Biology subjects

Yu, H.

Publications and source records attributed to Yu, H..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Structural basis of multimodal adsorption and infection initiation by Vibrio phage Peru-2

Phage Peru-2, isolated during the 1993 cholera outbreaks in Peru, is distinct from the three ICP phage lineages typically associated with epidemic Vibrio cholerae. The molecular basis of Peru-2 adsorption and infection initiation has remained unknown. Here, we combine single-particle cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) to define the architecture and infection mechanisms of Peru-2 at high resolution. The mature virion comprises an icosahedral capsid decorated with minor capsid proteins and a short tail apparatus surrounded by six structurally flexible tailspikes. These tailspikes are enzymatically active in mediating phage attachment to the Vibrio polysaccharide (VPS), a key component of biofilms. Three internal core proteins form a disordered core adjacent to the portal, positioning them for release before genome ejection during infection initiation. Structural analyses further resolve pre-ejection, genome-ejection, and post-ejection intermediates of the tail apparatus, while cryo-ET imaging of infected cells reveals a multimodal adsorption strategy during infection initiation. SignificanceVibrio phages play important ecological and evolutionary roles, yet the structural basis underlying their host recognition and adsorption strategies has remained poorly understood. Here, we determine the overall architecture of Vibrio phage Peru-2 at near-atomic resolution, showing that it shares a conserved molecular organization with T7-like podophages but possesses additional minor capsid proteins and a distinct tailspike. In addition, Peru-2 interacts extensively with both the bacterial cell surface and sheathed flagella, revealing multiple modes of adsorption strategy distinct from those of classic T7 infection. Our structural analyses and functional evidence that Vibrio polysaccharide is required for Peru-2 adsorption and infection provide a mechanistic framework for understanding host recognition and infection strategies among Vibrio phages.

microbiology↗

bioRxiv2026

STN-DBS frequency-tuned beta subband dynamics are associated with speech tempo in Parkinson's disease

In Parkinsons disease, subthalamic nucleus deep brain stimulation (STN-DBS) frequency modulates narrow beta subbands, with low-frequency stimulation (LFS) selectively attenuating 15-23 Hz power. The negative association between this subband and speech tempo, together with the LFS-related improvement in articulatory rate, suggests that 15-23 Hz subband dynamics may serve as a candidate neural marker associated with speech tempo modulation.

neuroscience↗

bioRxiv2026

Hepatic Acetate is an Essential Fuel for the Heart during Energy-Deprived States

Energy supply is fundamental to cardiac performance, yet the mechanisms by which the heart adapts to nutrient scarcity remain incompletely understood. Here, we identify acetate as a pivotal metabolic substrate that sustains cardiac contractile function during fasting-induced energy deficiency. Fasted mice reveal significant elevation of circulating acetate derived from hepatic fatty acid catabolism. Physiological concentrations of acetate alone can maintain ex vivo beating and electrical stability in Langendorff-perfused hearts. Primary mouse cardiomyocytes preferentially utilize acetate under energy-restricted conditions, which is abolished by knockdown of mitochondrial Acss1, the enzyme responsible for converting acetate to acetyl-CoA. Isotopic tracing with 13C-acetate demonstrated selective cardiac uptake during fasting. In vivo, acetate supplementation preserved heart rate and systolic function in fasted wild-type mice but not in Acss1-deficient hearts. These findings reveal an Acss1-dependent metabolic pathway enabling the heart to harness hepatic acetate as an endogenous fuel, representing a nutrient stress-responsive adaptation based on inter-organ crosstalk and implying therapeutic potential of acetate to energy-deficient heart diseases.

biochemistry↗

bioRxiv2026

A neuroimmune IL-13 axis is associated with human enteric nervous system development

The mechanisms governing maturation of the human enteric nervous system (ENS) during early postnatal life remain poorly defined. Here, we characterize the transcriptomic, cellular, and functional landscape of the neonatal human ileum and identify a neuro-immune axis associated with ENS expansion. Using human tissue transcriptomics, flow cytometry, iPSC-derived enteric neural lineages, and single-cell interactome analyses, we show that the neonatal ileum is enriched for pro-neurogenic transcriptional programs and harbors a greater abundance of enteric neurons and glia than the adult tissue. T cells emerge as a predominant source of interleukin-13 (IL-13) in the neonatal gut, and enteric neurons express its receptor IL13RA1, enabling direct immune-to-neuron signaling. Functional experiments demonstrate that IL-13 enhances expression of key enteric neuronal markers in a concentration-dependent manner. In parallel, single-cell analyses identify enteric neurons as a major predicted source of macrophage migration inhibitory factor (MIF), with signaling directed toward T and NK cell populations, suggesting that the ENS actively shapes the immune environment it depends upon. Together, these findings support a model in which bidirectional neuro-immune communication establishes a pro-neurogenic niche during a critical window of ENS development. This work positions the neonatal immune system as an active contributor to ENS maturation and offers a new perspective on how neuro-immune crosstalk shapes intestinal development in early life.

neuroscience↗

bioRxiv2026

Patient-Calibrated Dynamical Modeling and Embedded Trend-Zone Predictive Control for Closed-Loop Deep Brain Stimulation in Parkinson's Disease

Closed-loop deep brain stimulation (cDBS) for Parkinsons disease requires control strategies that tolerate noisy sensing, patient-specific stimulation responses, medication-related fluctuations, and embedded hardware constraints. We developed a patient-calibrated minute-scale dynamical model of subthalamic beta activity and an embedded explicit trend-zone predictive controller, eTZPC. The model combined a basal-ganglia mechanistic prior with stimulation-amplitude and medication-cycle recordings from five patients, and incorporated individualized stimulation-{beta}STN maps, fast- and slow-timescale stimulation responses, levodopa-related modulation, background drift, and observation noise. eTZPC was designed to maintain {beta}STN activity within a patient-specific target zone under stimulation-amplitude, step-size, and quantization constraints. Compared with dual-threshold (DT) and proportional-integral-derivative (PID) controllers across four disturbance scenarios, eTZPC achieved target-zone regulation close to PID while reducing stimulation-switching burden toward the low-switching profile of DT. Ablation analyses identified distinct contributions of smoothing, trend prediction, patient-specific action modeling, and embedded explicit implementation. Parameter-mismatch tests showed that eTZPC was relatively robust to dynamic and disturbance-parameter deviations, but remained sensitive to errors in the steady-state stimulation-{beta}STN map. Patient-in-the-loop recordings in five patients further confirmed execution consistency and compliance with stimulation-boundary and step-size constraints. These findings support patient-calibrated dynamical modeling combined with low-complexity explicit control as a feasible framework for further embedded cDBS evaluation.

neuroscience↗

bioRxiv2026

In-situ structure of the flagellar export apparatus in Borrelia burgdorferi

The transmembrane export apparatus is a conserved core of bacterial type III secretion systems, shared by the flagellum and injectisome. Powered by the proton-motive force (PMF), this machinery translocates protein substrates across the bacterial envelope to support motility and virulence. However, its assembly and operation within native membranes remain poorly understood. Here, using in-situ single-particle cryo-electron microscopy, we resolve near-atomic-resolution structures of the flagellar export apparatus within the periplasmic flagellar motor of the Lyme disease spirochete Borrelia burgdorferi. Structural and genetic analyses suggest that coordinated, stepwise assembly of the flagellar export apparatus and MS-ring drives local deformation of the cytoplasmic membrane through extensive protein-lipid-protein interactions, constructing a funnel-shaped conduit optimal for substrate translocation. In addition, a conserved hydrophilic pathway lies within core export protein FlhA, with key acidic residues essential for export activity and supporting PMF-driven substrate translocation. Together, these findings establish a mechanistic framework for export apparatus assembly and energy transduction, defining core principles of type III secretion.

microbiology↗

bioRxiv2026

The gut microbiota metabolite Urolithin A mitigates JAK signaling to suppress cytokine-mediated autoimmune diseases

Aberrant activation of type I interferon (IFN-I) is closely related to the development of autoimmune diseases. The metabolic regulation of cytokine signaling is essential for immune homeostasis. In this study, we characterized Urolithin A(UA), a natural gut-derived metabolite, as an inhibitor of Janus kinase (JAK) signaling. UA was found to broadly dampen JAK phosphorylation and the downstream signaling induced by cytokines such as type I interferons (IFN-I), type II interferons (IFN-II), and interleukin-6 (IL-6). UA can directly bind to JAK1 JH1 domain and treatment with UA attenuated autoimmune pathogenesis in Trex1-KO mice, IMQ-induced SLE and psoriasis models. Our findings unveil that UA is an anti-inflammatory metabolite that promotes immune homeostasis and could be used to treat inflammatory and autoimmune diseases.

immunology↗

bioRxiv2026

Migratory bird and marine mammal surveillance fails to find evidence for an HPAI H5N1 2.3.4.4b incursion into Australia in 2025

The panzootic caused by high pathogenicity avian influenza (HPAI) H5N1 clade 2.3.4.4b has been devastating for animals, globally. Despite global spread, the virus remains absent in Oceania. Herein we report the results of our fourth year of enhanced migratory bird surveillance, coinciding with the spring migration of wild birds in 2025; none of the 847 migratory wild birds or 38 marine mammals were positive for HPAI H5N1, although we did detect LPAI. Surveillance remains a critical tool for HPAI H5N1 response, with early detection and rapid response being critical to mitigate the impacts of this virus on animal, environment and human health.

microbiology↗

bioRxiv2026

Foxp4+ Mandibular Skeletal Stem Cells Orchestrate Bone/Tooth Development and Regeneration

The identity of stem/progenitor cells that drive mandible/tooth development and regeneration remains poorly understood. Here, we show that cranial neural crest-derived Foxp4+ mesenchymal cells condense to form Meckels cartilage, and simultaneously promote mandible development and tooth germ formation. In postnatal mandibles, Foxp4+ cells localize in the endosteum, periosteum and dental pulp, which undergo osteogenesis and odontogenesis under steady state, as well as chondrogenesis during fracture repair. Importantly, transplantation of embryonic or adult Foxp4+CD200+CD105- mandibular skeletal stem cells (mdSSCs) generate ectopic bone and tooth. In contrast, genetic ablation of Foxp4+ cells severely impairs mandible/tooth development and delays fracture healing. Mechanistically, we find that primary cilia critically regulate mdSSC maintenance and differentiation into bone and tooth. FOXP4+PDPN+CADM1+ mdSSCs also exist in adult human mandible, which generate ectopic bone and intact tooth upon transplantation into immunodeficient mice. Taken together, we identify Foxp4+ mdSSCs with potential therapeutic applications in regenerating mandibular bone and tooth.

cell biology↗

bioRxiv2026

Biological characterization and host-phage interaction of a novel Pectobacterium phage

Taro (Colocasia esculenta (L.) Schott) is an important vegetable and food crop in China, but in recent years, soft rot disease has frequently occurred during its cultivation and production. This disease damages the underground corms and petiole bases of taro, causing decay in the affected parts and emitting a foul odor, leading to wilting and lodging of the entire plant. This has resulted in significant economic losses to taro production in China, along with food safety issues and ecological problems caused by excessive pesticide use, making it urgent to find a green and efficient control method. Due to its specificity and environmental safety, phage therapy exhibits advantages that chemical pesticides cannot match, representing a promising alternative to chemical pesticides for controlling pathogenic bacteria. In the preliminary work of this study, a bacterial strain was isolated from taro soft rot in Shaoguan, Guangdong, and initially identified as Pectobacterium colocasium ZXC0623. Using this strain as the host bacterium, a Pectobacterium phage was screened and named QJphage. We analyzed its physicochemical properties and obtained its biological characteristics, including optimal titer, optimal infection latency period, optimal infection multiplicity, optimal storage solvent, and resistance to ultraviolet light, pH, and chloroform. Through homologous alignment analysis, eight tail fiber proteins encoded in the QJphage genome were predicted as putative receptor-binding proteins (RBPs). To validate this prediction, the corresponding genes were cloned downstream of the egfp gene via homologous recombination, and the resulting recombinant plasmids were transformed into a prokaryotic host to express EGFP-tagged tail fiber fusion proteins. Fluorescence detection and confocal laser scanning microscopy confirmed that the protein encoded by ORF04 functions as the RBP. Furthermore, lipopolysaccharide (LPS) was knocked out in the host strain P. colocasium ZXC0623. Both{Delta} LPS1 and{Delta} LPS2 mutants formed smaller plaques compared to the wild-type strain, and the{Delta} LPS1 mutant additionally exhibited a significant reduction in plaque number, indicating that LPS serves as a receptor involved in QJphage adsorption. Finally, transcriptomic analysis during the latent period of infection focused on 20 genes predicted to be associated with phage-host receptor binding and anti-phage immune systems. The results revealed that pilin proteins act as potential reversible adsorption receptors for QJphage, while the host strain ZXC0623 also possesses a diverse repertoire of anti-phage defense systems. Collectively, QJphage exhibits stable physicochemical properties, a well-defined LPS-dependent infection mechanism, and a host with diverse defense systems, providing a foundation for the control of taro soft rot and future phage-related research. ImportancePhage therapy has emerged as a highly effective biocontrol strategy against Pectobacterium, with its specificity making it particularly valuable. A critical aspect of this approach is the identification of phage receptors. The initial step in the phage life cycle involves adsorption to the bacterial host, beginning with reversible contact followed by irreversible binding between phage receptor-binding proteins and specific bacterial surface receptors. Potential receptors include glycolipids in the Gram-negative outer membrane, capsular polysaccharides, and various membrane proteins or appendages. In this study, we first characterized the physicochemical properties of the isolated QJphage. Through integrated transcriptomic and whole-genome analyses, we demonstrated that the LPS of Pectobacterium specifically interact with the tail fiber proteins of QJphage. This research provides the first evidence revealing the molecular mechanism of interaction between Pectobacterium and its phage, establishing a foundation for developing phage-based control strategies against soft rot diseases.

microbiology↗

bioRxiv2026

Characterization of the SKC mouse strain as a potential model for keratoconus

BackgroundKeratoconus (KC) is a multifactorial disorder with unclear etiology, characterized by localized thinning and a cone-like protrusion of the cornea. The complex etiology of KC exacerbates the lack of an animal model. Previous studies by Tachibana et al. (2002) described an inbred mouse strain (SKC) with a spontaneous, androgen-dependent, cone-like corneal morphology. This study aimed to investigate the corneal phenotypes of SKC mice through an in-depth ophthalmic examination. MethodsMice (n=53) were examined via slit lamp biomicroscopy with fluorescein staining. Spectral-domain optical coherence tomography (SD-OCT) enabled central corneal thickness (CCT) measurement in selected mice (n=26 eyes), and OCT-based pachymetry mapping (n=16 eyes). In vivo corneal confocal microscopy was conducted on eyes to assess cellular morphology (n= 9 eyes). Eyes were collected for histology analysis (n=22). ResultsLesions and epithelial breaks were present in [~]95% of eyes (n=101). Neovascularization, perforation, scarring, and hydrops were seen primarily in males. An opaque, unilateral cone-like morphology was exclusive to males (n=11). Male and female corneas showed no significant difference in CCT, though pachymetry mapping revealed regional thinning patterns in both sexes. Loosened epithelial tight junctions, stromal fibrosis, vascularization, and inflammation of variable severity were identified in both sexes. ConclusionThis study identified previously unreported corneal phenotypes in SKC mice through ophthalmic examination. Unlike previous studies, gross and histological abnormalities were observed in female SKC mice. Our findings suggest a lower penetrance of the cone-like phenotype ([~]20%) than previously reported ([~]33%) and support that the conical phenotype in male mice may be secondary to keratitis.

pathology↗

bioRxiv2026

High throughput single-cell RNA sequencing of intact adult cardiomyocytes and non-myocytes using a split-pool approach

MOTIVATIONAdult cardiomyocytes are difficult to profile by whole-cell single-cell RNA sequencing because of their large size and fragility, which make them poorly compatible with standard workflows. Current approaches for adult cardiomyocyte transcriptomics often require a trade-off between data quality and throughput, thus, studies instead rely heavily on sequencing of nuclei alone. Therefore, we set out to develop a high-quality and scalable workflow for adult heart cells using in-cell ligation and split-pool barcoding strategies to address this methodological gap. This workflow may be further generalisable to other large cell types or samples containing cell populations with highly unequal RNA content. SUMMARYAdult cardiomyocytes are difficult to profile by whole-cell single-cell RNA sequencing (scRNA-seq). Here, we developed a high-quality and scalable workflow for adult heart cells using in-cell ligation and split-pool barcoding. We identified per-cell RNA content as a significant variable that must be accounted for. Separation of cardiomyocytes (large cells) and non-cardiomyocytes (small cells) before library construction, and allocation of deeper sequencing to cardiomyocytes, produced high-quality whole-cell datasets for both compartments. Compared with single-nucleus RNA sequencing, whole-cell cardiomyocyte profiling better recovered metabolic, mitochondrial, cytoplasmic translational, and contractile gene programs. This workflow provides a practical method for scalable, high-quality cardiomyocyte whole-cell scRNA-seq and offers general strategies for other large cell types or samples containing cell populations with highly unequal RNA content.

cell biology↗

bioRxiv2026

All Models are Wrong, Some are Annotated: Automating Metadata in Biomedical Repositories

ObjectiveHigh-quality metadata is essential for scientific discovery, yet sparse annotations in rapidly growing repositories leave many biologically relevant details uncaptured. We evaluated whether large language models (LLMs) can accurately infer ion channel and receptor subtype metadata from source code in a neuroscience repository. Materials and MethodsWe extracted 5,133 model files from ModelDB. A subset of 1,100 was manually annotated; 253 were held out for testing, and the remainder split into training (80%) and validation (20%) sets. LLM-based approaches (GPT-5.2 and GPT-mini) were evaluated under zero-shot and heuristic-augmented prompting. Performance was assessed at type and subtype levels using accuracy, precision, recall, and F1 score. A feature-engineered XGBoost model using text- and simulation-derived features served as a baseline. ResultsLLMs outperformed the XGBoost baseline. At the type level, GPT-mini with heuristic augmentation achieved the highest performance (accuracy 96.0%, F1 0.962). At the subtype level, both GPT-5.2+heuristics and GPT-mini+heuristics achieved identical accuracy (88.1%), with GPT-5.2+heuristics achieving the highest F1(0.878). Model outputs were consistent across runs and errors confined to related mechanistic families. Discussion and ConclusionLLMs demonstrate strong potential for metadata annotation directly from source code, outperforming feature-engineering approaches with minimal tuning. However, performance varied across subtypes, and errors often reflected ambiguity or bias toward more common labels. These findings suggest LLMs may serve as practical tools for scalable metadata generation in biomedical repositories, although careful evaluation and domain-specific validation remain important. While demonstrated in computational neuroscience, this approach may generalize to repository-agnostic metadata annotation in other scientific code repositories.

neuroscience↗

bioRxiv2026

Pre-stimulus Cortical State Modulates Dimension-Specific Attentional Capture

Suppressing visual distraction depends on observers goals and learning, but also on the brain state in which the next display arrives. We reanalyzed an fMRI visual-search dataset (N = 34) to ask whether pre-stimulus global signal (GS), a broad state-sensitive BOLD measure, predicts performance and attention-network engagement during learned distractor suppression. Participants searched for an orientation target while ignoring salient distractors defined in the same orientation dimension or a different color dimension; across groups, spatial regularities were assigned to same- or different-dimension distractors. Behavioral and fMRI contrasts reproduced the expected functional architecture: same-dimension distractors slowed responses and recruited a frontoparietal capture-related network, whereas different-dimension distractors produced little interference. Learned spatial suppression was clearest for same-dimension distractors, which produced larger costs and stronger visual and frontoparietal responses in the rare than frequent region. Within this architecture, GS predicted performance in opposite directions across learning contexts: higher GS preceded slower responses when same-dimension distractors carried the spatial regularity, but faster responses when different-dimension distractors did. Higher GS also preceded weaker same-dimension distractor-evoked frontoparietal activation, without a reliable group difference in that neural effect. Default-mode-network activity showed the same behavioral pattern as GS, whereas pupil size showed weaker group-level convergence and its RT slopes did not correlate with GS-RT slopes across participants. Learned distractor suppression therefore appears embedded in a broader state-performance mapping, linking pre-stimulus cortical state to how learned priority settings guide the next trial.

neuroscience↗

bioRxiv2026

Structure-guided, physics-aware reconstruction expands scan-limited multiphoton imaging

Multiphoton microscopy is increasingly pushed toward deep, large-scale and fast functional imaging, where acquisition speed has become a bottleneck. Here we present SPARC, a structure-guided, physics-aware reconstruction framework for scan-limited multiphoton imaging. Rather than treating undersampled recovery as generic super-resolution, SPARC formulates it as a constrained reconstruction problem tailored to point-scanning microscopy by incorporating a sample-matched structural reference from the same field of view and the anisotropic acquisition physics of scan-limited imaging. SPARC jointly integrates denoising and deep upsampling, enabling stable recovery from noisy sparse measurements. In simulated calcium imaging with ground truth, SPARC improved spatial reconstruction fidelity and temporal signal recovery relative to existing methods. In vivo, SPARC improved temporal readout in three-photon and mesoscale two-photon calcium imaging, and enabled a more temporally informative 400-Hz voltage readout on a standard resonant-galvo two-photon microscope. These results suggest SPARC expands the functional operating range of existing multiphoton microscopes under scan-limited conditions.

neuroscience↗

bioRxiv2026

Combination of engineered cell type-specific promoters and a high-efficiency AAV capsid restores hearing in adult DFNB1 mice model with demonstrated safety in nonhuman primate

A major challenge in gene therapy for GJB2-related hearing loss (DFNB1)--the most common form of hereditary deafness--is achieving efficient and precise connexin 26 delivery. Herein, we engineered two cell type-specific promoters (GJB2-1 and WFS1-2274) and developed an AAV capsid, AAV-MAS012, with enhanced transduction efficiency in mature cochlear cells. Our AAV-mediated gene therapy systems restored hearing of low-to-mid-frequencies in newborn Gjb2 cKO mice to wild-type levels and maintained for 45 weeks. Additionally, our therapeutic systems restored low-to-mid-frequencies hearing function to wild-type levels in adult Gjb2 cKO mice. A humanized version of the therapy, AAV-MAS012-WFS1-2274-hGJB2, rescued hearing function in two distinct Gjb2-deficient mouse models, and demonstrated a favorable safety profile in nonhuman primates. This study represents the first successful hearing restoration in adult Gjb2-deficient mice. The significant therapeutic efficacy of the humanized gene therapy system shows great potential for clinical translation in DFNB1 patients.

genetics↗

bioRxiv2026

Systemic and tumor intrinsic expansion of FCRL5 expressing B cells associates with poor response to Bacillus Calmette-Guerin immunotherapy in patients with non-muscle invasive bladder cancer

The majority of patients treated with Bacillus Calmette-Guerin (BCG) immunotherapy, for non-muscle invasive bladder cancer (NMIBC), experience early recurrence due to pre-existing mucosal immune dysfunction. Since B cell are mucosal immune sentinels, we characterized the systemic and local B cell responses in 45 patients with NMIBC. Expansion of circulating atypical B cells (ABCs) following repeated BCG instillation, expanded IgG autoantibody repertoire, progressive IgG reactivity against BCG antigens, and higher tumor IgG deposition, were features of patients who recurred early. Integrated spatial immunophenotyping and single cell spatial transcriptomic analysis of corresponding tumors revealed increased ABCs within tertiary lymphoid structures, and co-localization with PD-1 B cells, regulatory T cells, and CD163 macrophages. Independent validation in two patient cohorts (total n = 409), revealed a significant association between high expression of the ABC specific, FCRL5, and poor outcomes. Our study identifies ABCs as key mediators of poor response to BCG in patients with high-risk NMIBC.

cancer biology↗

bioRxiv2026

Complementary constraints in germ and immune cells shape evolution of gene regulation and phenotype

New mutations arise in germ cells and must preserve fertility while altering somatic phenotype to confer a fitness advantage. To understand how whole organisms balance these constraints, we generated mice with humanized noncoding promoter sequence at Traf6, an NF-{kappa}B pathway component with recently diverged chromatin state in mouse germ cells. The humanized allele (Traf6h) reinstated human-like expression in germ and immune cells, which we traced to a 13 base pair deletion that impairs CTCF binding. Traf6h had no effect on fertility but induced a sensitized innate immune response to endotoxin. Other NF-{kappa}B pathway genes followed a similar pattern, suggesting that their expression has evolved in tandem and consistent with known mouse-human differences in inflammatory response. Our results reveal distinct roles for germ and immune cells in shaping gene regulatory evolution, where immune cells quickly adjust phenotype, enabling selection, while germ cells robustly maintain fertility despite changing expression levels, enabling inheritance.

genetics↗