Biology subjects

Yamaguchi, R.

Publications and source records attributed to Yamaguchi, R..

At least 19 recordsLinked to original sources

bioRxiv2026

Oxidized EGCG redirects α-synuclein aggregation through shear-selected interactions

-Synuclein (Syn) aggregation is central to Parkinson's disease pathology, and the green-tea polyphenol epigallocatechin gallate (EGCG) has been studied as an inhibit fibril formation. However, EGCG autoxidation and analyses under static, non-fibrillating conditions have obscured whether activity arises from EGCG itself or oxidized species and which interactions persist during Syn assembly. Here we combine HPLC, LC-MS, TEM and solution NMR to compare unoxidized and oxidized EGCG (oxEGCG), while Rheo-NMR monitors Syn during shear-promoted assembly. Unoxidized EGCG showed no detectable binding under static, reducing conditions, whereas oxEGCG bound Syn, inhibited fibrillation and remodeled fibrils. Under shear flow, many oxEGCG-dependent perturbations partially reverted toward free Syn, whereas interactions near the NAC-C-terminal boundary were preferentially retained, coinciding with formation of oligomers and short, thick fibrils. These findings identify oxidation state and flow as determinants of EGCG action on Syn and show that Rheo-NMR distinguishes interactions that persist during shear-promoted assembly.

biochemistry↗

bioRxiv2026

SPATNIC enables H&E-grounded cancer-cell identification across spatial and single-cell transcriptomic modalities in colorectal cancer

Tumors contain diverse non-cancer cells that constitute the tumor microenvironment; thus, identifying which cells are cancerous is a foundational and critical first step in cancer research. However, to our knowledge, no transcriptome-based classifier has been trained using pathologist-defined annotations from matched H&E images at single-cell resolution. Moreover, few tools can be shared across diverse platforms. Here, we present SPATNIC, a variational autoencoder that classifies individual cells as cancer or normal, trained on Xenium cells labeled by a pathologist review of matched H&E images. It matches or exceeds the performance of existing tools in primary colorectal tumors and liver and lung metastases. SPATNIC generalizes zero-shot across Visium, Visium HD, CosMx, Xenium, MERSCOPE, and single-cell RNA sequencing. In public single-cell atlases, it identified a rare POU2F3 tuft-like cancer stem cell population missed by existing annotations and associated with worse survival. In rectal cancer profiled before and after chemoradiotherapy, it separated cancer from normal epithelium in tissue, thus enabling per-patient screening of antibody-drug conjugate (ADC) targets.

cancer biology↗

bioRxiv2026

Adolescent prodromal phenotypes of psychiatric disorders: insights from a novel DISC1-perturbed monkey model

Neurodevelopmental deficits frequently lead to mild but significant adolescent social and cognitive changes, representing prodromal manifestations of adult-onset psychiatric disorders in a cross-disease manner. Although experimental medicine utilizes animal models to address the mechanisms, rodent brains lack critical structures for human higher brain functions such as the dorsolateral prefrontal cortex. To fill this translational gap, we generated monkeys with an impaired DISC1 gene locus, targeting the multifunctional protein essential for neurodevelopment and involved in transdiagnostic mental health risks. Here we analyze the F0 animals by minimizing mosaicism. At ages equivalent to human adolescence, these monkeys exhibited blunted responsiveness to social stimuli and increased internal drives, mirroring altered social behaviors in the prodromal stage in humans. Resting-state functional MRI data indicated disrupted global functional connectivity and reorganization of network topology, marked by a shift in the dominance of brain hubs from prefrontal regions to sensory areas. This primate model provides a unique platform for studying psychiatric disorders, such as schizophrenia, across the developmental trajectory.

neuroscience↗

bioRxiv2026

Distribution-Constrained Optimization for Reliable ML-Guided 5'UTR Sequence Design

The 5' untranslated region (5' UTR) shapes translation initiation, so its design is central to mRNA therapeutics and to improving protein-production cell lines. Deep-learning models that predict translation efficiency, measured as mean ribosome load (MRL), from the 5' UTR sequence have been combined with genetic algorithms (GAs) for sequence optimization. However, optimizing against a model trained on offline data risks reward hacking that exploits the models estimation error outside the training distribution, yielding sequences that score highly in prediction yet fail to perform in the wet lab. Yet for 5' UTR design, few studies have systematically examined which region should be treated as untrustworthy (the definition of out-of-distribution, OOD) or which constraints keep the search away from it. We present a constrained optimization that keeps candidates within a trust region where the predictors validated accuracy holds; here "reliable" denotes keeping candidates within the training distribution over which prediction has been validated, not a guarantee of measured performance. As the OOD score, we compare the k-nearest-neighbor (KNN) distance in the predictors embedding space against a pseudo-perplexity (PPPL) from the encoder and LM head, and show that for nucleotide sequences--whose vocabulary is small--PPPL fails to separate in- vs out-of-distribution, whereas the KNN distance is an effective OOD score that can define a trust region even from unlabeled native UTR sequences. Using the KNN distance as a hard GA constraint keeps all candidates inside the trust region while maintaining predicted MRL: under unconstrained optimization most final-generation candidates (72-96% across seeds) left the trust region (self-KNN p95), whereas the hard constraint holds predicted MRL at the unconstrained level and yields about 4.3x more selectable low-risk candidates than post-hoc filtering of the unconstrained output. Comparing an output extrapolation guard, reference-sequence similarity and structural accessibility (RNAplfold), we find that the guard and the similarity constraint also suppress OOD as a side effect, whereas making accessibility a secondary objective broadens the search without suppressing OOD.

bioinformatics↗

bioRxiv2026

Scale-dependent spatial organisation of action observation network responses to hand actions and emotional faces

Human social perception relies on multiple visual signals, including object-directed actions and emotional facial expressions. It remains unclear whether responses to these signals converge within action-observation regions and whether apparent convergence depends on the spatial scale of analysis. We scanned 39 healthy human adults during two block-design fMRI tasks, hand action observations contrasted with paper-tube controls, and emotional expression observations contrasted with neutral faces. Using independently defined meta-analytic action observation network (AON) ROIs in the inferior frontal gyrus (IFG), inferior parietal lobule (IPL), and posterior superior temporal sulcus (pSTS), we analysed responses at whole-brain, ROI-average, and AON-constrained voxelwise scales. Whole-brain overlap between the two contrasts was localised primarily to the left lateral occipitotemporal extrastriate cortex, outside the AON. At the regional ROI-average scale, the IFG showed positive responses to both contrasts, whereas the IPL and pSTS showed opposing task preferences. Crucially, regional IFG co-engagement did not imply that the same voxels responded to both contrasts. Suprathreshold voxelwise overlap within the AON was virtually absent, and individual-level analysis revealed a small but reliable posterior displacement of hand action relative to emotional face within IFG. These findings show that spatial convergence between hand and emotion observation responses depends on the scale of analysis. The same IFG region can be engaged by both stimulus domains while retaining distinct local response topographies.

neuroscience↗

bioRxiv2026

Evolutionary branching of male emergence timing: Trade-offs and variance asymmetry as drivers of dimorphism.

Classical models of protandry predict unimodal male emergence timing, yet empirical observations in butterflies and bees reveal dimorphism: early-emerging small males coexist with late-emerging large males. The evolutionary mechanisms underlying such discrete alternative reproductive strategies in emergence timing remain poorly understood. In this study, we developed a mathematical model using an adaptive dynamics framework to investigate the conditions under which dimorphic male emergence timing evolves. We explored two potential mechanisms: (1) a trade-off between emergence timing and male competitiveness, and (2) differences in the variance of emergence timing between the sexes. Our analysis demonstrates that both mechanisms produce evolutionary branching, and that extreme variance asymmetry between sexes can generate multiple branching events, yielding three or more distinct male clusters. These findings provide a theoretical foundation for understanding the evolution of alternative reproductive strategies in emergence timing, with implications for other systems where reproductive success depends on temporal overlap between the sexes. We provide testable predictions that a positive correlation between emergence timing and male body size or competitiveness should be observed under the trade-off mechanism, and that the variance in emergence timing within each male morph should be smaller than that of females under the variance asymmetry mechanism.

evolutionary biology↗

bioRxiv2025

Is hybridization evil? --Competition generates alternative stable states of coexistence of hybridizing species

Predicting ecological outcomes of hybridizing species remains challenging because of complex interactions between genetic and ecological processes. Previous studies have mainly focused on exclusion scenarios driven by genetic mechanisms, whereas few have explored the impact of competitive interactions among parent species and their hybrids on generating multiple coexistence regimes. Here, we develop a population dynamics model that explicitly couples hybridization genetics with population dynamics driven by competitive interactions among two parent species and their hybrids. Our analysis reveals that backcrossing can fundamentally reshape coexistence regimes, generating five alternative outcomes: (i) alternative stable states of coexistence of both parent species and hybrids, (ii) frequency-independent coexistence, (iii) frequency-dependent coexistence, (iv) competitive exclusion of a rarer species, and (v) extinction of all populations. These outcomes arise from the balance between two key processes: regeneration of parental genotypes through hybrid x hybrid mating and competitive exclusion mediated by hybrids. Thus, hybridization can generate multiple stable coexistence regimes even when species would otherwise be excluded. This eco-genetic mechanism provides a unifying theoretical basis for predicting the ecological consequences of hybridization, highlighting the crucial role of competitive interactions in determining coexistence outcomes.

ecology↗

bioRxiv2025

A Priori recognition for biological phenomena prior to empirical understanding

Biological phenomena include unrecognized events. These unrecognized events often unknowingly increase observer bias, which inhibits open and reproducible science. In this study, we focused on the recognition procedures underlying primary data and modeled cell population behavior. Using agent-based modeling (ABM), we demonstrated that cellular behaviors can be categorized into 11 distinct types, a framework we defined as the Behavioral Eleven Cell Class (BECC). We further validated BECC by describing the differential STAT3 phosphorylation patterns in leukocyte subsets and polarized T cell differentiation in OT-II transgenic mice. BECC serves as a novel descriptive method with three defining features: (i) it functions as a symbolic system independent of numerical or linguistic constraints, (ii) it represents the minimal unit of recognition, and (iii) it enables the expression of inherently unrecognizable phenomena. BECC allows for observer subjectivity and the relativity of results while enforcing rigorous recognition. This unique approach provides a practical and conceptual basis for advancing open and reproducible science.

systems biology↗

bioRxiv2025

Intergenerational effects of maternal and paternal childhood maltreatment on offspring cortical gyrification are sex-specific: the Transmit Radiant Individuality to Offspring (TRIO) study

The effects of parental childhood maltreatment (CM) can be transmitted across generations; however, the underlying sex-specific biological mechanisms are poorly understood. To better understand how parental adversity is passed on to offspring, we investigated the impact of maternal and paternal CM on the local gyrification index (LGI) of offspring using parent-offspring trio data. The LGI was selected as a key neurodevelopmental metric because it is thought to reflect the fetal environment and remain relatively stable postnatally, making it less susceptible to later life experiences. Using multiple regression, we analyzed sex- stratified associations between parental CM subtypes and the offspring LGI and tested for mediation by parental psychosocial functioning. The results revealed a distinct parent-of-origin, sex-specific pattern: maternal emotional abuse was associated with a lower LGI in male offspring, whereas paternal physical neglect was associated with a lower LGI in female offspring. These associations were not mediated by the current mental health or marital relationships of the parents. Collectively, these findings provide compelling evidence that the neurodevelopmental consequences of parental CM can be biologically embedded in the next generation even before birth.

neuroscience↗

bioRxiv2025

Evolutionary and structural basis of SLAM utilization in morbilliviruses - Its implications for host range and cross-species transmission

Morbilliviruses, including measles virus (MV), canine distemper virus (CDV), and cetacean morbillivirus, pose a significant threat to humans and animals. While the host range of morbilliviruses is generally well-defined, severe cross-species transmission events also have been reported. Their entry into immune cells, the primary targets of morbilliviruses, relies on the signaling lymphocytic activation molecule (SLAM), a receptor whose species-specific variations influence viral host range. However, the extent to which SLAM diversity is a barrier to cross-species transmission remains poorly understood. In this study, we systematically investigated SLAM-mediated host specificity. We found that most morbilliviruses efficiently utilize SLAM from multiple host species, except for human SLAM. Among the morbilliviruses tested, only MV efficiently utilized human SLAM. Bats are natural reservoirs for many zoonotic viruses. Recent discoveries of novel morbilliviruses in bats provide new insights into morbillivirus evolution. Bats may have played a significant role in morbillivirus evolution because bat (Myotis) SLAM also functioned as an efficient receptor for multiple morbilliviruses. Unlike other morbilliviruses, MV utilized Myotis bat SLAM inefficiently. We conducted an MV adaptation experiment with Myotis bat SLAM to better understand SLAM recognition by morbilliviruses. MV readily adapted to utilize Myotis bat SLAM by acquiring a single N187Y mutation in its hemagglutinin protein, and computational structural modeling and fragment molecular orbital calculations with molecular dynamics simulations revealed key interaction changes that facilitated MVs adaptation to Myotis bat SLAM. These findings highlight the adaptability of morbilliviruses in utilizing diverse animal SLAMs. Notably, hypothetical ancestral SLAMs reconstructed in this study acted as universal receptors for all morbilliviruses. These results reinforced that morbillivirus receptor usage is primarily supported by evolutionarily conserved structural features of SLAM, highlighting a molecular basis that enables morbilliviruses to rapidly adapt to diverse animal SLAMs. Author SummaryOur study explores how viruses in the genus morbillivirus, such as measles virus, canine distemper virus, and rinderpest virus, which are notorious for deadly outbreaks in humans and animals, can jump between species. The host range of morbilliviruses is significantly influenced by a receptor molecule on cell surfaces known as the signaling lymphocytic activating molecule (SLAM). By examining SLAMs from various animals, including humans, dolphins, dogs, seals, and bats, we observed how these viruses can infect or adapt to infect different hosts. We found that in some cases slight differences in SLAM may act as initial barriers to cross-species transmission. However, these viruses rapidly overcome such barriers, showing a remarkable ability to adapt. Our research highlights the importance of monitoring these viruses to predict and prevent potential cross-species infections, which is crucial for protecting public health and animal welfare over time.

microbiology↗

bioRxiv2025

Nanopore sequencing-based measurement of paramyxovirus RNA editing reveals virus-specific differences in editing efficiency of mRNA, antigenome and genome

Paramyxovirus polymerase recognizes an RNA editing signal on the viral genome and transcribes mRNA in which guanine nucleotides are inserted in a template-independent manner. This enables the synthesis of multiple proteins from a single gene, which is important for viral growth. We developed a method to quantify RNA editing efficiency using Oxford Nanopore Technologies MinION platform. We performed sequence analysis of reverse transcription (RT)-PCR amplicons with the RNA editing sites in cells infected with Sendai virus (SeV) and canine distemper virus (CDV). By modifying RT primers, we simultaneously assessed RNA editing efficiency in mRNA, antigenome and genome. We observed distinct differences in mRNA editing efficiency between SeV and CDV. Notably, while RNA editing in SeV is confined to mRNA, in CDV it is also observed in antigenome/genome. (Anti)genomes harboring extra nucleotides may deviate from a multiple-of-six sequence, suggesting that RNAs not following the "Rule of Six" are produced in CDV-infected cells. HighlightsO_LIA method was established to quantify RNA editing efficiency in RNAs from paramyxovirus-infected cells using the MinION platform. C_LIO_LIRNA editing efficiency in mRNA differs between Sendai virus and canine distemper virus. C_LIO_LIAlthough RNA editing is confined to mRNA during Sendai virus infection, it is also observed in the antigenome and genome during canine distemper virus infection. C_LI

microbiology↗

bioRxiv2024

Photodynamic Therapy for Deep Organ Cancer by Implantable Wireless OLEDs

Metronomic photodynamic therapy (mPDT) is a method of continuously delivering low-intensity light to a cancer lesion. Since high light intensity is not required, the light device can be miniaturized and implanted in the body. Nevertheless, for clinical implementation, it is essential to develop a light source apparatus that can effectively illuminate the entire tumor and operate stably without damaging internal organs. To address this issue, an organic light-emitting diode (OLED) optical device that has an area large enough to cover the entire lesion and is powered by a wireless power supply has been developed. The device is thin and lightweight and it functioned stably in the abdominal cavity of rats for more than two weeks without causing foreign body reactions. By covering the tumor site of rat liver cancer with this device and continuously illuminating the tumor with appropriate administration of a photosensitizer, the entire tumor under the emitting surface was eliminated through apoptosis without leaving any residual tumor margins. This is the first report of a robust antitumor effect on parenchymal organ cancers by mPDT using a biocompatible, wirelessly powered OLED device, which represents a potential new deep organ cancer therapy.

bioengineering↗

bioRxiv2024

Invasive mammals disrupt native dung beetle community coexistence

Biological invasions are among the major drivers of biodiversity and are increasing worldwide. Among the invasive species, mammals have a particularly profound impact on native ecosystems. As primary decomposers of mammalian feces, dung beetles are critical in ecosystem functioning, and their community structure is closely linked to their services. However, the introduction of invasive mammals threatens these beetles and potentially disrupts their ecosystem services. Therefore, it is necessary to understand the resulting changes in communities. We developed a novel population dynamics model focusing on the interactions among mammals, feces, and dung beetles. Our results indicate that such invasions increase the risk of extinction of specialist dung beetles that cannot utilize the feces of invasive mammals. The risk of extinction is particularly high when generalist dung beetles show a preference for native feces, leading to intensified interspecific competition for resources. Additionally, the extinction risk of specialist dung beetles increases when invasive mammals display irruptive population dynamics. In conclusion, our findings demonstrated that non-native mammalian invasions disrupt the coexistence of native dung beetle communities, potentially leading to losses in biodiversity and ecosystem function. These risks should be considered in future empirical studies to evaluate the impact of invasive mammals on dung beetle communities.

ecology↗

bioRxiv2024

Male Dimorphism and Emergence Strategies: A Mathematical Model of Protandry in Fabriciana nerippe Felder, 1862

In many butterfly species, males emerge earlier than females as part of a strategy to maximize male reproductive success. Although behavioral ecological studies using mathematical models have been conducted to explain this phenomenon, certain emergence patterns remain unexplained. In the butterfly species Fabriciana nerippe, some males emerge at the same time as females, in addition to males that emerge earlier than the females. However, it is unclear what emergence patterns occur in populations with male dimorphism, as observed in this species. In this study, we showed the existence of male body size dimorphism in Fabriciana nerippe by conducting a comparative analysis of forewing lengths between males and females. In addition, we developed a comprehensive mathematical model to investigate emergence patterns in the presence of dimorphic males. By introducing a trade-off between large size and early emergence, the model considered a scenario where small early-emerging and large late-emerging males could coexist. Numerical analysis demonstrated the emergence patterns of these two male types with a switch in emergence time. Furthermore, the higher the death rate before emergence, the earlier the emergence switch. These findings suggested that the timing of the switch depends on the death rate and is influenced by environmental factors. This work contributes to ecological and theoretical studies on timing dimorphism in life-history strategies across a broader range of species. HighlightsO_LIWe confirmed the existence of male body-size dimorphism corresponding to emergence timing in Fabriciana nerippe. C_LIO_LIWe developed a comprehensive model of male emergence patterns incorporateing male dimorphism. C_LIO_LIWe assumed a trade-off between early emergence and large body size. C_LIO_LIThe timing of male emergence switching is influenced by death rate and reproductive advantage of large males. C_LI

ecology↗

bioRxiv2024

Parent-offspring brain similarity: Specificities and commonalities across gender combinations - the Transmit Radiant Individuality to Offspring (TRIO) study

Research suggests that parent-offspring brain similarities may underlie intergenerational transmission of psychopathology. However, most studies have focused on mothers and offspring, with few including fathers. This study aimed to extend understanding of parent-offspring neural similarities by examining parent-offspring trios. The study included 152 Japanese biological parent-offspring trios who participated in the Transmit Radiant Individuality to Offspring (TRIO) study. We analyzed the parent-offspring similarities in brain structural features (cortical thickness, surface area, local gyrification index, and subcortical volume) across different parent-offspring gender combinations (father-son, father-daughter, mother-son, and mother-daughter). Additionally, we investigated the relationship between brain similarities and similarities in intelligence and personality traits in parents and offspring. Our findings confirmed that correlations in brain structural features between father-offspring or mother-offspring dyads were significantly stronger than those between unrelated individuals. Notably, both sons and daughters exhibited brain regions similar to their fathers only, mothers only, both parents, or neither parent. Furthermore, a significant association was observed between similarities in general intelligence and the surface area of auditory regions in both father-offspring and mother-offspring dyads. These results provide valuable insights into the genetic and environmental factors influencing brain development and aging across generations. This study is expected to contribute to future research elucidating the mechanisms underlying the intergenerational transmission of psychiatric disorders.

neuroscience↗

bioRxiv2024

Identifying Genetic Variations in emm89 Streptococcus pyogenes Linked to Severe Invasive Infections

Streptococcus pyogenes causes mild human infections as well as life-threatening invasive diseases. Since the mutations known to enhance virulence to date account for only half of the severe invasive infections, additional mechanisms/mutations need to be identified. Here, we conducted a genome-wide association study of emm89 S. pyogenes strains to comprehensively identify pathology-related bacterial genetic factors (SNPs, indels, genes, or k-mers). Japanese (n=311) and global (n=666) cohort studies of strains isolated from invasive or non-invasive infections revealed 17 and 1,075 SNPs/indels and 2 and 169 genes, respectively, that displayed associations with invasiveness. We validated one of them, a non-invasiveness-related point mutation, fhuB T218C, by structure predictions and introducing it into a severe invasive strain and confirmed that the mutant showed slower growth in human blood. Thus, we report novel mechanisms that convert emm89 S. pyogenes to an invasive phenotype and a platform for establishing novel treatments and prevention strategies.

microbiology↗

bioRxiv2023

Global disinhibition and corticospinal plasticity for drastic recovery after spinal cord injury

The induction of large-scale plasticity in the adult brain should be key for recovery from severe damage of the central nervous system. Here, drastic motor recovery was observed after subhemisection spinal cord injury in macaques that received intensive training and cortical electrical stimulation. During recovery, movement-related activity increased in ipsilesional sensorimotor areas and functional connectivity from ipsilesional to contralesional areas was strengthened. Electrical stimulation applied widely across bilateral sensorimotor areas induced muscle twitches in affected and intact forelimbs. The interhemispheric inhibition observed before injury was switched to facilitation. Furthermore, massive re-routing occurred in corticospinal axons from the contralesional motor cortex. Such global disinhibition and massive plasticity would open the workspace for the reorganization of motor networks to recruit novel areas for recovery. One Sentence SummaryGlobal disinhibition and corticospinal plasticity for drastic recovery after spinal cord injury in macaque monkeys.

neuroscience↗

bioRxiv2023

Isolation may select for earlier and higher peak viral load but shorter duration in SARS-CoV-2 evolution

During the COVID-19 pandemic, human behavior change as a result of nonpharmaceutical interventions such as isolation may have induced directional selection for viral evolution. By combining previously published empirical clinical data analysis and multi-level mathematical modeling, we found that the SARS-CoV-2 variants selected for as the virus evolved from the pre-Alpha to the Delta variant had earlier and higher infectious periods but a shorter duration of infection. Selection for increased transmissibility shapes the viral load dynamics, and the isolation measure is likely to be a driver of these evolutionary transitions. In addition, we showed that a decreased incubation period and an increased proportion of asymptomatic infection were also positively selected for as SARS-CoV-2 mutated to the extent that people did not isolate. We demonstrated that the Omicron variants evolved in these ways to adapt to human behavior. The quantitative information and predictions we present here can guide future responses in the potential arms race between pandemic interventions and viral evolution.

evolutionary biology↗