Biology subjects

Takeuchi, N.

Publications and source records attributed to Takeuchi, N..

11 recordsLinked to original sources

bioRxiv2026

Soluble CD155 immune complexes reprogram DNAM-1 signaling to potentiate antitumor immunity

Resistance to immune checkpoint inhibitors (ICIs) remains a major challenge in oncology, yet the mechanisms that selectively disable activating pathways are poorly defined. Here, we identify tumor-derived soluble CD155 (sCD155) as a systemic checkpoint that rewires DNAM-1 signaling to drive immunotherapy resistance. High plasma sCD155 levels correlate with impaired anti-PD-1 responses in patients with non-small cell lung cancer. Mechanistically, sCD155 selectively suppresses DNAM-1-dependent activation of CD8+ T and NK cells, uncoupling ICIs from cytotoxic function. Intriguingly, a selective anti-sCD155 monoclonal antibody does not neutralize the ligand, but rather converts it into an activating scaffold. This complex induces Fc{gamma}R-anchored DNAM-1 microcluster formation and robust downstream signaling, effectively switching the checkpoint into a co-stimulatory signal. This reprogramming restores CTL function, suppresses metastasis, and augments PD-1/TIGIT blockade to achieve durable immunity. Our findings establish antibody-mediated receptor architecture rewiring as a therapeutic principle to overcome cancer immune resistance.

immunology↗

bioRxiv2026

Coupling cell differentiation to dewetting can explain villus elongation

During vertebrate development, the flat surface of the gut epithelium undergoes a dramatic transformation into densely packed arrays of finger-like projections called intestinal villi. Recent studies show that the villus formation relies on a tissue dewetting process, in which mesenchymal tissues buckle the overlying epithelial layer into periodic folds. However, the mechanisms driving subsequent elongation of these folds into finger-like villi remain largely unexplored. Here, we propose a simple mechanism for villus elongation that couples tissue dewetting to cell differentiation, which emerged as a repeated outcome of multiple independent simulations of an evolutionary-developmental Cellular Potts Model. In this mechanism, a liquid-like mesenchymal tissue continuously differentiates into a solid-like mesenchymal tissue at the interface between them. This differentiation drives the liquid-like tissue to continuously retract from the solid-like tissue in the opposite direction of the interface through dewetting, ultimately creating a finger-like projection. A merit of our proposed mechanism is that it only requires two tissues with different viscosities, high surface tension, and cell differentiation. We develop a simplified phase-field model to determine exactly how villus morphology depends on these three requirements. Since these requirements are satisfied not only in intestinal villi but also in many other developing tissues, we propose that the same mechanism could also drive the elongation of other tissues.

developmental biology↗

bioRxiv2025

Self-Assembling Synthetic Peptides Remodel Mitochondrial Properties via Nanopore Formation

Pore-forming peptides (PFPs) are powerful tools for engineering biological membranes in vitro and in living cells. They can be derived from natural sources or designed de novo, with synthetic peptides offering distinct advantages in rational design unconstrained by natural sequences. While native PFPs have been targeted to specific organelles to modulate their functions, the potential of synthetic PFPs for organelle engineering remains largely unexplored. Here, we show that the 28-amino acid synthetic peptides, SVG28 and its variant SVG28D2, can be selectively targeted to mitochondria for functional alteration. More specifically, molecular dynamics simulations first confirmed the structural stability of the SVG28 nanopore even when fused to the TOM20 transmembrane domain, a mitochondrial targeting sequence. In isolated lipid bilayers, TOM20-SVG28 formed pores with a 0.3-nS, conductance, or 1.0-nm pore. The expression efficiency was further enhanced by two amino acid substitutions (SVG28D2). In cells, both TOM20-SVG28 and TOM20-SVG28D2 localized to the mitochondria, induced morphological alterations, and reduced both membrane potential and ATP production. These observations in silico, in vitro and in cellulo collectively indicate that the synthetic SVG28 peptides self-assemble into pores in the outer mitochondrial membrane, likely permitting proton permeation. Importantly, the matrix protein Su9 remained confined within mitochondria, suggesting preserved inner membrane integrity, and thus specific effect on the target. This work establishes a framework for the design and application of genetically-encoded synthetic PFPs in living cells, opening new avenues for cellular engineering.

synthetic biology↗

bioRxiv2024

Interaction range of common goods shapes Black Queen dynamics beyond the cheater-cooperator narrative

Dependencies among microorganisms often appear mutualistic in the lab, as microbes grow faster together than alone. However, according to the Black Queen (BQ) hypothesis, these dependencies are underpinned by the evolutionary benefits from loss-of-function mutations when others in the community can supply the necessary common goods. BQ dynamics often describe a cheater-cooperator scenario, where some ecotypes, the "cheaters," produce no common goods and rely on others, the "cooperators", for survival. We have previously proposed that in systems with multiple common goods, an alternative endpoint for BQ dynamics can emerge. This endpoint describes an ecosystem of interdependent ecotypes engaging in "mutual cheating", i.e. where common good production is distributed. However, even with multiple goods the common good production can be centralized, i.e. with one ecotype providing all common goods for the ecosystem. Here, we present an eco-evolutionary model that reveals that BQ dynamics can result in both distributed- or centralized common good production. The interaction range, i.e. the number of beneficiaries a producer can support, distinguishes between these two endpoints. While many ecosystems evolve to be maximally distributed or maximally centralized, we also find intermediate ecosystems, where ecotypes that appear redundant are coexisting for long periods of time. Due to the limited interaction range, these redundant ecotypes are unable to distribute the production of common goods fully due to the presence of non-producing types. Despite non-producers thus stalling the division of labor, we observe that sudden structural shifts can occur that purge the non-producers from the ecosystem. Overall, our findings broaden the understanding of BQ dynamics, unveiling complex interactions beyond the simple cheater-cooperator narrative.

evolutionary biology↗

bioRxiv2023

In Vitro Evolution to Increase the Titers of Difficult Bacteriophages: Rapid Appelmans Protocol

Bacteriophages are becoming increasingly important in the race to find alternatives to antibiotics. Unfortunately, bacteriophages that might otherwise be useful are sometimes discarded due to low titers making them unsuitable for downstream applications. Here, we present two distinct approaches to experimentally evolve novel New Zealand Paenibacillus larvae bacteriophages. The first approach uses the traditional agar-overlay method, whereas the other was a Rapid Appelmans Protocol (RAP) modelled after the established Appelmans Method. Both approaches resulted in an increase in plaque-forming units (PFU/mL). The RAP approach was significantly faster and simpler, and allowed us to evolve a set of bacteriophages in as little as four days, increasing titers 100-1000-fold relative to their ancestors. The resultant titers were sufficient to extract and sequence DNA from these bacteriophages. An analysis of these phage genomes is provided. We also propose a model that describes the parameters that allow the RAP approach to select improvement of bacteriophage titer. The RAP approach is an effective method for experimentally evolving previously intractable bacteriophages in a high-throughput and expeditious manner.

microbiology↗

bioRxiv2022

Genetic exchange shapes ultra-small Patescibacteria metabolic capacities in the terrestrial subsurface

Bacterial genomes are highly dynamic entities, mostly due to the extent of horizontal gene transfer (HGT) occurring in these organisms. HGT is thought to be the main driver of genetic variation and adaptation to local environment in bacteria. However, little is known about the modalities of HGT within natural microbial communities, especially the implications of genetic exchange for streamlined microorganisms such as Patescibacteria (Candidate Phyla Radiation). We searched for evidence of genetic exchange in 125 Patescibacteria genomes recovered from aquifer environments and detected the presence of hundreds of genomic islands, individually transferred genes and prophage combined, with up to 29% of genome length attributed to HGT. Results show that most individual gene transfer events occurred between Patescibacteria, but donors were also phylogenetically diverse groundwater microorganisms. Using gene donor-recipient information, we identified one potential host (Omnitrophota) of the ultra-small bacteria, and confirmed this by matching relative abundance patterns across 16 groundwater samples. A wide variety of metabolic functions were introduced in Patescibacteria genomes by HGT including transcription, translation and DNA replication, recombination and repair. This study illustrates the evolutionarily dynamic nature of Patescibacteria genomes despite the constraints of streamlining, and that HGT in these organisms is also mediated via viral infection.

evolutionary biology↗

bioRxiv2022

Prophages and plasmids display opposite trends in the types of accessory genes they carry

2Mobile genetic elements (MGEs), such as phages and plasmids, often possess accessory genes encoding bacterial functions, facilitating bacterial evolution. Are there evolutionary rules governing the arsenal of accessory genes MGEs carry? If such rules exist, they might be reflected in the types of accessory genes different MGEs carry. To test this hypothesis, we compare prophages and plasmids with respect to the frequencies at which they carry antibiotic resistance genes (ARGs) and virulence factor genes (VFGs) in the genomes of 21 pathogenic bacterial species using public databases. Our results indicate that prophages tend to carry VFGs more frequently than ARGs in three species, whereas plasmids tend to carry ARGs more frequently than VFGs in nine species. In Escherichia coli, where these trends are detected, prophage-borne VFGs encode a much narrower range of functions than do plasmid-borne VFGs, typically involved in damaging host cells or modulating host immunity. In the species where the above trends were not detected, ARGs and VFGs are barely found in prophages and plasmids. These results indicate that MGEs differentiate in the types of accessory genes they carry depending on their infection strategies, suggesting an evolutionary rule governing horizontal gene transfer mediated by MGEs.

microbiology↗

bioRxiv2021

Transposable elements drive the evolution of genome streamlining

Eukaryotes and prokaryotes have distinct genome architectures, with marked differences in genome size, the ratio of coding/non-coding DNA, and the abundance of transposable elements (TEs). As TEs replicate independently of their hosts, the proliferation of TEs is thought to have driven genome expansion in eukaryotes. However, prokaryotes also have TEs in intergenic spaces, so why do prokaryotes have small, streamlined genomes? Using an in silico model describing the genomes of single-celled asexual organisms that co-evolve with TEs, we show that TEs acquired from the environment by horizontal gene transfer can drive the evolution of genome streamlining. The process depends on local interactions and is underpinned by rock-paper-scissor dynamics in which populations of cells with streamlined genomes beat TEs, which beat non-streamlined genomes, in continuous and repeating cycles. Streamlining is maladaptive to individual cells, but delivers lineage-level benefits. Streamlining does not evolve in sexually reproducing populations because recombination partially frees TEs from the deleterious effects they cause.

evolutionary biology↗

bioRxiv2020

Bacteria maintain Slightly Beneficial Genes and Selfish Genetic Elements through the evolution of Horizontal Gene Transfer

Horizontal gene transfer (HGT) is a key component of bacterial evolution, which in concert with gene loss can result in rapid changes in gene content. While HGT can evidently aid bacteria to adapt to new environments, it also carries risks since bacteria may pick up selfish genetic elements (SGEs). Here, we use modeling to study how bacterial growth rates are affected by HGT of slightly beneficial genes, if bacteria can evolve HGT to improve their growth rates, and when HGT is evolutionarily maintained in light of harmful SGEs. We find that we can distinguish between four classes of slightly beneficial genes: indispensable, enrichable, rescuable, and unrescuable genes. Rescuable genes - genes that confer small fitness benefits and are lost from the population in the absence of HGT -- can be collectively retained by a bacterial community that engages in HGT. While this gene-sharing cannot evolve in well-mixed cultures, it does evolve in a spatially structured population such as a biofilm. Although HGT does indeed enable infection by harmful SGEs, HGT is nevertheless evolutionarily maintained by the hosts, explaining the stable coexistence and co-evolution of bacteria and SGEs.

microbiology↗

bioRxiv2019

The origin of the central dogma through conflicting multi-level selection

The central dogma of molecular biology rests on two kinds of asymmetry between genomes and enzymes: informatic asymmetry, where information flows from genomes to enzymes but not from enzymes to genomes; and catalytic asymmetry, where enzymes provide chemical catalysis but genomes do not. How did these asymmetries originate? Here we show that these asymmetries can spontaneously arise from conflict between selection at the molecular level and selection at the cellular level. We developed a model consisting of a population of protocells, each containing a population of replicating catalytic molecules. The molecules are assumed to face a trade-off between serving as catalysts and serving as templates. This trade-off causes conflicting multilevel selection: serving as catalysts is favoured by selection between protocells, whereas serving as templates is favoured by selection between molecules within protocells. This conflict induces informatic and catalytic symmetry breaking, whereby the molecules differentiate into genomes and enzymes, establishing the central dogma. We show mathematically that the symmetry breaking is caused by a positive feedback between Fishers reproductive values and the relative impact of selection at different levels. This feedback induces a division of labour between genomes and enzymes, provided variation at the molecular level is sufficiently large relative to variation at the cellular level, a condition that is expected to hinder the evolution of altruism. Taken together, our results suggest that the central dogma is a logical consequence of conflicting multilevel selection.

evolutionary biology↗

bioRxiv2019

Bacterial community changes with cryoconite granule size and their susceptibility to exogenous nutrients on 10 glaciers in northwestern Greenland

Cryoconite granules, which are dark-colored biological aggregates on glaciers, effectively accelerate the melting of glacier ice. Bacterial community varies with granule size, however, community change in space and their susceptibility to environmental factors has not been described yet. Therefore, we focused on bacterial community from 4 different granule sizes (30-249 m, 250- 750 m, 750-1599 m, more than 1600 m diameter) in 10 glaciers in northwestern Greenland and their susceptibility for exogenous nutrients in cryoconite hole. A filamentous cyanobacterium Phormidesmis priestleyi, which has been frequently reported from glaciers in Arctic was abundant (10-26%) across any size of granules on most of glaciers. Bacterial community across glaciers became similar with size increase, and whence smallest size fractions contain more unique genera in each glacier. Multivariate analysis suggests that phosphate, which is significantly higher in one glacier (Scarlet Heart Glacier), is primary associated with bacterial beta diversity. Correlation coefficients between abundance of major genera and nutrients largely changed with granule size, suggesting that nutrients susceptibility to genera changes with growth process of granule (e.g. P. priestleyi was affected by nitrate in early growth stage).

ecology↗