Biology subjects

Wu, Y.

Publications and source records attributed to Wu, Y..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Multi-parametric NIR-II fluorescence perfusion imaging towards quantitative stroke evaluation

Preclinical stroke research is severely hampered by the lack of high-throughput, quantitative perfusion imaging tools capable of bridging the gap between functional hemodynamics and structural injury. The emerging second near-infrared (NIR-II) fluorescence imaging offers superior spatial resolution and tissue penetration, but its utility remains restricted by a lack of standardized analysis protocols and inability to resolve in-depth infarct regions. Here, we introduce FIMPA, an integrated analytical framework for standardized, multi-parametric stroke evaluation based on NIR-II fluorescence perfusion imaging. FIMPA systematically processes the image sequence through motion correction and atlas registration to generate an anatomically aligned library of 125 vascular and hemodynamic parameters. Statistical screening identifies 67 stroke-correlated features, enabling objective, data-driven quantification of perfusion deficits. To resolve spatial infarct boundaries, we developed FIMPA-SI (FIMPA Stroke Index), a deep learning-based index utilizing a ViT-UNETR framework. By leveraging self-supervised pre-training with MRI data, FIMPA-SI suppresses dominant vascular signals to translate multi-parametric dynamics into anatomically precise stroke severity maps. Validated in tMCAO mice, FIMPA-SI achieves high spatial concordance with MRI and significantly outperforms conventional laser speckle contrast imaging and single-parameter metrics. FIMPA provides a robust solution for accelerating preclinical therapeutics and advancing optical neuroimaging.

bioengineering↗

bioRxiv2026

Near-infrared optoacoustic modulation of the blood-brain barrier permeability using size-tuned hyperbranched gold nanoconstructs

The blood-brain barrier (BBB) constitutes a major bottleneck for the systemic delivery of most therapeutic agents to the central nervous system. Here, we report near-infrared reversible optoacoustic modulation of the BBB permeability (NIR-ROAMBBB), leveraging endothelial tight junction targeting hyperbranched gold nanoconstructs (HBGNCs) to amplify localized optoacoustic transduction under femtosecond laser excitation. We first synthesized HBGNCs with tunable particle sizes (62-150 nm) and consistent branch morphologies via a seed-mediated growth approach, and uncovered a non-monotonic relationship between particle dimension and optoacoustic output, where the 62 nm HBGNCs generated nearly twofold stronger optoacoustic signal than gold nanorods and gold nanostars under matched excitations. Conjugation with BV11 antibodies against junctional adhesion molecule A increased HBGNC endothelial association and cerebral accumulation, enabling focal and fluence-dependent transient BBB opening (3-6 h) under 800 nm femtosecond pulsed laser excitation, as validated by in vitro trans-endothelial electrical resistance measurements, ex vivo Evans blue extravasation staining, and in vivo NIR imaging. Featuring deep tissue penetration of NIR light, robust optoacoustic conversion of HBGNCs, and negligible femtosecond laser-induced photothermal damage, this non-invasive strategy enables precise focal modulation of BBB permeability and potential drug delivery.

bioengineering↗

bioRxiv2026

Trans-Allosteric Activation Releases Distinct Conformational Traps in Kinase Heterodimers

Protein kinases function as dynamic, mechanically coupled nodes, yet the conformational drivers of multimeric activation remain unclear. Here, we present AlloQuant, a computational suite that translates AlphaFold3 structural ensembles into quantitative metrics of kinase regulation, including internal network rigidity, metastable-state populations, and sub-angstrom conformational drivers. Applying AlloQuant to CDK1, we demonstrate that binding of the Cyclin B1 (CCNB1) cofactor mechanically decouples a hyper-rigid inactive kinase core, allowing activating phosphorylation (pT161) to subsequently re-impose localized tension on the catalytic machinery. Conversely, the C-terminal Src kinase (CSK) faces a distinct conformational trap. While nucleotide-free monomeric CSK spontaneously samples a pre-active geometry, ATP binding excludes the active C-In conformation in all but 1 of 225 models. We show that docking partner engagement overcomes this blockade. Autophosphorylation of SRC at the activation loop (Y419) redistributes SRC conformational states without altering bulk rigidity. This redistribution is structurally coupled to the conformational state of CSK via the regulatory spine, not the catalytic machinery. Rather than mechanically deforming CSK, SRC engagement acts by conformational selection, committing roughly a quarter of CSK molecules to a fully active state. Thus, trans-allosteric kinase activation operates by defining the accessible conformational landscape of the receiver kinase. That control is exerted through mechanical remodeling in cofactor-dependent complexes and through conformational selection in transient kinase-kinase heterodimers. These findings establish AlloQuant as a general framework for quantifying how a binding partner reshapes a kinase's conformational landscape, applicable across the kinome because it assigns landmarks by profile-HMM alignment.

biophysics↗

bioRxiv2026

Hypothalamic Cell Type Evolution across Vertebrates

The hypothalamus regulates vital functions and is highly conserved among vertebrates occupying diverse niches, but little is known about the evolution of its cell types. Using comparative single-cell transcriptomics across major vertebrate classes, we identified deeply conserved and clade-specific cell types. While homologous cell types express conserved transcription factors and neuropeptides, their regulatory linkages are often rewired across evolution. The paraventricular nucleus largely retains its neuropeptide expression and responds to dehydration with fine cellular resolution from amphibians to mammals, whereas lamina terminalis neurons are specific to terrestrial vertebrates and exhibit gene expression divergence in cell types activated by dehydration and heat. We propose that a conserved set of keystone cell types sustain essential functions across vertebrates, while flexible gene regulatory programs alongside numerous clade-specific cell types offer evolutionary fluidity.

evolutionary biology↗

bioRxiv2026

Paralemmin 2 is a shared, alternatively-spliced regulator of axon initial segments and paranodal junctions in oligodendrocytes

Nervous system function depends on highly specialized axonal membrane domains. For example, axon initial segments (AIS), nodes of Ranvier, and paranodal junctions are essential for action potential initia-tion and saltatory conduction. These domains use shared molecular machinery converging on the master scaffolding protein AnkyrinG (AnkG). Using endogenous AnkG-TurboID proximity proteomics, we identify Paralemmin 2 (Palm2), a previously uncharacterized CNS protein, as a shared component of the AIS and nodes of Ranvier in neurons, and paranodes in oligodendrocytes. Palm2 localizes transiently to the AIS and nodes during development, but is found at paranodes throughout life, reflecting cell type-specific splicing of a lipid-modified domain both necessary and sufficient for AnkG interaction. Mice lacking oli-godendroglial Palm2 assemble normal paranodes during development, but aged mice lose paranode in-tegrity due to loss of paranodal AnkG and Neurofascin-155. Our findings identify Palm2 as a lipid raft-associated regulator of axonal and oligodendroglial membrane domains and reveal cell type-specific pro-tein variants as a recurring principle for specializing axonal and glial membrane architectures.

neuroscience↗

bioRxiv2026

Shared phylogeographic structuring and recurrent hybridization underlie the diversification of Microhyla frog complexes in the Indochinese biodiversity hotspot

Comparative phylogeography provides a powerful framework to identify the historical processes shaping biodiversity hotspots by testing whether co-distributed species exhibit shared patterns of diversification. Southeast Asia harbors exceptional biodiversity, yet the extent to which common paleogeographic and climatic drivers have structured diversification across taxa remains poorly understood. Here, we investigated the evolutionary history of five widespread Microhyla species complexes distributed across the Indochinese Peninsula and adjacent regions using dense mitochondrial sampling (1,388 individuals) combined with genome-scale ddRAD sequencing (280 individuals). Across all complexes, both approaches recovered multiple lineages and remarkably congruent phylogeographic breaks and contact/intergradation zones associated with major Indochinese regions, including Myanmar, the Tenasserim-Malay Peninsula, southern Vietnam, and northern Vietnam-southern China, supporting the hypothesis that Indochina functions as a mosaic of stable biogeographic units. However, lineage divergence varied substantially among complexes, suggesting that common biogeographic drivers interacted with species-specific demographic histories. Phylogenomic analyses and cyto-nuclear discordance further revealed historical introgression in every complex, indicating that diversification involved both long-term allopatric isolation and reticulate evolution. These findings portray the Indochinese biodiversity hotspot as a dynamic evolutionary system where cycles of fragmentation and reconnection have repeatedly reshaped lineage boundaries. Moreover, the complex phylogeographic structure recovered exemplifies the urgent need for taxonomic revisions, for which genome-scale data provide an essential framework to validate mitochondrial hypotheses and assess admixture patterns for species delimitation. Finally, regions such as the southern Annamites and Tenasserim Hills emerged as recurrent hotspots of genetic diversity across independent lineages, highlighting their importance for conserving not only species/lineage richness but also the evolutionary processes and adaptive potential that sustain biodiversity.

zoology↗

bioRxiv2026

Spatial cholesterol homeostasis gatekeeps T-cell development and activation by orchestrating signaling and fitness

Cholesterol is essential for T-cell immunity, and its spatial distribution is tightly regulated. Although cholesterol is synthesized in the endoplasmic reticulum (ER), it is predominantly transported to the plasma membrane (PM); however, the machinery mediating this anterograde transport in T cells remains unknown. Here, through a functional genetic screen, we identify oxysterol-binding protein (OSBP) as the principal mediator of ER-to-PM cholesterol transport in T cells. OSBP deficiency depletes accessible PM cholesterol while causing cholesterol accumulation in the ER, resulting in impaired T-cell receptor (TCR) signaling and disruption of ER homeostasis. Using stage-specific conditional knockout mice, we demonstrate that OSBP is required at multiple developmental checkpoints in the thymus, including {beta}-selection, positive selection, and post-selection maturation. Loss of OSBP during early thymocyte development causes a near-complete block in T-cell development, resulting in a profound absence of mature peripheral T cells. In mature T cells, activation markedly increases dependence on OSBP-mediated cholesterol transport, with its inhibition causing ER perturbation and extensive cell death. Finally, we show that disease-associated oxysterols disrupt OSBP-mediated cholesterol transport, leading to T-cell dysfunction and providing a mechanistic explanation for impaired T-cell immunity in pathological settings. Together, our findings identify OSBP as a central regulator of intracellular cholesterol transport that couples membrane cholesterol homeostasis to TCR signaling and ER integrity. These results establish the spatial distribution of cholesterol, rather than its abundance alone, as a fundamental metabolic determinant of thymocyte development and peripheral T-cell function.

immunology↗

bioRxiv2026

A neurofunctional signature of romantic love predicts rewards on social media, effects of oxytocin and drug-cue reactivity

Romantic love is a selective motivational state supporting pair bonding, yet its neural representation and relation to other affiliative-rewarding experiences remain unclear. Across eight fMRI studies (n=420) spanning naturalistic affiliative-reward, pharmacological and addiction-relevant experiments, we developed and evaluated multivariate whole-brain decoders of romantic love and friendship. Both signatures engaged mesocorticolimbic reward systems and the precuneus, yet were dissociable at the whole-brain level and in their recruitment of social-cognitive systems. The love signature generalized to reward on social media, was specific to positive valence, and did not track sweet-taste or monetary reward, indicating a distinct social-affiliative reward representation. Oxytocin selectively increased love - but not friendship - signature reactivity to the romantic partner. In an independent drug-cue-reactivity dataset, the love signature specifically identified heavy cannabis users. These findings establish a dissociable neurofunctional signature of romantic love in conserved bonding circuits that extend to digital affiliation and are co-opted in addiction.

neuroscience↗

bioRxiv2026

Contextual Evaluation of MicroRNA Sequencing Data Harmonization: Performance in Sample Clustering

Reliable translation of microRNA sequencing data depends on effective harmonization to mitigate artifacts from variable experimental handling. Although many harmonization methods exist, prior evaluations have focused mainly on differential expression analysis, leaving the impact on subgroup discovery understudied. We present a framework for evaluating harmonization in the context of sample clustering, which integrates AI-augmented datasets, statistical evaluation pipelines, and accessible software tools, enabling systematic comparisons across diverse signal-to-artifact ratios and cluster composition settings. Using this framework, we show that harmonization can, often partially, restore clustering accuracy lost to artifacts, especially at moderate signal-to-artifact ratios, with the level of gains depending on the specific harmonization method, the paired clustering technique, and the cluster composition setting. We further confirm these findings by analyzing reconstructed cohorts from The Cancer Genome Atlas breast cancer microRNA sequencing data. Collectively, the results underscore the need for tailored harmonization to support reliable subgroup discovery and highlight the broader importance of context-specific workflows in translational genomics.

bioinformatics↗

bioRxiv2026

GWAS and multi-omics uncover the SLC6A3 locus for canine stranger-directed social anxiety and implicate NRIP3 in dopaminergic network regulation

The social anxiety disorder (SAD) is one of the most common mental health disorders, often developing in adolescence. It can severely impair educational achievement, career progression, and social functioning. Certain individuals within the Chinese Kunming dog (CKD) population display spontaneous, SAD-like behaviors towards strangers, offering a valuable model for genetic investigation. Using whole-genome sequencing data, we conducted a genome-wide association study on this SAD-like behavior in 100 CKDs, identifying several genes previously linked to human psychiatric disorders. Notably, SLC6A3 reached genome-wide significance, whereas CADPS2 exceeded only the suggestive threshold and is therefore considered a network-supported candidate locus. By integrating weighted gene co-expression network analysis with public RNA-seq data from the VTA of 38 mice (after quality control), we further showed that Slc6a3 and Cadps2 are part of a co-expression network module associated with the dopamine system. These findings suggest that this specific module may play a functional role in the stranger-directed anxiety-related behaviours in CKDs. Furthermore, we identified Nrip3 as a key candidate transcriptional coregulator in this specific module. Subsequent virus-mediated overexpression and behavioural experiments showed that Nrip3 regulates gene expression within this network and induces a spectrum of behavioural alterations in mice, including social avoidance, anhedonia, and increased locomotor activity. Collectively, this study highlights the involvement of dopamine system genes in canine social anxiety and suggests Nrip3 as an upstream regulator of Slc6a3 associated with anxiety. The identification of conserved anxiety-related signatures between humans and dogs further supports the dog as a valuable translational model for psychiatric research.

genetics↗

bioRxiv2026

PlantAI: A Multi-Agent System for Plant Functional Genomics Analysis and Biological Knowledge Interpretation

Plant functional genomics requires the integration of sequence, expression, evolutionary, regulatory and literature evidence. However, the corresponding analyses are often distributed across disparate programs, scripts and databases, creating substantial barriers to task organization and result interpretation. Here, we present PlantAI, a multi-agent system that integrates bioinformatics analysis, project-level process tracking and knowledge-assisted interpretation. A Main Agent coordinates two complementary routes: an analysis route that invokes bioinformatics tools for RNA-seq and gene-family analyses, and a knowledge route that uses PlantAI-RAG for knowledge retrieval and evidence synthesis. PlantAI-RAG currently contains 31,207 plant-science literature records, comprising approximately 3.82 million normalized entities and 8.25 million literature-supported relation assertions. In an evaluation using plant-science questions, it achieved a Gold evidence-assertion recall of 86.7%, while strict accuracy ranged from 77% to 82% across three independent evaluator models. We further demonstrate an end-to-end task using 24 rice RNA-seq libraries collected under salt stress, spanning transcriptome analysis, candidate-family screening, HXK/HKL family analysis and knowledge-assisted interpretation, and prioritize OsHXK8 for experimental validation. By preserving analysis artifacts, run manifests, logs and environment records, PlantAI supports result verification and repeat execution while linking project-derived results to traceable literature evidence. Together, these capabilities provide an integrated and auditable framework to support plant functional genomics research.

bioinformatics↗

bioRxiv2026

Cyclase-generated 3,5-cGMP activates PucsarTIR antiphage defense through a stepwise zig-zag aligned filament assembly

Bacteria use nucleotide second messengers to couple phage recognition to antiviral effector activation. Here, we identify Pucsar, an ofshoot of the Pycsar-related antiphage family, whose cyclases generate 3,5-cGMP from GTP, that are associated with Toll/Interleukin-1 receptor (TIR) and transmembrane (TM) effectors. In the PucsarTIR system, cGMP produced by cyclase PucC, selectively activates the cognate PucTIR NADase. X-ray crystallography shows that PucC adopts a dimeric cyclase scaffold with a guanine-compatible base-recognition pocket. Cryo-EM and mutational analyses revealed that apo-PucTIR, composed of cyclic nucleotide binding and TIR domains, is self-sequestered as an inactive tetramer, in which TIR domains are proximal but misoriented. Sequential cGMP binding remodels this assembly through partially occupied intermediates and stabilizes a fully cGMP-bound dimer, that polymerizes into a zig-zag aligned filament, creating composite NAD+-binding pockets required for efficient NADase activity. These findings establish 3',5'-cGMP as an antiphage second messenger and reveal how cyclic purine signaling converts self-sequestered TIR effectors into a NADase-competent filament.

microbiology↗

bioRxiv2026

Integrated multi-omic analysis of pediatric metastatic osteosarcoma reveals endothelial cell plasticity and lineage infidelity.

While recent research has increasingly focused on the role of fibroblasts and macrophages in osteosarcoma, the tumor vasculature remains poorly understood, particularly in metastatic disease. To address this gap, we performed single-nuclei multi-ome (RNA+ATAC) sequencing on 24 human metastatic osteosarcoma specimens. We found that endothelial cells adopt a hybrid endothelial-mesenchymal state resembling endothelial-to-mesenchymal transition (EndMT) and that a subset of diploid endothelial cells expresses osteoblastic transcriptional profiles and gene regulatory networks (GRN). Joint copy-number analysis further identified osteosarcoma cells with endothelial transcriptional programs and GRNs, consistent with vascular mimicry. In vitro assays and syngeneic lineage-tracing experiments validated that tumor educated endothelial cells acquire osteoblast-like features. Together, these findings reveal substantial plasticity among endothelial and osteosarcoma cells in human and murine metastatic osteosarcoma, provide new insight into the how the metastatic microenvironment shapes the tumor vasculature, and challenge current models of osteosarcoma biology.

cancer biology↗

bioRxiv2026

Chemoenzymatic Synthesis of 6-Sulfo Sialyl Lewisx Containing Glycans to Probe the Receptor Specificity of MERS Coronavirus

The initial attachment of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) to host cell sialosides is critical for infection, yet its precise receptor specificity remains poorly understood. Here, we describe a chemoenzymatic methodology to synthesize a comprehensive panel of 6-sulfo sialyl Lewisx (6-sulfo-SLex) containing glycans. Our approach entails the enzymatic assembly of an oligo-lactosamine chain modified at specific positions with N-trifluoroacetyl-glucosamine (GlcNTFA) moieties. Mild base treatment removes the TFA group to yield glucosamine, which effectively blocks enzymatic fucosylation. By leveraging this approach alongside the unique substrate selectivity of GlcNAc-6-O-sulfotransferases 2 (CHST-2), we achieved the selective preparation of fucosylated 6-sulfo-SLex glycans. Microarray screening of these printed glycans revealed that a 6-sulfo-SLex derivative presented on an extended LacNAc chain is the preferred host receptor for MERS-CoV. Conjugation of this lead compound to a polyglycerol-based dendrimer generated a multivalent inhibitor that potently blocks hemagglutination of human red blood cells by the MERS-CoV spike protein N-terminal domain (NTD). Furthermore, computational modeling demonstrated that the fucose moiety does not directly contact the viral spike protein. Instead, it pre-organizes the ligand into a favorable conformation, enabling a critical salt bridge between the glycans sulfate group and the guanidinium side chain of viral residue Arg307.

biochemistry↗

bioRxiv2026

Bone Lymphatic Endothelial Cells Form a Distinct Skeletal Population and Drive Skeletal Repair

Bone regeneration relies on specialized vascular niches, yet the contribution of lymphatic vessels across distinct skeletal sites remains poorly understood. Here, we identify bone lymphatics as an essential component of the regenerative microenvironment in the mandible and long bones. We demonstrate that bone lymphatic endothelial cells (LECs) constitute a specialized endothelial population that is transcriptionally and spatially distinct from periosteal LECs. During skeletal repair, bone LECs reactivate a regenerative transcriptional programme, and promote mandibular and fracture healing. In osteonecrosis of the jaw and periodontitis, bone lymphatic-associated signalling is disrupted, identifying impaired lymphatic function as a shared feature of mandibular disease. Therapeutic activation of VEGFC-FLT4 signalling during injury or mandibular disease restores lymphangiogenesis, enhances osteogenesis, and markedly improves bone regeneration. Together, our findings advance the paradigm-shifting role of bone lymphatics positive regulators of bone regeneration and identify lymphatic activation as a promising therapeutic strategy to enhance bone regeneration in mandibular diseases.

cell biology↗

bioRxiv2026

CENO: A Genome-Scale World Model for Evolutionary Sequence Interpretation and Programmable Regulatory Design

DNA encodes biological function across a continuum of sequence scales, from single-nucleotide and motif-level grammar to regulatory neighborhoods, chromatin-scale organization and evolutionary constraint. A useful model of genomes should therefore do more than classify short sequence windows: it should maintain nucleotide-resolution state over long contexts, score counterfactual mutations, condition on homologous sequence evidence and generate candidates that can be evaluated against structural or functional objectives. We define such a system operationally as a genomic world model: a general-purpose generative model of genome sequence space that unifies sequence understanding and sequence design through a shared state and likelihood interface. Here we introduce CENO, a family of long-context generative genomic world models designed to preserve local DNA grammar while extending usable context to regulatory and chromatin scales. CENO combines Mamba sequence-mixing layers, sparse attention layers and mixture-of-experts capacity in a single autoregressive backbone, and is trained at 300M, 600M and 1B parameter scales with a staged curriculum that progresses from 8k-token cross-domain genomic pretraining to 131k- and 1M-token whole-genome long-context continuation. We evaluate CENO under a unified world-model benchmark paradigm spanning retrieval, representation, counterfactual perturbation, reconstruction, evolutionary conditioning and design. CENO retains practical long-context inference and retrieves distal sequence in synthetic assays. In zero-shot long-context analyses, without task-specific fine-tuning, long-context continuation yields annotation- and chromatin-boundary-associated attention patterns and frozen-state representations that generalize across human cell types and mouse cell or tissue settings. To incorporate evolutionary information, we further post-train CENO on packed real multiple-sequence-alignment contexts and score variants by reference-mutant likelihood deltas, improving matched variant-effect prediction and producing evolutionary enrichment signals across species. Complementing these perturbation-based variant tests, we evaluate zero-shot long-sequence generation by partial-gene continuation, asking whether the model can recover withheld gene-scale sequence structure across eukaryotic, bacterial and archaeal species; recovery improves with model scale and later whole-genome long-context training. Finally, we use CENO as the backbone for a cell-type-specific enhancer design workflow in mouse cortex, coupling a CENO-based accessibility oracle with conditional supervised fine-tuning and oracle-guided reinforcement learning. Together, CENO provides a genome-scale sequence world-model framework for sequence interpretation, evolutionary reasoning, gene-scale reconstruction and programmable regulatory sequence generation.

genomics↗

bioRxiv2026

A minimal kinase-phosphatase system and its lipid substrates self-organize into dynamic patterns

Competing lipid kinases and phosphatases are critical for organizing cellular membranes, but whether a minimal system can autonomously organize proteins and lipids into dynamic spatiotemporal patterns is unknown. Here, we report the in vitro reconstitution of the Legionella phosphatidylinositol (PI) 3-kinase MavQ and PI 3-phosphatase SidP. Together with their lipid substrates, PI and PI 3-phosphate (PI3P), these enzymes form a minimal self-organizing system that generates ATP-dependent spatiotemporal patterns, including traveling waves, on model membranes. These behaviors arise from MavQs cooperative membrane binding, SidPs phosphatase activity, and the continual interconversion and redistribution of PI and PI3P within a conserved membrane pool. A reaction-diffusion model reproduces the observed dynamics and predicts that lipid conservation prevents patterns from propagating across membrane discontinuities, which we verify experimentally. Together, these findings establish enzymatic modification of membrane lipids as a distinct molecular strategy for biological pattern formation.

biophysics↗

bioRxiv2026

Manganese Ion Inhibits Influenza A Virus Replication by Targeting the PA Endonuclease

Influenza A virus remains a major global health threat, with rapid mutation and emerging drug resistance underscoring the urgent need for novel antivirals. Manganese ions (Mn2+) are known to enhance host antiviral immunity, but their direct effects on influenza virus replication remain elusive. Here, we demonstrate that manganese chloride (MnCl2) potently inhibits the replication of both H1N1 and H3N2 subtypes in cultured cells at micromolar concentrations, with antiviral activity not shared by other divalent cations (Ca2+, Cu2+, Zn2+, Mg2+). Mechanistically, MnCl2 acts predominantly at post-entry stages, suppresses viral mRNA synthesis, and directly inhibits the RNA cleavage activity of the PA endonuclease. Pharmacological antagonism with the PA inhibitor baloxavir further supports PA as a key target. In a mouse model, intranasal MnCl2 administration alleviated body weight loss, reduced mortality, and decreased pulmonary viral RNA loads. Collectively, these findings identify Mn2+ as a direct inhibitor of influenza virus replication that acts, at least in part, by targeting the PA endonuclease, providing a conceptual framework for metal ion-based antiviral strategies.

microbiology↗