Biology subjects

Nakamura, T.

Publications and source records attributed to Nakamura, T..

At least 19 recordsLinked to original sources

bioRxiv2026

Secretory ferritins mediate iron delivery during magnetite tooth formation in chitons

Iron is essential to most organisms, yet unbound iron is toxic, necessitating tight regulation of its storage and transport. Chitons concentrate extraordinary amounts of iron in radular tissue to form magnetite-mineralized teeth, but how iron is supplied to developing teeth remains unclear. Here, synchrotron radiation X-ray fluorescence mapping resolved the spatiotemporal redistribution of iron from the radular epithelium toward developing teeth. Integrated transcriptomic and proteomic analyses identified secretory ferritin subunits in radular tissue whose genes were highly expressed in the midgut gland and whose proteins were also present in the hemolymph. In vivo fluorescence tracking showed that circulating ferritin was selectively taken up by the radular epithelium, and following injection of Ag-loaded hemolymph ferritin, Ag was detected in developing teeth. Together, these findings support a model in which secretory ferritins produced in the midgut gland transport iron through the hemolymph to the radula, enabling the pronounced iron accumulation required for tooth mineralization.

molecular biology↗

bioRxiv2026

Distance-AF Multimer: A Multi-Step Approach for Protein Complex Structure Modeling with User-Defined Distance Constraints

The three-dimensional structure of proteins provides essential insight into the molecular mechanisms underlying their function. Many biological activities are mediated through protein interactions, making accurate structural determination of protein complexes important. Despite significant advances in computational protein structure prediction, there are still many cases where protein complexes are not correctly assembled. In particular, there are cases where experimental data, such as distances between residue pairs in interacting proteins are available, yet existing prediction methods fail to produce models consistent with these data. Here, we present Distance-AF Multimer, a method that guides and refines AlphaFold-Multimer docking predictions using user-provided residue pair distance information. This approach extends our previously successful data-guided single-protein modeling method, Distance-AF. Distance-AF Multimer operates in a two-step process, starting from multiple initial conformations and iteratively refining them to satisfy the provided distance constraints. We evaluated Distance-AF Multimer on protein-complex benchmarks spanning different chain counts and docking errors, demonstrating competitive or superior performance compared to other existing deep-learning-based structure prediction methods. In addition to dimer cases, we also demonstrated the potential of Distance-AF Multimer for large-scale protein assemblies containing multiple chains, including those with more than 5 chains.

bioinformatics↗

bioRxiv2026

Distinct Patterns of Adaptive Decision-Making in Mouse Models of Neurodevelopmental Disorders

Neurodevelopmental disorders (NDDs) arise from diverse genetic alterations that can affect adaptive decision-making, but quantifying specific components of cognitive processes remains challenging. We developed a sequence of deterministic and probabilistic reversal learning tasks using an automated operant platform and applied reinforcement-learning models to quantify latent cognitive processes in mice. We applied this framework to three genetic NDD models: Mecp2+/- (Rett syndrome), MECP2-Tg1 (MECP2 duplication syndrome), and Kmt2c+/fs (KMT2C haploinsufficiency) mice. Mecp2+/- mice showed heterogeneous impairment in acquiring deterministic reversal learning, accompanied by reduced task engagement and increased premature responses. MECP2-Tg1 mice exhibited mild impairment of deterministic reversal learning but preserved performance in probabilistic reversal learning. Although Kmt2c+/fs mice showed largely preserved behavioral performance, reinforcement-learning modeling revealed increased learning from unrewarded outcomes and faster forgetting of unchosen options, which were not apparent from overall performance. These findings demonstrate that combining quantitative reversal learning tasks with computational modeling can distinguish specific alterations in cognitive processes, providing an effective framework for characterizing cognitive dysfunction across mouse models of NDDs.

neuroscience↗

bioRxiv2026

Associated Bacteria, Particularly Mucilaginibacter Species, Inhibit Sheath Formation in Nostoc commune

The terrestrial cyanobacterium Nostoc commune fixes atmospheric nitrogen and exhibits remarkable desiccation tolerance, making it a promising organism for biomass production on land unsuitable for conventional agriculture. However, reliable artificial cultivation of N. commune remains difficult because hormogonium formation cannot yet be induced reproducibly and mechanically prepared trichome fragments often fail to develop into sheath-enclosed colonies. In this study, we examined factors affecting sheath formation in short non-motile trichome fragments, referred to here as nas-trichomes. Microscopic observation revealed two distinct developmental outcomes: a curling type, in which trichomes formed sheaths and developed into compact colonies, and an elongation type, in which trichomes extended without forming a distinct sheath. Curling-rich cultures were obtained only from colonies subjected to drying and rehydration, and early bacterial proliferation around trichomes was negatively associated with subsequent sheath formation. Microbial community analysis showed that Mucilaginibacter was enriched in elongation-rich cultures. Co-culture experiments further demonstrated that M. segetis, M. oryzae, M. jinjuensis, and M. xinganensis significantly inhibited sheath formation at high bacterial density. These results indicate that associated bacteria, particularly specific Mucilaginibacter species, can inhibit sheath formation in N. commune and suggest that controlling early bacterial proliferation is essential for establishing reliable cultivation methods.

microbiology↗

bioRxiv2026

Bacteriophage susceptibility in clinical Enterococcus faecalis reflects host genomic background and Epa-associated phage adsorption

Cytolysin-positive Enterococcus faecalis has been implicated as a disease-associated pathobiont in alcohol-associated hepatitis, motivating development of selective bacteriophage-based strategies. However, strain-level determinants of phage susceptibility remain incompletely understood. We characterized the host range of three E. faecalis phages, {Phi}Ef2.1, {Phi}Ef2.2, and {Phi}Ef2.3Ev, across 45 clinical isolates and investigated bacterial and phage factors associated with adsorption and productive infection. Isolates were characterized by whole-genome sequencing, cytolysin status, antimicrobial resistance determinants, and predicted anti-phage defense systems. Phage susceptibility was measured by efficiency of plating (EoP) and adsorption assays. Thirty-five of the 45 isolates (77.8%), including all 15 cylLs-positive isolates, were susceptible to at least one of the three phages at EoP [≥]0.01. {Phi}Ef2.1 and {Phi}Ef2.2 showed greater activity against cylLs-positive isolates, which also carried higher burdens of predicted antimicrobial resistance determinants and anti-phage defense system types. Analysis of 367 complete E. faecalis RefSeq genomes classified the variable region of the enterococcal polysaccharide antigen (epa) locus into 15 recurrent architecture groups that were associated with phage-specific adsorption patterns. Efficient adsorption did not always result in productive infection, indicating additional post-adsorption barriers. AbiD emerged as a candidate factor associated with reduced {Phi}Ef2.2 productivity, although this signal was prediction-tool dependent, while unexplained post-adsorption blocks suggest the involvement of additional uncharacterized mechanisms. These findings link naturally occurring epa architecture to phage adsorption and highlight distinct post-adsorption constraints on host range, providing a framework for rational phage selection against clinically relevant E. faecalis populations.

microbiology↗

bioRxiv2026

Multi-modal ion-transport function of potassium channelrhodopsins

Light-gated K+ channelrhodopsins (KCRs) are recognized as an ideal neuronal silencing tool in optogenetics. KCRs contain functionally important residues for a light-driven H+ pump bacteriorhodopsin, but their roles have been unclear. Utilizing electrophysiological methods, we demonstrate that KCRs function as a light-driven H+ pump in the absence of K+. Transport experiments using pH electrodes further elucidated the function of the H+-pump, which operates even in the presence of K+. The hypothesis that the H+ pump exerts a blocking effect on K+ transport in KCRs has been postulated. Furthermore, we ascertained that there was conversion of KCRs from the H+ pump into the H+ channel by light, yet this conversion was never reversed. However, the addition of K+ resulted in the formation of the K+ channel. KCRs exhibit three distinct functional states, H+ pump, H+ channel, and K+ channel. These multifaceted functions are modulated by environmental ions and light.

biophysics↗

bioRxiv2026

On-demand surround suppression explains the spatiotemporal window of the tilt illusion

What we see at one location depends on what surrounds it. Such contextual e[ff]ects are thought to arise from neural signals that travel across the retinotopic representations.Because these signals need more time to travel longer distances, a more distant surround should influence perception most strongly when presented earlier, compensating for its delay. We tested this prediction in human observers using a visual illusion in which a central target appears tilted away from the orientation of its surround (tilt illusion). Measuring the temporal window of this illusion using psychophysical reverse correlation revealed the opposite: the most e[ff]ective surround occurred progressively later as distance increased. Computational modelling demonstrated that this reversal is explained if the visual system sends out a query that recruits contextual information on demand. Perceptual appearance may thus be constructed through temporally unfolding interactions in which context is actively gathered, not passively received.

neuroscience↗

bioRxiv2026

Extracellular vesicle cross-linking coupled with solid-phase purification facilitates discovery of ribonucleoprotein complexes assembled on EV RNAs.

Extracellular vesicles (EVs) are fundamental mediators of intercellular communication that transfer macromolecular cargo, including proteins and RNAs, to functionally reprogram recipient cells. However, the molecular processes by which transferred ribonucleoprotein (RNP) complexes engage recipient host machinery to influence cellular behavior are poorly understood, primarily due to a dearth of methods capable of tracking these post-transfer interactions. To address this gap, we developed two complementary chemical biology platforms: EV-CLASP and EV(r)-CLASP. While EV-CLASP maps the native, intra-vesicular RNP landscape packaged within the EV, EV(r)-CLASP captures post-transfer dynamics by identifying the host proteins that directly associate with EV-derived RNAs following cellular uptake. Both approaches leverage metabolic labeling and photo-crosslinking for high-specificity recovery. Donor cells are cultured with 4-thiouridine (4SU) to biosynthetically label newly synthesized RNAs during EV biogenesis. Purified EVs can be crosslinked using 365 nm UV light to capture intra-vesicular RNP composition. Alternatively, 4SU-labeled EVs can be delivered to recipient cells and subsequently crosslinked to identify the primary physical interactions formed within the recipient-cell environment. Crosslinked RNP complexes are isolated under stringent conditions using solid-phase reversible beads to minimize background, followed by quantitative mass spectrometry for protein identification. Together, EV-CLASP and EV(r)-CLASP provide a robust, versatile framework for defining the dynamic RNP assemblies that facilitate extracellular RNA communication, offering a powerful toolkit to uncover novel RNA-associated regulatory networks, therapeutic targets, and biomarkers across diverse biological and disease contexts.

cancer biology↗

bioRxiv2026

CycloCross: Adversarial single-cell RNA-seq data translation across species

Single-cell RNA sequencing (scRNA-seq) has transformed our understanding of cellular heterogeneity, yet most datasets are limited to a handful of model organisms, leaving critical gaps in cross-species biology. Existing computational methods for integrating multi-species scRNA-seq data often rely on one-to-one ortholog mapping, which fails to account for gene duplications, losses, or functional divergences. To address these challenges, we introduce CycloCross, an adversarial method based on the CycleGAN architecture, designed to translate scRNA-seq data between species without requiring a priori gene correspondences. Unlike generative models that synthesize data from noise, CycloCross leverages real data from a source species, enabling more realistic and data-efficient translations. We demonstrate its effectiveness in germ cell development, translating data between mouse, macaque, and human with conserved yet divergent transcriptional programs. CycloCross not only preserves temporal dynamics but also enables interpolation and extrapolation of gene expression at missing time points, offering predictions for experimentally inaccessible states. Furthermore, CycloCross generates biologically plausible samples even with limited data, outperforming traditional generative models.

bioinformatics↗

bioRxiv2026

Serial dependence in haptic perception during active manual exploration.

Serial dependence, whereby current perception is systematically biased toward the most recent sensory experience, has been demonstrated across multiple sensory modalities. However, whether serial dependence occurs during active haptic perception remains unknown. Moreover, because haptic perception of object geometry depends on hand movements for sensory acquisition (i.e., active touch), it remains unclear whether serial dependence, if any, originates from perceptual processing, movement, or both. Here, we investigated whether active haptic perception exhibits attractive serial dependence using a newly developed haptic device that let participants explore virtual slopes of different heights. Participants reported perceived slope heights, and we recorded their kinematics. Perceptual judgments were systematically attracted toward the most recently experienced slope, demonstrating serial dependence during active haptic perception. By contrast, none of the kinematic parameters exhibited corresponding serial dependence. These findings show that serial dependence extends to the somatosensory perceptual domain and suggest that the observed perceptual bias was not mediated by systematic changes in hand movements.

neuroscience↗

bioRxiv2026

IL-10 Overexpression Improves Cerebral Microcirculation and Attenuates Cerebral Vasospasm After Experimental SAH

BACKGROUND: Subarachnoid hemorrhage (SAH) induces inflammatory responses and subsequent immune cell activation, which may contribute in cerebral vasospasm, microcirculatory impairment and poor neurological outcomes. Although cerebral vasospasm has traditionally been considered a major cause of delayed cerebral ischemia after SAH, therapies targeting angiographic vasospasm have not consistently improved functional outcomes. Early inflammatory responses may contribute to microcirculatory impairment, cerebral vasospasm, and subsequent neurological injury. Herein, we investigated whether interleukin-10 (IL-10), an anti-inflammatory cytokine, improves these outcomes in an experimental SAH model. METHODS: Mice received intramuscular injections of either an adeno-associated virus encoding IL-10 (AAV/IL-10) vector or an AAV expressing green fluorescent protein (AAV/GFP) vector (control). India ink angiography was performed to assess the diameter of the sphenoidal segment of the middle cerebral artery (MCA), the total length of the visible cortical arteries, and cortical staining intensity, as indices of cerebral vasospasm, microcirculatory impairment, and cerebral perfusion, respectively. Perivascular inflammatory cell infiltration and cytokine levels were assessed using immunohistochemistry and ELISA. We also evaluated the therapeutic efficacy of the AAV/IL-10 vector when administered immediately after SAH induction. RESULTS: IL-10 overexpression significantly improved neurological outcomes after SAH and was associated with attenuated cerebral vasospasm and microcirculatory impairment, as well as preservation of cerebral perfusion. It also significantly reduced neutrophil and macrophage infiltration around the internal carotid artery and attenuated SAH-induced elevations in IL-6 and matrix metalloproteinase-3 levels. Mice treated with the AAV/IL-10 vector immediately after SAH induction showed significant improvements in neurological scores and cerebral perfusion. CONCLUSIONS: AAV-mediated IL-10 overexpression improves neurological outcomes after SAH, likely by attenuating inflammatory responses, cerebral vasospasm, and microcirculatory impairment. These findings suggest that IL-10-based anti-inflammatory therapy is a promising therapeutic strategy for SAH.

pathology↗

bioRxiv2026

Desialylated platelets promote hepatocyte proliferation via the ERK1/2 signaling pathway

Platelets are increasingly recognized as active regulators of tissue repair and liver regeneration beyond their classical roles in hemostasis and thrombosis. Loss of terminal sialic acid from platelet surface glycoproteins, a process known as desialylation, occurs during platelet aging or activation and has been linked to platelet clearance via the asialoglycoprotein receptor (ASGPR) on hepatocytes. However, the mechanisms by which desialylated platelets (D-plts) directly stimulate hepatocyte proliferation remain poorly understood. This study aimed to elucidate the proliferative effects of D-plts on hepatocytes and to identify the underlying signaling mechanisms. D-plts were generated and co-cultured with hepatocyte models exhibiting low or absent levels of asialoglycoprotein receptor 1 (ASGPR1) expression, including HepG2 cells, HuH-7 cells, and human chemically induced liver progenitors. Hepatocyte proliferation was assessed, and the roles of platelet-derived factors and downstream signaling pathways were investigated. Co-culture with D-plts significantly increased hepatocyte proliferation in all three cell models compared with the corresponding controls. Moreover, supernatants derived from stimulated D-plts also significantly enhanced hepatocyte proliferation, suggesting that soluble platelet-derived factors contribute to this effect. Mechanistically, the proliferative effects were mediated predominantly through the ERK1/2 signaling pathway rather than the JAK-STAT pathway in both hepatocytes co-cultured with D-plts and those treated with D-plt-derived supernatants. In conclusion, our findings demonstrate that D-plts directly promote hepatocyte proliferation through an ASGPR-independent pathway, in which ERK1/2 signaling plays a central role. These results highlight a novel mechanism through which platelet desialylation may contribute to liver regeneration. Graphical Abstract(A) Desialylated platelets are readily activated and release increased amounts of EGF, promoting hepatocyte proliferation via the EGF-ERK signaling pathway. (B) Normal platelets show lower reactivity and reduced EGF release than desialylated platelets, resulting in weaker hepatocyte proliferation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/740293v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@d8eb25org.highwire.dtl.DTLVardef@135e644org.highwire.dtl.DTLVardef@1a0a924org.highwire.dtl.DTLVardef@c092e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell 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

Folate-dependent one-carbon metabolism controls meiotic and post-meiotic epigenome remodeling in the male germline

Environmental exposures can influence offspring health through epigenetic alterations in the male germline. Folate deficiency, a dietary perturbation that disrupts one-carbon metabolism and S-adenosylmethionine (SAM) production, has been linked to altered histone methylation and developmental abnormalities in offspring. However, when and how folate availability shapes the germline epigenome during spermatogenesis remains unclear. In this study, unbiased metabolomic profiling of spermatogenic cells uncovers stage-specific metabolic remodeling, including downregulation of serine- glycine-one-carbon (SGOC) metabolism in meiotic spermatocytes. Using a post-weaning folate-deficient mouse model, we investigate how folate availability influences germline epigenome establishment during spermatogenesis. Consistent with this metabolic transition, genome-wide chromatin accessibility profiling demonstrates extensive, stage-dependent remodeling under folate-deficient conditions, particularly in meiotic spermatocytes and post-meiotic spermatids. These accessibility changes display cell-type-specific genomic distributions and preferential localization to repressive chromatin compartments in post-meiotic cells. Histone modification analyses further reveal bidirectional redistribution of the active histone mark H3K4me3 in round spermatids. Although genome-wide distribution of the repressive mark H3K27me3 remains largely stable, folate deficiency alters its nuclear organization. Notably, a subset of H3K4me3 alterations established in post-meiotic cells is retained in mature sperm, providing a mechanistic link between paternal metabolic perturbation and the germline epigenome. Together, these findings demonstrate that folate availability shapes germline epigenome establishment through stage-specific metabolic and chromatin remodeling during spermatogenesis, revealing a metabolic basis for paternal environmental effects on the germline epigenome.

developmental biology↗

bioRxiv2026

Concomitant DNA hydroxymethylation and histone H2B O-GlcNAcylation are prerequisites for zygotic genome activation in mice

The paternal chromatin undergoes extensive reprogramming, characterized by the loss of 5-methylcytosine (5mC) through Ten-eleven translocation 3 (Tet3)-mediated oxidation to 5-hydroxymethylcytosine (5hmC). Given the role of DNA methylation in gene silencing, it has long been posited that this loss of paternal DNA methylation facilitates zygotic genome activation (ZGA), which occurs predominantly on the paternal genome. However, recent evidence indicates that Tet3-mediated 5mC oxidation alone does not influence global transcription in zygotes, leaving the molecular mechanisms governing ZGA largely elusive. Here, we identify the functional significance of O-linked N-acetylglucosamine (O-GlcNAc) modification of histone H2B at Serine 112 (H2BS112GlcNAc), catalyzed by O-GlcNAc transferase (OGT), within the paternal chromatin of mouse zygotes. We demonstrate that OGT is selectively recruited to the paternal chromatin because Stella (also known as PGC7 or Dppa3) inhibits its binding to the maternal chromatin--a recruitment mechanism analogous to that of Tet3. Although Tet3 and OGT associate with the paternal chromatin independently, both Tet3-dependent 5hmC formation and OGT-mediated H2BS112GlcNAcylation are indispensable for successful ZGA. Together, our findings reveal that a dual epigenetic signature--the simultaneous coordination of DNA hydroxymethylation and histone O-GlcNAcylation by Tet3 and OGT--is essential for initiating transcriptional reprogramming during the maternal-to-zygotic transition.

developmental biology↗

bioRxiv2026

Phytoplankton size structure and biogeochemical responses to nutrient enrichment in an oligotrophic coral reef

Tropical coral reef ecosystems worldwide are being impacted by combined pressures of climate change and human activities that introduce large quantities of nutrients and sediments into coastal areas. In this context, phytoplankton represent a critical link between dissolved inorganic nutrients and coral reef food webs, yet their role in these ecosystems remains understudied. We investigated ecological responses of the summer phytoplankton community of Shiraho Reef (Ishigaki Island, Okinawa, Japan) to nutrient enrichment using field-based microcosm experiments under natural light and temperature conditions in September 2022 and 2023. Treatments included single and combined additions of nitrogen, phosphorus, and silicon. Chlorophyll a (Chl a) concentrations increased after three days under combined nutrient conditions, whereas single-nutrient additions produced limited responses, indicating a strong co-limitation by nitrogen and phosphorus in the reef. Analysis of size-fractionated Chl a revealed shifts from picophytoplankton that typically dominate tropical oligotrophic ecosystems toward larger groups supported by enhanced nutrient availability. Our results show short-term impacts of nutrient enrichment events on phytoplankton size structure and biogeochemical cycling in coral reefs, and highlight the importance of pelagic processes in coral reef carbon dynamics under nutrient-enrichment.

ecology↗

bioRxiv2026

Co-targeting an AMPK--MAPK axis reprograms CAFs and suppresses PDAC

Pancreatic ductal adenocarcinoma (PDAC) is a fatal cancer characterized by limited therapeutic options and a highly treatment-resistant tumor microenvironment. Beyond tumor-intrinsic genetic alterations, growing evidence indicates that host-microbiome interactions influence cancer progression through microbial metabolites. However, how microbiome-derived metabolites influence oncogenic signaling in PDAC remains unclear. Here, integrated profiling revealed a consistent reduction of the microbial metabolite acetic acid in fecal samples from treatment-naive patients with PDAC and in a genetically defined Drosophila model recapitulating key PDAC driver alterations. Acetic acid activates AMP-activated protein kinase, and pharmacological activation of this pathway together with inhibition of mitogen-activated protein kinase signaling suppressed tumor growth in fly and mouse models. Combined pathway targeting restored AMPK activity and suppressed cancer-associated fibroblast activation. These findings identify a microbiome-associated metabolic vulnerability in PDAC and suggest that coordinated targeting of metabolic and oncogenic signaling may restrain tumor progression and improve therapeutic strategies.

cancer biology↗

bioRxiv2026

Lack of Period1 accelerates colorectal tumorigenesis in ApcMin/+ mice

The circadian clock coordinates physiology and behavior through [~]24-h rhythms, and disruption of core clock genes has been implicated in tumorigenesis. However, the impact of Per1, a major clock gene, on colorectal tumor development remains unclear. Here, we investigated how Per1 deletion influences intestinal tumorigenesis using the ApcMin/+ mouse model and ApcMin/+Per1-/-mice generated by crossing ApcMin/+ and Per1-/- lines (C57BL/6J background). Mice were maintained under controlled light-dark conditions, and we assessed survival, intestinal polyp burden, histopathology using Swiss-roll sections, {beta}-catenin protein abundance (immunofluorescence and western blotting), Ctnnb1 mRNA expression (RT-qPCR), and crypt proliferation (5-bromo-2-deoxyuridine (BrdU) immunohistochemistry). Per1 deletion did not significantly alter overall survival in ApcMin/+ mice but increased inter-individual variability. In contrast, polyp number was markedly increased by Per1 deletion, affecting both small (<2 mm) and large ([≥]2 mm) polyps across intestinal segments. Histology confirmed aberrant crypt foci and polyps in both ApcMin/+ genotypes. {beta}-Catenin protein levels in the whole intestine were significantly increased by Per1 deficiency and Apc mutation (two-way ANOVA), whereas Ctnnb1 mRNA was largely unchanged across regions. BrdU-based crypt proliferation was increased by the Apc mutation but not by Per1 deletion. These results indicate that Per1 loss exacerbates intestinal polyp formation and elevates {beta}-catenin predominantly through non-transcriptional mechanisms, supporting a tumor-suppressive role of Per1 in colorectal tumorigenesis.

cancer biology↗