Biology subjects

Hase, K.

Publications and source records attributed to Hase, K..

17 recordsLinked to original sources

bioRxiv2026

Maternal progesterone signaling establishes lifelong oral homeostasis

Pregnancy is accompanied by profound endocrine remodeling, yet the mechanisms by which maternal hormonal signals establish long-term tissue homeostasis remain largely unknown. Here we identify maternal progesterone signaling as a developmental cue that establishes lifelong oral homeostasis through a hormone-lipid-microbiome axis. We show that the membrane progesterone receptor mPR{delta} is selectively expressed in the developing and maternal submandibular glands, where it mediates non-genomic progesterone signaling to promote epithelial differentiation by driving the selective mobilization of docosahexaenoic acid (DHA). Loss of this pathway disrupts salivary gland maturation, reshapes the oral microbial ecosystem through the selective expansion of Pasteurellaceae, and causes local inflammation as well as systemic metabolic dysfunction. Mechanistically, antibiotic treatment abolishes these phenotypes, whereas transfer of the oral microbiota recapitulates disease, demonstrating that developmental defects in the host are translated into long-term pathology through the oral microbiome. Remarkably, maternal--but not adult--DHA supplementation restores salivary gland development and microbial homeostasis and prevents adult disease phenotypes, identifying a critical developmental window during which oral homeostasis is durably established. Collectively, these findings reveal a previously unrecognized maternal endocrine mechanism that establishes lifelong host-microbiome homeostasis and identify developmental programming as a fundamental principle linking maternal physiology to adult health. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/743932v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@178cc90org.highwire.dtl.DTLVardef@1be04beorg.highwire.dtl.DTLVardef@29759dorg.highwire.dtl.DTLVardef@1e89994_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2026

LRP1 is an entry receptor for the botulinum toxin complex in the gut

Botulinum neurotoxin (BoNT) is an etiologic agent of food poisoning caused by Clostridium botulinum. The large progenitor toxin complex (L-PTC) crosses the intestinal epithelial barrier to deliver BoNT to target neurons; however, it is not clearly understood how BoNT enters the host. Here, we identified low-density lipoprotein receptor-related protein 1 (LRP1) as a major enterocyte transcytosis receptor for the hyper-oral-toxic L-PTC serotype B-Okra (L-PTC/BOkra). We found that hemagglutinin (HA), a neurotoxin-associated protein within the L-PTC/BOkra complex, binds to LRP1 via N-glycans. HA/BOkra co-localized with LRP1 within the internalized vesicles in cultured cells and enterocytes. LRP1 deletion inhibited the apical-to-basal transcytosis of L-PTC/BOkra in an intestinal epithelial cell line, and this effect was rescued by LRP1 re-expression. Finally, intestinal epithelial cell-specific LRP1-deficient mice displayed reduced susceptibility to toxicity caused by oral administration of L-PTC/BOkra. Taken together, these results indicate that N-glycosylated LRP1 mediates L-PTC/BOkra transcytosis via enterocytes, enabling BoNT to traverse the intestinal epithelial barrier.

microbiology↗

bioRxiv2026

Acquisition of Stickland-metabolizing bacteria during infancy prevents Clostridium botulinum infection

Infant botulism is caused by intestinal colonization with Clostridium botulinum, whereas healthy adults are resistant. Although the gut microbiota has long been implicated in protection against C. botulinum, its bacterial basis has remained unknown. Here, we show that specific amino acid-metabolizing bacteria confer resistance to C. botulinum colonization through nutrient competition. Longitudinally collected human infant microbiotas exhibited a transition from susceptibility to resistance after transplantation into germ-free mice. 5-Aminovalerate marked the resistant microbiota, implicating Stickland metabolism. Resistant microbiotas were enriched in Stickland-metabolizing Clostridia, including Clostridioides difficile. Metabolomics revealed overlapping amino acid utilization, and C. difficile suppressed C. botulinum expansion through amino acid competition. These findings demonstrate that acquisition of Stickland-metabolizing Clostridia during infancy prevents C. botulinum infection through competition for shared amino-acid-dependent nutritional niches.

microbiology↗

bioRxiv2026

Selective approach behavior toward context-dependent ultrasonic vocalizations in male mice

Ultrasonic vocalizations (USVs) are widely used in rodent social communication, yet the functional significance of male-male vocal interactions in mice remains unclear. Here, we investigated whether USVs produced during specific social behaviors influence the behavior of conspecifics. Using playback experiments, we compared responses to vocalizations recorded during chasing and being chased in male-male interactions. We found that USVs emitted by chased intruders consistently elicited approach behavior in receiver mice, whereas those emitted by chasing individuals did not. Acoustic analyses revealed that these vocalizations differed in syllable composition, with intruder calls containing a higher proportion of upward frequency-modulated syllables and exhibiting higher mean frequencies. In addition, the temporal organization of syllables appeared to contribute to the behavioral response. Together, these results suggest that male mice respond selectively to certain USV patterns associated with specific social contexts, indicating that acoustic features and temporal structure may jointly influence social approach behavior in mice. HighlightsO_LIBehavioral context (chased vs. chasing) shapes the composition of USV syllable types C_LIO_LIMale mice selectively approach USVs from chased intruders, but not chasing residents C_LIO_LIThe approach response exhibits high temporal synchrony across individual receivers C_LIO_LITemporal organization of syllables modulates approach behavior based on acoustic features C_LI

animal behavior and cognition↗

bioRxiv2026

Macrophage immunosenescence prolongs intraocular inflammation in aged mice via impaired induction of regulatory T cells

Immune-mediated intraocular inflammation, called uveitis, is a leading cause of global blindness, with the highest burden of visual impairment falling on older individuals. Immunosenescence, the functional changes in immune cells with aging, impacts the age-associated immune response, but how immunosenescence and the molecular regulators of the age-associated immune response affect the clinical course of uveitis remains unclear. In the murine model of experimental autoimmune uveitis (EAU), aged mice demonstrated a delayed onset and peak of intraocular inflammation compared to young mice. In contrast to the canonical monophasic inflammation that rapidly resolves in young mice, aged mice developed persistent, chronic inflammation. Transcriptomic and flow-cytometric analyses of immune cells and the receptor-ligand interactome revealed a dominant macrophage-CD4+ T cell signature. This signaling pathway was functionally altered on both ends: macrophages from aged mice had an impaired capacity to generate peripherally induced regulatory T cells (pTreg) through an IL-6 regulated pathway, while CD4+ T cells co-cultured with aged macrophages demonstrated increased proliferation. Our study establishes aging as a key regulator of the effector immune response in uveitis. Regulatory T cells, specifically pTreg, are essential for resolving inflammation in uveitis and an impaired ability to induce pTreg led to a sustained, chronic inflammatory uveitis phenotype in old mice, thereby linking immunosenescence to persistent neuroinflammation. These findings highlight potential therapeutic avenues for vision-threatening uveitis, especially in older patients.

immunology↗

bioRxiv2025

Microbiome-host interactions drive a trade-off between sleep quality and lifespan in Drosophila

Understanding the interactions between various aging processes and the resulting heterogeneity in aging is crucial for promoting healthy aging. Here, we provide evidence that heterogeneity in microbiome and host interactions contributes to diversifying aging phenotypes in sleep, gut integrity, and longevity in Drosophila. Aged flies exhibiting sleep fragmentation preserve gut integrity, accompanied by a shift in microbiota composition, particularly an increase in Acinetobacter junii. A. junii induces sleep fragmentation via its metabolite, urocanic acid, through serotonin receptor-dependent dopamine upregulation. In parallel, A. junii exploits the host response to promote its growth, leading to lifespan extension, which is recapitulated by genetically modified Escherichia coli, suggesting a trade-off between sleep quality and lifespan. Our study demonstrates a systematic mechanism underlying aging heterogeneity, suggesting interventions through bacterial supplements.

animal behavior and cognition↗

bioRxiv2025

The HDAC2-selective inhibitor KTT-1 attenuates autoimmune arthritis by inhibiting osteoclast differentiation in mice

Histone deacetylases (HDACs) are crucial epigenetic regulators of gene expression through the reversible acetylation of lysine residues, and their inhibition is known to exert anti-arthritic effects. Given the critical role of osteoclasts in bone destruction in rheumatoid arthritis (RA) pathogenesis, targeting HDAC2--whose expression is upregulated during osteoclast differentiation--represents a promising therapeutic strategy. Although the development of highly specific HDAC2 inhibitors has recently attracted considerable attention, no such inhibitor has yet been successfully developed. In the current study, we found that the kinetic-selective HDAC2 inhibitor KTT-1 effectively suppressed arthritis symptoms in the collagen-induced arthritis (CIA) mouse model without causing severe side effects. Furthermore, KTT-1 inhibited osteoclast differentiation at an early stage by downregulating c-Fos expression, suggesting that the KTT-1-mediated anti-arthritis effect was achieved by inhibiting osteoclast differentiation. These findings highlight KTT-1 as a promising therapeutic candidate for the development of targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs).

immunology↗

bioRxiv2025

Dietary soy shapes murine microbiota to consolidate the mucosal IgA response through T follicular helper cells

The commensal microbiota plays a crucial role in shaping mucosal immunity, particularly in the induction of T follicular helper (Tfh) cells and IgA production. Here, we demonstrate that dietary soy elicits a robust Tfh cell and IgA response in Peyers patches of weaning mice. Soy feeding promotes the expansion of two principal commensal bacterial species, Limosilactobacillus reuteri and Muribaculum intestinale. Mechanistically, L. reuteri provides cognate antigens for Tfh cell activation, while M. intestinale functions as an adjuvant by promoting IL-1{beta} production from myeloid cells. The resulting IgA exhibits polyreactivity and enhances protection against Salmonella infection. These findings highlight the specific interplay among dietary components, intestinal microbiota, and mucosal immunity, thereby establishing a diet-microbe-immune axis that shapes host defense in early life. This axis represents a promising therapeutic target for developing novel strategies to enhance resistance to enteric pathogens. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=170 HEIGHT=200 SRC="FIGDIR/small/669459v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1ae8277org.highwire.dtl.DTLVardef@1f787ceorg.highwire.dtl.DTLVardef@1f51fd6org.highwire.dtl.DTLVardef@1fd3439_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDietary soy promotes T follicular helper (Tfh) cell and IgA responses in the Peyers patches of weaning mice. C_LIO_LISoy enhances the colonization of two key commensals, Limosilactobacillus reuteri and Muribaculum intestinale, in the small intestine. C_LIO_LIThese two bacteria synergize to drive mucosal immunity: L. reuteri provides cognate antigens, while M. intestinale provides an adjuvant signal by promoting IL-1{beta} production from myeloid cells. C_LIO_LISoy-induced IgA is polyreactive and protects against Salmonella infection. C_LI

immunology↗

bioRxiv2025

Artificial Heterogeneity Drives Environment-Dependent Kin Discrimination in Toad Tadpoles

Genetic admixture could reinstate kin recognition ability in lineages where they appear lost. Many animals have been reported to exhibit kin recognition based on learned "odour cues," potentially linked to the major histocompatibility complex (MHC) genes. However, genetic components vary among lineages and local populations, and admixture may further amplify genetic differences within the group. Here, I compared the kin-biased associations of anuran tadpoles from two local populations: a naturally homogeneous population consisting solely of the Eastern Japanese toad (Bufo japonicus formosus), and an artificially disturbed heterogeneous population containing both Eastern and Western Japanese toads (B. j. japonicus). Genetic analyses revealed higher MHC haplotype diversity in the heterogeneous population. To examine the effects of social experience and aquatic environment on kin discrimination, tadpoles from each population were raised under four rearing conditions (group or solitary, using tap or pond water) and subjected to binary-choice tests. Only the heterogeneous group exhibited phenotype-matching-based kin discrimination, but pond water with higher microbial loads disrupted discrimination, suggesting that microbiota can obscure "odour cues." No kin bias emerged in the homogeneous group. These findings underscore how population structure, social experience, and environmental conditions shape kin recognition.

ecology↗

bioRxiv2025

Anti-amyloid beta therapy resolves stroke recovery impairment caused by Alzheimer's disease

Stroke and dementia are common comorbidities and a growing concern causing disability in aging societies worldwide. Although anti-amyloid beta (anti-A{beta}) antibodies have recently been anticipated to relieve preclinical Alzheimers disease pathology, we discovered that post-stroke administration of anti-A{beta} antibodies restored neural repair for stroke recovery impeded by cerebral A{beta} accumulation. Neuronal recovery-associated gene expression for stroke recovery was considerably impaired even by slight A{beta} accumulation in murine and human brain. Slight A{beta} accumulation had less impact on neurons without stroke but caused a unique myeloid immunity after an ischemic stroke that enhanced the inflammatory cascades impeding neural repair for stroke recovery. Aducanumab administration after ischemic stroke prevented formation of this malignant myeloid immunity, resolving the impairment of post-stroke neural repair caused by cerebral A{beta} accumulation. Thus, our study has revealed the ability of anti-A{beta} therapies to restore functional recovery after a stroke with cerebral A{beta} accumulation.

neuroscience↗

bioRxiv2024

Self-organized acoustic behavior in bats arises from simple rules

Although self-organized behavior has been extensively studied in the movement of group-behaving animals, such as fish or birds, far less attention has been paid to vocal behavior in animal groups, especially in mammals. Here, by testing the vocal response of echolocating bats (Miniopterus fuliginosus) to the playback of jamming stimuli in the lab, we discovered a mathematical model that can well describe vocal frequency control by bats in response to jamming stimuli mimicking echolocation sounds emitted in a group of bats. We then extended the model to a group of flying bats and observed frequency-adjusting behavior by which the frequency differences for the group increased overall, similar to a previous observation on group-flying bats. Further, we showed the frequency-adjusting behavior led to less potential misdetections by echolocation in a group. Our findings suggest this frequency-adjusting behavior is a self-organized vocal behavior that mitigates conflicts within a group, one achieved via simple behavioral rules, as in other types of collective animal behavior.

animal behavior and cognition↗

bioRxiv2024

The lysosomal membrane protein LAMP2B mediates microlipophagy to target obesity-related disorders

Lifestyle diseases, such as obesity, diabetes, and metabolic syndrome, are leading health problems, most of which are related to abnormal lipid metabolism. Lysosomes can degrade lipid droplets (LDs) via microautophagy. Here, we report the molecular mechanism and pathophysiological roles of microlipophagy, regulated by the lysosomal membrane protein LAMP2B. Our study revealed that LAMP2B interacts with phosphatidic acid, facilitating lysosomal-LD interactions and enhancing lipid hydrolysis via microlipophagy depending on endosomal sorting complexes required for transport. Correlative light and electron microscopy demonstrated direct LDs uptake into lysosomes at contact sites. Moreover, LAMP2B overexpression in mice prevents high-fat diet-induced obesity, insulin resistance, and adipose tissue inflammation; liver lipidomics analysis suggested enhanced triacylglycerol hydrolysis. Overall, the findings of this study elucidated the mechanism of microlipophagy, which could be promising for the treatment of obesity and related disorders.

cell biology↗

bioRxiv2024

Identification of M-Sec as a unique cellular regulator of CSF-1 receptor activation

Fms, the CSF-1 receptor encoding tyrosine kinase, is essential for tissue macrophage development, and the therapeutic target for many tumors. However, it is not completely understood how Fms activation is regulated. Here, we identify the cellular protein M-Sec as a unique regulator of Fms. In macrophages, Fms forms large aggregates via unknown mechanisms. We found that the inhibition or knockdown of reduced Fms aggregate formation and functional response of macrophages to CSF-1, which was consistent with reduced Fms activation after CSF-1 stimulation. When expressed in 293 cells, M-Sec augmented Fms aggregate formation and CSF-1-induced Fms activation. CSF-1 and M-Sec bind the cellular phosphatidylinositol 4,5-biphosphate (PIP2). The removal of PIP2-binding motif of Fms or M-Sec, or the depletion of cellular PIP2 reduced Fms aggregate formation. Moreover, M-Sec altered cellular distribution of PIP2. Since CSF-1-induced dimerization of Fms is critical for its activation, our findings suggest that M-Sec augments large Fms aggregate formation via PIP2, which brings Fms monomers close to each other and enables the efficient dimerization and activation of Fms in response to CSF-1.

molecular biology↗

bioRxiv2020

Direct uptake mechanism in lysosome required for neuromuscular homeostasis

The degradation of cellular components plays an essential role in homeostasis. However, the known degradation pathways cannot account for the levels of proteolysis in cells. Here, we demonstrate that cytosolic proteins are imported into lysosomes in an ATP-dependent manner for degradation through a direct uptake mechanism distinct from any known pathway. SIDT2, a lysosomal membrane protein previously reported as an RNA transporter, translocates substrate proteins across the lysosomal membrane. Furthermore, we identify a dominant-negative mutation in SIDT2 that causes neuropathy and distal myopathy with rimmed vacuoles, a protein aggregation disease in humans. We generate Sidt2 knockout mice, recapitulating the characteristic features of this disease. Our results reveal a novel degradation pathway and illustrate its crucial role in cellular proteostasis, physiology, and pathophysiology. One Sentence SummaryDiscovery of a novel proteolytic pathway in cells, the dysfunction of which leads to protein aggregation disease in humans.

cell biology↗

bioRxiv2019

Highly reliable, targeted photothermal cancer therapy combined with thermal dosimetry using indocyanine green lactosome

Indocyanine green (ICG) is a near-infrared light-absorbing substance. Thus, when a tumor in which ICG has accumulated is irradiated with a near-infrared (NIR) laser, only the tumor can be heated by a photothermal reaction. We developed ICG lactosome, a novel drug delivery system (DDS) composed of polymeric micelles and ICG that shows selective accumulation in tumor based on an enhanced permeability and retention (EPR) effect. We showed that ICG lactosome accumulated in a tumor by using an intradermal tumor mouse model of a murine colon cancer cell line (Colon26) transfected with Nano lantern luminescent protein (NLC26). Two days after the administration of ICG lactosome, the tumor was irradiated with an 808-nm diode-laser while monitoring tumor temperature. The results showed that the treated tumors were cured when the peak of tumor temperature during NIR irradiation reached 43{degrees}C or higher. To verify these results, photothermal therapy (PTT) using ICG lactosome was carried out using a newly developed system that can control the temperature at the NIR irradiation site at a constant level. All of the tumors that had been kept at 43{degrees}C during irradiation were cured, while 2 of 5 tumors that had been kept at 42{degrees}C were not cured, and none of tumors that had been kept at a temperature below 41{degrees}C were cured. ICG lactosome-assisted PTT combined with thermal dosimetry is a highly reliable method for cancer treatment and may afford further clinical opportunities for PTT.

bioengineering↗

bioRxiv2019

Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis

The dysbiosis of gut microbiota has been implicated in the pathogenesis of inflammatory bowel diseases (IBDs); however, the underlying mechanisms have not yet been elucidated. Heavily glycosylated mucin not only establishes a first-line barrier against pathogens, but also serves as a niche for microbial growth. We hypothesized that dysbiosis may cause abnormal mucin utilization and microbial metabolic dysfunction. To test this hypothesis, we analyzed short-chain fatty acids (SCFAs) and mucin components in the stool samples of 40 healthy subjects, 49 ulcerative colitis (UC) patients, and 44 Crohns disease (CD) patients from Japan. The levels of n-butyrate were significantly lower in the stools of both the CD and UC patients than in those of the healthy subjects. Correlation analysis identified 7 bacterial species positively correlated with n-butyrate levels, among which the major n-butyrate producer, Faecalibacterium prausnitzii, was particularly underrepresented in CD patients, but not in UC patients. In UC patients, there were inverse correlations between mucin O-glycan levels and the production of SCFAs, such as n-butyrate, suggesting that mucin O-glycans act as an endogenous fermentation substrate for n-butyrate production. Indeed, mucin-fed rodents exhibited enhanced n-butyrate production, leading to the expansion of RORgt+Treg cells and IgA-producing cells in the colonic lamina propria. Importantly, the availability of mucin-associated O-glycans to the microbiota was significantly reduced in n-butyrate-deficient UC patients. Taken together, our findings highlight the biological significance of the symbiosynthesis pathway in the production of n-butyrate, which maintains gut immune homeostasis.

microbiology↗

bioRxiv2018

Genetic distance and social compatibility in the aggregation behavior of Japanese toad tadpoles

From microorganism to vertebrates, living things often exhibit social aggregation. One of anuran larvae, dark-bodied toad tadpoles (genus Bufo) are known to aggregate against predators. When individuals share genes from a common ancestor for whom social aggregation was a functional trait, they are also likely to share common recognition cues regarding association preferences, while greater genetic distances make cohesive aggregation difficult. In this study, we conducted quantitative analyses to examine aggregation behavior among three lineages of toad tadpoles: Bufo japonicus japonicus, B. japonicus formosus, and B. gargarizans miyakonis. To determine whether there is a correlation between cohesiveness and genetic similarity among group members, we conducted an aggregation test using 42 cohorts consisting of combinations drawn from a laboratory-reared set belonging to distinct clutches. As genetic indices, we used mitochondrial DNA (mtDNA) and major histocompatibility complex (MHC) class II alleles. The results clearly indicated that aggregation behavior in toad tadpoles is directly influenced by genetic distances based on mtDNA sequences and not on MHC haplotypes. Cohesiveness among heterogeneous tadpoles is negatively correlated with the geographic dispersal of groups. Our findings suggest that social incompatibility among toad tadpoles reflects phylogenetic relationships.

animal behavior and cognition↗