Biology subjects

Tanaka, M.

Publications and source records attributed to Tanaka, M..

At least 19 recordsLinked to original sources

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

Seven gut microbiome types across two Japanese cohorts defined by co-abundance-based microbial guilds and associated with host physiology

Intensive efforts have been made to capture structural features of the gut microbiome for assessing microbiota status in relation to host health. However, gut microbiome function emerges not only from individual microbial taxa but also from their organization into ecological guilds, complicating microbiome structure-function relationships. To address this challenge, we applied a co-abundance-based analytical framework to identify gut microbiome types (GMTs) across a discovery cohort (D-cohort) and an independent validation cohort (V-cohort) of Japanese adults. Using paired fecal samples collected one month apart from 116 participants in the D-cohort, we identified 27 co-abundance groups (CAGs) based on 16S rRNA amplicon sequence variants. These CAGs defined seven GMTs (MT-1 to MT-7) with characteristic short-chain fatty acid and bile acid profiles. The GMTs showed temporal stability, with more than 70% of participants remaining in the same GMT across sampling points. The 27-CAG framework classified 404 participants in the independent V-cohort into the seven GMTs, which represented reproducible microbial ecological states across cohorts. MT-4 exhibited dysbiosis-like features, including reduced microbial diversity, depletion of Faecalibacterium and butyrate, and enrichment of inflammation-associated taxa, and was associated with higher alcohol consumption and elevated {gamma}-glutamyl transferase levels. In contrast, Bifidobacterium-enriched MT-5 was associated with favorable renal function profiles. Collectively, co-abundance-defined microbial guilds capture coherent ecological and functional states of the gut microbiota, providing a transferable framework for linking gut microbiome organization to host physiology beyond conventional taxonomy-based classification.

microbiology↗

bioRxiv2026

Whole-genome duplication underlies conserved sexually biased expression of meiotic cohesin genes unique to the teleost fish lineage

Meiosis is a fundamental process in producing both sperm and eggs, yet recombination landscapes often exhibit sexual differences, known as heterochiasmy. Since meiotic proteins are generally expressed in both sexes, the molecular mechanism driving heterochiasmy remains elusive. The -kleisin subunit gene of meiotic cohesin, Rec8, is expressed bisexually in mammals, while its putative teleost ortholog, rec8a, is expressed in a female-biased manner, presumably due to the presence of its paralog originating from the teleost-specific whole-genome duplication (TGD). Here, we elucidated the evolutionary history and expression dynamics of -kleisin genes across teleost lineages. Through comprehensive phylogenetic and synteny analyses, we revealed that major teleost lineages retain two copies of rec8 and rad21, with rec8 loci experiencing drastic chromosomal rearrangements immediately after the TGD. Using in situ hybridization and single-cell transcriptome data in medaka and zebrafish, we demonstrated a conserved sexually biased expression pattern: rec8a is predominantly female-biased, whereas rec8b exhibits male-biased expression during gametogenesis. Furthermore, comparative epigenetic analyses revealed that the conserved sexually biased expression is driven by lineage-specific cis-regulatory elements, rather than conserved ones. Motif analyses imply that regulatory rewiring by transcription factors, including foxl2l in particular, might have played a crucial role in the establishment and maintenance of this paralog divergence. Our findings highlight how whole-genome duplication and subsequent genomic and epigenetic rewiring subdivided the bisexual function of rec8, offering insights into sexually distinct meiotic regulation. HighlightsO_LITeleosts possess a unique -kleisin repertoire originating from the TGD. C_LIO_LITeleost rec8 paralogs exhibit conserved sex-biased expression during meiosis. C_LIO_LIDrastic genomic rearrangements after the duplication rewired the teleost rec8 loci. C_LIO_LIThe conserved expression pattern is governed by lineage-specific CREs. C_LIO_LIThose CREs harbor similar types of TFBSs such as Fox-family TFs. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/731870v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@c8c84dorg.highwire.dtl.DTLVardef@1d65668org.highwire.dtl.DTLVardef@c2d732org.highwire.dtl.DTLVardef@1be54a2_HPS_FORMAT_FIGEXP M_FIG C_FIG

Developmental Biology↗

bioRxiv2026

Cross-cue reconstruction of perceived 3D object structure from human visual cortex

The human brain assembles three-dimensional (3D) percepts from qualitatively different depth cues, yet the perceived 3D structure that the brain builds--a representation shared across cues--has remained difficult to measure directly. Here, we show that this cue-invariant 3D structure can be externalized as explicit 3D objects from human brain activity: fMRI responses are decoded into the latent features of a pretrained 3D point-cloud autoencoder, and a generator then maps these features back to a point cloud. A decoder trained exclusively on responses to 2D rendered objects passed three increasingly stringent tests: (i) it generalized to novel object categories; (ii) it generalized across depth cues to random dot stereograms (RDSs), which evoke 3D percepts through binocular disparity but share no pictorial shape information with the training images; and (iii) it tracked the 3D slant of contour-matched RDSs whose 2D outlines were held identical but whose disparity-defined slants varied, indicating that the reconstruction reflected depth-defined geometry rather than object category or image outline. Cross-cue generalization was strongest in higher visual areas, particularly along the dorsal stream. These results indicate that cross-cue generalization can serve as a criterion for externalizing perceived 3D structure and open a route toward reading out internal 3D representations that go beyond the momentary retinal input and could support predictions of how the world would appear under different viewpoints--a step toward externalizing the brains internal world model.

neuroscience↗

bioRxiv2026

Deficiency of CD239 increases susceptibility to chronic kidney disease

CD239, also known as Lutheran blood group glycoprotein (Lu) or basal cell adhesion molecule (B-CAM), is a transmembrane protein belonging to the immunoglobulin superfamily (IgSF). CD239 serves as a specific receptor for laminin 5, a subunit of laminin-511/-521, which are major components of renal basement membranes. A previous study of another group demonstrated that CD239-null mice are healthy and develop normally. Although no alteration in renal function was observed, most glomeruli in the mutant kidneys exhibited morphological abnormalities. In this study, we investigated the role of CD239 in renal tubules. We examined the distribution of CD239 using renal tubule-specific markers. CD239 was localized to the Henle's loop, distal tubule, and collecting duct, but not to the proximal tubule. Next, we analyzed the localization of renal tubular molecules in CD239-null mice. The localization of uromodulin (UMOD) and Na-K-Cl cotransporter (NKCC2) was disrupted in the distal tubules lacking CD239, suggesting that CD239 plays a role in maintaining the polarity of renal epithelial cells. Furthermore, to examine the stability of the distal tubules, CD239-null mice were subjected to chronic kidney disease (CKD) using an adenine-rich diet. Blood analysis revealed that CD239-null mice fed an adenine diet readily developed CKD. Adenine-fed null mice exhibited more marked histological injury along the distal tubules compared to that by controls. These results indicate that CD239 is essential not only for maintaining cellular polarity but also for ensuring the stability of the distal tubules. Although CD239-null humans exhibit no obvious associated pathology, it could be a predisposition to CKD.

pathology↗

bioRxiv2026

Epigenetic Control of Spatiotemporal Dynamics of Pancreatic Cancer Cells via Brg1-Rac1 Signaling

Pancreatic ductal adenocarcinoma (PDA) arises from distinct precursor lesions with different clinical outcomes, yet the mechanisms linking epigenetic regulation to invasive cell behavior remain poorly understood. Here, we investigate how the chromatin remodeler Brg1 influences the dynamic properties of cancer cell migration. Using a biomimetic supported membrane system combined with label-free interferometric imaging, we quantitatively analyze the spatiotemporal dynamics of PDA cells derived from pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMN). Despite their similar morphology under conventional conditions, PanIN- and IPMN-derived PDA cells exhibit markedly different migration behaviors. PanIN-derived cells migrate faster and display enhanced dynamic remodeling, whereas IPMN-derived cells show persistent elongation with limited displacement. These differences are captured by quantitative analyses of cell trajectories and deformation dynamics. Mechanistically, PanIN-derived PDA cells exhibit elevated Rac1 activity, supporting a model in which a Brg1-Rac1 axis regulates cytoskeletal dynamics and migration behavior. Together, our findings demonstrate that epigenetic regulation is linked to distinct dynamic phenotypes of cancer cells and highlight the importance of quantitative analysis of cell behavior for understanding invasive potential.

biophysics↗

bioRxiv2026

Spatiotemporal Patterns of Active Deformation Reveal Downregulation of Cell-Cell Adhesion in Patient-Derived Colorectal Cancer Organoids with BRAF Mutation

Colorectal cancer (CRC) is the second most common cause of cancer-related mortality. At the molecular level, CRC is associated with genetic mutations and epigenetic modifications that dysregulate various signaling networks. From the biophysical viewpoint, invasive and metastatic cell migration need to be empowered by mechanical forces. In this study, we analyze the dynamic deformation of patient-derived CRC organoids in Fourier space and demonstrate how organoids with protooncogene BRAF mutation exhibit deformation phenotypes at an early stage. The organoids with BRAFmut have significantly lower elasticity and higher viscosity than those with BRAFWT, which mathematically indicated as the weakening of cell-cell adhesion. Immunohistochemical images, qRT-PCR, and TCGA data analysis confirm the downregulation of E-cadherin (CDH1) in BRAFmut organoids as well as in BRAFmut CRC, suggesting that the decrease in cell-cell adhesion in BRAFmut CRC facilitates invasive and metastatic migration. Notably, the recovery of CDH1 expression by pharmacological inhibition of DNA methylation can quantitatively be detected as the change in mechanical properties, suggesting that the complementary combination of dynamic phenotyping, mathematical modelling, and molecular-level analyses has a potential to unravel the mechanistic causality of the critical gene mutation and CRCs prognosis and the response to therapeutic interventions.

biophysics↗

bioRxiv2025

PhenoDEL as a Novel Screening Strategy Based on Intracellular Protein Degradation Activity

Targeted protein degradation (TPD), including proteolysis targeting chimeras (PROTACs) and molecular glue degraders (MGDs), is a promising therapeutic approach. However, systematic discovery of such small molecules remains a major challenge. Here, we present PhenoDEL, a novel phenotypic DNA-encoded library (DEL) screening platform that integrates one-bead one-compound DEL (OBOC-DEL) with the Beacon(R) optofluidic system for high-throughput, single-cell analysis. By co-culturing individual OBOC-DEL beads and engineered reporter cells in nanoliter-scale chambers, PhenoDEL enables direct observation of compound-induced protein degradation at single-cell resolution. We demonstrate this approach by identifying compounds that induce degradation of FKBP12F36V-EGFP fusion proteins in PC-3 cells. The workflow allows precise linkage between compound identity and cellular phenotype via DNA barcoding and next-generation sequencing. PhenoDEL overcomes limitations of conventional screening methods, offering high sensitivity, spatial control, and scalability. This platform holds significant potential for mechanism-driven drug discovery, including identification of novel PROTACs and MGDs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/690606v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@fe27bforg.highwire.dtl.DTLVardef@1e38ef5org.highwire.dtl.DTLVardef@be958aorg.highwire.dtl.DTLVardef@4bc48a_HPS_FORMAT_FIGEXP M_FIG C_FIG

synthetic biology↗

bioRxiv2025

Anti-allergic Effect of Soluble Beta-glucan on Japanese Cedar Pollinosis and Mechanism Underlying Its Allergy-ameliorating Action

Japanese cedar (sugi) pollinosis is triggered by sensitization to sugi pollen, which contains sugi antigens, sugi basic proteins (SBP: Cryj1 and Cryj2), and adjuvant polysaccharides, insoluble {beta}-glucan particles (IBG: a dectin-1 agonist). The presence of IBG in sugi pollen enhances the production of SBP-specific IgE, which participates in inflammatory response via activation of mast cells to lead to their degranulation, resulting in sneezing. Another {beta}-glucan derived from black yeast, soluble {beta}-glucan (SBG: a dectin-1 antagonist), is known to have an anti-allergic function. Herein, we demonstrated that oral administration of SBG suppressed both SBP-specific IgE production and SBP-induced sneeze in sugi pollinosis mice model. DNA microarray analyses revealed previously unknown mechanisms underlying SBG-mediated anti-allergy action. SBG ameliorated the dysregulated expression of 16 immune-inflammatory genes that were unusually either up- or down-regulated in sugi pollinosis mice. Based on the DNA microarray informatics, it was suggested that SBG mitigated the IBG-mediated hyper-response of IgE production and inflammatory reaction in immune-inflammatory cells, B and T cells, antigen-presenting cells, and granulocytes (neutrophils and eosinophils) within iliac lymph nodes. The SBG-mediated inhibition of SBP-induced sneezing in pollinosis mice results from a decline in SBP-specific IgE level. The oral administration of SBG influenced gut microbiota, notably enhancing beneficial bacteria such as bifidobacteria. Consequently, it is plausible that short-chain fatty acids, produced by these beneficial bacteria, inhibited mast cell degranulation, leading to a reduction in sneezing. Collectively, SBG demonstrated anti-allergic effects against sugi pollinosis by inhibiting the immune response, specifically SBP-induced IgE production, as well as reducing the inflammatory reaction characterized by SBP-induced sneezing.

immunology↗

bioRxiv2025

Plasmodium falciparum diacylglycerol acyltransferase maintains phospholipid homeostasis to regulate sexual differentiation, ER stress, and cytoadhesion

Plasmodium falciparum is the causative agent of human malaria, a life-threating infectious disease that imposes a major global health burden. Lipid metabolism is indispensable for this parasites replication and survival, yet most of the molecular components and mechanisms involved remain poorly understood. In eukaryotes, lipid droplets (LDs) serve as dynamic organelles that store neutral lipids (NLs), buffer lipotoxic stress, and regulate signaling pathways, with their biogenesis controlled by diacylglycerol o-acyltransferases (DGATs). Although P. falciparum encodes a putative DGAT (PF3D7_0322300), its role in the parasite life cycle has not been elucidated. We generated conditional PfDGAT-knockout parasites to investigate the enzymes functional significance. PfDGAT deficiency led to parasite death, accompanied by reduced LD formation, elevated phospholipid levels, and induction of ER stress. Moreover, PfDGAT deletion altered protein trafficking, resulting in the decreased cytoadherence of parasite-infected erythrocytes to human brain microvascular endothelial cells, and suppressed parasite sexual differentiation. Thus, PfDGAT deletion affected multiple aspects of the parasites life cycle, highlighting its critical role in parasite survival and pathogenesis. Our findings provide new insights into parasite lipid homeostasis and highlight DGAT as a potential target of antimalarial intervention.

microbiology↗

bioRxiv2025

JAG2-related muscular dystrophy and Notch signaling dysfunction in muscle stem cells

We previously identified a muscular dystrophy caused by biallelic variants in JAG2, whose protein product Jagged2 is a canonical Notch ligand. However, the disease mechanism remains unclear, particularly with respect to muscle stem cell (MuSC) function and muscle regeneration. We examined the consequences of JAG2 deficiency and modeled pathogenic JAG2 variants in vitro and in vivo, the latter in mouse and fly models and with particular attention to the MuSC-muscle endothelial cell (MuEC) niche. We found that both Jag2 deficiency and overexpression of pathogenic JAG2 variants impaired Notch signaling and myogenic self-renewal and differentiation. Hypomorphic Jag2 mutant (Jag2sm) mice display depleted MuSCs, corresponding with impaired muscle regeneration in those mice. Co-culture experiments and the examination of cell-type-specific Jag2 conditional knockout mice demonstrated that MuEC-specific Jag2 knockout resulted in reduced MuSC self-renewal, while MuSC-specific Jag2 knockout resulted in reduced myogenic differentiation. Human reference JAG2, but not human pathogenic variants of JAG2, rescued the deficiency of Serrate (Ser), the Drosophila ortholog of JAG2. Therefore, pathogenic variants in JAG2 impair muscle development and regeneration through disrupted cell-autonomous cis- inhibition and non-autonomous trans-activation involving Notch signaling dysfunction. Our findings indicate that optimizing JAG2-mediated Notch signaling is a potential therapeutic approach for JAG2-related muscular dystrophy.

developmental biology↗

bioRxiv2025

Systemic aldehyde storm induced by allyl alcohol exposure results in extensive hepatic ferroptosis in Aldh2*2 knock-in mice

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that detoxifies multiple aldehyde species in the body. The ALDH2*2 allele (E487K) is one of the most common gene polymorphisms in humans, resulting in dysfunction of its enzyme activity. This study investigated in vivo mechanism of acute liver injury caused by exposure to allyl alcohol (AA) using Aldh2*2 knock-in (KI) mice with the same amino acid replacement as human ALDH2*2. A rapid burst of plasma acrolein as an active metabolite of AA, as well as plasma endogenous reactive aldehydes malondialdehyde (MDA) and formaldehyde, was observed at 10 min after exposure to 75 mg/kg of AA in the Aldh2*2 KI homozygous mice, which was not evident in the wild-type mice. Hepatocellular necrosis was more extensive in the Aldh2*2 KI homozygous mice than in the wild-type mice, which was preceded by hepatic glutathione depletion and was coincident with an accumulation of acrolein, MDA, and 4-hydroxy-2-nonenal adducts and iron deposition, suggesting an involvement of ferroptosis in the exacerbation of hepatic necrosis. Recovery from hepatic glutathione depletion was delayed in the homozygous mice compared with the wild-type mice, with a decreasing tendency of hepatic expression of cystine transporter xCT. These results suggest that increased hepatic glutathione consumption, due to decreased aldehyde detoxification capacity, can sensitize the Aldh2*2 KI homozygous mice to hepatic ferroptosis after the rapid "aldehyde storm". Our study revealed a crosstalk between aldehyde metabolism and ferroptosis pathways and potential health impacts of endogenous reactive aldehydes on ALDH2*2 carriers.

pathology↗

bioRxiv2025

Contribution of UbrA, a ubiquitin ligase essential for Arg/N-degron pathway, to peptidase gene expression in Aspergillus oryzae

The degradation of intracellular proteins by N-degron pathways depends on their N-terminal amino acids. In budding yeast, the Arg/N-degron pathway controls the expression of di/tri-peptide transporter gene by degrading transcriptional repressor. However, there is no detailed information on the N-degron pathway in filamentous fungi, and its role in regulating microbial nitrogen metabolism is unclear. Here, we demonstrated that the E3 ubiquitin ligase, UbrA, which is required for the Arg/N-degron pathway, regulates peptidase gene expression in the filamentous fungus Aspergillus oryzae. Using ubiquitin-fused green fluorescent protein as a reporter, we showed that the Arg/N-degron pathway in A. oryzae is similar to that in budding yeast. Disruption of ubrA significantly reduced activities of acidic endopeptidase and carboxypeptidase in submerged culture using soy protein as the nitrogen source. In addition, ubrA disruption dramatically reduced the mRNA expression of the major endopeptidase and carboxypeptidase genes but increased alkaline peptidase production. Moreover, ubrA disruption reduced the expression levels of di peptidyl- and tripeptidyl- peptidase genes and di/tri-peptide transporter genes. This regulation was independent of PrtR, the transcription factor of major extracellular peptidase genes. Our data showed that UbrA is involved in the expression of various peptidase genes in concert with di/tri-peptide transporter genes. IMPORTANCEPeptidases produced by Aspergillus oryzae are important in the production of Japanese fermented foods and are used as industrial enzymes for various food-processing and pharmaceutical applications. The expression of di/tri-peptide transporter gene in budding yeast is controlled by a positive feedback mechanism through the dipeptide-mediated activation of the E3 ubiquitin ligase, Ubr1, which is essential for the Arg/N-degron pathway, which determines the lifetime of intracellular proteins. In this study, we demonstrated that A. oryzae UbrA (an ortholog of yeast Ubr1) regulates peptidase gene expression in addition to di/tri-peptide transporter genes. Disruption of ubrA decreases the expression of major acidic peptidase genes and increases the expression of alkaline peptidase gene. In addition, the expression levels of di/tri-peptidyl peptidase genes and di/tri-peptide transporter genes were reduced by ubrA disruption. These results suggest that UbrA regulates the expression of various peptidase genes to facilitate positive feedback of di/tri-peptide transporter genes.

microbiology↗

bioRxiv2025

CIT tumor lines: A novel series of immunogenic squamous cell skin carcinoma cell lines derived from chemical carcinogenesis

Immunotherapy is now widely used to treat advanced-stage skin cancer, but it is effective for only approximately half of skin cancer patients, including both patients with melanoma and cutaneous squamous cell carcinoma (cSCC). To overcome current barriers, preclinical mouse models that faithfully recapitulate the tumor genetics, mutation burdens, and neoantigen patterns of specific human tumor types are essential. However, while many models exist for melanoma, there are currently relatively few transplantable murine models of cSCC, which is responsible for nearly as many deaths as melanoma each year. Here we describe a novel series of 11 cSCC tumor lines, the Carcinogen-Induced Tumor (CIT) lines, syngeneic to the FVB strain, that address this need. The CIT lines were established from skin carcinomas induced by DMBA and TPA treatment and harbor genetic drivers and overall tumor mutational burdens that recapitulate those found in cSCC. Each CIT line gives rise to tumors with a consistent immune infiltration pattern, ranging from T cell-rich "hot" tumors to T cell-poor "cold" tumors. Hot CIT lines exhibit partial responses to treatment with immune checkpoint inhibitors, and we have identified two neoantigens present in an immunotherapy-responsive CIT line. The CIT lines thus provide a valuable new series of preclinical models for studying anti-tumor immune responses and developing strategies to improve immunotherapy efficacy in cSCC.

cancer biology↗

bioRxiv2025

LM-GlycoRepo Version 1.0: A novel repository system for mouse tissue glycome mapping data

Lectin microarray (LMA) is a high-sensitive profiling method of protein glycosylation. The increasing use of this method in many studies has led to a growing demand for a repository system that meets the FAIR data principles (Findable, Accessible, Interoperable, and Reusable). Herein, we present a novel repository system, "LM-GlycoRepo," for lectin-based multimodal (LM) data, including LMA data, in accordance with the international guideline MIRAGE (Minimum Information Required for a Glycomics Experiment). As a first step in our efforts to provide a general repository for storing various types of LM data, LM-GlycoRepo Version 1.0 is specialized for mouse tissue glycome mapping data obtained using standardized laser microdissection (LMD)-assisted LMA procedures. This system allows users to deposit datasets containing LMD images, LMA data, and high-resolution lectin staining images as LM data. In addition, this repository adopted an "embargo" system that allows users to specify the release date of datasets, allowing compatibility with an article peer review system. Notably, after the release date, the deposited data were visualized using an existing web tool called LM-GlycomeAtlas. LM-GlycoRepo will evolve into a comprehensive tool for lectin-based multimodal data for various biospecimens, including human samples. LM-GlycoRepo is freely available at the GlyCosmos portal (https://lm-glycorepo.glycosmos.org/lm_glycorepo/).

bioinformatics↗

bioRxiv2025

Lifetime changes in Body map based on music prediction

This study aims to investigate the relationship between music, which is said to promote well-being, and emotions as well as bodily sensations across the lifespan. Using eight chord progressions based on predictive models, we conducted online experiments with 784 participants aged 10 to 80, evaluating bodily sensation mapping and emotional responses. The results revealed that bodily sensations peaked in the 20s to 30s and subsequently declined with age, particularly for chords with low prediction error and uncertainty. On the other hand, arousal levels increased with age and showed a strong correlation with predictable musical structures. These findings suggest that bottom-up bodily responses diminish with ageing, while supporting the relationship between top-down processing shaped by accumulated experience and the predictability of music, as indicated by previous research. This study enhances the development of music-based interventions that improve well-being across generations, considering the unique physical and emotional characteristics of each age group.

physiology↗

bioRxiv2025

Neural correlates of memory updating in the primate prefrontal cortex

Working memory is the ability to temporarily hold and manipulate information during cognitive tasks and is essential for complex behaviors and thinking. Although the primate lateral prefrontal cortex is involved in working memory and the neural representation of short-term memory has been reported, little is known about neuronal activity during memory updating. We trained macaque monkeys to perform an oculomotor version of the n-back task, in which the animals were required to remember the location of serially presented visual stimuli and generate a saccade to the location of the most recent or previous stimulus according to the instructions. We found that many neurons in the lateral prefrontal cortex showed transient activity when the memory of a particular stimulus location was no longer needed, whereas other neurons showed sustained activity when the stimulus location was maintained in memory. Decoding analysis successfully predicted future target selection from neuronal activity, indicating that these neuronal populations contain sufficient information to guide behavior. Furthermore, electrical stimulation applied to recording sites during the task erased specific spatial memories, suggesting that these neurons are causally involved in the retention of short-term memories and their dynamic control.

neuroscience↗

bioRxiv2025

Liver Lymphatic Dysfunction as a Driver of Fibrosis and Cirrhosis Progression

The liver lymphatic system plays a critical role in maintaining interstitial fluid balance and immune regulation. Efficient lymphatic drainage is essential for liver homeostasis, but its role in liver disease progression remains poorly understood. In cirrhosis, lymphangiogenesis initially compensates for increased lymph production, but impaired lymphatic drainage in advanced stages may lead to complications such as ascites and portal hypertension. This study aimed to evaluate how liver lymphatic dysfunction affects disease progression and to assess therapeutic strategies. Using a surgical model to block liver lymphatic outflow, we found that impaired drainage accelerates liver injury, fibrosis, and immune cell infiltration, even in healthy livers. Mechanistically, enhanced TGF-{beta} signaling in liver lymphatic endothelial cells (LyECs) contributed to reduced lymphatic vessel (LV) density and function in late-stage decompensated cirrhosis. This dysfunction was linked to the progression from compensated to decompensated cirrhosis, particularly in patients with primary sclerosing cholangitis (PSC). Conversely, liver-specific overexpression of VEGF-C via AAV8 improved lymphatic drainage, restored LV density, reduced fibrosis, mitigated liver injury, and alleviated portal hypertension in cirrhotic rats. These findings establish impaired liver lymphatic function as a pivotal driver of cirrhosis progression and identify VEGF-C as a promising therapeutic target to prevent decompensation.

pathology↗