Biology subjects

Yoshino, T.

Publications and source records attributed to Yoshino, T..

7 recordsLinked to original sources

bioRxiv2026

NECTIN4 defines a subtype-dependent tumor state coupling enfortumab vedotin targetability to antitumor immunity in bladder cancer

NECTIN4 is the target of enfortumab vedotin (EV), but its biological role in bladder cancer (BC) and its relationship to EV plus PD-1 blockade remain unclear. Integrating clinical multi-omics, spatial and single-cell immune profiling, and experimental models, we identify NECTIN4 as a subtype-dependent determinant of tumor state and antitumor immunity. In basal BC cells, NECTIN4 suppressed inflammatory and mesenchymal programs. Consistently, NECTIN4-high basal/squamous muscle-invasive BCs showed favorable survival, higher checkpoint inhibitor response rates, and a coordinated CD8+ T cell-inflamed microenvironment with no comparable associations in luminal papillary tumors. In orthotopic models, murine Nectin4 promoted CD8+ T cell-dependent tumor control, whereas human NECTIN4 conferred EV sensitivity. EV also attenuated NECTIN4-dependent TIGIT binding. Conversely, NECTIN4-low models were preferentially sensitive to HDAC inhibition. NECTIN4 therefore couples antibody-drug conjugate targetability to a subtype-specific tumor-immune state permissive for checkpoint blockade, whereas the NECTIN4-low state defines a distinct inflammatory-mesenchymal state with an alternative therapeutic vulnerability.

cancer biology↗

bioRxiv2026

Catalog of gut microbiota alterations associated with anticancer therapies across multiple cancer types

BackgroundAnticancer therapies can alter the gut microbiota and may affect gut bacteria associated with treatment response. However, most longitudinal studies have focused on specific cancer types or individual treatment regimens, and systematic analyses across diverse cancer therapies remain limited. We analyzed longitudinal fecal microbiota profiles using 16S ribosomal RNA gene amplicon sequencing in the pan-cancer SCRUM-Japan MONSTAR-SCREEN cohort. We included 528 paired pre- and post-treatment fecal samples from 264 patients with advanced solid tumors across 18 cancer types and characterized the gut microbiota alterations associated with 22 anticancer drugs and related clinical factors. ResultsAcross the cohort, Shannon diversity did not significantly change after treatment (mean, 3.81 vs. 3.78; P = 0.58), and pre- and post-treatment samples exhibited no clear separation in ordination space. However, within-patient analysis detected a subtle but significant longitudinal microbiota shift (paired PERMANOVA, P = 0.0001), highlighting the importance of accounting for paired sampling. Clustering of genus-level compositional alterations revealed patient groups with distinct degrees of microbiota alteration, with the largest shifts associated with antibiotic exposure, transition from normal stool to diarrhea, and specific treatment regimens. Multivariable regression analysis of 22 anticancer drugs identified drug-bacteria associations and demonstrated that drugs with similar mechanisms of action, including epidermal growth factor receptor (EGFR) inhibitors and immune checkpoint inhibitors, exhibited similar microbiota change profiles. Targeted analyses highlighted concordant reductions in the Christensenellaceae R-7 group among EGFR inhibitor-exposed patients and depletion of Faecalibacterium among immune checkpoint inhibitor-exposed patients. ConclusionsThis study provides a cross-cancer catalog of microbiota alterations associated with anticancer therapies and highlights therapy-related shifts in the gut ecosystem, including patterns shared by drugs with similar mechanisms of action.

microbiology↗

bioRxiv2025

Linking power, efficiency, and bifurcations in ecological systems

Three hypotheses help organize energetic thinking about living systems: Lotkas Maximum Power Principle, Odum-Pinkertons Intermediate Efficiency Principle, and Morowitzs Biological Cycling Principle. Here we show how these hypotheses fit together in consumer-resource systems, moving from qualitative principles to formal, testable statements. Using the Rosen-zweig-MacArthur model, we prove that the consumers maximum output power lies exactly on the Hopf boundary that separates stable points from cycles; at that point, the resulting power efficiency is intermediate. In the Rosenzweig-MacArthur model the Hopf is supercritical, so a stable limit cycle appears smoothly as the equilibrium loses stability. We treat the Hopf onset of time-periodic population oscillations as a population-level analogue of sustained cycling under energy flux. We then embed these energetic statements in adaptive dynamics: with convex trait costs, evolutionary singular strategies exist and are locally stable, but they coincide with the maximum-power state only under explicit marginal-cost conditions. Together, these results unify classic ideas in the concrete setting of consumer-resource systems and suggest measurements to evaluate when bifurcations, energetics, and evolution can converge.

ecology↗

bioRxiv2025

Small Extra-Large GTPase-like proteins influence rhizobial symbiosis in Lotus japonicus

Plants possess a unique class of heterotrimeric G subunits called extra-large GTPases (XLGs) which contribute to numerous developmental and stress responses. In addition to the canonical G domain, XLGs have an uncharacterized N-terminal domain and functions that are distinct from conventional G subunits. In this study, we identified homologs of XLG3 in Lotus japonicus responsive to rhizobial and mycorrhizal symbiosis. However, these proteins were approximately one-third the size of conventional XLGs and only aligned to the N-terminal domain, containing a putative nuclear localization signal and a cysteine-rich domain of unknown function. Multiple sequence alignment and phylogenetic analysis determined these small XLGs (SXLGs) did not share domains with other mono- or heterotrimeric G-protein classes and exhibited a pattern of duplication and neofunctionalization typical of genes involved in symbiotic signaling pathways. Transient expression of LjSXLGs in tobacco demonstrated their potential for localization to the plasma membrane, nucleus, and nucleolus. Analysis of L. japonicus sxlg2 mutants revealed transient impairment of immature nodule formation in a destructive experimental setup and inhibition of infection events in a nutrient-limited non-destructive experimental setup, with a delayed onset of established infection events and a potential impact on nodule maturation rate. Additionally, sxlg2 mutants showed a potential impairment of the root growth response in N-limited conditions. We discuss the potential utility of SXLGs in better understanding the evolution of XLGs and their possible function as transcriptional regulators, as well as the likelihood SXLGs are involved in the establishment of rhizobial and mycorrhizal symbioses through influencing membrane reorganization, such as during infection thread development.

plant biology↗

bioRxiv2024

Tumour specimen cold ischemia time impacts molecular cancer drug target discovery

Tumour tissue collections are used to uncover pathways associated with disease outcomes that can also serve as targets for cancer treatment, ideally by comparing the molecular properties of cancer tissues to matching normal tissues. The quality of such collections determines the value of the data and information generated from their analyses including expression and modifications of nucleic acids and proteins. These biomolecules are dysregulated upon ischemia and decomposed once the living cells start to decay into inanimate matter. Therefore, ischemia time before final tissue preservation is the most important determinant of the quality of a tissue collection. Here we show the impact of ischemia time on tumour and matching adjacent normal tissue samples for mRNAs in 1,664, proteins in 1,818 and phosphoproteins in 1,800 cases (tumour and matching normal samples) of four solid tumour types (CRC, HCC, LUAD and LUSC NSCLC subtypes). In CRC, ischemia times exceeding 15 minutes impacted 12.5% (mRNA), 25% (protein) and 50% (phosphosites) of differentially expressed molecules in tumour versus normal tissues. This hypoxia- and decay-induced dysregulation increased with longer ischemia times and was observed across tumour types. Interestingly, the proteomics analysis revealed that specimen ischemia time above 15 minutes is mostly associated with a dysregulation of proteins in the immune response pathway and less so with metabolic processes. We conclude that ischemia time is a crucial quality parameter for tissue collections used for target discovery and validation in prognostic cancer research.

cancer biology↗

bioRxiv2024

MS-DIAL 5 multimodal mass spectrometry data mining unveils lipidome complexities

Lipidomics and metabolomics communities comprise various informatics tools; however, software programs that can handle multimodal mass spectrometry (MS) data with structural annotations guided by the Lipidomics Standards Initiative are limited. Here, we provide MS-DIAL 5 to facilitate the in-depth structural elucidation of lipids through electron-activated dissociation (EAD)-based tandem MS, as well as determine their molecular localization through MS imaging (MSI) data using a species/tissue-specific lipidome database containing the predicted collision-cross section (CCS) values. With the optimized EAD settings using 14 eV kinetic energy conditions, the program correctly delineated the lipid structures based on EAD-MS/MS data from 96.4% of authentic standards. Our workflow was showcased by annotating the sn- and double-bond positions of eye-specific phosphatidylcholine molecules containing very-long-chain polyunsaturated fatty acids (VLC-PUFAs), characterized as PC n-3-VLC-PUFA/FA. Using MSI data from the eye and HeLa cells supplemented with n-3-VLC-PUFA, we identified glycerol 3-phosphate (G3P) acyltransferase (GPAT) as an enzyme candidate responsible for incorporating n-3 VLC-PUFAs into the sn-1 position of phospholipids in mammalian cells, which was confirmed using recombinant proteins in a cell-free system. Therefore, the MS-DIAL 5 environment, combined with optimized MS data acquisition methods, facilitates a better understanding of lipid structures and their localization, offering novel insights into lipid biology.

bioinformatics↗

bioRxiv2021

Chromosome scale assembly of allopolyploid genome of the diatom Fistulifera solaris

Microalgae including diatoms are of interest for environmentally-friendly manufacturing such as biofuel production. However, only a very few of their genomes have been elucidated owing to their diversified and complex evolutionary history. The genome of the marine oleaginous diatom Fistulifera solaris, an allopolyploid diatom possessing two subgenomes, has been analyzed previously by pyrosequencing. However, many unsolved regions and unconnected scaffolds remained. Here we report the entire chromosomal structure of the genome of F. solaris strain JPCC DA0580 using a long-read nanopore sequencing platform. From just one single run using a MinION flow-cell, the chromosome scale assembly with telomere-to-telomere resolution was achieved for 41 out of 44 chromosomes. Centromere regions were also predicted from the chromosomes, and we discovered conserved motifs in the predicted regions. The function of the motifs was experimentally confirmed by successful transformation of the diatom via bacterial conjugation. This discovery provides insights into chromosome replication, facilitating the rational design of artificial chromosomes for large-scale metabolic engineering of diatoms. The chromosome scale assembly also suggests the potential existence of multi-copy mini-chromosomes and tandemly repeated lipogenesis genes related to the oleaginous phenotype of F. solaris. The nanopore sequencing also solved the sequential arrangement of the repeat region in the F. solaris mitochondrial genome. Findings of this study will be useful to understand and further engineer the oleaginous phenotype of F. solaris.

genomics↗