Biology subjects

Kinoshita, S.

Publications and source records attributed to Kinoshita, S..

At least 19 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

Efficient Optimization of Genotype Pairs for Intercropping using Genomic Prediction and Bayesian Optimization

Intercropping is a promising strategy to improve productivity and sustainability in agricultural systems, but designing effective genotype combinations remains a major challenge owing to the rapid increase in possible pairings as the number of candidate genotypes increases. This creates a practical bottleneck because field evaluation of all combinations is infeasible under realistic resource constraints. Here, we propose a framework that integrates genomic prediction and Bayesian optimization to support efficient decision-making for intercropping system design. Using genome-wide marker data from sorghum and soybean, we simulated intercropping performance across 5,214 genotype pairs under certain genetic architectures, including variation in heritability, correlations between direct and indirect genetic effects, and the contribution of pair-specific interactions. Genomic prediction models incorporating direct and indirect genetic effects substantially improved prediction accuracy compared with models based on direct genetic effects alone, and inclusion of specific mixing ability further enhanced the performance under high-heritability conditions. When coupled with Bayesian optimization, the models rapidly identified superior genotype pairs, requiring fewer evaluation cycles than random or prediction-only search strategies. Acquisition functions that account for predicted uncertainty were most effective in complex scenarios involving interaction effects or negative correlations between direct and indirect effects. These results demonstrate that combining genomic prediction with Bayesian optimization can substantially reduce the experimental burden associated with intercropping design, while improving the efficiency of identifying high-performing genotype pairs. The proposed framework provides a practical approach for prioritizing candidate mixtures in breeding and field evaluation, and contributes to the development of data-driven strategies for sustainable agricultural systems. HighlightsO_LIA data-driven framework was developed to optimize genotype pairs in intercropping. C_LIO_LIModeling indirect effects improved prediction accuracy across genotype pairs. C_LIO_LIPair-specific interactions enhanced prediction under high-heritability conditions. C_LIO_LIBayesian optimization identified superior pairs under limited evaluation capacity. C_LIO_LIThe framework reduces field-testing requirements for intercropping system design. C_LI

genomics↗

bioRxiv2026

Functional characterization of bat limb regulatory elements

Bats are the only mammals capable of powered flight and roost head-down. However, the molecular changes shaping bat limbs remain largely unknown. Here, we used comparative functional genomics coupled with mouse-bat sequence swaps to identify key regulatory elements important in bat limb development. We generated and compared bat and mouse forelimb and hindlimb genomic datasets at key wing developmental timepoints, followed by mouse enhancer assays to characterize sequences showing differences between species. We then swapped six mouse enhancer sequences with their corresponding bat sequences, obtaining a variety of bat limb associated phenotypes, including ossification delay, longer digits, thicker skin and symmetrical hindlimb digits. Our work provides a genomic catalog of genes and regulatory elements involved in bat limb development and through extensive characterization in mice shows how changes in regulatory elements lead to small phenotypic changes that together contribute to bat limb development.

developmental biology↗

bioRxiv2025

Progeny-based genomic selection reveals untapped genetic potential in an underutilized medicinal plant, Perilla frutescens

O_LIDespite their substantial therapeutic value, medicinal plants have undergone limited genetic improvement through breeding because of the scarcity of expert breeders. Moreover, quantifying bioactive compounds is expensive. Genomic selection (GS), which leverages genome-wide markers to predict breeding values and assemble favorable alleles, offers a practical way to unlock latent genetic potential. As a model case, we evaluated GS in red perilla (Perilla frutescens). C_LIO_LIBuilding on previous work, we implemented a cross-selection strategy that prioritized segregation variance by selecting crosses based on predicted additive genotypic values of the progeny, and evaluated its effectiveness through actual crossing experiments targeting three key medicinal compounds. C_LIO_LIProgeny from GS-based crosses (Crs1-Crs7) outperformed those from phenotypic selection (Crs8) in the G2 generation, demonstrating a higher mean, greater variance, and superior top individuals. The best G2 individual exhibited nearly twofold higher levels of two target compounds relative to the existing cultivar Sekiho. C_LIO_LIThis study provides the first empirical demonstration that GS can improve multiple medicinal compounds in red perilla and highlights the effectiveness of cross-selection based on predicted progeny performance. In addition, the evidence presented here supports the broader application of GS in underutilized medicinal plants. C_LI

genetics↗

bioRxiv2025

Environmental exosomes: Evidence of extracellular RNA release by aquatic organisms

Aquatic organisms continuously interact with surrounding water, yet whether they release extracellular vesicles remains unknown. We hypothesized that pearl oysters (Pinctada fucata) release exosomes/small extracellular vesicles (sEVs) into the aquatic environment. To this end, we collected exosomes/sEV-sized components by ultrafiltration from tank water and open-sea culture areas. Microscopy revealed abundant vesicles consistent with exosome/sEV size, and RNA sequencing identified oyster-specific piRNAs that matched sequences previously detected in hemolymph exosomes. These findings demonstrated that pearl oysters actively released exosomes containing species-specific nucleic acids into surrounding water. We propose referring to these vesicles as environmental exosomes/environmental sEVs (eExosomes/esEVs). This finding suggests that aquatic exosomes serve as carriers of RNA and may contribute to inter-organismal communication networks. Beyond their functional role, eExosomes/esEVs also hold promise as novel targets for environmental DNA/RNA (eDNA/eRNA) analysis, offering new opportunities for ecological monitoring and biodiversity research.

ecology↗

bioRxiv2025

The minimal endosymbiosis between Spurilla braziliana (Aeolidiidae, Nudibranchia) and Symbiodiniaceae

Symbiotic relationships between dinoflagellates of the family Symbiodiniaceae and marine invertebrates underpin the functioning of certain shallow-water marine ecosystems. Although the Symbiodiniaceae-Cladobranchia nudibranch association has been proposed as a promising model for symbiosis research, interspecific variation in the extent of this association remains poorly resolved. Here, we assessed the algal symbiotic characteristics of the nudibranch Spurilla braziliana. Histological analyses revealed limited branching of the digestive gland and the presence of intact Symbiodiniaceae cells within lysosome-rich epithelial digestive cells. Metagenomic profiling further showed a complete absence of Endozoicomonas--bacteria typically linked to Symbiodiniaceae symbioses--in this species. These findings indicate that S. braziliana can harbor Symbiodiniaceae but exhibits only primitive morphological and microbial adaptations to the symbiotic state. Collectively, these results provide new insights into the evolutionary and structural diversity of nudibranch-algal symbioses.

zoology↗

bioRxiv2025

Generation of iPSC-derived CD4+ Th1 cells enhancing chimeric antigen receptor-T cell cytotoxicity

CD4+ T cells are anticipated to enhance the overall immune response, including the anti-tumor activity of chimeric antigen receptor (CAR)-T cell therapy. In the past, we established a culture system to generate CD8+ T cells from iPS cells (iPSCs); however, it was challenging to generate CD4+ T cells. Drawing inspiration from the observation that adult T cell leukemia (ATL) cells are consistently CD4+ and possess Treg characteristics, we successfully generated CD4+ Treg cells by reprogramming ATL cells into iPSCs and then differentiating them into T cells. Gene expression analysis of this generation system suggested that RUNX3 serves as a key regulator in T cell differentiation within the ex vivo generation system. By knocking out RUNX3, we demonstrated the generation of antigen-specific CD4+ Th1 cells via the iPSC route, thereby enhancing the activity of CD8+ CAR-T cells against GD2-expressing lymphoma. These technologies hold significant promise for contributing to "off-the-shelf" immunotherapies against malignant tumors, including solid tumors.

immunology↗

bioRxiv2025

The Greenland shark genome: insights into deep-sea ecology and lifespan extremes

The Greenland shark (Somniosus microcephalus) is known for its slow metabolism and deep-sea habitat. It is considered the longest-lived vertebrate on Earth, with an estimated lifespan of 392{+/-}120 years. Despite its remarkable longevity and lifestyle, there have been no genomic studies on this species. Here, we report the first, chromosome-level assembly of the Greenland shark genome, which is 5.9 Gb in size with an N50 length of 233 Mb, and contains 37,125 predicted genes with a completeness score of 86.5%. We found that the copy numbers of three gene families (TNF, TLR, LRRFIP), which are involved in activating the NF-{kappa}B signaling pathway, are significantly increased in the Greenland shark compared to short-lived shark species. In the rhodopsin of this deep-sea dweller, we detected amino acid substitutions that result in spectral tuning for the so-called blue shift, suggesting adaptive evolution to dim-light vision. We also elucidate the dynamics of the effective population size (Ne) of the Greenland shark and its close relative, the Pacific sleeper shark (Somniosus pacificus). These genomic analyses offer new insights into the molecular basis of the exceptional longevity of the Greenland shark and highlight potential genetic mechanisms that could inform future research into longevity.

genomics↗

bioRxiv2025

Optimization of crossing strategy based on the usefulness criterion in inter-population crosses considering different genetic effects among populations

In the breeding programs of self-pollinated plants, achieving genetic improvement in multiple traits can be challenging when relying solely on a single biparental population. Interpopulation crosses are employed to integrate favorable alleles from multiple biparental populations to overcome this limitation. In this context, it is crucial to consider the distinct genetic effects in different populations. In this study, we utilized a selection method based on the usefulness criterion (UC) to identify cross pairs suitable for interpopulation crosses. We expanded this approach to enhance breeding programs accounting for varying genetic backgrounds within the genomic selection framework. Using the medicinal plant red perilla as the study material, we conducted simulations to compare the efficacy of selection based on estimated genomic breeding values with that based on UC. Our findings demonstrate that the proposed method is effective in facilitating the simultaneous improvement of multiple traits, particularly by considerably increasing genetic gains among the top-performing individuals in the population. Furthermore, we provide guidelines for implementing interpopulation crosses, including recommendations for the optimal generation for crossing and the appropriate reference generation for calculating the UC. The results obtained in this study offer valuable insights for small-scale breeding programs aimed at simultaneously enhancing multiple traits through inter-population crosses and are applicable to a wide range of crops, including neglected and underutilized species. Key MessageHerein, a method has been proposed for selecting optimal cross pairs based on the genetic potential of progeny in inter-population crosses, considering different genetic effects among populations.

bioinformatics↗

bioRxiv2023

Assessing the potential for genome-assisted breeding in red perilla using quantitative trait locus analysis and genomic prediction

Red perilla is an important medicinal plant used in Kampo medicine, and the development of elite varieties of this species is urgently necessary. Medicinal compounds are generally considered target traits in medicinal plant breeding; however, selection based on the phenotypes of the compounds (i.e., conventional selection) is expensive and time-consuming. Here, we proposed genomic selection (GS) and marker-assisted selection (MAS) as suitable selection methods for medicinal plants, and evaluated the effectiveness of GS and MAS in red perilla breeding. Three breeding populations generated from crosses between one red and three green perilla genotypes were used to elucidate the genetic mechanisms underlying the production of major medicinal compounds using quantitative trait locus analysis and to evaluate the accuracy of genomic prediction (GP). We found that GP had sufficiently high accuracy for all traits, confirming that GS was an effective method for perilla breeding. Moreover, the three populations showed varying degrees of segregation, suggesting that use of these populations in breeding may yield simultaneous enhancements of different target traits. This study can contribute to research on the genetic mechanisms of the major medicinal compounds of red perilla as well as the breeding efficiency of this medicinal plant.

genomics↗

bioRxiv2023

The highly developed symbiotic system between the solar-powered nudibranch Pteraeolidia semperi and Symbiodiniacean algae

The intricate coexistence of Symbiodiniacean algae with a diverse range of marine invertebrates underpins the flourishing biodiversity observed within coral reef ecosystems. However, the phenomenon of coral bleaching--precipitated by the dissolution of symbiotic relationships with Symbiodiniaceae--poses a significant threat to these ecosystems, thereby necessitating an urgent investigation into the underlying symbiotic mechanisms. The symbiosis between nudibranchs and Symbiodiniaceae has been identified as an efficacious model for examining these mechanisms, yet a comprehensive understanding of their histological structures and cellular processes remains elusive. In this study, we concentrate on the nudibranch host Pteraeolidia semperi, renowned for its exceptional symbiotic capabilities, and we elucidate its sophisticated symbiotic architecture. Furthermore, we delineate the bleaching process within the nudibranch, uncovering the associated cellular processes. Collectively, these findings furnish invaluable insights into the intricate relationship between nudibranchs and Symbiodiniaceae, thereby contributing to our understanding of the symbiosis that sustains these critical marine ecosystems.

cell biology↗

bioRxiv2023

The complete mitochondrial genome of Spurilla braziliana MacFarland 1909 (Nudibranchia, Aeolidiidae).

Spurilla braziliana MacFarland 1909 is a morphologically diverse nudibranch found in the Pacific and Western Atlantic. The complete mitochondrial genome of S. braziliana has been constructed using next-generation sequencing technology. The mitochondrial genome is 14,291 bp and contains 13 protein-coding genes, 2 rRNA genes, and 23 tRNA genes. Molecular phylogenetic analysis using the maximum likelihood method revealed that S. braziliana is included in the superfamily Aeolidioidea and forms a monophyletic group with Berghia stephanieae, a nudibranch of the family Aeolidiidae. This study reinforces existing taxonomic insights and provides a basis for further molecular phylogenetic analysis.

genomics↗

bioRxiv2023

DNA methylation signature in NSD2 loss-of-function variants appeared similar to that in Wolf-Hirschhorn syndrome

PurposeWolf-Hirschhorn syndrome (WHS), a contiguous gene syndrome caused by the hemizygous deletion of the distal short arm of chromosome 4 where NSD2 is, reportedly exhibits specific DNA methylation signatures in peripheral blood cells. However, responsible genomic loci for signatures are unreported. The objective of the study is to define the loci of WHS-related DNA methylation signatures and to explore the role of NSD2 for the signatures. MethodsWe conducted genome-wide methylation analysis of individuals with WHS or NSD2 variants using array. We studied genome-edited knock in mice or induced pluripotent stem cells to explore the function of NSD2 variants which are observed in congenital anomaly cases. ResultsThree undiagnosed cases with NSD2 variants showed WHS-related DNA methylation signatures. These variants were validated to be NSD2 loss-of-function in induced pluripotent stem cells or genome-edited knock-in mice. p.Pro905Leu variant decreased Nsd2 protein levels, and changed Histone H3-Lysine 36 demethylation levels in similar way in the same genomic regions as Nsd2 knock out mice regulated. Nsd2 knock out mice exhibited common DNA methylation changes. ConclusionThese results revealed that WHS-related DNA methylation signatures are dependent on NSD2 dysfunction and are useful in diagnosing NSD2 variants of unknown significance.

genetics↗

bioRxiv2022

G307S DNAM-1 mutation exacerbates autoimmune encephalomyelitis via enhancing CD4+ T cell activation

Although rs763361, which causes a non-synonymous glycine-to-serine mutation at residue 307 (G307S mutation) of the DNAM-1 immunoreceptor, is a single-nucleotide polymorphism (SNP) associated with autoimmune disease susceptibility, little is known about how the SNP is involved in pathogenesis. Here, we established CD4+ T cells expressing wild-type or G307S DNAM-1 and showed that the costimulatory signal from G307S DNAM-1 induced greater pro-inflammatory cytokine production and cell proliferation than that from wild-type DNAM-1. The G307S mutation also enhanced the recruitment of the tyrosine kinase Lck and augmented tyrosine phosphorylation at residue 322 (Tyr322) of DNAM-1. However, conversion of Tyr322 of DNAM-1 to phenylalanine (Y322F mutation) canceled the enhanced activation of CD4+ T cell transfectants expressing G307S DNAM-1. Adoptive transfer of myelin-antigen-specific CD4+ T cells expressing G307S DNAM-1 into mice exacerbated experimental autoimmune encephalomyelitis compared with the transfer of cells expressing wild-type DNAM-1. These findings suggest that rs763361 is a gain-of-function mutation that enhances DNAM-1-mediated costimulatory signaling for proinflammatory responses.

immunology↗

bioRxiv2022

MitoSearch: Construction of fish species composition database with environmental DNA using public databases

Existing fish species distribution databases have the following problems: the possibility of species identification errors due to plasticity of morphological characteristics, the impossibility of quantitative composition, and the difficulty of geographically and time-series integrated interpretation. To solve the above problems, we constructed MitoSearch database. It is a fish species distribution database using 2,160 samples of variable regions of 12S rRNA genes amplified by MiFish primers registered at NCBI/EBI/DDBJ, and visualizes the fish species composition data on a map. By integrating a large amount of data registered in public databases, MitoSearch was aimed to provide the comprehensive understanding of spatial and temporal distribution of organisms on a global scale.

ecology↗

bioRxiv2021

Drosophila hemocytes recognize lymph gland tumors of mxc mutants and activate the Toll pathway in reactive oxygen species-dependent manner

Mechanisms of cancer cell recognition and elimination by the innate immune system remains unclear. Circulating hemocytes are associated with the hematopoietic tumors in Drosophila mxcmbn1 mutant larvae. The innate immune signalling pathways are activated in the fat body to suppress the tumor growth by inducing antimicrobial peptides (AMP). Here, we investigated the regulatory mechanism underlying the activation in the mutant. Reactive oxygen species accumulated in the hemocytes due to induction of dual oxidase and its activator. The hemocytes were also localized on the fat body. These were essential for transmitting the information on tumors toward the fat body to induce AMP expression. Regarding to the tumor recognition, we found that matrix metalloproteinase 1 (MMP1) and MMP2 were highly expressed in the tumors. Ectopic expression of MMP2 was associated with AMP induction in the mutants. Furthermore, the basement membrane components in the tumors were reduced and ultimately lost. The hemocytes may recognize the disassembly in the tumors. Our findings highlight the underlying mechanism via which macrophage-like hemocytes recognize tumor cells and relay the information toward the fat body to induce AMPs. and contribute to uncover the immune systems roles against cancer. SUMMARY STATEMENTDrosophila blood cells transmit information regarding the existence of tumor cells to the fat body and induce the production of anti-tumor peptides via the generation of reactive oxygen species.

developmental biology↗

bioRxiv2021

Zebrafish Danio rerio trunk muscle structure and growth from a spatial transcriptomics perspective

Compared to mammals, some fish exhibit indeterminate growth characteristics, meaning they can continue growing throughout their lives. Zebrafish trunk skeletal muscle can in general be classified into slow, intermediate, and fast based on morphological and physiological characteristics. After hatching, hyperplasia can be observed in the muscles of juvenile zebrafish, and with growth, hyperplasia in the fast muscles gradually decreases until it stagnates, after which fast muscle development relies on hypertrophy. In slow muscle, hyperplasia continues throughout life. Teleost muscle structure and growth has been described mainly by morphological and physiological features based on the expression of a limited number of proteins, transcripts, and metabolites. The details of mechanism remain unclear. Visium Spatial Gene Expression solution was used in this study. On the adult slide, 10 clusters were obtained based on whole gene expression similarities. The spatial expression of myosin heave chains, myosin light chains and myosin-binding proteins was investigated. GO enrichment analysis was also performed on different muscle regions of aged zebrafish. Dorsal and ventral slow muscles share the same processes such as myofibril assembly and muscle tissue development. On the larvae slide, 3 clusters were obtained, GO enrichment analysis suggest active muscle formation in zebrafish larvae.

genomics↗

bioRxiv2020

Suppression of amyloid-β secretion from neurons by cis-9, trans-11-octadecadienoic acid, an isomer of conjugated linoleic acid

Conjugated linoleic acid (CLA) comprises several geometric and positional isomers of the parental linoleic acid (LA). Two of the isomers, cis-9, trans-11 CLA (c9,t11 CLA) and trans-10, cis-12 CLA (t10,c12 CLA) exert various biological activities. However, the effect of CLA on generation of neurotoxic amyloid-{beta} (A{beta}) protein remains unclear. We found that c9,t11CLA significantly suppressed generation of A{beta} in primary cultures of mouse neurons. CLA treatment did not affect the levels of {beta}-site APP-cleaving enzyme 1 (BACE1), a component of active {gamma}-secretase complex presenilin 1 amino-terminal fragment (PS1 NTF), or A{beta} protein precursor (APP) in cultured neurons. BACE1 activity in lysate of neurons treated with c9,t11 CLA, but not t10,c12 CLA, decreased slightly, although c9,t11 CLA did not directly affect the activity of recombinant BACE1. Interestingly, localization of BACE1 and APP in early endosomes increased in neurons treated with c9,t11 CLA; concomitantly, the localization of both proteins was reduced in late endosomes, where APP is predominantly cleaved by BACE1. c9,t11 CLA and t10,c12 CLA appeared to be incorporated into membrane phospholipids, as the level of CLA-containing lysophosphatidylcholine (CLA-LPC) increased dramatically in neurons incubated with CLA. Taken together, our findings indicate that accumulation of c9,t11 CLA-LPC, but not t10,c12 CLA-LPC, in neuronal membranes suppresses amyloidogenic cleavage of APP, thereby contributing to preservation of brain neurons by suppressing neurotoxic A{beta} production in aged subjects.

biochemistry↗