Biology subjects

Sasaki, T.

Publications and source records attributed to Sasaki, T..

At least 19 recordsLinked to original sources

bioRxiv2026

The vagus nerve drives cognitive function through the default mode network

The afferent vagus nerve transmits interoceptive signals to the brain but a systematic understanding of how vagal signals affect brain-wide neuronal dynamics remains elusive. Here, comprehensive spatiotemporal analyses across the entire mouse brain revealed that vagus nerve stimulation activated neuronal ensembles within the default mode network (DMN). In contrast, vagal-independent mechanisms predominantly affected the salience network. The vagal-DMN association was mediated by locus coeruleus neuronal subpopulations. Selective activation or silencing of vagal-responsive DMN neuronal ensembles replicated or abolished VNS-induced enhancement of cognitive behaviors and progressive problem-solving behaviors. These findings establish a unifying framework for how the vagus nerve drives cognitive functions by engaging the DMN.

neuroscience↗

bioRxiv2026

Hippocampal interferon-response, unfolded-protein-response and synaptic transcriptional signatures in RORγt-transgenic mice

Aim: ROR{gamma}t-transgenic mice provide a model of sustained T helper 17-cell bias, but the associated hippocampal transcriptional profile is incompletely characterized. We investigated gene-level and gene-set expression differences in this model. Methods: Bilateral hippocampal samples from 10-week-old male ROR{gamma}t-transgenic mice and wild-type littermates (n = 3 per genotype) underwent bulk RNA sequencing. Gene-level differential expression was evaluated using the Empirical Analysis of DGE tool in CLC Genomics Workbench. Preranked gene set enrichment analysis examined coordinated expression differences after expression filtering and exclusion of Rorc (13,813 genes). Results: Sixteen genes met a false discovery rate < 0.05 (nine higher and seven lower in transgenic mice), including Rorc, C4b, Xbp1, Nptx2 and Mt2. Of 212 candidates selected using unadjusted P < 0.05 and a twofold-change threshold, 155 (73.1%) had a mean expression below 0.5 reads per kilobase of transcript per million mapped reads. Hallmark interferon--response, interferon-{gamma}-response, and unfolded-protein-response gene sets showed positive enrichment. Thirteen Gene Ontology biological-process sets met a false discovery rate < 0.05, including negatively enriched sets related to excitatory postsynaptic potential, glutamatergic transmission, and calcineurin-mediated signaling. Il17a and Il17f had zero reported counts, and none of the displayed leukocyte or central nervous system cell-marker genes met false discovery rate < 0.05. Conclusion: This exploratory dataset identifies interferon-response, unfolded-protein-response and synaptic transcriptional signatures associated with the ROR{gamma}t-transgenic genotype. The cellular sources, causal mediators and functional consequences remain unresolved.

neuroscience↗

bioRxiv2026

PLCXD2 preferentially hydrolyzes phosphatidylinositol and supports retinal lipid homeostasis and photoreceptor integrity

PLCXD proteins have been linked to phosphoinositide metabolism for more than a decade, and PLCXD2 activity has been associated with phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] depletion, yet its preferred direct substrate has remained unresolved. Here, cellular lipidomics showed that catalytically active PLCXD2 reduced the major phosphatidylinositol (PI) 38:4 species, with more modest phosphoinositide changes and increased diacylglycerol (DAG) and phosphatidic acid (PA). Using recombinant PLCXD2 and acyl-chain-matched substrates, we found that PLCXD2 hydrolyzed PI substantially more efficiently than PI(4,5)P2 and most other phosphoinositides tested. In Plcxd2-deficient retina, PI abundance was preserved, whereas DAG and PA were reduced without broad changes in major membrane phospholipid classes. PLCXD2 loss was associated with early structural abnormalities at the photoreceptor-bipolar synaptic interface, followed by outer nuclear layer thinning and reduced electroretinographic a-wave responses. These findings identify PLCXD2 as a PI-preferring mammalian PLC and reveal an endogenous role in retinal lipid homeostasis and outer retinal integrity.

biochemistry↗

bioRxiv2026

Male RORγt-transgenic mice exhibit lower body weight and an altered locomotor response to a novel environment

ROR{gamma}t, encoded by Rorc, is a key transcriptional regulator of T helper 17 (Th17) cell differentiation, and IL-17A signaling has been implicated in neural development and behavior. We examined behavioral phenotypes in male ROR{gamma}t-transgenic mice with T-cell-biased ROR{gamma}t overexpression and their wild-type littermates. Mice were assessed using the resident-intruder paradigm and the light-dark box test, followed by body-weight measurement. ROR{gamma}t-transgenic mice had significantly lower body weight than wild-type mice. No genotype differences were detected in attack latency, attack frequency, light-compartment occupancy, light-dark transitions, or transition latency. In contrast, analysis of locomotor activity in 1-min bins revealed a significant genotype x time interaction. Transgenic mice showed nominally reduced locomotor activity during the first minute of the light-dark box test, although this single-bin comparison did not remain significant after correction for multiple comparisons. These findings indicate that T-cell-biased ROR{gamma}t overexpression is associated with altered temporal dynamics of locomotor activity in a novel environment rather than a generalized anxiety-like or aggression-related phenotype.

animal behavior and cognition↗

bioRxiv2026

Evolution of transposons as controlling elements

Transposons were originally described as controlling elements, yet the molecular basis and evolutionary origin of their transcriptional regulatory activities remain elusive. Here, we show that transcriptional regulatory activity is an intrinsic property of transposases (TPases). We demonstrate that the Arabidopsis AtMu1 TPase is sufficient to induce sequence-specific transcriptional activation of cognate copies, revealing a pre-existing cis-regulatory network. We further demonstrate that long-recognized Spm transposon-encoded transcriptional regulator TnpA evolved from an ancestral TPase, linking transcriptional regulators to TPases. Across eukaryotes, we identify multiple domesticated TPase-derived proteins that recurrently lack catalytic residues for transposition, consistent with a one-step regulatory co-option through loss of catalytic activity. Together, our results reveal TPases as autonomous sequence-specific transcriptional regulators and provide a direct evolutionary route from TPases to transcription factors.

genetics↗

bioRxiv2026

Nautilus shell morphomics reveals microstructural heterogeneity alongside structural continuity across component boundaries

The nautilus (Nautilus sp.) is an early-branching cephalopods. It retains several conchiferan synapomorphies, including an external planispiral biomineralized shell. The shells complex structure allows it to withstand hydrostatic pressure, control buoyancy, and protect against external hazards. In this study, we comprehensively examined shell microstructures across different shell components and regions representing various ontogenetic stages in two adult museum shell specimens. We found that the nautilus shell is composed of five microstructural types (spherulitic, prismatic, nacreous, semi-prismatic, and irregularly oriented prismatic structures) organized into layered architectures within individual shell components and coordinated across the shell as an integrated system. Our observations highlight transitions between distinct microstructures within and across shell components and local variation within individual components such as the dorsal and ventral shell walls, suggesting that these patterns may contribute to shell strength and overall mechanical performance. Variation in caecum morphology suggests that this structure may be developmentally plastic and subject to relatively relaxed structural constraints. These findings show that the Nautilus shell is an integrated biomineral system in which diverse microstructures are organized across shell components to meet functional demands and provide the mechanical strength needed for survival.

evolutionary biology↗

bioRxiv2026

Stressor-specific dynamic patterns of noradrenaline release in the paraventricular nucleus of the hypothalamus in freely moving mice

An organism is constantly challenged with various stressors. These stress signals ultimately converge on the hypothalamic paraventricular nucleus (PVN), where they are integrated by corticotropin-releasing hormone (CRH)-producing neurons that are primarily involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Noradrenaline (NA), among others, is recognized as the major transmitter that regulates the PVN-CRH neurons, and thereby is involved in the regulation of the HPA axis as well as the autonomic outflow. Previous studies have demonstrated that stress increases NA release within the PVN1 and that NA activates CRH neurons2. However, NA release patterns from the axon terminals in the PVN upon stress exposure have not yet been studied, because continuous monitoring of transmitter release became possible only recently. In the present study, we aimed to monitor stressor-dependent NA release patterns in the PVN. To continuously monitor NA release in freely moving mice, a fluorescent NA sensor (GRABNA)3,4 was expressed in the PVN, and the emitted signals were recorded via fibre photometry. Following stress exposure, NA release took place over distinct timescales ranging from seconds to hours. For example, a pulsatile NA release was observed in seconds in response to an acute nociceptive stressor. In contrast, sustained physical stressors, such as tail suspension and restraint, induced much more prolonged NA release that persists throughout the stress exposure period over tens of minutes. Intraperitoneal administration of lipopolysaccharide produced a gradual increase in NA release that persisted for several hours. These findings demonstrate that NA is released into the PVN in a stress-specific manner. In addition, elevated NA release was associated with increased behavioural activity, characteristic of each stressor. Together, these findings provide a framework for understanding how the temporal dynamics of NA release in the PVN encode diverse stress signals, and regulate neuroendocrine outputs.

neuroscience↗

bioRxiv2026

Rapid coordination of followership and leadership roles in homing pigeons navigating with unfamiliar partners

Collective movement requires coordination between individuals, yet how this emerges during early interactions remains poorly understood. We investigated how partner familiarity influences coordination, leader-follower dynamics, and learning in homing pigeon pairs navigating from novel sites. Birds were released repeatedly with either familiar or unfamiliar partners, followed by solo releases to assess learning. By quantifying bidirectional information flow, we found familiarity influenced information-transfer dynamics during the first release: familiar pairs exhibited more asymmetric information transfer, likely reflecting established leader-follower relationships, whereas unfamiliar pairs showed more symmetric exchange. These differences disappeared after one release. Conversely, familiarity had little effect on cohesion or navigational performance. There was some evidence for an influence on learning: birds from familiar pairings had higher homing efficiency on a subsequent solo release. Finally, across partnerships, followership was more predictable than leadership with respect to individual identity and flight speed, indicating stable variation in individuals tendency to follow rather than lead. This suggests that a shift in emphasis from leadership to followership might enhance our understanding of collective decision-making dynamics. Our results demonstrate how flight partners rapidly coordinate, producing limited downstream effects on navigation and learning, with implications for many animals that travel in fission-fusion transitory collectives.

animal behavior and cognition↗

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

Machine learning-based decoding of emotional valence from electrophysiological signals in the monkey brain

Understanding how the brain operates in naturalistic settings requires methods that go beyond conventional repeated-measurement approaches, necessitating the development of single-trial neural activity analysis. Recent advances in machine learning offer new opportunities for analyzing brain electrophysiological signals. Here, we recorded surface electrocorticography (ECoG) and intracranial local field potentials (LFPs) from emotion-related brain regions in a monkey performing a Pavlovian conditioning task, in which sensory cues predicting reward or punishment were presented randomly, followed by the actual unconditioned outcome. We evaluated the performance of two machine learning algorithms, a Convolutional neural network (CNN) model and a Transformer-based model (EEG-Conformer), in classifying raw ECoG/LFP traces. Both models successfully classified valence type during conditioned and unconditioned stimulus presentation. Furthermore, the Transformer achieved significantly superior classification performance compared to the CNN, particularly in multi-state classification including baseline periods. By optimizing the training dataset for the Transformer model, we could detect dynamic fluctuations in emotional valence consistent with task type from continuously evolving ECoG/LFP patterns recorded throughout the task. These results demonstrate the utility of Transformer-based models for decoding emotional valence from neurophysiological signals in non-human primates.

neuroscience↗

bioRxiv2026

Decoding Anadara shell morphology with deep learning

Accurate shell shape quantification is critical for studying biodiversity and evolution, yet intraspecific variability in bivalves makes morphology-based identification difficult. Traditional methods, including landmark-based analyses and elliptic Fourier descriptors, suffer either from subjectivity in homologous point selection or from limited use of contour information. Here, we introduce Morpho-VAE, a deep generative framework integrating a variational autoencoder with a supervised classifier, to analyze shell images of five Anadara species. Morpho-VAE outperforms conventional approaches in species classification by embedding morphological variation into a low-dimensional space where species cluster distinctly. To highlight species-specific morphological patterns, we develop a patch masking assay, revealing the hinge line as a shared morphological marker across species and species-specific regions near the umbo and anterior ventral margin. The decoder further enables morphological visualization via image reconstruction and interpolation. Our results show that Morpho-VAE can automatically extract species-defining morphological patterns from raw images, providing complementary or novel insights beyond traditional morphometric methods.

biophysics↗

bioRxiv2026

PITPβ Drives JAK2 V617F-Mediated Myeloproliferative Neoplasms by Promoting PtdIns(3,4)P2-Dependent AKT Hyperactivation

JAK2 is a key regulator of cytokine-mediated proliferative signaling in hematopoietic stem and progenitor cells. Activating mutations, most commonly JAK2 V617F, trigger aberrant cytokine signaling driving the pathogenesis of myeloproliferative neoplasms (MPNs). Phosphatidylinositol transfer proteins (PITPs) facilitate phosphoinositide synthesis by delivering phosphatidylinositol to lipid kinases, though their roles in oncogenic signaling have remained poorly defined. Here we show that PITP{beta} is critical for the development of JAK2V617F-driven MPN in mice. Deleting Pitp{beta} across the hematopoietic system, but not Pitp, prolonged 25-week survival of Jak2V617F mice from 10% to 85%. Loss of Pitp{beta} attenuated disease-associated splenomegaly and curtailed erythroid progenitors expansion both in vivo and in vitro. Mechanistically, PITP{beta} is necessary for AKT hyperactivation in hematopoietic progenitors, while STAT5 and ERK signaling remain unaffected. In alignment with this role, PITP{beta} promotes the production of PtdIns(3,4)P2, a phosphoinositide that sustains aberrant AKT signaling in Jak2V617F progenitors. Pharmacologic inhibition of AKT with the FDA-approved inhibitor capivasertib in Jak2V617F-transplanted mice similarly reduced splenomegaly and erythroid proliferation, mimicking the effects of Pitp{beta} loss. Collectively, these results identify a novel PITP{beta}-PtdIns(3,4)P2 signaling axis that selectively maintains pathological AKT activation in JAK2V617F-driven MPN, revealing a promising therapeutic vulnerability.

cancer biology↗

bioRxiv2026

A pistil peptide toxin-pollen antidote system for reproductive barrier

Summary paragraphPrezygotic reproductive barriers in angiosperms are crucial for female-mediated selection of compatible male gametes. In this study, we identified a biological activity within the stylar tissues of Arabidopsis thaliana pistils that inhibits the elongation of heterospecific pollen tubes. Using genome-wide association studies, we identified a cysteine-rich peptide predominantly expressed in the style as the responsible barrier. This secreted peptide, named Femme fatale (FEM), inhibited pollen tube elongation of heterospecific species and some conspecific strains, both in vivo and in vitro. Importantly, FEMs function was independent of the known reproductive barrier component SPRI1 that functions in the stigmatic papilla cell surface. This means two factors act spatially in sequence to create a multilayered reproductive barrier system against pollen in pistils. We also identified a secreted protein expressed in pollen, Homme capable (HOM), which is encoded by a gene next to FEM. HOM interacts with FEM to counteract its barrier effect and allow pollen tube elongation. The FEM-HOM locus has undergone frequent tandem duplications during Brassicaceae evolution. Dosage differences between the two factors can lead to reproductive incompatibility among lineages. Together, our findings suggest that FEM and HOM form a toxin-antidote system that helps establish reproductive barriers.

plant biology↗

bioRxiv2026

Microhomology-mediated end joining acts directly on replication forks to repair single-ended double strand breaks

Replication stress, intrinsic to oncogenesis, often leads to fork breakage and double-strand break (DSB) formation. Conventionally, break-induced replication (BIR) is considered the primary mechanism for repairing replication-associated single-ended DSBs (seDSBs). Here, we demonstrate that microhomology-mediated end joining (MMEJ) acts directly to repair seDSBs at broken replication forks (fork-MMEJ), preferentially on the leading strands, and functions cooperatively with BIR. We also showed that while fork-MMEJ is promoted by Pol{theta}, it operates independently of MRE11/CtIP-mediated end resection, relies on RPA, and produces asymmetric deletion patterns, which is distinct from canonical MMEJ (cMMEJ) defined at replication-independent double-ended DSBs (deDSBs). ATR, activated as end resection proceeds, serves as a pivotal switch to suppress fork-MMEJ while promoting BIR. Combined inactivation of ATR and Pol{theta} synergistically kills cancer cells under high replication stress with minimal toxicity to normal cells. Together, our study provides fundamental insights into the MMEJ mechanism and offers new strategies for cancer treatment.

molecular biology↗

bioRxiv2026

MAP70-2 is required for division plane orientation during 3D differential growth within a tissue

Communication between tissues and cell division orientation are essential for organ development. During lateral root formation in Arabidopsis thaliana, three-dimensional differential growth is established within a tissue of interconnected and pressurized cells. To emerge, the new organ needs to overcome the mechanical constraints provided by the overlying tissues. How the division plane orientation within the growing organ encountering mechanical constrains is coordinated remains unclear. Here, we show that MICROTUBULE ASSOCIATED PROTEIN 70-2 contributes to this integration of mechanical feedback during lateral root development by being associated with division plane orientation during primordium formation. MAP70-2 expression in the lateral root primordium is dynamic, localizing to cell corners and the cortical division zone prior to cytokinesis. Loss of MAP70-2 leads to misoriented cell divisions in the early stage of lateral root development and defective morphogenesis. Here we propose that MAP70-2 integrates biochemical and mechanical cues to establish correct division plane orientation during three-dimensional differential growth to facilitate lateral root organogenesis.

plant biology↗

bioRxiv2025

Selective induction by statins of FAM134B-mediated sarcoplasmic reticulum (SR)-phagy degrades the SR calcium pump SERCA1 and contributes to myopathy

Statins, HMG-CoA reductase inhibitors, are the most prescribed medication for lowering low-density lipoprotein cholesterol. Although statin intolerance due to statin-associated muscle symptoms (SAMS) has been a clinically important issue for decades, the molecular mechanisms of statin myopathy remain incompletely understood. To seek to clarify how statins induce myopathy, here we perform transcriptome analysis and identify FAM134B short isoform (FAM134B-S), an endoplasmic reticulum (ER)-phagy receptor, as a statin-inducible gene. FAM134B-S expression is regulated by the mevalonate pathway and sterol regulatory element-binding proteins. We further show that FAM134B plays a critical role in the regulation of skeletal muscle integrity both in the steady-state and statin-treated conditions in human iPS cell-derived myocytes and mice. Mechanistically, FAM134B-S interacts with the sarcoplasmic reticulum (SR) calcium pump SERCA1 and promotes its autophagic degradation. Collectively, our work reveals a hitherto undisclosed mechanism of statin myopathy; blocking the mevalonate pathway induces SERCA1 degradation through FAM134B-mediated SR-phagy, exerting myotoxicity.

pharmacology and toxicology↗

bioRxiv2025

Expert-led priorities for a response diversity research agenda in ecology

Response diversity aims to capture and explain the variation in ecological responses to environmental change. Response diversity is expected to drive ecological stability since a wider variety of responses to one or more environmental factors should stabilise fluctuations of ecosystem functions. However, uptake of empirical response diversity research has been slow. Here we assess current thinking around response diversity by conducting a targeted expert survey of response diversity researchers. Our survey revealed that one barrier to a unified research agenda on response diversity is the lack of agreement among respondents on the definition of response diversity, and to which dimension(s) of ecological stability response diversity might relate. When asked to select the temporal, spatial, and biological scales at which response diversity may be most relevant for ecological stability, respondents chose a wide range of scales indicating differences in how experts view response diversitys stabilising effect. Respondents considered studies incorporating both biotic interactions and abiotic environmental responses to be especially challenging, as were those thinking about responses to multiple environmental changes simultaneously. Moreover, respondents thought inconsistencies in the definitions of, and methods for measuring, response diversity were a major challenge facing the field. Despite these barriers, the survey revealed a desire for globally coordinated research efforts on response diversity in the form of syntheses, workshops, and distributed experiments, but that a standardised response diversity metric across diverse use-cases could be too restrictive. Our findings suggest we can shift response diversity from a loose collection of conceptual studies and inconsistent empirical applications towards a quantitative and coordinated research programme mechanistically linking biodiversity and ecological stability. As such, we are launching the Response Diversity Network--a research community interested in the science and application of response diversity-- whose activities we hope will benefit both individual studies of response diversity and globally coordinated research efforts.

ecology↗

bioRxiv2025

RIF1 orchestrates a multi-step restoration of post-replicative H3K9me3

DNA replication causes the dilution of parental histones along with their specific post-translational modifications. The kinetics of restoring these marks on newly incorporated histones dictate how quickly genomic domains regain their epigenetic identity after replication. H3K9me3 is restored extremely slowly; the process of reconstitution, to achieve the pre-replication levels, continues throughout the following G1 phase. The molecular mechanisms behind this slow reconstitution are unknown. We show here that RIF1s reassociation with heterochromatin during mitotic exit is required to set up a chromatin environment permissive for histone methyltransferases to resume H3K9me3 deposition. RIF1 facilitates the recruitment of SUV39H1, HP1 and HP1{beta} and is required for the increased tri-methylation of H3K9 that occurs during G1 phase. RIF1 is also indispensable for recruiting Protein Phosphatase 1 (PP1) to heterochromatin, and the interaction between RIF1 and PP1 is essential for the maintenance of H3K9me3 levels. In addition, RIF1-PP1 complex temporally restrains the activity of Aurora kinase at heterochromatin, ensuring that phosphorylation of H3S10 does not precede replication. This creates a time- window permissive for SUV39Hs to initiate the reinstatement of H3K9me3.

cell biology↗