Biology subjects

Suzuki, T.

Publications and source records attributed to Suzuki, T..

At least 19 recordsLinked to original sources

bioRxiv2026

Conserved patterns of mammal-microbe codiversification and interspecific bacterial sharing

What determines whether a gut microbial lineage has fidelity to one host species or is shared freely across multiple species? Factors that predict microbial community composition, including host species, diet, and environmental variation, have been well documented in wild animals. However, the eco-evolutionary processes maintaining host species- or population-specific microbial lineages remain unresolved. Here, we analyze 519 gut microbiome samples collected from 15 species of wild rodents across two mountains in the Madrean Sky Islands of southeastern Arizona using full-length 16S rRNA sequencing. This montane system provides a natural experiment in which adjacent replicated elevational gradients bring different combinations of rodent species into sympatry, allowing host evolutionary history to be disentangled from shared environmental effects. We find that host phylogeny, rather than environment, is the primary driver of microbial strain sharing across host species. We recover replicated signatures of codiversification on both mountains, indicating shared evolutionary history between hosts and their microbes, despite ample opportunities for cross-species environmental transmission. This evolutionary coupling is associated with predicted differences in bacterial oxygen tolerance and optimal growth temperature: codiversifying lineages are predominantly obligate anaerobes with optimal growth near host body temperature, suggesting more limited out-of-host persistence than non-codiversifying taxa. This pattern mirrors findings from the human gut microbiome, suggesting conserved constraints on microbial dispersal across mammalian hosts. The cost-effectiveness of long-read amplicon sequencing for phylogenetic inference within bacterial species opens new opportunities for large-scale evolutionary and ecological studies of host-microbe interactions in wildlife.

ecology↗

bioRxiv2026

Quantitative host-response mapping enables phenotypic profiling of viruses detected by virome sequencing

Animal-derived viruses have repeatedly caused human outbreaks, motivating efforts to identify and characterize viruses circulating in animals. Virome sequencing has accelerated animal virus discovery, but phenotypic characterization remains difficult to scale. Although generated for viral detection, virome RNA-seq data also capture host transcriptional responses to infection. Here, we developed ViroChart, a comparative transcriptomic framework that quantifies activities across biological pathways and maps diverse mammalian host responses into a common, interpretable low-dimensional space. ViroChart enables clustering of infected samples by host response pattern and quantitative assessment of host response similarity between samples. In virome data sets from wild and farmed animals, some lung samples infected with poorly characterized betacoronaviruses showed host responses resembling those induced by viruses capable of causing fatal disease. ViroChart also revealed host-response heterogeneity in natural infections: among rats with zoonotic rodent-borne viruses, most showed weak responses, consistent with asymptomatic infection, but some showed pronounced inflammation characteristic of acute infection. ViroChart thus enables phenotypic characterization and prioritization of newly detected viruses by leveraging the same RNA-seq data from which their genomes were detected.

microbiology↗

bioRxiv2026

GM-CSF Programs Alveolar Macrophages to Maintain Pulmonary Lymphocyte Homeostasis

Pulmonary lymphocytosis is a common feature of chronic lung disease, but the mechanisms governing lymphocyte accumulation within the lung remain poorly understood. Here, we identify granulocyte-macrophage colony-stimulating factor (GM-CSF) as a central regulator of pulmonary lymphocyte homeostasis. Using genetic models, single-nucleus and spatial transcriptomics, cell trafficking analyses, and pulmonary macrophage replacement studies, we show that loss of GM-CSF signaling causes profound pulmonary lymphocytosis characterized by lymphoid follicle formation, local immunoglobulin production, and expansion of multiple lymphocyte lineages. Mechanistically, GM-CSF signaling deficiency blocks terminal alveolar macrophage differentiation and reprograms alveolar macrophages into inflammatory states marked by reduced PU.1 and PPAR{gamma} expression, enhanced NF-{kappa}B signaling, and expression of lymphocyte-recruiting chemokines. These changes promote lymphocyte recruitment, local proliferation, and lymphoid lineage commitment. Restoration of GM-CSF-responsive alveolar macrophages re-established macrophage identity, suppressed inflammatory chemokine programs, and reversed pulmonary lymphocytosis. Together, these findings identify alveolar macrophages as gatekeepers of adaptive immune homeostasis in the lung.

immunology↗

bioRxiv2026

Non-linear growth models combined with survival rates identify the optimal rearing temperature and harvest timing in edible crickets, Gryllus bimaculatus and Teleogryllus occipitalis

Crickets are gaining attention as sustainable protein sources because of their high nutritional value and low environmental impact. Growth models are essential tools for optimising production by predicting growth characteristics. However, previous studies have not compared multiple non-linear growth models for crickets or explicitly considered environmental factors. We analysed the growth patterns of the two-spotted cricket (Gryllus bimaculatus) and the Asian cricket (Teleogryllus occipitalis) at multiple temperatures (25.0, 27.5, 30.0, 32.5 and 35.0 {degrees}C) using three non-linear models (Gompertz model, logistic model, and von Bertalanffy model) and combined the predicted body mass with observed survival rates to predict the optimal harvest time and temperature. All three models fitted the data well (R2 [≥] 0.97 in both species). The asymptotic body mass was highest at 30.0 {degrees}C, and the growth rate constant increased with temperature, reaching its maximum at 35.0 {degrees}C except for the logistic model in G. bimaculatus (32.5 {degrees}C). In addition, the predicted value of harvest, calculated by combining predicted body mass and observed survival probability, was highest at 30.0 {degrees}C in both species, reaching 13.82 kg/m3 at 38 days in G. bimaculatus and 7.12 kg/m3 at 62 days in T. occipitalis. These results suggest that 30.0 {degrees}C is the most suitable constant-temperature condition for maximising predicted productivity, although the optimal harvest timing differs between species.

physiology↗

bioRxiv2026

YfiM is a lipid-linked oligosaccharide pyrophosphatase

Lipid-linked oligosaccharides (LLO), such as Lipid II and O-antigen precursors in bacteria, and dolichol-linked oligosaccharides (DLO) in eukaryotes, are universal metabolic intermediates required for cell wall assembly and protein glycosylation across all domains of life. The oligosaccharide moiety of LLO is synthesized through the sequential addition of various monosaccharides, a process catalyzed by a series of glycosyltransferases, to form the final mature structure. However, the existence of a homeostasis and quality control mechanism to degrade surplus and aberrant LLO has long remained a mystery. Although we recently identified the yeast LLP1 as an LLO pyrophosphatase involved in the homeostasis and quality control of DLO in fungi, the corresponding mechanism in bacteria and plants has remained elusive. Here, we identify YfiM and AT1G15900 as LLO pyrophosphatases in Escherichia coli and Arabidopsis thaliana, respectively. Phylogenetic profiling revealed that while YfiM is broadly conserved among Gram-negative bacilli, its plant ortholog displays a unique lineage-specific distribution shaped by selective gene loss. In vitro, purified YfiM and AT1G15900 exhibit LLO pyrophosphatase activity. In vivo, deletion mutant of yfiM caused vancomycin sensitivity in E. coli. Conversely, overexpression of YfiM triggered osmotic lysis under hypotonic conditions. Moreover, overexpression of YfiM in an outer membrane-compromised strain partially rescued detergent-chelator sensitivity, revealing a compensatory envelope stress response. Together, our findings uncover an ancient, conserved cross-kingdom system for LLO quality control bridging prokaryotes and plants.

microbiology↗

bioRxiv2026

Structural and functional insights into multiple BAM-bound conformations of BepA enabling substrate triage at the outer membrane

The outer membrane (OM) of Gram-negative bacteria acts as a selective permeability barrier against toxic compounds, and for this function, requires proper assembly of outer membrane proteins (OMPs) by the {beta}-barrel assembly machinery (BAM) complex. A periplasmic metalloprotease BepA promotes maturation of LptD, an essential OMP, while degrades LptD intermediates aberrantly stalled at BAM. However, how BepA switches between these functions remains unclear. Here, we report cryo-EM structures of BAM- BepA complexes that capture multiple BepA conformations. In vivo crosslinking and cysteine-accessibility analyses show that possible regulatory elements, 6- and 9-loops that cover the proteolytic active site, can assume open conformations in living cells. Functional analyses reveal that 6-loop opening supports substrate interaction, degradation, and membrane association, whereas 9-loop opening is required for proteolytic activation and stabilizes BAM association. These findings provide insights into how distinct loop rearrangements regulate BepA-mediated substrate triage at BAM.

molecular biology↗

bioRxiv2026

West Nile virus capsid protein promotes viral replication and pathogenesis through PKCα-dependent lamin phosphorylation and nuclear deformation

The genus Orthoflavivirus comprises several medically important pathogens such as the West Nile virus (WNV), which causes encephalitis in humans. Although viral replication occurs in the cytoplasm, the capsid (C) protein of the orthoflavivirus is localized to both the cytoplasm and nucleus. Nuclear C protein contributes to viral replication and disease progression. However, the underlying mechanisms remain unclear. Here, we investigated whether the WNV C protein induces nuclear deformation and examined the underlying mechanism. We also assessed the contribution of this deformation to viral replication and pathogenesis. WNV infection and C protein expression induced morphological alterations in the nuclear lamina, leading to nuclear deformation. C protein expression enhanced lamin phosphorylation and the disassembly of the polymerized lamin network. In addition, C protein interacted with protein kinase C alpha (PKC) and localized PKC near the nuclear lamina. Downregulation of PKC expression inhibited C protein-induced lamin phosphorylation and nuclear deformation. In addition, both the downregulation of PKC expression and pharmacological inhibition of PKC reduced WNV replication. In contrast, the expression of phosphorylation-deficient lamin mutants attenuated the inhibitory effect of downregulated PKC expression on WNV replication. Furthermore, the pharmacological inhibition of PKC increased the survival rate of WNV-infected mice and suppressed both viral replication and nuclear deformation in the brain. Collectively, these results demonstrate that C protein remodels the nuclear lamina architecture through the PKC-lamin pathway, and that virus-induced nuclear deformation contributes to WNV replication and pathogenesis. Author summaryThe West Nile virus (WNV), a neurotropic orthoflavivirus, causes severe neurological diseases in humans. In host cells, orthoflaviviruses exclusively replicate in the cytoplasm. However, their capsid (C) proteins are localized to both the nucleus and cytoplasm. Although the nuclear C protein has been implicated in viral replication and disease progression, its underlying mechanisms remain unclear. Here, we demonstrate that the WNV C protein induces nuclear deformation, accompanied by the phosphorylation of lamin and disassembly of the nuclear lamina, a structural scaffold that maintains the nuclear shape. The C protein promotes the localization of PKC, a host kinase protein, near the nuclear lamina. Suppression of PKC expression or activity reduces lamin phosphorylation, nuclear deformation, and WNV replication. Importantly, pharmacological inhibition of PKC in WNV-infected mice reduced nuclear deformation and viral replication in the brain and improved survival rates. Collectively, our findings identify the host nucleus as an important site of WNV-host interaction and provide a new perspective that WNV, despite replicating in the cytoplasm, remodels host nuclear architecture to promote viral replication and pathogenesis.

microbiology↗

bioRxiv2026

Preclinical efficacy and safety of Tegavivint in Wnt-activated hepatocellular carcinoma

Background & AimsHepatocellular carcinoma (HCC), a predominant form of liver cancer, remains a significant clinical unmet need. Given that 30-50% of HCC cases harbour mutations in the Wnt/{beta}-catenin signalling pathway, targeting this cascade represents a promising therapeutic strategy. However, the clinical translation of Wnt inhibitors has been hindered by severe adverse events observed in preclinical models and early-phase clinical trials, primarily due to the essential role of Wnt signalling in maintaining normal tissues such as the intestine and bone. MethodsWe examined the efficacy of Tegavivint, a first-in-class Wnt pathway inhibitor that targets TBL1, against HCC to elucidate its underlying mechanism of action. We evaluated the dose-response of Tegavivint and its effects on the cell cycle, apoptosis, and Wnt target gene expression using HepG2, HUH6, and HUH7 cell lines in vitro. Furthermore, we employed an orthotopic xenograft transplant model using HepG2 cells in immunodeficient mice to assess the safety profile and on-target anti-cancer efficacy of Tegavivint in vivo. ResultsTegavivint exhibited potent Wnt pathway-suppressing effects in cancer cells with constitutive Wnt pathway activation. Notably, Tegavivint displayed robust anti-tumour activity across a broad range of HCC cell lines, regardless of their Wnt pathway activation status. While Tegavivint inhibited the Wnt pathway and triggered the activation of apoptotic pathways in most cell lines, our findings suggest that it also can induce cell death by activating alternative non-apoptotic pathways in apoptosis-resistant cancer cells. In an orthotopic transplant mouse model, Tegavivint significantly downregulated Wnt pathway target genes, inhibited cell proliferation, induced apoptosis and suppressed growth in tumours. ConclusionsTaken together, our data establish a robust foundation for evaluating Tegavivint as a novel therapeutic option, specifically tailored for HCC patients harbouring Wnt-driven hepatic malignancies.

cancer biology↗

bioRxiv2026

Axolotl regeneration reveals a dormant cis-regulatory grammar conserved across vertebrate genomes

Unlike most mammals, which lack the capacity to regenerate complex tissues following injury, other vertebrates such as the axolotl rebuild complete limbs throughout life, yet the regulatory mechanisms underlying this striking difference have remained elusive. Here, we define the core cis-regulatory motif grammar driving axolotl limb regeneration and demonstrate that this grammar is conserved within the syntenic neighborhoods of regeneration-gene orthologs in human and mouse genomes, despite being epigenetically sealed in adult mammalian tissues. Integrating this cross-species grammar projection with AlphaGenome, a multimodal genomic AI capable of predicting epigenomic states from long sequence context, we find that the highest-ranking candidate loci are predicted to occupy a state of bivalent dormancy marked by the co-enrichment of poising and repressive histone modifications alongside suppression of transcriptional activity and chromatin accessibility. Systematic in silico motif perturbation further predicts that this dormant state is actively enforced by specific dormancy-stabilizing sequence elements, and that disrupting these elements shifts candidate loci toward a regeneration-competent chromatin configuration. Our findings support a model in which the regenerative blueprint has not been erased from the mammalian genome but locked within it, opening new avenues for understanding the evolution of regenerative competence and for the rational reactivation of latent regenerative programs.

systems biology↗

bioRxiv2026

Repetitive sequence material shapes the earliest stages of de novo gene evolution in insects

A fundamental unresolved question in molecular evolution is how novel genes arise from noncoding DNA and become fixed within stable gene repertoires. Here, we performed comparative genomic analyses across evolutionary timescales in insects using chromosome-scale genome assemblies of two cricket species, Teleogryllus occipitalis and Tarbinskiellus portentosus. Using conservative criteria, we identified 41 de novo gene candidates derived from intergenic regions in the Te. occipitalis lineage. These genes are simple and compact, exhibit hallmarks of evolutionarily young genes, and frequently contain fragments of transposable elements and simple sequence repeats. Across insects, such repetitive sequence fragments show positional homology but lack sequence conservation in older genes, suggesting that they serve as sequence material for gene emergence during early stages of gene evolution. In contrast, insertions after gene establishment are strongly constrained. We propose a model in which stages of gene evolution are characterized by shifts in selective pressure on the incorporation of sequence material.

evolutionary biology↗

bioRxiv2026

Discovery and structural analysis of glycoside hydrolase family 176 α-1,2 glucosidase from Arthrobacter humicola A8F5

Glycoside hydrolases (GHs) exhibit remarkable specificity dictated by the structural configuration of their target glycosidic linkages. While enzymes that process -1,4- and -1,6-linkages in starch or glycogen are well-characterized, those acting on less common bonds, such as -1,2-glucosidic linkages, remain largely underexplored. In this study, we report the discovery and structural elucidation of a novel -1,2-glucosidase from Arthrobacter humicola A8F5 (A8F5 glucosidase), representing a newly uncovered activity within the poorly characterized GH176 family. Biochemical characterizations revealed that A8F5 glucosidase exclusively cleaves -1,2-linkages via an anomer-inverting mechanism, with a distinct preference for short kojioligosaccharides. To circumvent crystallization obstacles caused by high loop flexibility and translational non-crystallographic symmetry, we engineered a loop-truncated variant. This strategy enabled the determination of high-resolution (up to 1.79 [A]) crystal structures of the enzyme in its ligand-free form and in complex with kojibiose, kojitriose, and selaginose. A8F5 glucosidase adopts a (/)6-barrel fold characteristic of clan GH-G. Complementing the crystal structures with AlphaFold3 prediction demonstrated that two prominent active-site loops (loops 3 and 4) adopt a closed conformation that constricts the catalytic pocket, rendering the architecture suitable for short oligosaccharide recognition while restricting access to larger polymers. Furthermore, sequence similarity network analysis highlights vast, uncharacterized functional diversity within the GH176 family. These findings revealed that the GH176 enzyme recognizes and hydrolyses -1,2-glucosidic bonds through a structural framework distinct from that of the previously known clan GH-L GH65 kojibiose hydrolase, expanding the known functional landscape of this enzyme group toward rare -glucans.

biochemistry↗

bioRxiv2026

CRISPR-mediated Stxbp1 gene activation ameliorates epileptic and aggressive phenotypes in Stxbp1-haploinsufficient mice

Mutations in the syntaxin-binding protein 1 (STXBP1) gene, which encodes the presynaptic protein Munc18-1, cause a spectrum of severe epileptic encephalopathies and neurodevelopmental disorders, including Ohtahara syndrome, for which no curative treatment is currently available. Because the disease pathomechanism is thought to be driven by haploinsufficiency, restoring expression of the wild-type allele to physiological levels could provide therapeutic benefit. Here, we evaluated CRISPR-mediated transcriptional activation (CRISPR-ON), based on a dCas9-VPR transcriptional activator, as a strategy to upregulate endogenous Stxbp1 expression in a Stxbp1-haploinsufficient (Stxbp1+/-) mouse model. Screening of guide RNAs (gRNAs) targeting the Stxbp1 promoter in Neuro2A cells identified a multiplexed four-gRNA cassette that elevated Stxbp1 mRNA approximately six-fold. AAV-PHP.eB vectors co-expressing this 4xgRNA cassette and Cre recombinase under the EF1a promoter were administered intracerebroventricularly to neonatal Stxbp1+/-/dCas9-VPRfl/+ mice. CRISPR-ON treatment restored not only brain Stxbp1 mRNA but also Munc18-1 protein levels to those of wild-type controls. Electrocorticographic recordings revealed an approximately 50% reduction in the frequency of spike-wave discharges in CRISPR-ON-treated Stxbp1+/- mice compared with untreated Stxbp1+/- controls, and aggressive behavior in the resident-intruder test was also partially attenuated. In contrast, locomotor activity remained unaffected, indicating that CRISPR-ON treatment achieves selective rescue of disease-related phenotypes without inducing motor side effects. Together, these findings demonstrate that CRISPR-ON-mediated activation of endogenous Stxbp1 is a promising therapeutic strategy for STXBP1-related encephalopathies and support endogenous gene activation as a broadly applicable platform for haploinsufficiency disorders.

neuroscience↗

bioRxiv2026

Beyond distance-decay: The Mississippi River shapes gut microbiome communities in the Peromyscus maniculatus species complex

Biogeographic barriers are fundamental in shaping the distribution of animals and plants, yet the role of discrete landscape features in constraining microbial dispersal remains poorly understood. Identifying the barriers that partition gut microbial communities is essential for modeling the distribution of hosts and their symbionts across physical space and evolutionary time. The deer mouse (Peromyscus maniculatus species complex), which inhabits nearly all terrestrial environments in North America, provides an ideal model for testing these biogeographic drivers of the mammalian gut microbiome. Using NSF NEON biorepository samples, we characterized the gut microbiomes of 13 populations across the contiguous United States using full-length 16S rRNA long-read sequencing. While we observed a consistent distance-decay relationship across the continent, our results reveal that the Mississippi River acts as a major biogeographic break, significantly increasing microbial dissimilarity beyond the levels predicted by geographic distance alone. This "river effect" suggests that large fluvial systems impose a discrete barrier to microbial transmission, likely due to restricted host dispersal. Furthermore, we identified specific microbial lineages that exhibit differential sensitivity to this barrier, suggesting a gradient in microbial acquisition patterns ranging from the environment to host-host transmission. Together, these findings demonstrate that the gut microbiome may act as a sensitive bio-indicator of landscape-level ecological connectivity, revealing that large-scale landscape barriers disrupt microbial transmission even among closely related host populations that lack reproductive barriers.

microbiology↗

bioRxiv2026

PCP-dependent polarity propagation across neuronal columns in the Drosophila medulla

Planar cell polarity (PCP) signaling establishes coordinated tissue polarity through asymmetric localization of core PCP factors and propagation of polarity information between neighboring cells. While PCP mechanisms are well characterized in continuous epithelial tissues, whether PCP-dependent polarity propagation can operate across discontinuous neuronal structures remains unclear. During pupal development of the Drosophila medulla, R8 photoreceptor axon terminals transiently form horseshoe-shaped structures whose orientation reflects neuronal column polarity. Here, we show that Frizzled (Fz) progressively becomes asymmetrically localized within developing horseshoe structures, whereas Van Gogh (Vang) transiently accumulates in adjacent glial cells during early developmental stages. Conditional disruption of Vang in glial cells impaired asymmetric Fz localization and disrupted horseshoe orientation polarity. Glial Vang localization preceded the emergence of robust Fz asymmetry, suggesting that glial Vang functions during an early polarity establishment phase. Furthermore, mosaic knockdown of fz in R8 neurons altered Fz localization in neighboring R8 terminals, suggesting local propagation of polarity information between adjacent neuronal columns. Together, our results suggest that PCP-dependent polarity propagation operates across discontinuous neuronal columns in the developing medulla and provide a framework for understanding coordinated polarity formation in neural tissues lacking continuous epithelial organization.

developmental biology↗

bioRxiv2026

A single PLAT domain protein couples reproductive arrest and carotenoid pigmentation during diapause in the two-spotted spider mite, Tetranychus urticae Koch

Adult females of the two-spotted spider mite, Tetranychus urticae Koch, enter a photoperiodically induced diapause to overwinter. Diapause in T. urticae is accompanied by reproductive arrest and the orange body coloration that arises from the accumulation of astaxanthin esters. How these two traits are coordinated at the molecular level remains poorly understood. Here, we compared the proteomes of adult females reared under diapause-inducing (long-night) and non-diapause-inducing (short-night) photoperiods using liquid chromatography-tandem mass spectrometry, followed by RNA interference (RNAi) of candidate genes. The carotenoid biosynthesis enzymes phytoene desaturase (TuPDS) and lycopene cyclase/phytoene synthase (TuLCPS), both encoded by genes horizontally transferred from fungi, were more abundant in diapausing females than in non-diapausing females. RNAi of the genes encoding TuPDS and TuLCPS markedly reduced orange pigmentation as well as {beta}-carotene and astaxanthin contents, demonstrating that these enzymes are required for diapause-associated pigmentation. Our proteomic analysis further identified a single PLAT (Polycystin-1, Lipoxygenase, Alpha-toxin) domain protein, TuPLAT10, as one of the most strongly upregulated proteins in diapausing females. The PLAT domain is a lipid-binding module, suggesting a role for TuPLAT10 in lipid metabolism. In addition to the suppression of orange pigmentation, RNAi of the TuPLAT10 gene restored reproduction even under diapause-inducing conditions and selectively reduced TuPDS and TuLCPS protein levels, despite the absence of sequence similarity to their genes. We propose that TuPLAT10 acts as a lipid-allocation switch that, in response to photoperiodic information, partitions fatty acids between astaxanthin esterification and yolk lipid supply, thereby coupling reproductive arrest and carotenoid pigmentation during diapause in T. urticae.

physiology↗

bioRxiv2026

Reduction of Nav1.1 in the dorsal striatum preferentially increases hyperthermia-induced generalized seizures compared with the neocortex and nucleus accumbens

Mutations in SCN1A, which encodes the voltage-gated sodium channel Nav1.1 (I subunit), are the major cause of Dravet syndrome, a severe developmental and epileptic encephalopathy. Although Nav1.1 haploinsufficiency preferentially impairs inhibitory interneuron function, the region-specific contributions of distributed brain circuits to seizure susceptibility, particularly in subcortical structures that have received less attention than the neocortex and hippocampus, remain unclear. Here, we examined the effects of region-specific Nav1.1 deficiency on hyperthermia-induced seizures by selectively deleting Scn1a in the neocortex, nucleus accumbens (NAc), and dorsal striatum (caudate-putamen, CPu) of adult mice using an adeno-associated virus-mediated Cre-loxP approach. Contrary to expectations based on prior cortical studies, homozygous Scn1a deletion in the neocortex produced only modest effects on seizure generalization. In contrast, homozygous deletion in the NAc and CPu induced generalized seizures to varying degrees. Notably, heterozygous Scn1a deletion in the CPu alone was sufficient to trigger generalized seizures, whereas similar manipulations in the neocortex or NAc were not. Seizure threshold temperatures were largely comparable across regions. These findings identify the dorsal striatum as particularly vulnerable to partial Nav1.1 loss and reveal functional heterogeneity within striatal circuits. Our results underscore a previously underappreciated role of striatal inhibitory networks in hyperthermia-induced seizure susceptibility and provide new insights into the circuit mechanisms underlying Dravet syndrome.

neuroscience↗

bioRxiv2026

Dietary and gut microbial variation among urban and rural populations of house mice (Mus musculus domesticus)

Urbanization can result in shifts in abiotic and biotic factors, including temperature, pollution, habitat type, pathogens, and diet, among others. These shifts can, in turn, shape the ecological and evolutionary trajectory of urban wildlife. The gut microbiota has the potential to mediate host-environment interactions, especially in the context of diet and disease, and thus may be a useful lens for understanding the impacts of urbanization. House mice (Mus musculus domesticus) are a cosmopolitan human commensal with a wealth of genomic and metagenomic resources. Here, we investigate patterns of variation in diet and gut microbial diversity, community composition, and function using a paired urban-rural sampling design in house mice from three metro regions in the eastern United States. First, using stable isotope analysis, we found that habitat--urban versus rural--was a major driver of variation in {delta}15N, suggesting a diet richer in animal proteins in cities. Next, using short-read sequencing of the 16S rRNA gene, we found that urban mice have lower gut microbial taxonomic diversity than their rural counterparts. We also found that community composition varied among urban and rural habitats, with differences largely reflecting shifts among closely related taxa. In particular, Prevotellaceae, a family known to be responsive to dietary quality, was differentially abundant, with lower abundance in urban habitats. Finally, we found differentiation in a few predicted microbial functions across habitat, primarily related to metabolism. Together, data across three independent sampling regions provide strong evidence that urbanization has the potential to shape the diet and the microbiome of house mice.

microbiology↗

bioRxiv2026

Cardiac-Detargeted MyoAAV Enables Systemic Nrl-Mediated Fast Myofiber Remodeling and Hypertrophy Across Multiple Skeletal Muscles

Inducing fast myofiber programs offers therapeutic potential for skeletal muscle disorders such as sarcopenia, where fast myofibers are preferentially lost. Engineered muscle-specific AAV (MyoAAV) vectors enable efficient transduction of skeletal muscles after systemic administration; however, cardiac transgene expression limits applications requiring skeletal muscle-selective delivery. We generated modified MyoAAV vectors by incorporating cardiac-specific miR-208a target sequences into the transgene 3'UTR. This design markedly suppressed cardiac expression while preserving skeletal muscle output, with target-site variation enabling tunable trade-offs between cardiac detargeting and skeletal muscle expression levels. We validated this platform using neural retina leucine zipper (Nrl), a large Maf transcription factor regulating type IIb myofiber identity. Systemic delivery of conventional MyoAAV-Nrl caused severe cardiac hypertrophy and uniform lethality within one month. Conversely, incorporating miR-208a target sequences prevented detectable hypertrophy and eliminated mortality during the experimental observation period. This modification significantly reduced cardiac Nrl expression while maintaining skeletal muscle levels, successfully promoting type IIb myofiber formation and hypertrophy across multiple skeletal muscles. These findings demonstrate that miR-208a-mediated cardiac detargeting combined with MyoAAV-Nrl enables safe systemic induction of fast myofiber remodeling and hypertrophy, establishing a platform for gene therapies targeting skeletal muscle disorders associated with fast myofiber loss.

cell biology↗