Biology subjects

Takahashi, S.

Publications and source records attributed to Takahashi, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

In vivo xenogenic reconstitution of human alveolar epithelial architecture and function

An urgent need exists for lung models that accurately replicate human physiological profiles. We developed a chimeric mouse model enabling targeted ablation of alveolar type 2 (AT2) cells and lung macrophages, creating niches for endoscopically transplanted human induced pluripotent stem cell (hiPSC)-derived lung progenitors (hLPs). These engrafted cells were retained for 24 weeks, demonstrating self-renewal and differentiation potential, surfactant protein secretion, and maintaining alveolar phosphate homeostasis, suggesting their maturation into AT2 cells. Furthermore, transplantation of hLPs derived from disease-specific hiPSCs recapitulated the phenotype of pulmonary alveolar microlithiasis. The architecture, function, and metabolism of human alveolar epithelium were accurately replicated in vivo. This model has the potential to link experimental models and first-in-human studies, facilitating the development of novel therapies for intractable lung diseases.

developmental biology↗

bioRxiv2026

A Glycaemia-Prolonging Carbohydrate Gel Reduces Hunger and Cognitive Fatigue During Prolonged Esports Play

AbstractProlonged esports play can induce cognitive fatigue by placing sustained demands on executive control, decision-making, and stress regulation. Since the brain relies primarily on glucose as an immediate energy source, we hypothesized that a carbohydrate gel designed to prolong post-ingestion glycaemia stabilizes interstitial glucose, attenuates hunger and cognitive fatigue, and helps preserve performance during extended esports play. Eleven healthy young men completed a randomized, double-blind crossover study with two sessions in which they ingested one of two carbohydrate gels matched for total energy and total carbohydrate but differing in carbohydrate composition (high-fructose corn syrup [HFCS]-dominant vs maltodextrin [MDX]-dominant) before gameplay. Interstitial glucose was monitored continuously, while hunger, salivary cortisol, pupil diameter, executive function, and in-game performance were assessed repeatedly. Compared with the control (HFCS-dominant) condition, the glycaemia-prolonging formulation maintained higher interstitial glucose levels during the later phase of gameplay, blunted the progressive increase in hunger, and attenuated cortisol responses. These physiological and subjective advantages were accompanied by better executive control and more adaptive defensive behaviors in-game, including fewer fouls and more interceptions. In contrast, pupil diameter, an index of global arousal, remained unchanged across conditions, suggesting that benefits were not driven by altered arousal but by improved glycaemic stability and appetite regulation. These findings indicate that a carbohydrate formulation that prolongs glycaemia can reduce hunger-linked cognitive fatigue and support task-relevant behavior during prolonged esports play. This low-burden nutritional strategy may help sustain mental performance during prolonged digital activities that impose high cognitive demands. Highlights- A glycaemia-prolonging gel maintained higher interstitial glucose late in esports play - Hunger and salivary cortisol increased less with the glycaemia-prolonging formulation - Executive control and defensive performance improved (fewer fouls, more interceptions) - Pupil diameter was unchanged, suggesting benefits were not driven by altered arousal - A low-burden, glycaemia-stabilizing strategy may help sustain cognitive stamina

neuroscience↗

bioRxiv2026

Sparkling Water Co-Consumption Enhances Oxytocin-Linked HR Synchrony and Social Connection in Live Sports Spectatorship

Live sport spectatorship can promote social connection, yet scalable, low-burden strategies to strengthen bonding in real-world spectator settings remain limited. We here tested the hypothesis that co-consuming sparkling water during spectating attenuates hunger and fatigue and strengthens enjoyment and perceived unity, potentially via HR synchrony linked to oxytocin dynamics. In an individually randomized field experiment at a collegiate womens basketball home game (sparkling water: n = 21; plain water: n = 19), spectators consumed 200 mL of sparkling water or plain water in synchrony before tip-off and before the end of halftime, with additional ad libitum intake of the assigned beverage permitted thereafter. We assessed acute freshness and hunger, repeated fatigue and enjoyment, interpersonal HR synchrony from the first half to 15-min post-game, perceived unity toward players and fellow spectators, and salivary oxytocin levels. Relative to plain water, sparkling water increased freshness and reduced hunger after intake, attenuated post-game fatigue, and enhanced enjoyment and perceived unity. HR synchrony was preserved in association with attenuated post-game fatigue after the game, and sustained synchrony was associated with higher perceived unity. Oxytocin decreased more in the sparkling-water group, and this decrease was associated with preserved HR synchrony as well as with changes in unity toward fellow fans. These findings support our hypothesis and suggest that co-consuming sparkling water serves as an alcohol-free, low-burden ritual to enhance social connection during and after live sport events. Highlights- Sparkling water increased freshness and reduced hunger after intake in spectators. - Sparkling water attenuated the post-game increase in subjective fatigue. - Sparkling water increased enjoyment and perceived unity. - Post-game HR synchrony was preserved in association with lower fatigue and higher unity. - Oxytocin decreased more with sparkling water and tracked HR synchrony and fan unity. - Co-consuming sparkling water is a low-burden, alcohol-free ritual for social connection.

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

HDA19-mediated deacetylation of histone H3.3 lysine 27 and 36 regulates plant sensitivity to salt stress

Plants survive extreme environments through rapid chromatin reprogramming, yet the epigenetic marks that confer stress resilience remain poorly understood. Histone deacetylase HDA19 is a key epigenetic regulator in Arabidopsis, and hda19-deficient mutants display tolerance to multiple abiotic stresses, including drought, heat, and salinity. Using lysine acetylome profiling, we identified a non-canonical K27/K36 di-acetylation mark on histone H3.3, among nine H3 variants, as a specific substrate of HDA19. Under salinity stress, this mark decreased in wild-type plants but increased in hda19 mutants, while other known H3 modifications were similarly affected in both genotypes. Mimicking constitutive di-acetylation of H3.3 K27/K36 through lysine-to-glutamine substitutions promoted accumulation of stress-responsive late embryogenesis abundant (LEA) proteins and conferred salinity tolerance in seedlings, phenocopying hda19 mutants. Furthermore, generating the lea7-1/lea29-1/rab18-1 triple mutant abolished hda19-dependent salinity tolerance, confirming the LEA proteins role downstream of HDA19. Our findings demonstrate that H3.3 K27/K36 di-acetylation, modulated by HDA19, drives LEA protein accumulation and enables plants to withstand environmental stress, revealing a previously unknown core mechanism of plant stress resilience. Significance statementHistone acetylation is crucial for regulating chromatin states and transcription, yet the specific histone codes controlled by histone deacetylases and acetyltransferases during plant stress acclimation remain unclear. Arabidopsis mutants lacking histone deacetylase 19 show enhanced tolerance to drought, heat, and salinity. Using acetylome profiling and genetic analyses, we identify a previously unknown di-acetylation of histone H3.3 at lysines 27 and 36 as a key epigenetic switch activating late embryogenesis abundant proteins essential for salt tolerance in seedlings. This discovery reveals a novel mechanism linking histone H3.3 K27/K36 di-acetylation to stress-resilient protein accumulation, offering new insights into epigenetic control of plant stress responses and informing strategies to improve crop resilience under climate change.

plant biology↗

bioRxiv2025

Parallel Evolution of a Drimenol Biosynthetic Gene Cluster Unique to Marine Bacteria

Natural bacterial communities represent a rich resource for the discovery of enzymes and natural compounds including terpenoids. However, the biosynthetic potential of marine bacteria remains poorly explored due to limitations in studying fastidious microorganisms. In a recent study, we discovered unusual haloacid dehalogenase (HAD)-like drimenol synthases (DMSs) of marine bacterial origin, including Aquimarina spongiae AsDMS and Flavivirga eckloniae FeDMS, which produce drimenol in vitro. In the present study, we conducted an in vivo investigation of the biosynthesis of this drimane-type sesquiterpene in marine bacteria. To verify drimenol accumulation in cultures of F. eckloniae, we mined the drimenol biosynthetic genes encoded in the F. eckloniae genome and found a putative AraC family transcriptional regulator in the drimenol gene cluster. Upon the addition of arabinose, we observed drimenol biosynthesis in F. eckloniae, demonstrating the importance of genomics-driven strategies in investigating natural products. Syntenic comparisons of drimenol gene clusters across bacteria revealed the unique evolution of drimenol biosynthesis in marine bacteria. Moreover, the distinct nature of drimenol pathways and relevant enzymes in bacteria compared to those in plants and fungi suggests parallel evolution. Remarkably, we describe two individual proteins from Sorangium cellulosum, HAD and terpene synthase with {beta} domain architecture, similar to HAD-like and terpene synthase {beta} domains of AsDMS, respectively, suggesting the fusion of monodomain proteins during the evolution of bacterial bifunctional DMSs. Our findings shed light on the evolutionary trajectory of the drimenol gene cluster unique to marine bacteria, while also demonstrating the new bacterial mono-{beta}-domain sesquiterpene synthase. ABSTRACT GRAPHIC O_FIG O_LINKSMALLFIG WIDTH=183 HEIGHT=200 SRC="FIGDIR/small/677545v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1883b5borg.highwire.dtl.DTLVardef@f0eab7org.highwire.dtl.DTLVardef@c1bad1org.highwire.dtl.DTLVardef@cff6e8_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2025

Sparkling Water Limits Cognitive Fatigue with Stable Pupil Diameter during Real World Esports Training

Prolonged esports play induces cognitive fatigue with reduced executive function and pupil constriction as a neurobiomarker of prefrontal activity across expertise levels. Since this pupil-linked cognitive fatigue is mitigated by sparkling water intake in casual players, we hypothesized that sparkling water prevents cognitive fatigue and sustains esports performance in esports athletes under real training conditions that reflect competitive practice. To test this hypothesis, nineteen hardcore esports players participated in a randomized crossover trial. Each completed two 3-hour sessions of head-to-head virtual football matches while consuming either sparkling water or plain water. Subjective fatigue, enjoyment, and executive function (flanker task) were assessed, and pupil diameter, heart rate, and salivary cortisol were continuously monitored. In-game performance was also recorded. Accuracy declined and pupil constriction progressed under the plain water condition, whereas executive accuracy was preserved and pupil diameter was maintained over the three-hour session in the sparkling water condition. Subjective ratings of fatigue and enjoyment increased similarly in both conditions. Heart rate, including both mean and peak values, and salivary cortisol concentrations showed no significant differences between conditions. In terms of in-game performance, goals, passes, and interceptions did not differ between conditions, whereas the number of fouls was lower and the number of shots was higher in the sparkling water condition. These findings demonstrate that sparkling water mitigates cognitive fatigue and sustains esports performance in esports athletes under real training conditions. As a caffeine- and sugar-free beverage, sparkling water may serve as a practical, low-risk intervention for managing cognitive fatigue and supporting daily practice in modern esports settings.

neuroscience↗

bioRxiv2025

CXCR6⁺ CD127- Tr1 Cells Balance Immunity and Persistence in Plasmodium falciparum Infection

Plasmodium falciparum (Pf) induces the clonal expansion of antigen-specific type 1 regulatory T (Tr1) cells with a capacity for long-term memory. Tr1 cells comprise nearly 90% of the Pf blood stage antigen-specific CD4+ T cell pool in children. Though, whether Tr1 cells contribute to protection from malaria remains undetermined. To address this critical gap in knowledge, we first performed scRNAseq on gated cell populations to validate CXCR6+ CD127- as new phenotypic markers to enrich for bona-fide Tr1 cells. Importantly, these Tr1 cells potently suppressed the proliferation of other CD4+ T cells in vitro via IL-10 secretion. Among children living in malaria-endemic Uganda, CXCR6+ CD127- Tr1 cells were the dominant responding subset to Pf-infected red blood cell stimulation in vitro. They also rapidly expanded following malaria and expressed IL-10 and IFNg during infection in vivo. Tr1 abundance correlated with plasma concentrations of granzyme A, IFNg, IL-10, and LAG3, suggesting that these cells act systemically. Higher CXCR6+ CD127- Tr1 cell frequencies correlated with a lower probability of symptoms given parasitemia but were also associated with delayed parasite clearance among untreated, asymptomatic children. These data suggest that Tr1 cells help mediate clinical immunity to malaria but may also facilitate parasite persistence through mechanisms of immune regulation.

immunology↗

bioRxiv2025

Live sports spectating promotes oxytocin dynamics and heart rate synchrony in casual fans

Oxytocin has been proposed as a pharmacological target for social dysfunction. However, clinical trials of exogenous oxytocin have yielded modest and inconsistent benefits, highlighting the need for naturalistic, non-pharmacological approaches that recruit endogenous oxytocin. This prospective observational field study examined whether live sports spectating in a modest collegiate setting engages endogenous oxytocin and heart rate synchrony, and how these processes relate to social bonding. Sixty casual spectators at two university basketball games provided salivary samples for oxytocin and cortisol and completed psychological questionnaires before the game, at halftime, and after the game, while heart rate was continuously recorded. Oxytocin dynamics were baseline dependent: individuals with low pre-game oxytocin showed clear increases during spectating, whereas those with high pre-game oxytocin maintained elevated concentrations; across both groups, cortisol decreased and the oxytocin-to-cortisol ratio increased, indicating a shift toward an oxytocin-dominant, low-stress hormonal profile. Live spectating also enhanced heart rate synchrony between spectators, and higher oxytocin levels and stronger synchrony were associated with greater enjoyment, stronger unity with players and fellow fans, higher flow, and stronger intention to revisit. Mediation analyses indicated that perceived unity mediated links between physiological responses and experiential outcomes. These findings identify coordinated oxytocin dynamics and physiological synchrony as candidate mechanisms through which live sports spectating can foster social connection and positive psychological states in everyday, low-stakes settings. Live sports events may represent a simple, scalable non-pharmacological approach to engaging oxytocin-related systems and interpersonal synchrony to promote social connection in everyday life.

neuroscience↗

bioRxiv2025

Clonal Dynamics in the Male Germline from Development to Next Generation

Germ cells secure the continuity and evolutionary potential of species. Yet how reproductive success is allocated among the founder cells of the mammalian male germline, the primordial germ cells (PGCs), remains unknown. Here, we quantitatively traced individual PGCs, non-invasively barcoded in mouse embryos, across their establishment, lifelong maintenance within the testis, spermatogenesis, and transmission to the next generation. We found that highly skewed clonal contributions arise from a very early stochastic bottleneck during migration to the developing testes and remain stable throughout adult reproductive life. Reproductive success during adulthood was proportional to the embryonically established PGC clone size. Mathematical modeling shows that the patchy compartmentalization of PGC clones within the extended thin seminiferous tubules maintain clonal diversity and safeguard against the expansion of clones that gain a selective advantage. These findings uncover fundamental principles governing the development, stability, and evolutionary transmission of the mammalian germline.

developmental biology↗

bioRxiv2025

DECREASE IN DNA METHYLATION 1-mediated epigenetic regulation maintains gene expression balance required for heterosis in Arabidopsis thaliana

Heterosis, or hybrid vigor, is characterized by superior phenotypic performance in F hybrids compared to their parental lines, and its expression is influenced by both genetic and epigenetic factors. In this study, we investigated the role of epigenetic regulation, particularly DNA methylation mediated by DECREASE IN DNA METHYLATION 1 (DDM1), in early seedling biomass heterosis using hybrids between Arabidopsis thaliana accessions Columbia-0 and C24. Loss of DDM1 function in F hybrids resulted in a significant reduction of rosette diameter, confirming that DDM1 is essential for heterosis. Transcriptomic and epigenomic analyses revealed extensive genotype-specific changes in gene expression and DNA methylation patterns in ddm1 mutants. Notably, ddm1-F hybrids exhibited upregulation of genes categorized into xyloglucan:xyloglucosyl transferase activity and downregulation of genes categorized into circadian rhythm, which may contribute to reduced growth vigor. Whole-genome bisulfite sequencing showed widespread hypomethylation in ddm1 mutants, yet the overlap between differentially methylated and expressed genes was limited, suggesting indirect or context-dependent regulatory effects. Additionally, we examined the role of salicylic acid (SA) in heterosis using SA-deficient mutants and found that variations in endogenous SA levels did not correlate with biomass heterosis under normal conditions. Our findings suggest that heterosis in A. thaliana is dependent on the maintenance of parental epigenetic divergence, particularly in DNA methylation patterns mediated by DDM1. Disruption of DDM1 compromises this epigenetic complementarity, leading to transcriptomic imbalances that reduce heterosis. HighlightLoss of DDM1 reduces biomass heterosis in Arabidopsis thaliana hybrids by disrupting DNA methylation and transcriptome stability, revealing a novel salicylic acid-independent epigenetic mechanism.

plant biology↗

bioRxiv2025

Title Mafb Deficiency in Myeloid Cells Increases Susceptibility to Mycobacterium tuberculosis Infection in Mice

v-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) is a candidate gene associated with early tuberculosis onset identified by a genome-wide association study. Here, we investigated the role of Mafb in susceptibility to Mycobacterium tuberculosis (Mtb) infection in myeloid-specific Mafb-knockout (Mafb-cKO) mice. We infected bone marrow-derived macrophages (BMMs) from Mafb-cKO mice and Mafb-cKO mice with Mtb. The absence of Mafb promoted Mtb proliferation in BMMs. RNA sequencing (RNA-seq) revealed activation of the metabolic process and impairment of the response to type interferons (IFNs) in Mtb-infected BMMs from Mafb-cKO mice, which conforms to our previous findings in Mtb-infected human macrophages with MAFB knockdown. Mafb deficiency increased mortality and bacterial burden in the lungs and spleens during Mtb infection in mice. RNA-seq revealed weakened leukocyte or lymphocyte chemotaxis in Mtb-infected Mafb-cKO mouse lungs. Flow cytometry demonstrated an alteration in the proportion of immune cells in Mtb-infected mouse lungs due to Mafb deficiency. Together, Mafb in myeloid cells is involved not only in the functional antibacterial process of macrophages but also in immune cell recruitment in the lungs, thereby contributing to host defense against Mtb infection.

immunology↗

bioRxiv2025

Sparkling Water Consumption Mitigates Cognitive Fatigue during Prolonged Esports Play

Prolonged esports play induces cognitive fatigue, characterized by diminished executive function with pupil constriction. Players often rely on caffeinated or sugary drinks to combat fatigue, but regular use poses health risks. Sparkling water, a sugar- and caffeine-free beverage, stimulates brainstem and prefrontal activity via sensory pathways mediated by transient receptor potential (TRP) channels in the throat. We here tested the hypothesis that sparkling water mitigates cognitive fatigue during prolonged esports play. Fifteen young adult players participated in a randomized crossover trial, each completing two 3-hour sessions of a virtual football game while consuming either sparkling water or plain water. Subjective fatigue, enjoyment, and executive function (via a flanker task) were measured at baseline and hourly, while pupil diameter and heart rate were monitored continuously. Blood glucose and salivary cortisol were also assessed periodically. Compared to plain water, sparkling water significantly attenuated increases in subjective fatigue, enhanced enjoyment, and preserved executive function, along with preventing pupil constriction. Heart rate, blood glucose, and salivary cortisol levels did not differ between conditions. Notably, players committed fewer in-game fouls with sparkling water, while offensive and defensive performance remained unchanged. These findings demonstrate that sparkling water alleviates both subjective and objective signs of cognitive fatigue during prolonged esports play, supporting our hypothesis. This non-caffeinated intervention may help sustain inhibitory control and promote fair behavior, offering a safe and sustainable strategy for managing mental fatigue in modern life. HighlightsO_LISparkling water alleviates cognitive fatigue and boosts enjoyment during esports. C_LIO_LISparkling water prevents pupil constriction linked to cognitive fatigue. C_LIO_LISparkling water keeps players alert without raising blood glucose or cortisol. C_LIO_LISparkling water reduces fouls in virtual football without impairing performance. C_LIO_LISparkling water offers a caffeine- and sugar-free option to manage mental fatigue. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/662064v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1e9058dorg.highwire.dtl.DTLVardef@16b7110org.highwire.dtl.DTLVardef@cbe294org.highwire.dtl.DTLVardef@1886d36_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Dual inhibition of glutaminolysis and autophagy suppresses proliferation of Rheumatoid arthritis fibroblast-like synoviocytes and mitigates arthritis in SKG mice

Recent evidence highlights the critical role of immune metabolism in the pathogenesis of rheumatoid arthritis (RA). We previously demonstrated that glutaminase 1 (GLS1), a key enzyme in glutamine metabolism, is upregulated in fibroblast-like synoviocytes from RA patients (RA-FLS) and that GLS1 inhibition exerts an antiproliferative effect on RA-FLS. Glutaminolysis has also been shown to suppress autophagy, raising the possibilitiy that inhibiting glutaminolysis may enhance autophagy. Given this interplay, we hypothesized that dual inhibition of glutaminolysis and autophagy could synergistically suppress RA-FLS proliferation. This study aimed to investigate the effects of combining autophagy and glutaminolysis inhibition on RA-FLS and arthritis in SKG mice. We utilized chloroquine (CQ) as an autophagy inhibitor and compound 968 (C968), a GLS1 inhibitor, to suppress glutaminolysis. Treatment with C968 upregulated LC3B and ATG5 expression and increased LC3-II protein levels in RA-FLS, indicative of enhanced autophagy. Furthermore, C968 promoted autophagosome formation in RA-FLS. These findings confirm that glutaminolysis inhibition enhances autophagy in RA-FLS. The combination of C968 and CQ significantly inhibited RA-FLS proliferation and increased apoptotic cell death. Moreover, C968-CQ co-treatment markedly alleviated arthritis severity in SKG mice. Our findings suggest that concurrent suppression of glutaminolysis and autophagy represents a promising therapeutic strategy for RA.

immunology↗

bioRxiv2025

Transplantation of GABAergic Interneuron Progenitors Restores Cortical Circuit Function in an Alzheimer's Disease Mouse Model

In addition to dementia, Alzheimers patients suffer from sleep impairments and aberrations in sleep-dependent brain rhythms. Deficits in inhibitory GABAergic interneuron function disrupt one of those rhythms, slow oscillation in particular, and actively contribute to Alzheimers progression. We tested the degree to which transplantation of healthy donor interneuron progenitors would restore slow oscillation rhythm in young APP mice. We harvested medial ganglionic eminence (MGE) progenitors from mouse embryos and transplanted them into host APP mutant cortices. 3D light-sheet and structured illumination microscopy revealed that transplanted MGE progenitors survived and matured into healthy interneurons. In vivo multiphoton calcium imaging and voltage-sensitive dye imaging showed functional integration and slow oscillation rescue in absence or presence of optogenetic stimulation. Our work provides proof-of-concept evidence that stem cell therapy may serve as a viable strategy to rescue functional impairments in cortical circuits of APP mice and potentially those of Alzheimers patients.

neuroscience↗

bioRxiv2025

Muc6-expressing gastric isthmus progenitors contribute to regeneration and metaplasia supported by myeloid-mesenchymal interactions

Gastric mucosal homeostasis is maintained by tissue-resident stem and progenitor cells residing in the isthmus region. Following mucosal injury, surviving cells contribute to regeneration, coinciding with characteristic pathological changes such as atrophic gastritis and metaplasia. To comprehensively understand the cellular dynamics involved in this process, we performed single-cell and spatial transcriptomics using newly generated transgenic mice. In human samples and mouse models, loss of gastric chief cells precedes, and even induces, loss of parietal cells during the progression of atrophy and metaplasia, validating the causal relationship underlying the decrease of these two lineages. Single-cell analysis confirmed robust stemness and metaplastic changes in the Muc6-expressing neck lineage following either chief or parietal cell ablation, and lineage-tracing experiments revealed that Muc6-expressing isthmus progenitors serve as a source of metaplasia and regeneration. Mechanistically, mucosal injury recruits IL-1-expressing myeloid cells, which stimulates NRG1 production in stromal fibroblasts, leading to mucosal proliferation and regeneration mediated by Myc activation in isthmus progenitors. These findings highlight the injury-responsible stem cell-like function of Muc6-expressing isthmal progenitors, which play a critical role in mucosal homeostasis and disease progression. Visual abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/648856v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@10fc2eaorg.highwire.dtl.DTLVardef@1c5b82corg.highwire.dtl.DTLVardef@1be747dorg.highwire.dtl.DTLVardef@d1d722_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Tff2 marks gastric corpus progenitors that give rise to pyloric metaplasia/SPEM following injury

In BriefTu et al. show that Tff2+ corpus isthmus cells are TA progenitors, and they, not chief cells, are the primary source of SPEM following injury. Upon Kras mutation, these progenitors directly progress to dysplasia, bypassing metaplasia, highlighting them as a potential origin of gastric cancer. HighlightsO_LITff2+ corpus cells are TA progenitors that give rise to secretory cells. C_LIO_LITff2+ progenitors, not chief cells, are the primary source of SPEM after injury. C_LIO_LIKras-mutant Tff2+ progenitors progress directly to dysplasia, bypassing metaplasia. C_LIO_LIMulti-omics analysis reveals distinct trajectories for SPEM and gastric cancer. C_LI O_FIG O_LINKSMALLFIG WIDTH=191 HEIGHT=200 SRC="FIGDIR/small/647847v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@48a2d1org.highwire.dtl.DTLVardef@b96642org.highwire.dtl.DTLVardef@1e89a4dorg.highwire.dtl.DTLVardef@1ea6a86_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG Pyloric metaplasia, also known as spasmolytic polypeptide-expressing metaplasia (SPEM), arises in the corpus in response to oxyntic atrophy, but its origin and role in gastric cancer remain poorly understood. Using Tff2-CreERT knockin mice, we identified highly proliferative Tff2+ progenitors in the corpus isthmus that give rise to multiple secretory lineages, including chief cells. While lacking long-term self-renewal ability, Tff2+ corpus progenitors rapidly expand to form short-term SPEM following acute injury or loss of chief cells. Genetic ablation of Tff2+ progenitors abrogated SPEM formation, while genetic ablation of GIF+ chief cells enhanced SPEM formation from Tff2+ progenitors. In response to H. pylori infection, Tff2+ progenitors progressed first to metaplasia and then later to dysplasia. Interestingly, induction of KrasG12D mutations in Tff2+ progenitors facilitated direct progression to dysplasia in part through the acquisition of stem cell-like properties. In contrast, Kras-mutated SPEM and chief cells were not able to progress to dysplasia. Tff2 mRNA was downregulated in isthmus cells during progression to dysplasia. Single-cell RNA sequencing and spatial transcriptomics of human tissues revealed distinct differentiation trajectories for SPEM and gastric cancer. These findings challenge the conventional interpretation of the stepwise progression through metaplasia and instead identify Tff2+ progenitor cells as potential cells of origin for SPEM and possibly for gastric cancer.

cell biology↗

bioRxiv2025

A single dimer of the SARS-CoV-2 N protein can associate with multiple fragments of single-stranded and stem-loop RNAs

The nucleocapsid (N) protein of SARS-CoV-2 associates with the viral genomic RNA (gRNA) and forms the ribonucleoprotein (RNP) granules. However, the detailed molecular structures of RNP and their formation mechanism are largely unknown. We used circular dichroism (CD) spectroscopy, fluorescence correlation spectroscopy (FCS) and single-molecule Forster resonance energy transfer (sm-FRET) spectroscopy to understand the interaction between the N protein and different structural units of RNA. We chose polyadenylate chains with 40, 30 and 20 bases possessing a single-stranded structure and three stem loops with 50, 41 and 29 bases selected from gRNA, and labeled their 5 and 3 ends by Alexa488 and Alexa647, respectively, for the FCS and sm-FRET measurements. We found that the N protein started to bind to the single-stranded RNAs at the concentrations between 10 and 100 nM. The binding of the N protein to one of the stem loops occurred at the concentration less than 10 nM without melting the stem loop. For all the samples, the binding of multiple molecules of the RNA fragments to a single dimer of the N protein was observed. These results demonstrate that the N protein acts as a non-specific binder to both single-stranded and stem-loop structures of RNA, and that the N protein might contract a long RNA chain by bridging its multiple segments. We propose that the RNP granules might be folded by the association of the numerous stem loops of gRNA triggered by the assembly of the N protein.

biophysics↗