society. Macrophages play central roles in left ventricular (LV) remodeling after MI. Mitochondria consistently change their morphology, including fission and fusion, but the role of these mitochondrial morphological changes, especially in macrophages, is unknown. This study aims to illuminate the effects and mechanisms of Dynamin-related protein 1 (Drp1), a molecule mediating mitochondrial fission, in macrophages for cardiac remodeling after MI. MethodsThis study utilized genetically altered mice lacking Drp1 in monocytes/macrophages (Drp1-KO) to elucidate the specific role of macrophage Drp1 in post-infarct LV remodeling. ResultsDeletion of Drp1 in macrophages exacerbated LV remodeling, including reduced ejection fraction and increased LV diameters, which resulted in decreased survival after MI. Histological analysis indicated increased fibrosis and sustained macrophage accumulation in Drp1-KO mice. Blockade of Drp1 in macrophages decreased mitochondrial fission and impaired mitophagy, leading to the subsequent release of mitochondrial DNA (mtDNA) to the cytosol and induction of inflammatory cytokines. This induction was abrogated by an autophagy inducer, Tat-beclin1, or siRNA-mediated knockdown of Z-DNA Binding Protein 1 (ZBP1). Deletion of ZBP1 in bone marrow-derived cells abrogated LV remodeling induced by Drp1 inhibitor, Mdivi-1. ConclusionMacrophage Drp1 plays a critical role in the pathobiology of LV remodeling after MI, especially mitochondria quality control mechanisms. Macrophage Drp1 could be a novel therapeutic molecule to mitigate the progression of LV remodeling and consequent heart failure after MI.

biochemistry↗

bioRxiv2023

Cyclophilin D induces necrotic core formation by promoting mitochondria-mediated macrophage apoptosis in advanced atherosclerotic lesions

BackgroundIn advanced atherosclerotic lesions, apoptotic cell death of plaque macrophages results in necrotic core formation and plaque vulnerability. Cyclophilin D (CypD) is a mitochondria-specific cyclophilin involved in the process of cell death after organ ischemia-reperfusion. However, the role of CypD in atherosclerosis, especially in necrotic core formation, is unknown. MethodsTo clarify the specific role of CypD, apolipoprotein-E/CypD-double knockout (ApoE-/-CypD-/-) mice were generated. These mice were fed a high-fat diet containing 0.15% cholesterol for 24 weeks to accelerate atherosclerotic lesion development. ResultsThe deletion of CypD decreased the necrotic core size, accompanied by a reduction of macrophage apoptosis compared to control ApoE-/- mice. In RAW264.7 cells treated with endoplasmic reticulum stress inducer thapsigargin, the release of cytochrome c to the cytosol was attenuated by siRNA-mediated knockdown of CypD. Ly-6Chigh inflammatory monocytes in the peripheral blood leukocytes and mRNA expression of Il1b in the aorta were decreased by the deletion of CypD. In contrast, siRNA-mediated knockdown of CypD did not significantly decrease Il1b nor Ccl2 mRNA expression in RAW264.7 cells treated with LPS and IFN-{gamma}, suggesting that inhibition of inflammation in vivo is likely due to decreased cell death in the atherosclerotic lesions rather than a direct action of CypD deletion on the macrophage. ConclusionsThis is the first report showing that CypD induces macrophage death and promotes necrotic core formation in advanced atherosclerotic lesions. CypD could be a novel therapeutic target for treating atherosclerotic vascular diseases.

molecular biology↗

bioRxiv2020

2MV/cm Pulsed Electric Fields Promote Transthyretin Amyloid Disintegration

Exposing transthyretin amyloid to 1000 sub-nanosecond 2 MV/cm pulsed electric fields (PEFs) promotes both amyloid disassembly and amyloid-derived transthyretin disintegration. The process produced no change in pH, and the resulting temperature increase was less than 1 {degrees}C. We conclude that PEFs physical effects facilitate amyloid disassembly, rather than thermal or chemical effects, and provoke amyloid-derived transthyretin disintegration, the latter of which is reported here for the first time.

biophysics↗

bioRxiv2019

Liposomes Under Real Cell Conditions Behave Like Real Cells with a Single Pulsed Electric Field

Liposomes are widely assumed to present a straightforward physical model of cells. However, almost all previous liposome experiments with pulsed electric fields (PEFs) have been conducted in low-conductivity liquids, a condition that differs significantly from that of cells in medium. Here, we prepared liposomes consisting of soy bean lecithin and cholesterol, at a molar ratio of 1:1, in higher-conductivity liquid that approximated the conditions of red blood cells in phosphate-buffered saline, with inner and outer liquid conductivities of 0.6 and 1.6 S/m, respectively. We found that a single 1.1 kV/cm, 400 s PEF promoted cell-like spontaneous division of liposomes.

biophysics↗

bioRxiv2019

Intense Pulsed Electric Fields Denature Urease Protein

This paper describes the effects of nanosecond pulsed electric fields (nsPEFs) on the structure and enzyme activity of three kinds of proteins. Intense (up to 300 kV/cm), 5-ns-long electrical pulses were applied to solutions of lysozyme (14 kDa, monomer), albumin (67 kDa, monomer), and urease (480 kDa, hexamer). We analyzed the tertiary and quaternary structures of these proteins as well as their enzyme activity. The results indicated the deformation of both the quaternary and tertiary structures of urease upon exposure to an electric field of 250 kV/cm or more, whereas no structural changes were observed in lysozyme or albumin, even at 300 kV/cm. The enzyme activity of urease also decreased at field strengths of 250 kV/cm or more. Our experiments demonstrated that intense nsPEFs physically affect the conformation and function of some kinds of proteins. Such intense electric fields often occur on cell membranes when these are exposed to a moderate pulsed electric field.

biophysics↗