Biology subjects

Imamura, K.

Publications and source records attributed to Imamura, K..

8 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↗

bioRxiv2025

Non-linear gene sets for digital biomarkers of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the loss of motor neurons. Accurate and accessible blood-based diagnosis of neurodegenerative diseases, including ALS, is becoming increasingly critical. It would be of a major clinical advantage to be able to distinguish ALS based on gene expression profiles of blood cells, but this still remains to be established. We analyzed existing data of peripheral blood mononuclear cells (PBMCs) of ALS patients by machine learning, the Maximum Mean Discrepancy (MMD), minimizing the issue of multi-collinearity shown in a multiple regression model, and identified a non-linear combination of gene sets to classify healthy controls and ALS, since non-linear approaches can capture intricate gene-gene interactions and threshold effects, which are often critical for accurately distinguishing disease from healthy states. In the gene expression profiles of PBMCs, a combination of expression levels in 3 genes, PRKAR1A, QPCT, and TMEM71, enabled us to classify ALS with an area under the curve (AUC) accuracy of 0.83 from the public database, which were then confirmed by laboratory blood samples with an AUC accuracy of 0.85. Furthermore, we found the expression levels of PRKAR1A, QPCT, and TMEM71 in motor neurons derived from induced pluripotent stem cells (iPSCs), the cell type at the core of the pathology, classified ALS with an accuracy of AUC 0.79. This approach of discriminating ALS with non-linear gene combinations may be useful for identifying ALS molecular biomarkers for blood-based diagnosis as well as for arriving at a completely new perspective of ALS pathogenesis.

molecular biology↗

bioRxiv2025

Sequence-encoded conformational biases shape self-assembly modes of intrinsically disordered proteins

Self-assembly of intrinsically disordered proteins (IDPs) underlies cellular functions and disease pathogenesis. This process is mediated by two intermolecular interaction modes: transient point-to-point contacts described by the sticker-and-spacer framework, and persistent surface-to-surface contacts proposed in the cross-{beta} hypothesis. We investigated the molecular basis of these modes in the context of conformational biases, defined as sequence-encoded structural preferences of local segments. Using a five-residue model, we generated lag-series IDPs from the TIA-1 prion-like domain by systematically modulating conformational biases while preserving amino acid composition. The lag-series IDPs demonstrated distinct condensate properties and varying capacities for amyloid fibril formation. Their structural analyses revealed that strongly biased regions preferentially adopt extended structures, including {beta}-strands, and the spacing between these regions influences metastable {beta}-sheet formation. Our findings demonstrate that local conformational biases shape interaction modes of IDPs, thereby linking sequence to condensate properties and amyloid fibril formation. Significance StatementProteins fold into three-dimensional structures defined by their amino acid sequences. In contrast, intrinsically disordered proteins (IDPs) lack stable structures, yet their sequences encode unique self-assembly behaviors, including phase separation and amyloid fibril formation. Can such behaviors be explained within structure-based frameworks? Using a five-residue model, we showed that IDP sequences encode local structural preferences, termed conformational biases, within short segments. These biases determine whether segments engage in transient point-to-point interactions driving phase separation or persistent surface-to-surface interactions leading to amyloid fibril formation. By bridging sequence, structure, and interaction modes, our work provides a comprehensive mechanism for self-assembly and conceptual tools for understanding IDP-related biological functions and disease mechanisms.

biophysics↗

bioRxiv2025

A probiotic bacterium modulates antitumor γδ T-cell responses in lung cancer

The link between the intestinal microflora and cancer outcomes has been recognized for over a decade. Several recent studies have demonstrated that the gut microbiome is associated with the efficiency of T-cell checkpoint blockade therapy for cancer raising interest in strategies to harness this effect via consumption of live microorganisms (probiotics). The probiotic Clostridium butyricum strain MIYAIRI 588 (CBM588) enhances both response rates and overall survival in patients receiving immune checkpoint blockade therapy for non-small cell lung cancer and metastatic renal cell carcinoma but the mechanism underpinning this benefit remains unclear. Here, we show that CBM588 spores induce a population of V{gamma}9V{delta}2 T-cells from the peripheral blood of healthy donors and lung cancer patients. A subset of these T-cells responded to, and directly lysed, cancer cell lines via a butyrophilin 3A-dependant mechanism. In patients taking CBM588 alongside checkpoint blockade, peripheral V{delta}2 T-cells expressed the activation marker CD69 more frequently than those receiving checkpoint blockade alone and the frequency of V{delta}2CD69 cells increased following initiation of CBM588 treatment (p = 0.0041). Our findings provide a potential mechanism by which the manipulation of the intestinal microflora might directly contribute to cancer prognosis by activating immune effector cells with intrinsic anticancer properties.

immunology↗

bioRxiv2025

β-III tubulin identifies anti-fibrotic state of pericytes in pulmonary fibrosis

Pericytes have been implicated in pulmonary fibrosis, yet their activated cellular states and functional roles remain largely unclear. Here, we identified {beta}-III tubulin (Tuj1) as a distinctive marker for fibrosis-associated lung pericytes. Most pericytes in fibrotic regions are Tuj1-positive and interact uniquely with multiple endothelial cells, localizing near collagen-producing fibroblasts and pro-fibrotic SPP1+/arginase+ macrophages. Tuj1 expression is predominantly induced in pericytes during the fibrotic phase, and Tuj1 gene (Tubb3) knockout in mice exacerbates lung fibrosis, accompanied by an increase in the neighboring pro-fibrotic fibroblasts and macrophages, suggesting an anti-fibrotic role for Tuj1-expressing pericytes. Mechanistically, the anti-fibrotic chemokine CXCL10 is upregulated in Tuj1-expressing pericytes, whereas this upregulation is not observed in Tubb3 knockout. Moreover, CXCL10 inhibits the pro-fibrotic differentiation of macrophages induced by lung fibroblasts in culture, implying that CXCL10 may mediate the anti-fibrotic effects of Tuj1-expressing pericytes. These findings underscore the role of lung pericytes in negatively regulating fibrotic process and their potential as therapeutic targets for pulmonary fibrosis patients. SummaryIn response to fibrotic stimuli, lung pericytes upregulate {beta}-III tubulin (Tuj1) expression, adopting an anti-fibrotic phenotype. This phenotype acts as a negative immune regulator of pro-fibrotic macrophage differentiation by releasing CXCL10, thereby counteracting the progression of pulmonary fibrosis.

pathology↗

bioRxiv2024

From Monomers to Oligomers: Structural Mechanism of Receptor-Triggered MyD88 Assembly in Innate Immune Signaling

MyD88 plays a pivotal role in Toll-like receptor (TLR) and interleukin-1 family signaling through its oligomerization upon receptor activation, leading to downstream protein recruitment. The Toll/interleukin-1 receptor domain of MyD88 (TIRMyD88) is responsible for this receptor-mediated oligomerization, but the detailed mechanism involved remains elusive. We investigated the structure of TIRMyD88 oligomers and their interactions with TLRs. Cryoelectron microscopy revealed that tandemly arrayed TIRMyD88 subunits formed an antiparallel double-stranded filament that could further form rings and cylindrical filaments. Moreover, the self-assembly of TIRMyD88 in vitro was markedly accelerated by dimeric rather than monomeric receptor TIRs, possibly reflecting the signal initiation step in vivo. High-speed atomic force microscopy further captured the dynamic processes of oligomerization of TIRMyD88, in addition to its direct interaction with the receptor TIRs. Based on these results, a novel regulatory mechanism of TIRMyD88 oligomerization underlying the signal initiation step was revealed.

biophysics↗

bioRxiv2024

Stable platelet production via the bypass pathway explains the long-term reconstitution capacity of hematopoietic stem cells

Precise understanding how hematopoietic stem cells (HSCs) differentiate in vivo is difficult because we can not trace the in vivo differentiation of HSCs. The single-cell transplantation assay and our own paired daughter cell assay of phenotypic HSCs has revealed the presence of HSCs with reconstitution capacity whose differentiation potential is restricted to the myeloid lineage (MySCs) and the presence of novel direct differentiation pathway form HSCs to MySCs (named myeloid bypass pathway). However, how HSCs differentiate in vivo during hematopoiesis has remained unclear since the paired daughter cell assay was performed partially ex vivo. Aiming to characterize HSCs, including the myeloid bypass pathway, we examined the kinetics of HSC differentiation using a mathematical model. We analyzed data from single-cell transplantation assays in which five blood cell lineages were followed successively after transplantation. An age-related skewing to the myeloid lineage was quantitatively indicated as the production of B cells reduced with age. Dependence on platelet bypass increased with aging and consistently high dependence was associated with long-term reconstitution capacity of the HSCs. Focusing on the ratio of chimerism among cell lineages, the characteristics of dependence on platelet bypass can be accurately determined by the ratio of erythrocyte to platelet chimerism at 8 weeks after transplantation. This new identification criterion is an indicator of long-term reconstitution of HSCs that does not rely on observation of long-term transplantation experiments. These findings reveal the novel characteristics of HSCs related to aging and stemness and highlight the importance of the bypass pathway in HSC differentiation. Significance statementIn vivo differentiation of hematopoietic stem cells (HSCs) is important for understanding blood cell production. Here we investigated the differentiation kinetics of HSCs in single-cell transplantation assays by using a mathematical model. Our findings demonstrate the importance of the bypass pathway in platelet production for the long-term reconstitution capacity of HSCs. These results also suggest the utility of studying time changes in HSC differentiation. The new HSC characteristics and its detection criteria identified in this study are expected to be useful in understanding HSC diversity and aging.

cell biology↗

bioRxiv2018

Identification of Functional Targets Reveals that the Suppression of Pumilio mediated mRNA Decay Increases Cell Resistance to DNA Damage in Human Cells

RNA-binding proteins (RBPs) play a pivotal role in gene expression by modulating the stability of transcripts; however, the identification of degradation targets of RBPs remains difficult. Here, we identified 48 target mRNAs of human Pumilio 1 (PUM1), an evolutionally conserved RBP, by combined analysis of transcriptome-wide mRNA stabilities and the binding of mRNAs to PUM1. Here, we developed an approach to identify mRNA targets of Pumilio 1 (PUM1), an evolutionally conserved RBP. By combined analysis of transcriptome-wide mRNA stabilities and the binding of mRNAs to PUM1, we identified 48 mRNAs that both bound to PUM1 and exhibited PUM1-dependent degradation. Analysis of changes in the abundance of PUM1 and its targets in RNA-seq data indicated that DNA-damaging agents negatively regulated PUM1-mediated mRNA decay. Cells exposed to cisplatin had reduced PUM1 abundance and increased PCNA and UBE2A mRNAs, encoding proteins involved in DNA repair by translesion synthesis (TLS). Cells overexpressing PUM1 exhibited impaired DNA synthesis and TLS and increased sensitivity to the cytotoxic effect of cisplatin. Thus, our method identified targets of PUM1-mediated decay and revealed that cells respond to DNA damage by inhibiting PUM1-mediated mRNA decay to activate TLS.

molecular biology↗