Biology subjects

Zhang, Z.

Publications and source records attributed to Zhang, Z..

At least 505 records · Page 28Linked to original sources

bioRxiv2025

5-ethynyluridine perturbs nuclear RNA metabolism to promote the nuclear accumulation of TDP-43 and other RNA binding proteins

TDP-43, an essential nucleic acid binding protein and splicing regulator, is broadly disrupted in neurodegeneration. TDP-43 nuclear localization and function depend on the abundance of its nuclear RNA targets and its recruitment into large ribonucleoprotein complexes, which restricts TDP-43 nuclear efflux. To further investigate the interplay between TDP-43 and nascent RNAs, we aimed to employ 5-ethynyluridine (5EU), a widely used uridine analog for click chemistry labeling of newly transcribed RNAs. Surprisingly, 5EU induced the nuclear accumulation of TDP-43 and other RNA-binding proteins and attenuated TDP-43 mislocalization caused by disruption of the nuclear transport apparatus. RNA FISH demonstrated 5EU-induced nuclear accumulation of polyadenylated and GU-repeat-rich RNAs, suggesting increased retention of both processed and intronic RNAs. TDP-43 eCLIP confirmed that 5EU preserved TDP-43 binding at predominantly GU-rich intronic sites. RNAseq revealed significant 5EU-induced changes in alternative splicing, accompanied by an overall reduction in splicing diversity, without any major changes in RNA stability or TDP-43 splicing regulatory function. These data suggest that 5EU may impede RNA splicing efficiency and subsequent nuclear RNA processing and export. Our findings have important implications for studies utilizing 5EU and offer unexpected confirmation that the accumulation of endogenous nuclear RNAs promotes TDP-43 nuclear localization.

cell biology↗

bioRxiv2025

Comprehensive Atomic-Scale 3D Viral-Host Protein Interactomes Enable Dissection of Key Mechanisms and Evolutionary Processes Underlying Viral Pathogenesis

Viral-human protein interactions are critical for viral replication and modulation of the host immune response. Structural modeling of these interactions is vital for developing effective antiviral therapies and vaccines. However, 99% of experimentally determined binary host-viral interactions currently lack structural information. We aimed to address this gap by leveraging computational protein structure prediction methods. Using extensive benchmarking, we found AlphaFold to be the most accurate structure prediction model for host-pathogen protein interactions. We then predicted the structures of 11,666 binary protein interactions across 33 viral families and created the most comprehensive atomic-scale 3D viral-host protein interactomes till date (https://3d-viralhuman.yulab.org). By integrating these interactomes with genetic variation data, we identified population-specific signatures of selection on variants coding for interfaces of viral-human interactions. We also found that viral interaction interfaces were less conserved than non-interface regions, a striking trend that is opposite to what is observed for host interfaces, suggesting different evolutionary pressures. Systematic analyses of interface sharing between host and viral proteins binding to the same host protein revealed mutation rate-dependent differences in interface mimicry. Similar mutation rate-dependent differences were seen in the interface sharing between viral proteins binding to a host protein. We also found that the patterns of E6 protein binding to KPNA2 differed between high- and low-risk oncogenic human papillomaviruses (HPVs), and clustering based on these binding patterns allowed the classification of HPVs with unknown oncogenic risk. Our interface mimicry analyses also unveiled a novel mechanism by which herpes simplex virus-1 UL37 suppresses the antiviral immune response through disruption of the TRAF6-MAVS signalosome interaction. Overall, our comprehensive 3D viral interactomes provide a resource at unprecedented scale and resolution that will enable researchers to explore how variation and signatures of selection influence viral interactions and disease progression. This tool also facilitates the identification of conserved and unique interaction patterns across viruses, empowering researchers to generate testable hypotheses and ultimately accelerate the discovery of novel therapeutic targets and intervention strategies.

systems biology↗

bioRxiv2025

AquIRE reveals multiple mechanisms of clinically induced RNA damage and the conservation and dynamics of glycoRNAs

RNA is subject to many modifications, from small chemical changes such as methylation through to conjugation of biomolecules such as glycans. As well as these endogenously written modifications, RNA is also exposed to damage induced by its environment. Certain clinical compounds are known to drive covalent modifications of RNA with a growing appreciation for how these affect function. To understand the regulation of these modifications we need a reliable, sensitive and rapid methodology for their quantification. Thus, we developed AquIRE and applied it to the analysis of drug-induced RNA damage, showing this to be widespread with intricate temporal dynamics. Using the same methodology we identify RNA:protein crosslinking and the rewriting of the epitranscriptome as a consequence of clinical RNA damage. We also demonstrate how liquid-liquid phase separation increases RNA damage and expand the horizons of the glycoRNA world across the kingdoms of life and into cell-free glycoRNA.

molecular biology↗

bioRxiv2025

Prior cocaine use disrupts identification of hidden states by single units and neural ensembles in orbitofrontal cortex

The orbitofrontal cortex (OFC) is critical to identifying task structure and to generalizing appropriately across task states with similar underlying or hidden causes. This capability is at the heart of OFCs proposed role in a network responsible for cognitive mapping, and its loss can explain many deficits associated with OFC damage or inactivation. Substance use disorder is defined by behaviors that share much in common with these deficits, such as an inability to modify learned behaviors in the face of new information about undesired consequences. One explanation for this similarity would be if addictive drugs impacted the ability of OFC to recognize underlying similarities, hidden states, that allow information learned in one setting to be used in another. To explore this possibility, we trained rats to self-administer cocaine and then recorded single unit activity in lateral OFC as these rats performed in an odor sequence task consisting of unique and shared positions. In well-trained controls, we observed chance decoding of sequence at shared positions and near chance decoding even at unique positions, reflecting the irrelevance of distinguishing these positions in the task. By contrast, in cocaine-experienced rats, decoding remained significantly elevated, particularly at the positions that had superficial sensory differences that were collapsed in controls across learning. These neural differences were accompanied by increases in behavioral variability at these positions. A tensor component analysis showed that this effect of reduced generalization after cocaine use also extended across positions in the sequences. These results show that prior cocaine use disrupts the normal identification of hidden states by OFC.

neuroscience↗

bioRxiv2025

Genomic and Transcriptomic Signatures of SETD1A Disruption in Human Excitatory Neuron Development and Psychiatric Disease Risk

Genetic disruption of SETD1A markedly increases the risk for schizophrenia. To elucidate the underlying mechanisms, we generated isogenic organoid models of the developing human cerebral cortex harboring a SETD1A loss-of-function schizophrenia risk mutation. Employing chromatin profiling combined with RNA sequencing, we identified high-confidence SETD1A target genes, analyzed the impact of the mutation on SETD1A binding and transcriptional regulation and validated key findings with orthogonal approaches. Disruption of SETD1A function disturbs the finely tuned temporal gene expression in the excitatory neuron lineage, yielding an aberrant transcriptional program that compromises key regulatory and metabolic pathways essential for neurodevelopmental transitions. Although overall SETD1A binding remains unchanged in mutant neurons, we identified localized alterations in SETD1A binding that correlate with shifts in H3K4me3 levels and gene expression. These changes are enriched at enhancer regions, suggesting that enhancer-regulated genes are especially vulnerable to SETD1A reduction. Notably, target genes with enhancer-bound SETD1A are primarily linked to neuronal functions while those with promoter-bound SETD1A are enriched for basic cellular functions. By mapping the SETD1A binding landscape in excitatory neurons of the human fetal frontal cortex and integrating multimodal neuroimaging and genetic datasets, we demonstrate that the genomic context of SETD1A binding differentially correlates with macroscale brain organization and establish a link between SETD1A-bound enhancers, schizophrenia-associated brain alterations and genetic susceptibility. Our study advances our understanding of the role of SETD1A binding patterns in schizophrenia pathogenesis, offering insights that may guide future therapeutic strategies.

neuroscience↗

bioRxiv2025

SIRT6 activator fucoidan extends healthspan and lifespan in aged wild-type mice

SIRT6 is a protein deacylase, deacetylase, and mono-ADP-ribosylase (mADPr) regulating biological pathways important for longevity including DNA repair and silencing of LINE1 retrotransposons. SIRT6 knockout mice die by 30 days of age, whereas SIRT6 overexpression increases lifespan in male mice. Finding safe pharmacological activators of SIRT6 would have clinical benefits. Fucoidan, a polysaccharide purified from brown seaweed, has been identified as an activator of SIRT6 deacetylation activity. Here, we show that fucoidan also activates SIRT6 mADPr activity, which was shown to be elevated in certain human centenarians. Administering fucoidan to aged mice led to a significant increase in median lifespan in male mice. Both male and female mice demonstrated a marked reduction in frailty and epigenetic age. Fucoidan-treated mice showed repression of LINE1 elements suggesting that the beneficial effects of fucoidan are mediated, at least in part, by SIRT6. As brown seaweed rich in fucoidan is a popular food item in South Korea and Japan, countries with the highest life expectancy, we propose that fucoidan supplementation should be explored as a safe strategy for activating SIRT6 and improving human healthspan and lifespan.

molecular biology↗

bioRxiv2025

Human Body Single-Cell Atlas of 3D Genome Organization and DNA Methylation

Higher-order chromatin structure and DNA methylation are critical for gene regulation, but how these vary across the human body remains unclear. We performed multi-omic profiling of 3D genome structure and DNA methylation for 86,689 single nuclei across 16 human tissues, identifying 35 major and 206 cell subtypes. We revealed extensive changes in CG and non-CG methylation across almost all cell types and characterized 3D chromatin structure at an unprecedented cellular resolution. Intriguingly, extensive discrepancies exist between cell types delineated by DNA methylation and genome structure, indicating that the role of distinct epigenomic features in maintaining cell identity may vary by lineage. This study expands our understanding of the diversity of DNA methylation and chromatin structure and offers an extensive reference for exploring gene regulation in human health and disease.

genomics↗

bioRxiv2025

High-resolution NMR spectroscopy of proteins in intact mitochondria

Understanding protein structure and function within mitochondria is essential for unraveling the molecular mechanisms underlying cellular energy production, stress response, and disease. Here, we present a novel approach for NMR observation of proteins within intact mitochondria by delivering proteins directly into isolated mitochondria via electroporation. Using this method, we investigate the interaction of -synuclein (-syn) with the mitochondria membrane and examine how post-translational modifications regulate this interaction. Additionally, we assessed the stability of GB1 and the dimerization of its variant within mitochondria, achieving quantitative insights into mitochondrial environmental impact on protein function. This approach offers a valuable framework for exploring mitochondrial related biomolecular events at atomic-resolution within intact mitochondria, paving the way for a more comprehensive understanding of the molecular events governing mitochondrial health and dysfunction.

biochemistry↗

bioRxiv2025

Fast in vivo deep-tissue 3D imaging with selective-illumination NIR-II light-field microscopy and aberration-corrected implicit neural representation

Near-infrared II (NIR-II) microscopy, which enables in vivo deep-tissue visualization of vasculature and cell activities, has been a promising tool for understanding physiological mechanisms. However, the volumetric image speed of the NIR-II microscopy is hindered by scanning strategy, causing limitations for observing instantaneous biological dynamics in 3D space. Here, we developed a NIR-II light-field microscopy (LFM) based on selective-illumination and self-supervised implicit neural representation (INR)-reconstruction, which allows ultra-fast 3D in vivo imaging (100 volumes/s). Through integrating INR with view-wise aberration correction, we could conquer the artifacts induced by the angular subsampling and refractive index variation, achieving single-cell resolution at a volume of 550 m diameter and 200 m thickness. The volumetric selective-illumination overcomes the influence of out-of-focus background, together with the low scattering advantage of NIR-II wavelength, extending the imaging depth to 600 m. The developed aberration-corrected implicit neural representation reconstruction (AIR) NIR-II LFM showcases its capability by monitoring hemodynamics of mouse brain under norepinephrine and flow redistribution of ischemic stroke in 3D vasoganglion, as well as noninvasively tracking immune cell activities inside subcutaneous solid tumor through intact skin. This approach represents a significant advancement in 3D in vivo imaging, holding great potential in biomedical research and preclinical studies.

neuroscience↗

bioRxiv2025

Effects of alcohol on gut microbiome in adolescent and adult MMTV-Wnt1 mice

Breast cancer is the most commonly diagnosed cancer in women worldwide, with alcohol consumption recognized as a significant risk factor. While epidemiological studies consistently show a positive correlation between alcohol consumption and increased breast cancer risk, the underlying mechanisms remain unclear. Recent evidence suggests that the gut microbiome--the diverse collection of microorganisms, including bacteria, viruses, and fungi, residing in the gastrointestinal tract--plays a pivotal role in systemic health and disease. This is achieved through its regulation of key physiological processes such as metabolism, immune function, and inflammatory responses. Disruption of the gut microbiome (dysbiosis) has recently been implicated in the development of breast cancer. We hypothesized that alcohol exposure induces gut dysbiosis, which in turn drives systemic inflammation and carcinogenic processes. Previously, we demonstrated that alcohol exposure promotes mammary tumor growth and aggressiveness in MMTV-Wnt1 (Wnt1) transgenic mice, an established model for investigating mechanisms of alcohol-induced tumor promotion. In this study, we sought to determine whether alcohol exposure induces gut dysbiosis in adolescent and adult Wnt1 transgenic mice and their wild-type FVB counterparts. Our findings revealed that alcohol exposure significantly reduced microbiome richness in adult Wnt1 and FVB mice. Alcohol exposure also markedly altered microbiome composition in adolescents and adults in both strains. Additionally, we identified specific microbial taxa that were significantly affected by alcohol exposure. These results demonstrate that alcohol disrupts the gut microbiome in a preclinical breast cancer model, providing insights into the potential role of gut dysbiosis in alcohol-induced mammary tumor promotion and offering avenues for future research.

cancer biology↗

bioRxiv2025

Unveiling Gene Modules at Atlas Scale through Hierarchical Clustering of Single-Cell Data

A major challenge in scRNAseq analysis is how to recover the biologically meaningful cell ontology tree and conserved gene modules across datasets. Data integration and batch-effect correction have been the key to effectively analyze multiple datasets, but often fail to disentangle cell states in heterogeneous samples, such as in cancer and the immune system. Here we present super single cell clustering (SuperSCC), a novel algorithm that utilizes machine-learning models to discover cell identities and gene modules from multiple datasets without the need of data integration. Of note, SuperSCC can be implemented both in cell lineage and cell state level, thereby building the hierarchy of cell programs with specific cell identity and gene modules. Such information has the great potential to identify the shared rare populations across datasets regardless of batch effect and benefits label transfer for mapping cell labels from reference to query. We used SuperSCC to perform atlas level data analysis on more than 90 datasets and build a cell state map of complex tissue in healthy and diseased stages, such as human lung. We show that SuperSCC outperforms existing approaches in identifying cellular context, has better annotation accuracy, and outlines gene modules that indicate conserved immune cell status in lung microenvironments.

bioinformatics↗

bioRxiv2025

Nucleosome Engagement Regulates RORγt Structure and Dynamics

ROR{gamma}t is a key transcriptional regulator that supports protective pathogen clearance but also drives autoimmune disorders. Genetic studies have identified ROR{gamma}t mutations that selectively protect from autoimmunity without compromising host defense. Herein, we describe the molecular principles governing how ROR{gamma}t selectively drives these context-dependent gene programs. Structural studies revealed the selectivity-determining mutations lie in an -helix, the C-terminal extension (CTE), which nucleates when ROR{gamma}t engages partially occluded DNA response elements at nucleosome entry/exit sites. In ex vivo Th17 cells, the CTE is required for full genomic occupancy and expression of inflammatory effector genes, while residual DNA binding supports partial occupancy that, alongside context-dependent transcription factors, induces lineage-stabilizing gene expression. These findings support a model where ROR{gamma}t uses distinct chromatin binding modes to engage an expansive chromatin landscape to activate target gene programs, explaining the complex phenotypes of CTE mutant mice.

biophysics↗

bioRxiv2025

High-Speed Neural Imaging with Multiplexed Miniature Two-Photon Microscopy (M-MINI2P)

Head-mounted miniaturized two-photon microscopes are powerful tools to record neural activity with cellular resolution deep in the mouse brain during unrestrained, free-moving behavior. Two-photon microscopy, however, is traditionally limited in imaging frame rate due to the necessity of raster scanning the laser excitation spot over a large field-of-view (FOV). Here, we present two multiplexed miniature two-photon microscopes (M-MINI2Ps) to increase the imaging frame rate while preserving the spatial resolution. Two different FOVs are imaged simultaneously and then demixed temporally or computationally. We demonstrate large-scale (500x500 m2 FOV) multiplane calcium imaging in visual cortex and prefrontal cortex in freely moving mice for spontaneous activity and auditory stimulus evoked responses. Furthermore, the increased speed of M-MINI2Ps also enables two-photon voltage imaging at 400 Hz over a 380x150 m2 FOV in freely moving mice. M-MINI2Ps have compact footprints and are compatible with the open-source MINI2P. M-MINI2Ps, together with their design principles, allow the capture of faster physiological dynamics and population recordings over a greater volume than currently possible in freely moving mice, and will be a powerful tool in systems neuroscience.

neuroscience↗

bioRxiv2025

SARS-CoV-2 Exploits Host Translation and Immune Evasion Pathways via Viral RNA-Host Protein Interactions

RNA viruses, including SARS-CoV-2, Influenza A Virus (IAV), Zika Virus, and Dengue Virus (DENV) pose serious global health challenges by manipulating host cellular mechanisms. SARS-COV-2, in particular exploits host translational machinery to enhance replication and evade immune response. Here, we investigated how SARS-CoV-2 circumvents host immune defenses through RNA - host protein interactions. By integrating multiple datasets, ClusterProfiler, KEGG, Reactome, WikiPathways, and Gene Ontology, we performed functional enrichment analyses on host protein interactions with SARS-CoV-2 RNA. Our results identified key pathways involved in viral replication, translation regulation, and immune evasion. Comparing SARS-CoV-2 interactomes from IAV, Zika, and DENV, we uncovered a subset of 275 common host proteins serving as promising targets for broad-spectrum antiviral strategies. Network analysis highlighted critical translation factors (EEF1A1, EIF4A1, EIF3H) and RNA-binding proteins (NCL, ILF3) as key nodes in viral replication. These findings provide insights into RNA virus pathogenesis and support the development of targeted therapeutics.

immunology↗

bioRxiv2025

Methadone blockade of IK1 promotes both long QT and Brugada-like arrhythmias: Mechanistic insights from computational modeling

BackgroundMethadone is widely used for chronic pain relief and in the maintenance therapy of opioid use disorder, however, it also increases the risk of ventricular arrhythmias and sudden cardiac death. Methadone blocks several ionic currents with different half-maximal inhibitory concentrations (IC50), including the rapid component of the delayed rectifier potassium current (IKr), the inward rectifier potassium current (IK1), the L-type calcium current (ICa,L), and the late component of the sodium current (INaL). Despite the well-known proarrhythmic effect of IKr blockade, the effects of blocking other ionic currents on arrhythmogenesis remain less well understood. MethodsComputer simulations were used to explore the proarrhythmic effects of methadone by investigating how its blocking effects on ionic currents act alone or together in arrhythmogenesis. ResultsThe major findings are: 1) blocking IK1 potentiates QT prolongation-related arrhythmogenesis by enhancing a tissue-scale dynamical instability for the spontaneous genesis of ectopic excitations. Blocking IK1 and IKr together results in a synergistic effect, greatly increasing the arrhythmia propensity, much larger than that of blocking either one alone; 2) blocking IK1 in combination with lowering ICa,L potentiates phase-2 reentry caused by spike-and-dome action potential morphology, an arrhythmia mechanism of Brugada syndrome. Blocking IKr exhibits little effect for this mechanism of arrhythmias; and 3) hypoxia, often comorbid in methadone populations, can potentiate QT prolongation-related arrhythmias at high sympathetic activity and phase-2 reentry at low or basal sympathetic activity, mainly via its effect on ICa,L. ConclusionsThese simulation results provide mechanistic insights into the genesis of QT prolongation-related Torsades de Pointes and Brugada-like ECG related arrhythmias caused by methadone use.

pharmacology and toxicology↗

bioRxiv2025

Restoration of excitation/inhibition balance enhances neuronal signal-to-noise ratio and rescues social deficits in autism-associated Scn2a-deficiency

Social behavior is critical for survival and adaptation, which is profoundly disrupted in autism spectrum disorders (ASD). Social withdrawal due to information overload was often described in ASD, and it was suspected that increased basal noise, i.e., excessive background neuronal activities in the brain could be a disease mechanism. However, experimental test of this hypothesis is limited. Loss-of-function mutations (deficiency) in SCN2A, which encodes the voltage-gated sodium channel NaV1.2, have been revealed as a leading monogenic cause of profound ASD. Here, we revealed that Scn2a deficiency results in robust and multifaceted social impairments in mice. Scn2a-deficient neurons displayed an increased excitation-inhibition (E/I) ratio, contributing to elevated basal neuronal noise and diminished signal-to-noise ratio (SNR) during social interactions. Notably, the restoration of Scn2a expression in adulthood is able to rescue both SNR and social deficits. By balancing the E/I ratio and reducing basal neuronal firing, an FDA-approved GABAA receptor-positive allosteric modulator improves sociability in Scn2a-deficient mice and normalizes neuronal activities in translationally relevant human brain organoids carrying autism-associated SCN2A nonsense mutation. Collectively, our findings revealed a critical role of the NaV1.2 channel in the regulation of social behaviors, and identified molecular, cellular, and circuitry mechanisms underlying SCN2A-associated disorders. HIGHLIGHTSO_LINaV1.2 deficiency leads to pronounced social deficits in mice. C_LIO_LINaV1.2 deficiency results in an overall enhanced E/I ratio, elevated basal neuronal activity, and impaired signal-to-noise ratio. C_LIO_LIBoth the enhanced E/I ratio and impaired sociability are reversible through the restoration of NaV1.2 expression in adulthood. C_LIO_LITargeted restoration of NaV1.2 in striatum-projecting neurons rescues social impairments. C_LIO_LIGABA transmission is reduced in both mouse and human organoid models of SCN2A deficiency, and acute systemic administration of GABAA receptor-positive allosteric modulators restores sociability. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/641498v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@154a323org.highwire.dtl.DTLVardef@1a27fbaorg.highwire.dtl.DTLVardef@16fa3beorg.highwire.dtl.DTLVardef@6712c2_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical abstract: Severe Scn2a deficiency leads to a predominate decrease in GABA transmission with an overall enhanced E/I ratio, elevated basal neuronal activity, impaired SNR, and social deficits in adult NaV1.2-deficient mice.

neuroscience↗

bioRxiv2025

Cryo-ET of IgG bivalent binding on SARS-CoV-2 provides structural basis for antibody avidity

The bivalent nature of IgG enhances its neutralization potency against enveloped viruses; however, on-virion structural details of IgG bivalent binding with antigens remain elusive. Here we used cryo-ET to investigate how two potent IgGs P17 and S309 interact with S-trimers on the SARS-CoV-2 surface. We found that these antibodies exploit the mobility of S-trimers to form diverse bivalent binding patterns. P17 stabilizes S-trimers in a one-RBD-up conformation and gathers S-trimer into linear multimers within minutes, whereas S309 primarily forms circular S-trimer assemblies that extend into lattice-like structures. Additionally, both IgGs can facilitate inter-virion coupling through bivalent binding of opposing S-trimers. These findings provide a structural basis for understanding IgG avidity and offer insights for antibody engineering and vaccine design.

biophysics↗

bioRxiv2025

Elucidating the Characteristics and Clonal Evolutionary Trajectory of Influenza Neuraminidase Broadly Reactive B Cell

Influenza virus neuraminidase (NA) is receiving increasing attention as a target for universal flu vaccines. Several broad NA inhibition monoclonal antibodies (BImAbs) targeting the highly conserved enzymatic pocket have been previously described. However, the molecular characteristics, clonal evolutionary trajectory, and B cell sources of BImAbs remain poorly understood. Here, using NA-mutant probes, we comprehensively profiled the immune signatures of NA-specific memory B cells (MBCs) from a healthy individual with NA cross-inhibition activity. From the NA-specific MBC repertoires, we identified a series of NA BImAbs with molecular features characterized by long HCDR3 regions with an "xxxDRxxx" motif, which exhibited broad inhibition against diverse influenza NAs. Clonal lineage tracing revealed that these BImAbs followed a clonal evolutionary trajectory encompassing classical MBC (cMBC) and atypical MBC (aMBC). Both cMBC- and aMBC-derived NA BImAbs displayed similar inhibitory activity against the influenza NAs. These findings enhance our understanding of the development of NA BImAbs and provide a foundation for the rational design of NA-based universal flu vaccines.

immunology↗