Biology subjects

Hara, T.

Publications and source records attributed to Hara, T..

17 recordsLinked to original sources

bioRxiv2026

Screening of Stereochemically Defined 2,5-Diketopiperazines Identifies Autophagy Inducers without mTORC1 Suppression

Modulating autophagy has emerged as a potential strategy for treating age-related diseases. However, commonly used pharmacological approaches to induce autophagy, particularly inhibition of mechanistic target of rapamycin complex 1 (mTORC1), can be associated with adverse effects, including immunosuppression and insulin resistance. This has prompted interest in autophagy modulators that act without directly inhibiting mTORC1. 2,5-Diketopiperazines (DKPs) are bioactive cyclic dipeptide scaffolds with diverse biological activities. However, systematic evaluation of their structure-activity relationships has been hindered by racemization during conventional chemical synthesis, leaving the contribution of stereochemistry to autophagy regulation poorly understood. Here, we used a stereoselective one-pot chemoenzymatic synthesis based on the adenylation domain of tyrocidine synthetase A to generate a DKP library with defined stereochemistry. Phenotypic screening in Caco-2 cells stably expressing the GFP-LC3-RFP autophagic flux probe identified four DKPs that increased autophagic flux: c(DW-DP), c(DW-LP), c(DF-DP), and c(DM-LP). Structure-activity analysis revealed stereochemistry-dependent effects associated with amino acid side-chain properties: D-configured residues were favored among DKPs containing aromatic amino acids or methionine, whereas L-configured residues were favored among those containing branched-chain amino acids. Substitution of the proline residue further altered activity, with glycine substitution tending to increase autophagic flux in some DKP scaffolds. Importantly, the active DKPs did not detectably reduce the phosphorylation of the mTORC1 downstream targets p70 S6K and 4EBP1, indicating that their autophagy-inducing effects do not require detectable suppression of canonical mTORC1 signaling. These findings establish stereochemically defined DKPs as candidate scaffolds for the development of autophagy inducers that act through mechanisms distinct from direct mTORC1 inhibition.

biochemistry↗

bioRxiv2026

Antiglycation effects of imidazole dipeptides and 2-oxo-imidazole dipeptides on glyceraldehyde-induced intracellular protein glycation and neuronal cell death

Glyceraldehyde (GA) contributes to the development of various diseases, such as diabetes and Alzheimers disease via protein glycation and the formation of advanced glycation end products (AGEs); however, effective strategies for neutralizing GA are limited. Carnosine (Car), an imidazole dipeptide (IDP) that is abundant in meat, suppresses protein glycation by scavenging reactive aldehydes. There are only a few reports on the antiglycation activity of Car against GA. For other IDPs, such as anserine, balenine (Bal), and homocarnosine, there are almost no reports on their antiglycation activity. In this study, we demonstrated the antiglycation activity of four types of IDPs and 2-oxocarnosine (2-oxo-Car), an oxidized form of Car, against GA-induced intracellular protein glycation and neuronal cytotoxicity. Car and Bal exhibited significantly higher reactivity with GA compared with other IDPs and 2-oxo-Car. An in silico analysis suggested that the difference in reactivity is dependent upon intramolecular hydrogen bond formation and the conformation of each IDP. Although there were differences in reactivity with GA, LC-MS analysis revealed that all of the IDPs and 2-oxo-Car reacted with two molecules of GA to form adducts containing pyridinium rings. Car and Bal exhibited high reactivity with GA and markedly suppressed GA-induced cytotoxicity in SH-SY5Y cells. Western blot and qPCR analyses revealed that IDPs suppressed GA-induced protein glycation and the upregulation of endoplasmic reticulum and oxidative stress response genes. Our results indicate that IDPs represent a novel preventive approach to AGE-related diseases and provide a foundation for the development of strategies to treat GA-related neurotoxicity. Graphical abstractCarnosine and balenine, which are imidazole dipeptides (IDPs), scavenged two molecules of glyceraldehyde to form adducts containing pyridinium rings and suppressed intracellular protein glycation and neuronal cell death. The formation of intramolecular hydrogen bond of IDPs played a crucial role in the strength of antiglycation activity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/734660v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@11d82dorg.highwire.dtl.DTLVardef@187aff0org.highwire.dtl.DTLVardef@12fe482org.highwire.dtl.DTLVardef@14327ee_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

AtGPP2 encodes a 3-deoxy-manno-octulosonate-8-phosphatase required for the synthesis of KDO in rhamnogalacturonan II

3-Deoxy-D-manno-oct-2-ulosonic acid (KDO) is an essential component of rhamnogalacturonan II (RG-II), a complex pectic polysaccharide required for plant growth and development. While most steps of the KDO biosynthetic pathway have been characterized in plants, KDO-8-phosphatase (KDO8Pase), the phosphatase responsible for converting KDO 8-phosphate (KDO8P) to KDO, remained unidentified. To identify this missing component, we performed gene co-expression analysis and identified At5g57440 (GPP2) as the primary candidate in Arabidopsis (Arabidopsis thaliana L.). Recombinant GPP2 protein exhibited KDO8P-specific phosphohydrolase activity in vitro. A GFP-tagged GPP2 protein was predominantly localized to mitochondria, consistent with the compartmentation of the subsequent step in KDO biosynthesis. Null mutants of GPP2 exhibited significant growth retardation under boron-limited conditions, in which expression of GPP2 and other KDO biosynthetic genes was up-regulated. The growth retardation was also observed in liquid culture in normal media, a condition that induces rapid growth and thus likely increases metabolic demand for KDO. Despite this growth defect, the KDO content per unit cell wall in gpp2 remained equivalent to that in wild-type plants. These results are consistent with the identification of GPP2 as the elusive plant KDO8Pase and suggest a model where KDO availability becomes the rate-limiting factor for cell wall production. Our findings complete the plant KDO biosynthetic pathway and provide new insights into the physiological significance of RG-II in cell wall biosynthesis. Significance statementThis study identifies the previously unknown plant KDO-8-phosphatase, thereby completing the biosynthetic pathway for KDO in rhamnogalacturonan II. Our findings demonstrate that KDO synthesis is up-regulated under boron deficiency, and its supply becomes a rate-limiting factor for cell wall formation.

plant biology↗

bioRxiv2026

Single-cell RNA sequencing reveals collagen interactions between detached osteoclasts and activated fibroblasts in granulation tissue surrounding sequestra in medication-related osteonecrosis of the jaw

ObjectivesMedication-related osteonecrosis of the jaw (MRONJ) is a rare but serious complication of anti-resorptive agents used for osteoporosis and bone metastasis. As the global population ages, the number of patients with MRONJ continues to rise. Resorptive osteoclasts firmly attached to bone surfaces cannot be detected using single-cell RNA-Seq (scRNA-Seq); however, we hypothesized that multinucleated giant and detached osteoclasts (DetOCs) can be detected by this method. This study aimed to characterize DetOCs with scRNA-seq. Materials and MethodsscRNA-Seq and immunohistochemistry staining was performed on granulation tissues surrounding sequestra from four patients with MRONJ and radicular cysts, a common odontogenic infectious disease with normal bone metabolism. ResultsscRNA-Seq and immunohistochemistry staining revealed that DetOCs were detected exclusively in the granulation tissues of MRONJ. These DetOCs expressed well-known osteoclast markers as well as COL27A1. Subcluster analysis revealed that SPP1+ TREM2+ macrophages differentiated into DetOCs and expressed several types of collagens. Immunostaining confirmed the expression of COL27A1 not only in DetOCs in MRONJ but also in osteoclasts in mandibular cancer. CellChat analysis revealed interactions mediated by collagen signaling pathways between DetOCs, myeloid cells, and activated fibroblasts. ConclusionsWe successfully characterized DetOCs and identified a distinctive microenvironment involving DetOCs and activated fibroblasts in the granulation tissues surrounding sequestra in MRONJ. Clinical RelevanceIdentification of DetOCs and their unique interaction with activated fibroblasts in MRONJ lesions provides novel insight into the pathophysiology of sequestrum formation, suggesting potential therapeutic targets to ameliorate MRONJ.

immunology↗

bioRxiv2026

A Quantitative Benchmark of Visual Information in Human Brain Recordings Across fMRI, MEG, and EEG

Noninvasive human brain recordings such as fMRI, MEG, and EEG are widely used to study visual representations, yet their relative information content has never been quantitatively benchmarked under matched experimental conditions. Here, we develop a unified decoding framework that enables fair cross-modal comparison using identical naturalistic stimuli (THINGS) and a common decoding analysis. Using a matched stimulus set, we first quantify modality performance via object-category decoding accuracy. Under these conditions, fMRI yielded the highest accuracy (mean 87%), MEG showed intermediate performance (mean 35%), and single-subject EEG achieved lower accuracy (mean 7%), while remaining reliably above chance level (1%). Notably, EEG performance improved substantially when decoding outputs were aggregated across participants in the form of a stimulus-level relational structure, yielding a group-level EEG measure (28%) with accuracy comparable to MEG. We then examined how decoding performance scales with the number of training stimuli and effective measurement time. These analyses revealed distinct efficiency-precision trade-offs across modalities: MEG and group-level EEG were most efficient for short measurement times, whereas fMRI achieved the highest asymptotic performance when sufficient data were collected. Together, these findings demonstrate that modality performance differs systematically even under tightly matched conditions and that decoding provides a principled way to assess the information content of fMRI, MEG, and EEG. The proposed unified framework offers practical guidelines for modality selection, experimental design, and data collection planning in neuroscience. Highlights{checkmark} Unified decoding framework enables quantitative, matched comparison of fMRI, MEG, and EEG. {checkmark}fMRI shows the highest decoding accuracy; MEG intermediate; EEG lower. {checkmark}Aggregating EEG decoding outputs into a stimulus level relational structure across subjects markedly improves performance to near MEG levels. {checkmark}MEG and EEG (aggregated across subjects) are most efficient for short recordings, whereas fMRI achieves the highest performance with longer measurement time.

neuroscience↗

bioRxiv2025

Enhanced release of ciliary extracellular vesicles suppresses cell migration and promotes cell aggregation

A primary cilium is a hair-like organelle that protrudes from the cell surface in many cell types. Growing evidence indicates that extracellular vesicles are released from primary cilia, and research is increasingly focused on defining the functions of these cilia-derived extracellular vesicles (EVs). EVs are known to modulate the behavior of various cancer cells, and structural and functional abnormalities in primary cilia have been reported in multiple cancer types. We previously demonstrated that PANC-1 cells, a human pancreatic ductal adenocarcinoma cell line, acquire enhanced primary cilia formation after surviving solitary culture conditions, and that their cilia contribute to tumor-like cell mass formation. Here, we explored part of the underlying mechanism of this phenotype by investigating the contribution of EVs released from the primary cilia of PANC-1 cells. PANC-1 clones generated by limiting dilution exhibited enhanced ciliogenesis and distinct ciliary morphologies compared with parental cells. These clones also released higher levels of cilia-derived EVs, including an expanded population of freely floating EVs within the culture environment. Biochemical analyses further showed that this increase was selective for primary cilia-derived EVs rather than reflecting a global rise in total EV production. Functionally, EV fractions enriched in cilia-derived EVs suppressed parental PANC-1 cell migration, altered cell morphology, and promoted cell aggregation, mimicking key behavioral traits of solitary condition-surviving PANC-1 clones. Together, these findings identify enhanced release of primary cilia-derived EVs as a distinct feature of PANC-1 cells adapted to solitary growth and suggest their potential involvement in the malignant and metastatic behaviors of pancreatic cancer.

cell biology↗

bioRxiv2025

Discovery of a Selective Inhibitor of ZIP14 with Therapeutic Potential for Cancer-associated Cachexia

ZIP14/SLC39A14, a membrane-bound metal transporter, is essential for systemic metal homeostasis and has been implicated in inflammatory and metabolic disorders, including cancer-associated cachexia. Despite its biological and therapeutic significance, no selective inhibitors have been identified. Here, we identify 1-phenyl-8-(2-phenylethyl)-1,3,8-triazaspiro[4.5]decan-4-one (PPTD) as the first selective small-molecule inhibitor of ZIP14. PPTD efficiently blocks ZIP14-mediated uptake of zinc, iron, manganese, and cadmium, while sparing the closely related transporter ZIP8/SLC39A8. Mechanistically, PPTD binds specifically to a pocket formed at the dimer interface of ZIP14, as revealed by AlphaFold3 structural prediction, ligand-interaction profiling, structure-activity analyses, and site-directed mutagenesis, providing direct evidence for a targeted inhibition mechanism. ZIP14-driven metal influx promotes reactive oxygen species and lipid peroxidation, leading to cytotoxicity, which PPTD effectively reverses. In vivo, PPTD ameliorates major features of cancer cachexia in mice, including weight loss, reduced survival, muscle wasting, impaired locomotor activity, and disease progression. PPTD thus provides both a chemical probe to dissect ZIP14 function and a potential therapeutic candidate for cancer cachexia, establishing a foundation for the development of therapies targeting ZIP14-mediated metal dysregulation.

biochemistry↗

bioRxiv2025

FOXM1 Modulation Alleviates Epithelial Remodeling and Inflammation in Eosinophilic Esophagitis

BackgroundEosinophilic esophagitis (EoE) is a chronic allergic disease characterized by esophageal epithelial remodeling, barrier dysfunction, and inflammation. Despite histologic remission, molecular and structural changes in the epithelium persist, contributing to ongoing symptoms and relapse. The transcription factor FOXM1 has been shown to be a key regulator of epithelial proliferation and inflammation in allergic asthma. ObjectiveTo investigate the role of FOXM1 in epithelial disruption in EoE and to evaluate the therapeutic potential of FOXM1 inhibition. DesignFOXM1 expression was analyzed in human esophageal biopsies, patient-derived organoids, and murine EoE models. IL-13 stimulation was used to model EoE in vitro. The effects of FOXM1 inhibition via the small molecule RCM-1 and siRNA-mediated knockdown were assessed by histology, gene expression profiling, organoid formation rates, and barrier integrity assays. RNA sequencing and chromatin immunoprecipitation were performed to elucidate molecular mechanisms. ResultsFOXM1 was significantly upregulated in patients with active EoE and localized to the basal epithelium. IL-13 increased FOXM1 expression, which impaired epithelial differentiation and enhanced basal cell hyperplasia. FOXM1 inhibition restored differentiation markers, reduced basal hyperplasia, and improved barrier function. In murine models, RCM-1 ameliorated epithelial changes and decreased eosinophil infiltration. Mechanistically, FOXM1 directly regulated cell cycle gene, CCNB1, which was upregulated in EoE and downregulated upon FOXM1 inhibition. FOXM1 expression was driven by an IL-13-PI3K/AKT axis. ConclusionFOXM1 plays a pivotal role in epithelial disruption in EoE by driving proliferation and impairing differentiation. Targeting FOXM1 restores epithelial homeostasis, mitigates inflammation, and offers a novel therapeutic approach for EoE. Key MessagesWhat is already known on this topic: Eosinophilic esophagitis is marked by epithelial remodeling and barrier dysfunction driven by Th2 inflammation. Despite remission, molecular and histologic changes in the esophageal epithelium persist, contributing to symptoms and relapse. The mechanisms underlying this epithelial dysregulation remain poorly understood. What this study adds: This study identifies FOXM1 as a key transcriptional regulator of epithelial disruption in EoE, demonstrating that FOXM1 inhibition restores epithelial differentiation, reduces basal cell hyperplasia, improves barrier integrity, and mitigates inflammation. How this study might affect research, practice, or policy: Targeting FOXM1 offers a novel therapeutic strategy to restore epithelial homeostasis and reduce inflammation in EoE. This dual approach, addressing both epithelial and immune dysregulation, may guide future therapeutic development and improve patient outcomes.

molecular biology↗

bioRxiv2023

DrugMap: A quantitative pan-cancer analysis of cysteine ligandability

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors of a wide-range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed DrugMap, an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF{kappa}B1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF{kappa}B1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription factor activity.

systems biology↗

bioRxiv2023

Lysyl oxidase regulates epithelial differentiation and barrier integrity in eosinophilic esophagitis

Background & AimsEpithelial disruption in eosinophilic esophagitis (EoE) encompasses both impaired differentiation and diminished barrier integrity. We have shown that lysyl oxidase (LOX), a collagen cross-linking enzyme, is upregulated in the esophageal epithelium in EoE. However, the functional roles of LOX in the esophageal epithelium remains unknown. MethodsWe investigated roles for LOX in the human esophageal epithelium using 3-dimensional organoid and air-liquid interface cultures stimulated with interleukin (IL)-13 to recapitulate the EoE inflammatory milieu, followed by single-cell RNA sequencing, quantitative reverse transcription-polymerase chain reaction, western blot, histology, and functional analyses of barrier integrity. ResultsSingle-cell RNA sequencing analysis on patient-derived organoids revealed that LOX was induced by IL-13 in differentiated cells. LOX-overexpressing organoids demonstrated suppressed basal and upregulated differentiation markers. Additionally, LOX overexpression enhanced junctional protein genes and transepithelial electrical resistance. LOX overexpression restored the impaired differentiation and barrier function, including in the setting of IL-13 stimulation. Transcriptome analyses on LOX-overexpressing organoids identified enriched bone morphogenetic protein (BMP) signaling pathway compared to wild type organoids. Particularly, LOX overexpression increased BMP2 and decreased BMP antagonist follistatin. Finally, we found that BMP2 treatment restored the balance of basal and differentiated cells. ConclusionsOur data support a model whereby LOX exhibits non-canonical roles as a signaling molecule important for epithelial homeostasis in the setting of inflammation via activation of BMP pathway in esophagus. The LOX/BMP axis may be integral in esophageal epithelial differentiation and a promising target for future therapies.

cell biology↗

bioRxiv2022

Defining ancestry, heritability and plasticity of cellular phenotypes in somatic evolution

The broad application of single-cell RNA sequencing has revealed transcriptional cell state heterogeneity across diverse healthy and malignant somatic tissues. Recent advances in lineage tracing technologies have further enabled the simultaneous capture of cell transcriptional state along with cellular ancestry thus enabling the study of somatic evolution at an unprecedented resolution; however, new analytical approaches are needed to fully harness these data. Here we introduce PATH (Phylogenetic Analysis of Transcriptional Heritability), an analytical framework, which draws upon classic approaches in species evolution, to quantify heritability and plasticity of somatic phenotypes, including transcriptional states. The PATH framework further allows for the inference of cell state transition dynamics by linking a model of cellular evolutionary dynamics with our measure of heritability versus plasticity. We evaluate the robustness of this approach by testing a range of biological and technical features in simulations of somatic evolution. We then apply PATH to characterize previously published and newly generated single-cell phylogenies, reconstructed from either native or artificial lineage markers, with matching cellular state profiling. PATH recovered developmental relationships in mouse embryogenesis, and revealed how anatomic proximity influences neural relatedness in the developing zebrafish brain. In cancer, PATH dissected the heritability of the epithelial-to-mesenchymal transition in a mouse model of pancreatic cancer, and the heritability versus plasticity of transcriptionally-defined cell states in human glioblastoma. Finally, PATH revealed phenotypic heritability patterns in a phylogeny reconstructed from single-cell whole genome sequencing of a B-cell acute lymphoblastic leukemia patient sample. Altogether, by bringing together perspectives from evolutionary biology and emerging single-cell technologies, PATH formally connects the analysis of cell state diversity and somatic evolution, providing quantification of critical aspects of these processes and replacing qualitative conceptions of "plasticity" with quantitative measures of cell state transitions and heritability.

evolutionary biology↗

bioRxiv2022

A microglia-CD4+ T cell partnership generates protective anti-tumor immunity to glioblastoma

The limited efficacy of immunotherapies against glioblastoma illustrates the urgent need to better understand the interactions between the central nervous system and the immune system. Here, we showed that a protective response to CTLA-4 therapy depended on a mutualistic relationship between microglia and CD4+ T cells. Suppression of gliomas by CD4+ T cells did not require tumor-intrinsic MHC-II expression, but rather was dependent on the selective expression of MHC-II and antigen presentation by local microglia that in turn, sustained CD4+ T cell tumoricidal effector functions. CD4+ T cell secretion of IFN{gamma} made the glioma cells vulnerable to enhanced tumor surveillance and phagocytosis by microglia via the AXL/MER tyrosine kinase receptors that were necessary for tumor suppression. This work illustrates a novel partnership between CD4+ T cells and microglia that unleashes the tumoricidal properties of microglia that can be harnessed to improve immunotherapies for glioblastoma.

immunology↗

bioRxiv2022

Virological characteristics of SARS-CoV-2 BA.2 variant

Soon after the emergence and global spread of a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron lineage, BA.1 (ref1, 2), another Omicron lineage, BA.2, has initiated outcompeting BA.1. Statistical analysis shows that the effective reproduction number of BA.2 is 1.4-fold higher than that of BA.1. Neutralisation experiments show that the vaccine-induced humoral immunity fails to function against BA.2 like BA.1, and notably, the antigenicity of BA.2 is different from BA.1. Cell culture experiments show that BA.2 is more replicative in human nasal epithelial cells and more fusogenic than BA.1. Furthermore, infection experiments using hamsters show that BA.2 is more pathogenic than BA.1. Our multiscale investigations suggest that the risk of BA.2 for global health is potentially higher than that of BA.1.

microbiology↗

bioRxiv2021

The transcriptional hallmarks of intra-tumor heterogeneity across a thousand tumors

Each tumor contains malignant cells that differ in genotype, phenotype, and in their interactions with the tumor micro-environment (TME). This results in distinct integrated cellular states that govern intra-tumor heterogeneity (ITH), a central challenge of cancer therapeutics. Dozens of recent studies have begun to describe ITH by single cell RNA-seq, but each study typically profiledonly a small number of tumors and provided a narrow view of transcriptional ITH. Here, we curate, annotate and integrate the data from 77 different studies to reveal the patterns of ITH across 1,163 tumor samples covering 24 tumor types. Focusing on the malignant cells, we find thousands of transcriptional ITH programs that can be described by 41 consensus meta-programs (MPs), each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many different tumors. The MPs cover diverse cellular processes and differ in their cancer-type distribution. General MPs associated with processes such as cell cycle and stress vary within most tumors, while context-specific MPs reflect the unique biology of particular cancer types, often resembling developmental cell types and suggesting the co-existence of variable differentiation states within tumors. Some of the MPs are further associated with overall tumor proliferation or immune state, highlighting their potential clinical significance. Based on functional similarities among MPs, we propose a set of 11 hallmarks that together account for the majority of observed ITH programs. Given the breadth and scope of the investigated cohort, the MPs and hallmarks described here reflect the first comprehensive pan-cancer description of transcriptional ITH.

cancer biology↗

bioRxiv2021

Elevated METTL9 is associated with peritoneal dissemination in human scirrhous gastric cancers

Methylation, the most common chemical modification of cellular components such as DNA, RNA, and proteins, impacts biological processes including transcription, RNA processing, and protein dynamics. Although abnormal expression of methyltransferase can lead to various diseases including cancers, little is known about the relationship between methyltransferase and cancers. Here we aimed to understand the role of methyltransferase in cancer metastasis. We found that elevated methyltransferase-like 9 (METTL9) is closely associated with the acquisition of metastatic activity in human scirrhous gastric cancers. The stable knockdown of METTL9 via an shRNA vector technique in our original metastatic cells from scirrhous gastric cancer patients significantly inhibited migration and invasion. In metastatic cells, METTL9 protein is predominantly localized in mitochondria, and the METTL9 knockdown significantly reduced mitochondrial Complex I activity. METTL9 can be a promising molecular target to inhibit peritoneal dissemination of scirrhous gastric cancers. This report is the first to describe the relationship between METTL9 and cancer metastasis. HighlightsO_LIElevated METTL9 correlates with metastasis in human scirrhous gastric cancer. C_LIO_LIThis is the first report on the biological relationship between METTL9 and metastasis. C_LIO_LIMETTL9 protein localizes mainly in mitochondria in metastatic scirrhous gastric cancer. C_LIO_LIMETTL9 knockdown reduces mitochondrial Complex I activity to decrease cell migration and invasion in metastatic scirrhous gastric cancer. C_LIO_LIMETTL9 holds promise against peritoneal dissemination of scirrhous gastric cancer. C_LI

cancer biology↗

bioRxiv2021

An autonomous tail-beating cycle period expressed by a region-specific swimming pattern generator in the Ciona larva

Swimming locomotion in aquatic vertebrates, such as fish and tadpoles, is expressed through orchestrated operations of central pattern generators. These parallel neuronal circuits are ubiquitously distributed and mutually coupled along the spinal cord to express undulation patterns accommodated to efferent and afferent inputs. While such sets of schemes have been shown in vertebrates, the evolutionary origin of those mechanisms along the chordate phylogeny remains unclear. Ascidians, representing a sister group of vertebrates, give rise to tadpole larvae that freely swim in seawater. In this study, we tried to locate the swimming pattern generator in larvae of the ascidian Ciona by examining locomotor ability of segmented body fragments. Our experiments demonstrated necessary and sufficient pattern generator activity in a short region ([~]10% of the body length as the longest estimation) including the trunk-tail junction but excluding most of the trunk and tail with major sensory apparatuses therein. Moreover, we found that these "mid-piece" body fragments express periodic tail beating bursts with [~]20-s intervals without any exogenous stimuli. Comparisons among temporal patterns of tail beating bursts expressed by the mid-piece fragments and by whole larvae placed under different sensory conditions suggested that the presence of parts other than the critical mid-piece had effects to shorten swimming burst intervals, especially in the dark, and also to expand the variance in burst durations. We propose that Ciona larvae perform swimming as modified representations of autonomous and periodic pattern generator drives, which operate locally in the region of the trunk-tail junction. Summary statementMid-piece fragments of tadpole larvae of the ascidian Ciona, lacking most of the anterior trunk and posterior tail, autonomously and periodically express tail beating bursts.

zoology↗

bioRxiv2020

Role of an atypical cadherin gene, Cdh23 in prepulse inhibition and its implication in schizophrenia

We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest LOD score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression-QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility.

genetics↗