Biology subjects

Yuan, M.

Publications and source records attributed to Yuan, M..

At least 91 records · Page 5Linked to original sources

bioRxiv2022

A Chitin-Binding Protein Ultra-highly expressed in the Outer Fold of Mantle is Related to Shell Colour in Pacific Oyster Crassostrea gigas

Molluscs constitute the second largest phylum of animals in the world, and shell colour and stripes are one of their most important phenotypic characteristics. Studies on the mechanism of shell pigmentation help understand the evolutionary and ecological significance of shell colour and serve as the basis for shell colour breeding. In this study, a matched-pair design was used in comparing the black- and white-striped mantles of the same oyster. The result showed that the stripes of shell surface are corresponding to the stripes of the mantle edge. Transcriptomic analysis identified an uncharacterized protein gene (we named it as Crassostrea gigas chitin-binding protein, CgCBP) highly expressed in the black mantles. Three folds (inner fold, middle fold and outer fold) were found on the mantle edge of oyster, but only the outer fold has the same colour as the shell. Transcriptomic comparison indicated that the three folds of the mantle edge are functionally differentiated, and the CgCBP gene is ultra-highly expressed only in the outer fold. We obtained new black and white shell periostraca from the shell notching experiment and found their structural differences by scanning electron microscope. Chitin was successfully extracted and identified from the shell periostraca. Proteomic analysis revealed differences in protein composition between the two shell periostraca. Particularly, the black shell periostraca have more proteins related to melanin biosynthesis and chitin binding compared with the white ones, and melanin particles were observed in the black mantle edge using transmission electron microscope. Magnetic bead binding and Western blot experiments showed that the CgCBP protein can specifically bind to chitin and in vivo RNAi screening indicated that CgCBP knockdown can change the structure of the shell periostracum and reduce its pigmentation. All these results suggest that the outer fold of mantle may have more important roles in shell pigmentation, shell periostracum structure is functionally correlated with shell pigmentation, and the CgCBP gene ultra-highly expressed in the outer fold may influence shell pigmentation by affecting its periostracum structure.

physiology↗

bioRxiv2022

CPGL: Prediction of compound-protein interaction by integrating graph attention network with long short-term memory neural network

Recent advancements of artificial intelligence based on deep learning algorithms have made it possible to computationally predict compound-protein interaction (CPI) without conducting laboratory experiments. In this manuscript, we integrated a graph attention network (GAT) for compounds and a long short-term memory neural network (LSTM) for proteins, used end-to-end representation learning for both compounds and proteins, and proposed a deep learning algorithm, CPGL (CPI with GAT and LSTM) to optimize the feature extraction from compounds and proteins and to improve the model robustness and generalizability. CPGL demonstrated an excellent predictive performance and outperforms recently reported deep learning models. Based on 3 public CPI datasets, C.elegans, Human and BindingDB, CPGL represented 1 - 5% improvement compared to existing deep-learning models. Our method also achieves excellent results on datasets with imbalanced positive and negative proportions constructed based on the above two datasets. More importantly, using 2 label reversal datasets, GPCR and Kinase, CPGL showed superior performance compared to other existing deep learning models. The AUC were substantially improved by 15% to 50% on the Kinase dataset, indicative of the robustness and generalizability of CPGL.

bioinformatics↗

bioRxiv2022

Broadly neutralizing antibodies target the coronavirus fusion peptide

The potential for future coronavirus outbreaks highlights the need to develop strategies and tools to broadly target this group of pathogens. Here, using an epitope-agnostic approach, we identified six monoclonal antibodies that bound to spike proteins from all seven human-infecting coronaviruses. Epitope mapping revealed that all six antibodies target the conserved fusion peptide region adjacent to the S2 cleavage site. Two antibodies, COV44-62 and COV44-79, broadly neutralize a range of alpha and beta coronaviruses, including SARS-CoV-2 Omicron subvariants BA.1 and BA.2, albeit with lower potency than RBD-specific antibodies. In crystal structures of Fabs COV44-62 and COV44-79 with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine at the S2 cleavage site. Importantly, COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings identify the fusion peptide as the target of the broadest neutralizing antibodies in an epitope-agnostic screen, highlighting this site as a candidate for next-generation coronavirus vaccine development. One-Sentence SummaryRare monoclonal antibodies from COVID-19 convalescent individuals broadly neutralize coronaviruses by targeting the fusion peptide.

immunology↗

bioRxiv2022

Effect of TSS on anti-CVB3 through TLR3 pathway

Toll-like receptors (TLRs) can recognize molecular patterns associated with microorganisms and induce immune responses. TLR3 is responsible for recognizing viruses and making hosts resistant to Coxsackie B3 (CVB3) infection. In this study, we found that Tectorigenin Sodium Sulfonate (TSS) has a TLR3 inhibitory effect and exerts strong anti-CVB3 activity through the TLR3 pathway both in vivo and in vitro. Balb/c mice were infected by ip injection of CVB3 virus, and subcutaneously injected with TSS at 264mg{middle dot}Kg-1{middle dot}d-1 for 7 d. The life extension rate of CVB3-infected mice was up to 46.67%, and the mean time to death was prolonged from 6.00 {+/-} 0.47 d to 8.80 {+/-} 2.78 d (P < 0.01). TSS was also able to reduce the level of weight loss in mice, significantly reduce the symptoms of myocarditis caused by CVB3, reduce the virus titer in the heart, improve the spleen and thymus index, and enhance immune function. We further explored the underlying mechanism of TSS in CVB3-infected HT-29 cells and mice: TSS reduced TLR3 expression and downregulated its downstream TRIF, TRAF6, IRF3, NF-{kappa} B. MAPK, AP1 expression, reduced expression of IFN-{beta}IL-6TNF-. TSS has strong anti-CVB3 activity in vitro and in vivo and has the effect of inhibiting the activation of TLR3 pathway. IMPORTANCETSS is expected to be an antiviral drug for the treatment of CVB3 infection. Its regulatory effect on the immune system provides a new approach for antiviral research.

pharmacology and toxicology↗

bioRxiv2022

Spatial turnover of soil viral populations and genotypes overlain by cohesive responses to moisture in grasslands

Although soil viral abundance, diversity, and potential roles in microbial community dynamics and biogeochemical cycling are beginning to be appreciated1-5, little is known about the patterns and drivers of soil viral community composition that underlie their contributions to terrestrial ecology. Here, we analyzed 43 soil viromes from a precipitation manipulation experiment in a Mediterranean grassland in California, USA. We recovered 5,315 viral population sequences (vOTUs), and viral community composition exhibited a highly significant distance-decay relationship within the 18 m long field. This pattern was recapitulated in the microheterogeneity of 130 prevalent vOTUs (detected in >=90% of the viromes), which tended to exhibit significant negative correlations between genomic similarity of their predominant allelic variants and distance. Although spatial turnover was also observed in the bacterial and archaeal communities from the same soils, the signal was dampened relative to the viromes, suggesting differences in assembly drivers at local scales for viruses and their microbial hosts and/or differences in the temporal scales captured by viromes and total DNA. Despite the overwhelming spatial signal, vOTUs responsive to a decrease in soil moisture were significantly enriched in a predicted protein-sharing subnetwork of 326 vOTUs linked to 191 known actinobacteriophages, suggesting a genomically cohesive viral response to soil moisture evocative of environmental filtering, potentially by way of actinobacterial hosts. Overall, soil viral ecological processes appear to be highly constrained in space and tightly coupled to the heterogeneous, dynamic soil environment and thus fundamentally different from those of their well-mixed and more thoroughly studied marine counterparts.

microbiology↗

bioRxiv2022

A broad and potent neutralization epitope in SARS-related coronaviruses

Many neutralizing antibodies (nAbs) elicited to ancestral SARS-CoV-2 through natural infection and vaccination generally have reduced effectiveness to SARS-CoV-2 variants. Here we show therapeutic antibody ADG20 is able to neutralize all SARS-CoV-2 variants of concern (VOCs) including Omicron (B.1.1.529) as well as other SARS-related coronaviruses. We delineate the structural basis of this relatively escape-resistant epitope that extends from one end of the receptor binding site (RBS) into the highly conserved CR3022 site. ADG20 can then benefit from high potency through direct competition with ACE2 in the more variable RBS and interaction with the more highly conserved CR3022 site. Importantly, antibodies that are able to target this site generally neutralize all VOCs, albeit with reduced potency against Omicron. Thus, this highly conserved and vulnerable site can be exploited for design of universal vaccines and therapeutic antibodies.

microbiology↗

bioRxiv2022

Broadly neutralizing anti-S2 antibodies protect against all three human betacoronaviruses that cause severe disease

Pan-betacoronavirus neutralizing antibodies may hold the key to developing broadly protective vaccines against coronaviruses that cause severe disease, for anticipating novel pandemic-causing viruses, and to respond more effectively to SARS-CoV-2 variants. The emergence of the Omicron variant of SARS-CoV-2 has illustrated the limitations of solely targeting the receptor binding domain (RBD) of the envelope Spike (S)-protein. Here, we isolated a large panel of broadly neutralizing antibodies (bnAbs) from SARS-CoV-2 recovered-vaccinated donors that target a conserved S2 region in the fusion machinery on betacoronavirus spikes. Select bnAbs show broad in vivo protection against all three pathogenic betacoronaviruses, SARS-CoV-1, SARS-CoV-2 and MERS-CoV, that have spilled over into humans in the past 20 years to cause severe disease. The bnAbs provide new opportunities for antibody-based interventions and key insights for developing pan-betacoronavirus vaccines.

immunology↗

bioRxiv2022

Superparamagnetic iron oxide enclosed hollow gold nanostructure with tunable surface plasmon resonances to promote near-infrared photothermal conversion

In this study, to enhance deep tissue penetration by near-infrared (NIR) light, a novel superparamagnetic iron oxide enclosed hollow gold nanoshell (SPIO-HGNS) structure with tunable size and surface plasmon resonance (SPR) in the NIR range was designed and synthesized through a 2-step template-enabled galvanic replacement reaction. Here, Ag coated SPIO (SPIO-Ag) was prepared as a template with tunable outer diameters by way of adjusting the Ag content. SPIO-HGNS with variable hollow gold inner diameters can then be synthesized based on the determined outer diameter of the SPIO-Ag template through a galvanic replacement reaction between HAuCl3 and Ag coating on the SPIO surface. With incrementing amounts of Ag, three SPIO-HGNS structures were synthesized with comparable shell thicknesses around 6.7 nm and an average inner diameter of 38.7, 39.4, and 40.7 nm, respectively, evidenced by TEM and ICP results. The structure of SPIO-HGNS was confirmed by identifying Au111 lattice and the elemental mapping of Fe and Au using energy-dispersive X-ray spectroscopy. The Ultraviolet-Visible-NIR absorption spectra showed red-shifted SPR peaks (820, 855, and 945 nm) with the increasing inner diameters of SPIO-HGNS, which was also supported by an absorption cross-section simulation. The photothermal results showed that the three SPIO-HGNS structures, when exposed to ~30 s of 400 mW laser irradiation, exhibited photothermal temperature rises of 5.9, 4.6, and 2.9 {degrees}C, respectively. This study explored the tuning of SPR properties in NIR-responsive magneto-plasmonic nanoparticles through a facile preparation procedure, paving the way for potential applications in photothermal therapies.

bioengineering↗

bioRxiv2022

Therapeutic vulnerability to ATR inhibition in concurrent NF1 and ATRX-deficient high-grade solid tumors

Subsets of Neurofibromatosis Type 1 (NF1)-associated solid tumors have been shown to display high frequencies of ATRX mutations and presence of alternative lengthening of telomeres (ALT). In addition, a potential biologic vulnerability of ALT-positive cancer cells is ATR inhibition, a regulator of homologous recombination. We studied the phenotype of combined NF1 and ATRX deficiency in malignant solid tumors. For these experiments, cell lines derived from NF1-deficient sporadic glioblastomas (U251, SF188), a NF1-associated ATRX mutant glioblastoma cell line (JHH-NF1-GBM1), a NF1-derived sarcoma cell line (JHH-CRC65), and two NF1-deficient MPNST cell lines (ST88-14, NF90.8) were utilized. Cancer cells were treated with ATR inhibitors (AZD6738 and VE-822), in vitro, with or without a MEK inhibitor (AZD6244, selumetinib) or temozolomide. In contrast to the glioma cell line SF188, combined ATRX knockout (KO) and TERC KO led to ALT-like properties and sensitized U251 glioma cells to ATR inhibition (AZD6738 and VE-822) in vitro and in vivo. In addition, ATR inhibitors sensitized U251 cells to temozolomide, but not MEK inhibition (AZD6244), irrespective of ATRX level manipulation; whereas, the JHH-NF1-GBM1 cell line (ATRX loss/ALT-positive) demonstrated sensitivity to ATR inhibition (AZD6738), but not temozolomide. Similar effects were noted using the MPNST cell line NF90.8 after combined ATRX knockdown and TERC KO; however, not in the MPNST cell line ST88-14. Taken together, our study supports the feasibility of targeting the ATR pathway in subsets of NF1-deficient and associated tumors. Tumors with pre-existing ALT, or that subsequently develop ALT after ATRX downregulation, are particularly vulnerable to this therapeutic approach.

cancer biology↗

bioRxiv2022

CHDbase: A Comprehensive Knowledgebase for Congenital Heart Disease-related Genes and Clinical Manifestations

Congenital heart disease (CHD) is the most common cause of major birth defects, with a prevalence of 1%. Although an increasing number of studies reporting the etiology of CHD, the findings scattered throughout the literature are difficult to retrieve and utilize in research and clinical practice. We therefore developed CHDbase, an evidence-based knowledgebase with CHD-related genes and clinical manifestations manually curated from 1114 publications, linking 1124 susceptibility genes and 3591 variations to more than 300 CHD types and related syndromes. Metadata such as the information of each publication and the selected population and samples, the strategy of studies, and the major findings of study were integrated with each item of research record. We also integrated functional annotations through parsing ~50 databases/tools to facilitate the interpretation of these genes and variations in disease pathogenicity. We further prioritized the significance of these CHD-related genes with a gene interaction network approach, and extracted a core CHD sub-network with 163 genes. The clear genetic landscape of CHD enables the phenotype classification based on the shared genetic origin. Overall, CHDbase provides a comprehensive and freely available resource to study CHD susceptibility, supporting a wide range of users in the scientific and medical communities. CHDbase is accessible at http://chddb.fwgenetics.org/.

genetics↗

bioRxiv2021

Blood-brain Barrier Crossing using Magnetic Stimulated Nanoparticles

Due to the low permeability and high selectivity of the blood-brain barrier (BBB), existing brain therapeutic technologies are limited by the inefficient BBB crossing of conventional drugs. Magnetic nanoparticles (MNPs) have shown great potential as nano-carriers for efficient BBB crossing under the external static magnetic field (SMF). To quantify the impact of SMF on MNPs in vivo dynamics towards BBB crossing, we developed a physiologically based pharmacokinetic (PBPK) model for intraperitoneal (IP) injected superparamagnetic iron oxide nanoparticles coated by gold and conjugated with poly(ethylene glycol) (PEG) (SPIO-Au-PEG NPs) in mice. Unlike most reported PBPK models that ignore brain permeability, we first obtained the brain permeabilities with and without SMF by determining the concentration of SPIO-Au-PEG NPs in the cerebral blood and brain tissue. This concentration in the brain was simulated by the advection-diffusion equations and was numerically solved in COMSOL Multiphysics. The results from the PBPK model after incorporating the brain permeability showed a good agreement (regression coefficient R2 = 0.825) with the in vivo results, verifying the capability of using the proposed PBPK model to predict the in vivo biodistribution of SPIO-Au-PEG NPs under the exposure to SMF. Furthermore, the in vivo results revealed that the brain bioavailability under the exposure to SMF (4.01%) is slightly better than the control group (3.68%). In addition, the modification of SPIO-Au-PEG NPs with insulin (SPIO-Au-PEG-insulin) showed an improvement of the brain bioavailability by 24.47 % in comparison to the non-insulin group. With the SMF stimulation, the brain bioavailability of SPIO-Au-PEG-insulin was further improved by 3.91 % compared to the group without SMF.

pharmacology and toxicology↗

bioRxiv2021

A recurring YYDRxG pattern in broadly neutralizing antibodies to a conserved site on SARS-CoV-2, variants of concern, and related viruses

Studying the antibody response to SARS-CoV-2 informs on how the human immune system can respond to antigenic variants as well as other SARS-related viruses. Here, we structurally and functionally characterized a potent human antibody ADI-62113 that also neutralizes SARS-CoV- 2 variants of concern and cross-reacts with many other sarbecoviruses. A YYDRxG motif encoded by IGHD3-22 in CDR H3 facilitates targeting to a highly conserved epitope on the SARS-CoV-2 receptor binding domain. A computational search for a YYDRxG pattern in publicly available sequences identified many antibodies with broad neutralization activity against SARS-CoV-2 variants and SARS-CoV. Thus, the YYDRxG motif represents a common convergent solution for the human humoral immune system to counteract sarbecoviruses. These findings also suggest an epitope targeting strategy to identify potent and broadly neutralizing antibodies that can aid in the design of pan-sarbecovirus vaccines and antibody therapeutics. Short SummaryDecryption of a recurrent sequence feature in anti-SARS-CoV-2 antibodies identifies how potent pan-sarbecovirus antibodies target a conserved epitope on the receptor binding domain.

immunology↗

bioRxiv2021

A large-scale systematic survey of SARS-CoV-2 antibodies reveals recurring molecular features

In the past two years, the global research in combating COVID-19 pandemic has led to isolation and characterization of numerous human antibodies to the SARS-CoV-2 spike. This enormous collection of antibodies provides an unprecedented opportunity to study the antibody response to a single antigen. From mining information derived from 88 research publications and 13 patents, we have assembled a dataset of [~]8,000 human antibodies to the SARS-CoV-2 spike from >200 donors. Analysis of antibody targeting of different domains of the spike protein reveals a number of common (public) responses to SARS-CoV-2, exemplified via recurring IGHV/IGK(L)V pairs, CDR H3 sequences, IGHD usage, and somatic hypermutation. We further present a proof-of-concept for prediction of antigen specificity using deep learning to differentiate sequences of antibodies to SARS-CoV-2 spike and to influenza hemagglutinin. Overall, this study not only provides an informative resource for antibody and vaccine research, but fundamentally advances our molecular understanding of public antibody responses to a viral pathogen.

immunology↗

bioRxiv2021

Recombination landscape dimorphism contributes to sexchromosome evolution in the dioecious plant Rumexhastatulus

There is growing evidence across diverse taxa for sex differences in the genomic landscape of recombination, but the causes and consequences of these differences remain poorly understood. Strong recombination landscape dimorphism between the sexes could have important implications for the dynamics of sex chromosome evolution and turnover because low recombination in the heterogametic sex can help favour the spread of sexually antagonistic alleles. Here, we present a sex-specific linkage map and revised genome assembly of Rumex hastatulus, representing the first characterization of sex differences in recombination landscape in a dioecious plant. We provide evidence for strong sex differences in recombination, with pericentromeric regions of highly suppressed recombination in males that cover over half of the genome. These differences are found on autosomes as well as sex chromosomes, suggesting that pre-existing differences in recombination may have contributed to sex chromosome formation and divergence. Analysis of segregation distortion suggests that haploid selection due to pollen competition occurs disproportionately in regions with low male recombination. Our results are consistent with the hypothesis that sex differences in the recombination landscape contributed to the formation of a large heteromorphic pair of sex chromosomes, and that pollen competition is an important determinant of recombination dimorphism.

genetics↗

bioRxiv2021

Immunoglobulin-producing AT2-like cells secrete IgA into the extracellular matrix in pulmonary fibrosis

Pulmonary fibrosis is an interstitial lung disease that can be caused by various factors. Here, we first observed extensive IgA deposition in the extracellular matrix (ECM) of the lungs of mice with pulmonary fibrosis induced by silica inhalation. Consistent with this phenomenon, spatial transcriptomic sequencing of fresh mouse lung tissues from control mice and model mice showed that Igha transcripts were highly expressed in the lesion area. Single-cell RNA sequencing (scRNA-seq) and reconstruction of B cell receptor (BCR) sequences revealed a new cluster of cells with a shared BCR and high expression of genes related to immunoglobulin IgA production. Surprisingly, these clonal cells had more characteristics of AT2 (alveolar epithelial cell type 2) cells than B cells; thus, these cells were named AT2-like cells. Therefore, we propose that secretion of IgA into the ECM by AT2-like cells is an important process that occurs during lung fibrosis.

cell biology↗

bioRxiv2021

Non-conserved metabolic regulation by LKB1 distinguishes human and mouse lung adenocarcinoma

KRAS is the most frequently mutated oncogene in human lung adenocarcinomas (hLUAD) and activating mutations in KRAS frequently co-occur with loss-of-function mutations in the tumor suppressor genes, TP53 or STK11/LKB1. However, mutation of all three genes is rarely observed in hLUAD, even though engineered mutations of all three genes produces a highly aggressive lung adenocarcinoma in mice (mLUAD). Here we provide an explanation of this difference between hLUAD and mLUAD by uncovering an evolutionary divergence in regulation of the glycolytic enzyme triosephosphate isomerase (TPI1). Using KRAS/TP53 mutant hLUAD cell lines, we show that TPI1 enzymatic activity can be altered via phosphorylation at Ser21 by the Salt Inducible Kinases (SIKs) in an LKB1-dependent manner; this allows modulation of glycolytic flux between completion of glycolysis and production of glycerol lipids. This metabolic flexibility appears to be critical in rapidly growing cells with KRAS and TP53 mutations, explaining why loss of LKB1 creates a metabolic liability in these tumors. In mice, the amino acid at position 21 of TPI1 is a Cys residue which can be oxidized to alter TPI1 activity, allowing regulation of glycolytic flux balance without a need for SIK kinases or LKB1. Our findings reveal an unexpected role for TPI1 in metabolic reprogramming and suggest that LKB1 and SIK family kinases are potential targets for treating KRAS/TP53 mutant hLUAD. Our data also provide a cautionary example of the limits of genetically engineered murine models as tools to study human diseases such as cancers.

cancer biology↗

bioRxiv2021

SARS-CoV-2 Beta variant infection elicits potent lineage-specific and cross-reactive antibodies

SARS-CoV-2 Beta variant of concern (VOC) resists neutralization by major classes of antibodies from non-VOC COVID-19 patients and vaccinated individuals. Here, serum of Beta variant infected patients revealed reduced cross-neutralization of non-VOC virus. From these patients, we isolated Beta-specific and cross-reactive receptor-binding domain (RBD) antibodies. The Beta-specificity results from recruitment of novel VOC-specific clonotypes and accommodation of VOC-defining amino acids into a major non-VOC antibody class that is normally sensitive to these mutations. The Beta-elicited cross-reactive antibodies share genetic and structural features with non-VOC-elicited antibodies, including a public VH1-58 clonotype targeting the RBD ridge independent of VOC mutations. These findings advance our understanding of the antibody response to SARS-CoV-2 shaped by antigenic drift with implications for design of next-generation vaccines and therapeutics. One sentence summarySARS-CoV-2 Beta variant elicits lineage-specific antibodies and antibodies with neutralizing breadth against wild-type virus and VOCs.

immunology↗

bioRxiv2021

Targeted isolation of panels of diverse human broadly neutralizing antibodies against SARS-like viruses

The emergence of current SARS-CoV-2 variants of concern (VOCs) and potential future spillovers of SARS-like coronaviruses into humans pose a major threat to human health and the global economy 1-7. Development of broadly effective coronavirus vaccines that can mitigate these threats is needed 8, 9. Notably, several recent studies have revealed that vaccination of recovered COVID-19 donors results in enhanced nAb responses compared to SARS-CoV-2 infection or vaccination alone 10-13. Here, we utilized a targeted donor selection strategy to isolate a large panel of broadly neutralizing antibodies (bnAbs) to sarbecoviruses from two such donors. Many of the bnAbs are remarkably effective in neutralization against sarbecoviruses that use ACE2 for viral entry and a substantial fraction also show notable binding to non-ACE2-using sarbecoviruses. The bnAbs are equally effective against most SARS-CoV-2 VOCs and many neutralize the Omicron variant. Neutralization breadth is achieved by bnAb binding to epitopes on a relatively conserved face of the receptor binding domain (RBD) as opposed to strain-specific nAbs to the receptor binding site that are commonly elicited in SARS-CoV-2 infection and vaccination 14-18. Consistent with targeting of conserved sites, select RBD bnAbs exhibited in vivo protective efficacy against diverse SARS-like coronaviruses in a prophylaxis challenge model. The generation of a large panel of potent bnAbs provides new opportunities and choices for next-generation antibody prophylactic and therapeutic applications and, importantly, provides a molecular basis for effective design of pan-sarbecovirus vaccines.

immunology↗