Biology subjects

Harada, N.

Publications and source records attributed to Harada, N..

11 recordsLinked to original sources

bioRxiv2026

Opposing GIPR brainstem circuits differentially control feeding behaviour

Central glucose-dependent insulinotropic polypeptide receptor (GIPR) signalling is required for the efficacy of GIP-based obesity therapeutics, yet how distinct subpopulations of GIPR neurons shape appetite remains undefined. Here we show that GIPR neurons in adjacent brainstem nuclei, the area postrema (AP) and nucleus tractus solitarius (NTS), exert opposing control over ingestion. We find GIPRAP neurons dampen post-ingestive satiation, permitting hyperphagia, whereas GIPRNTS neurons are anorectic. In line with this model, we show Gipr expression in AP, but not NTS, neurons is necessary for appetite suppression following GIPR antagonism. Additionally, we reveal that GIPR neurons in the AP and NTS occupy distinct gut-brain circuits, and are differentially sensitive to obesity-driven circuit remodelling. These data offer a framework for understanding how current GIPR agonist and antagonist strategies elicit weight loss.

neuroscience↗

bioRxiv2026

FXR and BET signaling orchestrate to protect β cells

In both type 1 and type 2 diabetes (T1D and T2D), insulin-producing {beta} cells undergo progressive dysfunction due to inflammation, leading to impaired glucose responsiveness, dedifferentiation, and cell loss. While bile acid (BA) dysregulation under diabetic conditions is known to influence metabolic and inflammatory pathways, its mechanistic role in {beta} cell regulation remains incompletely defined1-3. Here we show that bile acid sensor Farnesoid X receptor (FXR) and Bromodomain and Extra-Terminal motif (BET) signaling cooperatively regulates {beta} cell inflammatory response and {beta} cell identity. We identified the physiological protein-protein interaction between FXR and the bromodomain-containing protein 4 (BRD4) as a regulatory axis that protects against {beta} cell dysfunction. We show that FXR activation by Fexaramine (Fex) together with BRD4 inhibition by JQ1 synergistically suppressed IL-1{beta}-induced inflammation while also improving {beta} cell identity and insulin secretion in both db/db model and high-fat diet (HFD) plus multi low-dose streptozotocin (MLD-STZ) model of diabetes. Importantly, this cooperative effect is abolished in {beta} cell-specific FXR knockout ({beta}FXRKO) mice, establishing that FXR is required for the functional synergy between these pathways in vivo. Mechanistically, structure-guided modeling and mutational analyses identified a direct interaction between FXR and the BD2 domain of BRD4, depending on specific lysine acetylation sites. Additionally, inhibition of the BD2 domain of BET combined with FXR activation markedly improved {beta} cell survival in human T1D and T2D models established from human pluripotent stem cell (hPSC)-derived islet-like organoids (HILOs). Collectively, these findings establish a BA-bromodomain axis as a transcriptional interface linking metabolic signaling and chromatin regulation, and highlight FXR-BET targeting as a promising strategy to counter progressive {beta} cell failure in diabetes.

molecular biology↗

bioRxiv2025

Predator-driven local convergence fosters global microbial community divergence

Understanding the rules that govern microbial community assembly is essential for predicting ecosystem function. While microbial predators are key biotic agents that shape bacterial communities through predation, yet their ecological consequences have been studied mostly in isolated and in vitro systems1-3. In contrast, large-scale studies of microbial diversity have primarily emphasized abiotic factors as drivers of community assembly 4-7, while the role of microbial predators modulating global microbial divergence and convergence patterns remains largely neglected. Here, we show that bacterivorous protists (predators) exert dual, scale-dependent effects on microbial communities: promoting local convergence by suppressing dominant bacterial taxa, while generating global divergence through species-specific predation effects. By integrating global meta-analyses, controlled field experiments, and reconstructions of natural and synthetic communities, we find that predator identity and prey susceptibility jointly determine convergence outcomes. Communities dominated by predator-resistant taxa exhibit reduced convergence under predation pressure, revealing a predictable trait-based filtering mechanism. This framework reconciles previous contradictory findings3,8-11 and highlights predators as selective, context-dependent agents of microbial biogeography. Predator-driven convergence suggests new opportunities for microbiome engineering 12: targeted use of predators may steer microbial communities toward functional configurations that enhance soil health, disease suppression, carbon cycling, and ecosystem resilience 2,13,14.

ecology↗

bioRxiv2025

Intestinal fructose metabolism/GLP-1/β-cell axis counteracts hyperglycemia after short-term fructose ingestion

Fructose ingestion increases circulating GLP-1 and insulin, yet the specific contributions of these hormonal responses to glycaemic control remain incompletely defined. We hypothesised that fructose metabolism in intestinal L-cells triggers GLP-1 secretion, which then potentiates insulin secretion and counteracts fructose-induced hyperglycaemia. To test this hypothesis, we systematically characterised metabolic responses across multiple mouse strains after 24 h ad libitum fructose ingestion. In both lean (NSY.B6-a/a) and obese diabetic (NSY.B6-Ay/a) mice, fructose elevated plasma insulin, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP). The insulin response was preserved in GIP receptor-deficient mice (Gipr-/-) but was abolished in proglucagon-deficient mice (Gcg-/-) by pharmacological GLP-1 receptor antagonism, indicating a requirement for GLP-1, but not GIP. Across strains, fructose-induced insulin response correlated with attenuation of post-fructose glycaemia, consistent with insulin being essential for suppressing fructose-induced hyperglycaemia. To explore the mechanism underlying fructose-induced GLP-1 secretion, we combined ATP-sensitive potassium channel-deficient mice (Kcnj11-/-), GLUTag L-cell line, and metabolic tracing of 13C-labelled fructose in freshly isolated intestinal crypts. These complementary approaches support a model in which fructolysis increases the ATP/ADP ratio in L-cells, closes KATP channels, and stimulates GLP-1 secretion. In obese diabetic mice, increased fructolytic flux and a higher ATP/ADP ratio were associated with elevated GLP-1 levels, further corroborating this model. Collectively, our findings indicate that intestinal fructose metabolism drives GLP-1 secretion required to potentiate insulin secretion, thereby establishing a gut-pancreas axis that counter-regulates fructose-induced hyperglycaemia. KEY POINTS SUMMARYO_LIFructose ingestion acutely increases plasma insulin levels, but the underlying mechanisms and physiological significance remain elusive. C_LIO_LIOur study demonstrates that short-term (24h) fructose ingestion in mice elevates both insulin and glucagon-like peptide 1 (GLP-1) levels in the blood, with the plasma insulin response being GLP-1-dependent. C_LIO_LIWe found that fructose metabolism in intestinal L-cells triggered GLP-1 secretion by increasing the ATP/ADP ratio and closing ATP-sensitive K+ channels (KATP channels). C_LIO_LIThis intestinal fructose metabolism/GLP-1/{beta}-cell axis plays a crucial role in preventing fructose-induced hyperglycaemia, an effect that is compromised in obese diabetic mice. C_LIO_LIThese insights highlight the previously unclear metabolic responses following short-term fructose ingestion and their importance in glucose homeostasis. C_LI 1. ABSTRACT FIGURE LEGENDThis study investigated the hormonal effects of short-term fructose consumption in mice, allowing them ad-lib access to fructose solution for 24 h. Fructose metabolism in intestinal L-cells increases the intracellular ATP/ADP ratio, leading to GLP-1 secretion via KATP channel closure and Ca2+ influx. GLP-1 promotes insulin secretion from pancreatic {beta}-cells. The fructose metabolism/GLP-1/insulin pathway is essential for mitigation of fructose-induced hyperglycaemia. Figures were drawn using BioRender.com.

physiology↗

bioRxiv2025

Enhancing role of nitrogen fixation in biogeochemical cycles of the Pacific Arctic

The Arctic Ocean is warming rapidly, prompting increased attention to the ecosystems response to sea-ice loss and the influx of organisms from lower latitudes. Here we found that nitrogen fixation in the Pacific Arctic region was significantly elevated when sea ice in the Chukchi shelf region retreated earlier. UCYN-A2 was determined to be the dominant diazotroph, with numerical simulation and water mass analyses implying its origin to be in the Bering Sea. UCYN-A2 abundance was positively correlated with temperature, and it extended into the Arctic off-shelf region, which is undergoing oligotrophication as a result of sea-ice loss. In this region, nitrogen fixation contributed significantly to new production (4.6- 100%, average: 34%), underscoring its impact on the biogeochemical cycles. This study highlights the increasing importance of nitrogen fixation in the Pacific Arctic region, driven by warming, sea-ice loss, and borealization.

microbiology↗

bioRxiv2024

Live-cell single-molecule fluorescence microscopy for protruding organelles reveals regulatory mechanisms of MYO7A-driven cargo transport in stereocilia of inner ear hair cells

Stereocilia are unidirectional F-actin-based cylindrical protrusions on the apical surface of inner ear hair cells and function as biological mechanosensors of sound and acceleration. Development of functional stereocilia requires motor activities of unconventional myosins to transport proteins necessary for elongating the F-actin cores and to assemble the mechanoelectrical transduction (MET) channel complex. However, how each myosin localizes in stereocilia using the energy from ATP hydrolysis is only partially understood. In this study, we develop a methodology for live-cell single-molecule fluorescence microscopy of organelles protruding from the apical surface using a dual-view light-sheet microscope, diSPIM. We demonstrate that MYO7A, a component of the MET machinery, traffics as a dimer in stereocilia. Movements of MYO7A are restricted when scaffolded by the plasma membrane and F-actin as mediated by MYO7As interacting partners. Here, we discuss the technical details of our methodology and its future applications including analyses of cargo transportation in various organelles.

cell biology↗

bioRxiv2022

Exome-wide benchmark of difficult-to-sequence regions using short-read next-generation DNA sequencing

Next-generation DNA sequencing (NGS) in short-read mode has been recently used for genetic testing in various clinical settings. NGS data accuracy is crucial in clinical settings, and several reports regarding quality control of NGS data, focusing mostly on establishing NGS sequence read accuracy, have been published thus far. Variant calling is another critical source of NGS errors that remains mostly unexplored despite its established significance. In this study, we used a machine-learning-based method to establish an exome-wide benchmark of difficult-to-sequence regions using 10 genome sequence features on the basis of real-world NGS data accumulated in The Genome Aggregation Database (gnomAD) of the human reference genome sequence (GRCh38/hg38). We used the obtained metrics, designated "UNMET score," along with other lines of structural information of the human genome to identify difficult-to-sequence genomic regions using conventional NGS. Thus, the UNMET score could provide appropriate caveats to address potential sequential errors in protein-coding exons of the human reference genome sequence GRCh38/hg38 in clinical sequencing.

genomics↗

bioRxiv2022

Distribution and survival strategies of diazotrophs in the Arctic Ocean revealed by global-scale metagenomic analysis

Nitrogen fixation is the major source of reactive nitrogen in the ocean and has been considered to occur specifically in low-latitude oligotrophic oceans. Recent studies have shown that nitrogen fixation also occurs in the polar regions and thus is a global process, although the physiological and ecological characteristics of polar diazotrophs are not yet known. Here, we successfully reconstructed genomes, including that of cyanobacterium UCYN-A (Candidatus Atelocyanobacterium thalassa), from metagenome data corresponding to 111 samples isolated from the Arctic Ocean. These diazotrophs were highly abundant in the Arctic Ocean (max., 1.28% of the total microbial community), suggesting that they have important roles in the Arctic ecosystem and biogeochemical cycles. Diazotrophs in the Arctic Ocean were either Arctic-specific or universal species. Arctic-specific diazotrophs, including Arctic UCYN-A, had unique gene sets (e.g., aromatics degradation) and/or a very small cell size (<0.2 {micro}m), suggesting adaptations to Arctic-specific conditions. Universal diazotrophs were generally heterotrophs and commonly had the gene that encodes the cold-inducible RNA chaperone, which presumably makes their survival possible even in deep, cold waters and polar regions. Thus both types of diazotroph have physiological traits adaptable to their environments, which allow nitrogen fixation on a global scale.

ecology↗

bioRxiv2021

Hydrodynamics of gliding penguin flipper suggests the adjustment of sweepback with swimming speeds

Hydrodynamic performance of a gliding penguin flipper (wing) considering the backward sweep was estimated with computational fluid dynamics (CFD) simulation. A flipper of a gentoo penguin (Pygoscelis papua) was 3D scanned, smoothed, and a numerical fluid mesh was generated. For accurate yet resource-saving computation, an embedded large-eddy simulation (ELES) methods was employed, where the flow near the flipper was solved with large-eddy simulation (LES) and flow far away from the flipper was solved with Reynolds-averaged Navier-Stokes (RANS). The relative flow speed was fixed at 2 m s-1, close to the typical foraging speed for the penguin species. The sweep angle was set to be 0{degrees}, 30{degrees}, and 60{degrees}, while the angle of attack was varied between -40{degrees} and 40{degrees}, both are within the realistic ranges in the wing kinematics measurement of penguins in an aquarium. It was revealed that a higher sweep angle reduces the lift slope, but the lift coefficient is unchanged at a high angle of attack. Drag coefficient was reduced across the angles of attack with increasing the sweep angles. The drag polars suggest the sweep angle may be adjusted with the change in swimming speed and anhedral (negative dihedral) angle to minimise drag while maintaining the vertical force balance to counteract the positive buoyancy. This will effectively expand the swimming envelope of the gliding penguin, similar to a flying counterpart such as swift.

zoology↗

bioRxiv2021

Noradrenergic alpha-2A receptor activation suppresses courtship vocalization in male Japanese quail.

Male Japanese quail produce high-frequency crow vocalizations to attract females during the breeding season. The nucleus of intercollicularis (ICo) is the midbrain vocal center in birds and electrical stimulation of the ICo produces calls that include crowing. Noradrenaline plays a significant role in sexual behavior but the contribution of noradrenaline in the control of courtship vocalizations in quail has not been well established. Using dose-dependent intracerebroventricular injection of clonidine, an 2-adrenergic receptor- specific agonist, crowing vocalization was immediately suppressed. At the same time as crow suppression by clonidine there was a reduction of immediate early gene, zenk mRNA, in the ICo; no zenk mRNA expression was detected in the dorsomedial division of the nucleus. Using histochemistry, we determined that the ICo receives noradrenergic innervation and expresses 2A-adrenergic receptor mRNA. Taken together, these data suggest that noradrenaline regulates courtship vocalization in quail, possibly via the alpha2A- adrenergic receptor expressed on ICo neurons.

animal behavior and cognition↗

bioRxiv2019

Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation

Neointimal lesion and medial wall thickness of pulmonary arteries (PAs) are common pathological findings in pulmonary arterial hypertension (PAH). Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling contribute to intimal and medial vascular remodeling in PAH. Nintedanib is a tyrosine kinase inhibitor whose targets include PDGF and FGF receptors. Although the beneficial effects of nintedanib were demonstrated for human idiopathic pulmonary fibrosis, its efficacy for PAH is still unclear. Thus, we hypothesized that nintedanib is a novel treatment for PAH to inhibit the progression of vascular remodeling in PAs. The inhibitory effects of nintedanib were evaluated both in endothelial mesenchymal transition (EndMT)-induced human pulmonary microvascular endothelial cells (HPMVECs) and human pulmonary arterial smooth muscle cells (HPASMCs) stimulated by growth factors. We also tested the effect of chronic nintedanib administration on a PAH rat model induced by Sugen5416 (a VEGF receptor inhibitor) combined with chronic hypoxia. Nintedanib was administered from weeks 3 to 5 after Sugen5416 injection, and pulmonary hemodynamics and PAs pathology were evaluated. Nintedanib attenuated the expression of mesenchymal markers in EndMT-induced HPMVECs and HPASMCs proliferation. Phosphorylation of PDGF and FGF receptors was augmented both in both intimal and medial lesions of PAs. Nintedanib blocked these phosphorylation, improved hemodynamics and reduced vascular remodeling involving neointimal lesions and medial wall thickening in PAs. Additionally, expressions Twist1, transcription factors associated with EndMT, in lung tissue was significantly reduced by nintedanib. These results suggest that nintedanib may be a novel treatment for PAH with anti-vascular remodeling effects.

physiology↗