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Otani, Y.

Publications and source records attributed to Otani, Y..

17 recordsLinked to original sources
bioRxiv2026

Mapping human-macaque encounter potential by integrating visitor-use and macaque-use intensity in Kamikochi, Japan

Managing visitor-wildlife interactions in high-use protected areas requires identifying not only where visitors concentrate but also where visitor use overlaps with wildlife space use. We estimated relative human- macaque encounter potential in Kamikochi, Chubu Sangaku National Park, Japan, where Japanese macaques (Macaca fuscata) and visitors use the same frontcountry landscape. We integrated Mobile Spatial Statistics derived from mobile phone network data, trail-camera counts, and direct-follow location data from macaques along a frontcountry-backcountry gradient. Broad-scale 500-m grid estimates of daytime visitor presence for the 2023 and 2024 open seasons were allocated to 50-m trail sections and adjusted using counts from 10 trail cameras. Automated video counts based on YOLO11 and ByteTrack showed high agreement with manual counts of 100 validation videos (MAE = 0.10 persons/video, MAPE = 1.26%, exact agreement rate = 92.0%). Visitor-use and macaque-use data were converted into kernel density surfaces, and encounter potential was calculated as their normalized product. High encounter potential was concentrated in the central frontcountry: 87.1% of areas with index values [≥] 0.9 fell within the frontcountry and 12.9% within the backcountry. Areas with high visitor use or high macaque use alone did not necessarily show high encounter potential when the two distributions were spatially offset. These results show that spatial overlap provides management information not captured by visitor counts alone. Relative encounter potential can help prioritize patrols, visitor messaging, viewing management, and other interventions in protected areas where wildlife does not consistently avoid heavily used visitor spaces.

zoology↗
bioRxiv2026

An internal PDZ-binding motif in Densin-180 promotes activity-dependent SHANK scaffold remodelling

SHANK proteins form core postsynaptic density (PSD) scaffolds that organise synaptic signalling complexes through multiple protein-protein interaction domains, including PDZ domains that typically recognise C-terminal peptide motifs. Here, we identify an internal PDZ recognition mechanism that links the synaptic protein Densin-180 to SHANK and promotes SHANK scaffold assembly. We map SHANK binding to an internal PDZ-binding motif in Densin-180 (residues 843-863) and show by NMR spectroscopy and fluorescence polarisation that this motif binds SHANK1-3 PDZ domains with high affinity and specificity, competing with canonical C-terminal ligands. The crystal structure of the Densin-180-SHANK complex reveals that Phe858 inserts into the hydrophobic pocket of the PDZ domain despite the absence of a terminal carboxylate. In neurons, this interaction mediates Densin-180 recruitment to dendritic spines and drives activity-dependent reorganisation of postsynaptic SHANK3 assemblies, whereas mutation of Phe858 disrupts both processes. Disrupting the Densin-180-SHANK interaction using a Densin-180-derived peptide impairs activity-dependent structural plasticity of spines, accompanied by defects in PSD organisation and actin cytoskeleton remodelling. These findings define an internal mode of PDZ recognition and reveal how Densin-180 couples neuronal activity to the remodelling of postsynaptic SHANK scaffolds.

neuroscience↗
bioRxiv2026

Geometric-Evolutionary Deep Learning Decodes the Human GPCR-Metabolome Interactome and Enables Systematic De-Orphanization

G protein-coupled receptors (GPCRs) are the largest class of drug targets, yet hundreds of orphan GPCRs lack known endogenous ligands, limiting our understanding of human physiology and therapeutic development. Existing computational approaches often fail to generalize to these unseen targets due to a reliance on target-specific priors and linear feature integration. Here, we present G-LEAP, a deep learning framework that learns generalizable principles of GPCR-ligand recognition by synergizing evolutionary protein language models with 3D-aware geometric molecular representations. By implementing a bilinear interaction module, G-LEAP explicitly models non-linear cross-modal interactions and achieves superior generalization on stringent benchmarks, outperforming state-of-the-art methods by 22.4% in error reduction. Crucially, G-LEAP demonstrates robust chemical discrimination by effectively distinguishing active ligands from property-matched physicochemical decoys in the DUDE-Z benchmark and correctly rejecting 67% of hard-negative artifacts prioritized by physics-based docking simulations. Leveraging this capacity, we constructed a comprehensive atlas of over 120 million predicted interactions between 217,000 human metabolites and the GPCR superfamily, which ranked the true endogenous ligand within the top 1% of candidates for 33.7% of known pairs and identified putative orphan ligands validated by significant tissue-specific co-expression with their biosynthetic enzymes. Furthermore, large-scale virtual screening retrieved potent hits with novel chemical scaffolds distinct from known GPCR ligands, demonstrating robust scaffold hopping. G-LEAP thus provides a systematic and biologically validated platform to accelerate de-orphanization and expand the therapeutic chemical space.

systems biology↗
bioRxiv2025

Proteogenomic profiling of soft tissue leiomyosarcoma reveals distinct molecular subtypes with divergent outcomes and therapeutic vulnerabilities

Soft tissue leiomyosarcoma (STLMS) is an aggressive malignancy for which robust molecular subclassification and mechanism-based therapeutic strategies still remain limited. We performed integrative proteogenomic analyses of primary and metastatic STLMS to define subtype-associated molecular programs. Joint analysis of the proteome and phosphoproteome identified 3 biologically distinct subtypes. P1 was characterized by relative genomic stability, low proliferative activity, and enrichment of FGFR2- and PDK-associated signaling. In contrast, P2 and P3 showed greater chromosomal instability and more aggressive clinical behavior, but with distinct molecular features. Notably, P2 was associated with inflammatory and RTK-RAS pathway programs, activation of CDK-AURKA/B-mTOR-ERK kinase networks, IGF1R/PDGFRA alterations, and the poorest outcomes. On the other hand, P3 showed strong cell cycle and DNA repair programs, elevated NCOR1 expression, and increased expression of nonhomologous end joining components, including PARP1. Homologous recombination deficiency analyses distinguished HRD-low P1 from HRD-high P2/P3, and paired analyses suggested increased HRD-related features in metastatic lesions within P3. Immune profiling identified an immune-hot yet potentially suppressive state in P2, marked by higher LGALS9 expression and M2-like macrophage infiltration. To support clinical translation, we developed a tissue microarray-based immunohistochemical classifier that enabled surrogate assignment of proteome-defined subtypes in an independent cohort and showed recurrence-free survival differences across inferred subtypes. These findings together establish a proteogenomic framework for STLMS heterogeneity and nominate subtype-associated biological vulnerabilities for future translational and clinical investigation.

cancer biology↗
bioRxiv2025

Cyclin-dependent kinase-like 5 (CDKL5) binds to talin and is anchored at the postsynaptic density via direct interaction with PDZ domains

Cyclin-dependent kinase-like 5 (CDKL5) is a serine/threonine kinase essential for brain development and function. Mutations in the CDKL5 gene cause CDKL5 deficiency disorder (CDD), a severe early-onset epileptic encephalopathy characterised by defects in synapse formation and function. Despite extensive research, the molecular mechanisms by which CDKL5 mutations disrupt synaptic function and lead to epilepsy remain unclear. Here, we report that the major neuronal isoform of CDKL5 contains a C-terminal PDZ domain-binding motif. We demonstrate that this motif mediates interactions with the PDZ domains of PSD-95 and SHANK proteins, facilitating the recruitment of CDKL5 to the postsynaptic density. Disruption of CDKL5s PDZ-binding motif results in its mislocalisation and impaired spine formation. Additionally, we show that CDKL5 directly interacts with the mechanosensitive synaptic scaffold protein talin, via the N-terminal kinase domain of CDKL5 and the R8 rod domain of talin. Our findings establish how CDKL5 is targeted to synapses and suggest that its activity may be spatially regulated through talin-mediated mechanical signalling. We propose that the spatial positioning of the CDKL5 kinase domain might be mechanically-operated and regulated by talin domain unfolding. As talin undergoes structural transitions in its force-dependent binary switch domains, the kinase domain bound to R8 would be moved up and down within the synaptic compartment as a function of the changing talin conformation. These insights enhance our understanding of the pathogenic mechanisms underlying CDKL5 variants with premature stop codons and highlight the need to re-evaluate studies that have used C-terminally tagged or the non-PDZ-binding isoform of CDKL5 to assess its neuronal function. O_FIG O_LINKSMALLFIG WIDTH=188 HEIGHT=200 SRC="FIGDIR/small/672337v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@a11d72org.highwire.dtl.DTLVardef@19428b7org.highwire.dtl.DTLVardef@1fd1693org.highwire.dtl.DTLVardef@d5299c_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO Cyclin-dependent kinase-like 5 (CDKL5) is a mechanically regulated enzyme. The C-terminal PDZ-binding motif in CDKL5 anchors CDKL5 at the postsynaptic density (PSD). (A) The large unstructured region serves to tether the CDKL5 kinase domain at the synapse. i) The kinase domain is restricted to the blue semi-circle, giving CDKL5 a zone of activity, with radius the length of the tether (>200 nm). ii) Epilepsy-causing mutations that introduce premature stop codons untether CDKL5. (B) The mechanosensitive synaptic scaffold protein talin is also tethered to the membrane by interaction with integrins and/or amyloid precursor protein (APP). The CDKL5-binding domain, R8 is shown in dark green. The force-dependent binary switch domains in the talin rod region open and close in response to force and change the length of the molecule and the location of the CDKL5-binding site. (C) As talin changes its conformation, the CDKL5-binding site on R8 is moved up and down within the synapse, as a result the kinase activity of CDKL5 is targeted to discrete locations within the synapse. Loss of this localisation or incorrect positioning of the kinase within the synapse would result in loss of synchronisation of the synapse in the context of the circuit it is part of and, we propose, result in re-entry circuits and epilepsy. See also Supplementary Movie 1. C_FIG

neuroscience↗
bioRxiv2025

High-Resolution Mapping of the Human E3-Substrate Interactome using Ubicon Uncovers Network Architecture and Cancer Vulnerabilities

Mapping the intricate network of E3 ubiquitin ligase-substrate interactions (ESIs), essential for cellular regulation and implicated in numerous diseases including cancer, remains a central challenge limiting mechanistic understanding. Existing experimental and computational methods suffer from limitations in throughput, accuracy, and contextual relevance. Here, we introduce Ubicon, a deep learning framework designed to overcome these hurdles for accurate, proteome-wide human ESI prediction. Ubicon achieves high fidelity by synergistically integrating multimodal features: sequence embeddings from a protein language model specifically adapted for ESI prediction via parameter-efficient fine-tuning (PEFT), predicted 3D structures, and subcellular localization context. Validated extensively, Ubicon achieves state-of-the-art performance (AUROC = 0.9305, AUPRC = 0.6812), significantly surpassing previous approaches. Applying Ubicon, we constructed a high-resolution map of the human E3-substrate interactome, revealing its systems-level architecture characterized by hub proteins and functional modules linked to distinct biological processes. Integrating predictions with cancer genomics further uncovered disease-specific ESI network rewiring, involving oncogenic ligases like AURKA and CDC20, linked to poor prognosis. Ubicon provides a powerful platform to dissect ubiquitin signaling, uncover disease mechanisms, and inform targeted protein degrader development.

bioinformatics↗
bioRxiv2025

BaCNet: Deep Learning Accelerates Novel Antibiotic Discovery Against Resistant Pathogens

Drug-resistant infections pose a global health challenge and necessitate the rapid development of novel antibiotics. Although high-speed and high-accuracy in silico drug discovery methods using AI have been established, only a few approaches that specifically target antibiotic development have been developed. This gap significantly limits our ability to rapidly discover effective antibacterials against emerging resistant pathogens. Here, we have developed BaCNet, an AI system that accurately predicts the binding affinity between bacterial proteins and compounds using only amino acid sequences and compound SMILES representations. Our approach integrates a protein language model with three complementary compound embedding methods, achieving high prediction accuracy and effectively maintaining performance when tested on previously unseen bacterial species. BaCNet successfully rediscovered known antibiotics and identified promising novel candidates, with molecular dynamics simulations confirming stable binding of top hits. Moreover, by integrating a compound generation and optimization system with BaCNet, we discovered novel compounds not present in existing databases with significantly enhanced predicted antibacterial activity. BaCNet represents a promising platform that could accelerate the identification of urgently needed treatments against resistant pathogens.

pharmacology and toxicology↗
bioRxiv2025

AMP-Atlas: Comprehensive Atlas of Antimicrobial Peptides to Combat Multidrug-resistant Bacteria

The escalating threat of infections caused by drug-resistant bacteria poses a significant global health challenge, with projections estimating 10 million annual deaths by 2050. While the development of conventional antibiotics has stagnated since the late 1990s, antimicrobial peptides (AMPs), short amino acid sequences exhibiting potent antimicrobial activity, have emerged as a promising alternative, demonstrating efficacy even against drug-resistant bacteria. However, despite the identification of numerous AMPs, their translation into clinically approved therapeutics remains limited, highlighting the critical need for accelerated discovery methods that transcend traditional experimental screening. Here, we introduce AMP-Atlas, an AI system inspired by cutting-edge natural language processing, designed to accurately predict antimicrobial activity from peptide sequences alone. AMP-Atlas achieves state-of-the-art performance, outperforming existing methods in AMP identification. Furthermore, we leveraged AMP-Atlas to screen human indigenous bacterial flora species, revealing a vast reservoir of previously unexplored AMP candidates. Our findings underscore the transformative potential of AI-powered approaches to revolutionize AMP discovery and development, paving the way for innovative therapeutic strategies to combat the looming threat of drug-resistant infections.

systems biology↗
bioRxiv2024

Aberrant axon initial segment is an indicator for task-independent neural activity in autism model mice

Autism spectrum disorder (ASD) is a developmental disorder characterized by impairments in several communicative behaviors. Identification of biomarkers for ASD based on task-independent neural activity has been elusive. The axonal initial segment (AIS), located at the proximal part of the axon, is crucial for initiating action potentials (APs) and adaptable through activity-dependent AIS plasticity. In our study, we discovered decrease in AIS length in layer V pyramidal neurons (PyNs) of the prelimbic cortex (PrL) and increase in layer II/III PyNs in the somatosensory cortex of duplicated human 15q11-13 region (15q dup) ASD model mice. Electrophysiological studies using whole-cell patch-clamp recordings in the PrL revealed diminished ability to generate APs. We discovered lack of AIS plasticity in 15q dup mice under conditions of elevated potassium chloride. Retrograde tracing demonstrated that AIS shortening depends on the projection targets. These results indicate that activity-dependent aberrant AIS structures can serve as indicators of altered task-independent neural activity in ASD mouse models.

neuroscience↗
bioRxiv2023

The focal adhesion protein talin is a mechanically-gated A-kinase anchoring protein (AKAP)

The cAMP-dependent protein kinase (Protein Kinase A; PKA) is a ubiquitous, promiscuous kinase whose activity is focused and specified through subcellular localization mediated by A-kinase anchoring proteins (AKAPs). PKA has complex roles as both an effector and a regulator of integrin-mediated cell adhesion to the extracellular matrix (ECM). Recent observations demonstrate that PKA is an active component of focal adhesions (FA), intracellular complexes coupling ECM-bound integrins to the actin cytoskeleton, suggesting the existence of one or more FA AKAPs. Using a combination of a promiscuous biotin ligase fused to PKA type-II regulatory (RII) subunits and subcellular fractionation, we identify the archetypal FA protein talin1 as an AKAP. Talin is a large, mechanosensitive scaffold that directly links integrins to actin filaments and promotes FA assembly by recruiting additional components in a force-dependent manner. The rod region of talin1 consists of 62 -helices bundled into 13 rod domains, R1-R13. Direct binding assays and nuclear magnetic resonance spectroscopy identify helix41 in the R9 subdomain of talin as the PKA binding site. PKA binding to helix41 requires unfolding of the R9 domain, which requires the linker region between R9 and R10. Finally, single-molecule experiments with talin1 and PKA, and experiments in cells manipulated to alter actomyosin contractility demonstrate that the PKA-talin interaction is regulated by mechanical force across the talin molecule. These observations identify the first mechanically-gated anchoring protein for PKA, a new force-dependent binding partner for talin1, and thus a new mechanism for coupling cellular tension and signal transduction.

cell biology↗
bioRxiv2021

Homogeneity of antibody-drug conjugates critically impacts the therapeutic efficacy in brain tumors

Glioblastoma multiforme (GBM) is characterized by aggressive growth and the poorest prognosis of all brain tumor types. Most therapies rarely provide clinically meaningful improvements in outcomes of patients with GBM. Antibody-drug conjugates (ADCs) are emerging chemotherapeutics with stunning success in cancer management. Although promising, clinical studies of three ADCs for treating GBM, including Depatux-M, have been discontinued because of safety concerns and limited therapeutic benefits. Here, we report that ADC homogeneity is a critical parameter to maximize the therapeutic potential in GBM therapy. We demonstrate that homogeneous conjugates generated using our linker show enhanced drug delivery to intracranial brain tumors. Notably, compared to heterogeneous ADCs, including a Depatux-M analog, our ADCs provide greatly improved antitumor effects and survival benefits in orthotopic brain tumor models, including a patient-derived xenograft model of GBM. Our findings warrant the future development of homogeneous ADCs as promising molecular entities toward cures for intractable brain tumors.

bioengineering↗
bioRxiv2021

The Exon Junction Complex Core Represses Caner-specific Mature mRNA Re-splicing: A Potential Key Role in Terminating Splicing

Using the TSG101 pre-mRNA, we previously discovered cancer-specific resplicing of mature mRNA that generates aberrant transcripts/proteins. The fact that mRNA is aberrantly re-spliced in various cancer cells implies there must be an important mechanism to prevent deleterious re-splicing on the spliced mRNA in normal cells. We thus postulated that the mRNA re-splicing is controlled by specific repressors, and we searched for repressor candidates by siRNA-based screening for mRNA re-splicing activity. We found that knockdown of EIF4A3, which is a core component of the exon junction complex (EJC), significantly promoted mRNA re-splicing. Remarkably, we could recapitulate cancer-specific mRNA resplicing in normal cells by knock-down of any of the core EJC proteins, EIF4A3, MAGOH or RBM8A (Y14), implicating the EJC core as the repressor of mRNA re-splicing often observed in cancer cells. We propose that the EJC core is a critical mRNA quality control factor to prevent over-splicing of mature mRNA.

molecular biology↗
bioRxiv2020

Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance

Breast tumors generally consist of a diverse population of cells with varying gene expression profiles. Breast tumor heterogeneity is a major factor contributing to drug resistance, recurrence, and metastasis after chemotherapy. Antibody-drug conjugates (ADCs) are emerging chemotherapeutic agents with striking clinical success, including T-DM1 for HER2-positive breast cancer. However, these ADCs often suffer from issues associated with intratumor heterogeneity. Here, we show that homogeneous ADCs containing two distinct payloads are a promising drug class for addressing this clinical challenge. Our conjugates show HER2-specific cell killing potency, desirable pharmacokinetic profiles, minimal immunogenicity, and marginal toxicity at therapeutic doses. Notably, a dual-drug ADC exerts greater treatment effect and survival benefit than does co-administration of two single-drug variants in a xenograft mouse model representing intratumor HER2 heterogeneity and elevated drug resistance. Our findings highlight the therapeutic potential of the dual-drug ADC format for treating refractory breast cancer and perhaps other cancers.

bioengineering↗
bioRxiv2020

Individual identification of Japanese macaques (Macaca fuscata) using a face recognition system and a limited number of learning images

Individual identification is an important technique in animal research that requires researcher training and specialized skillsets. Face recognition systems using artificial intelligence (AI) deep learning have been put into practical use to identify in humans and animals, but a large number of annotated learning images are required for system construction. In wildlife research cases, it is difficult to prepare a large amount of learning images, which may be why systems using AI have not been widely used in field research. To investigate the development of a system that identifies individuals using a small number of learning images, we constructed a system to identify individual Japanese macaques (Macaca fuscata yakui) with a low error rate from an average of 20 images per individual. The characteristics of this system were augmentation of data, simultaneous determination by four individual identification models and identification from a majority of five frames to ensure reliability. This technology has a high degree of utility for various stakeholders and it is expected that it will advance the development of individual identification systems by AI that can be widely used in field research.

zoology↗
bioRxiv2020

Factors influencing riverine utilization patterns in two sympatric macaques

Many species of terrestrial animals, including primates, live in varied association with the aquatic (e.g., riverine or coastal) environment. However, the benefits that each species receive from the aquatic environment are thought to vary depending on their social and ecological characteristics, and thus, elucidating those benefits to each species is important for understanding the principles of wild animal behaviour. In the present study, to gain a more complete picture of aquatic environment use, including social and ecological factors in primates, factors affecting riverine habitat utilization of two macaque species (Macaca nemestrina and M. fascicularis) were identified and qualitative comparisons were made with sympatric proboscis monkeys (Nasalis larvatus), which have different social and ecological characteristics. Temporal variation in sighting frequency of macaques at the riverbanks was positively related to the fruit availability of a dominant riparian plant species and negatively related to the river water level which affects the extent of predation pressure. Riverine utilization of macaques was greatly influenced by distribution and abundance of food (especially fruit) resources, possibly in association with predation pressure. Additionally, qualitative ecological comparisons with sympatric proboscis monkeys suggest that the drivers of riverine utilization depend on the feeding niches of the species, and different anti-predator strategies resulting from their differing social structures.

ecology↗
bioRxiv2019

Comparison of prokaryotic communities between the fields showing different disinfestation effects by anaerobic soil disinfestation

Anaerobic soil disinfestation (ASD) is a chemical-independent fumigation method used for reducing the abundance of pathogens at soil depths of <40 cm. However, its disinfestation efficiency is unstable under field conditions. The microbial community reflects the soil environment and is a good indicator of soil health. Therefore, soil with a good disinfestation efficiency may have a unique microbial community. The aim of the present study was to compare the prokaryotic communities among soils obtained from 17 geographically different greenhouses that experienced tomato bacterial wilt but exhibited different disinfestation efficiencies after ASD treatment with the same substrate. In the present study, soil prokaryotic communities in the field, which indicate difference in disinfestation effects after ASD treatment among several fields, were compared using next-generation sequencing. The prokaryotic communities in the fields showing different disinfestation effects were roughly separated into sampling fields. The relative abundances of Betaproteobacteria and Clostridia were significantly increased in well-disinfested fields. Overall, 25 operational taxonomic units (OTUs) were specifically increased in various well-disinfested soils and 18 OTUs belonged to phylogenetically diversified Clostridia. Other OTUs belonged to aerobic bacteria and were not previously detected in sample collected from ASD-treated fields. The results showed that the changes to the prokaryotic communities did not affect ASD efficiency, whereas changes in the abundance of specific microbes in the community were related to disinfestation.

microbiology↗