Biology subjects

Tang, N.

Publications and source records attributed to Tang, N..

At least 19 recordsLinked to original sources

bioRxiv2026

Oncolytic Newcastle disease virus promotes tumor cell apoptosis through SUMO-1-dependent PRKN-mediated degradation of c-Myc

The oncogenic transcription factor c-Myc is aberrantly upregulated in many cancers and plays a central role in tumor cell proliferation and survival. However, direct pharmacological targeting of c-Myc remains challenging because of its intrinsically disordered structure. Newcastle disease virus (NDV) is an oncolytic virus with selective antitumor activity, but the molecular mechanisms by which NDV disrupts oncogenic signaling remain incompletely understood. Here, we show that NDV induces apoptosis in multiple tumor cell lines and suppresses tumor growth in an A549 xenograft model. NDV infection markedly reduced c-Myc protein levels in tumor cells in a time- and dose-dependent manner, and c-Myc knockdown further enhanced NDV-induced intrinsic apoptosis. Mechanistically, NDV promoted ubiquitin-proteasome-dependent degradation of c-Myc through ubiquitination at Lys142. Screening of candidate E3 ubiquitin ligases identified PRKN as a key mediator of NDV-induced c-Myc degradation. NDV infection induced SUMO-1-dependent nuclear translocation of PRKN, allowing PRKN to interact with nuclear c-Myc and promote its degradation. Disruption of this pathway by SUMO-1 or PRKN knockdown impaired PRKN nuclear accumulation, restored c-Myc stability, and attenuated NDV-induced apoptosis. Functionally, expression of the degradation-resistant c-Myc K142R mutant or restoration of c-Myc in c-Myc-knockdown cells protected tumor cells from NDV-induced apoptosis. Together, these findings identify a SUMO-1-PRKN-c-Myc signaling axis that mediates NDV-induced tumor cell apoptosis and reveal c-Myc destabilization as an important mechanism underlying the oncolytic activity of NDV.

cell biology↗

bioRxiv2026

Multiplexed hormone immunoassays for women's health on a regenerable silicon photonic chip

Hormone dynamics are central to a multitude of conditions in women's health; however, limitations in the cost, convenience, and multiplexing capacity of current hormone assays preclude routine longitudinal hormone testing. This limitation severely restricts our understanding in this historically neglected field, presenting a need for improved bioanalytical tools to support hormone-informed care. Silicon photonic resonator sensors have excellent multiplexing capacity and scalable fabrication, and offer strong potential to meet this important need. Here we demonstrate, for the first time, multiplexed silicon photonic detection of two urinary hormone biomarkers, follicle-stimulating hormone (FSH) and pregnanediol-3-glucuronide (PdG), using sub-wavelength grating ring resonators and a polydopamine-based, regenerable surface chemistry. We combine a sandwich immunoassay for FSH and an antigen-down competitive immunoassay for PdG on the same chip, both amplified using a commercially available quantum-dot-streptavidin conjugate and with on-chip regeneration over multiple measurement cycles. In artificial urine, this proof-of-principle multiplexed assay achieves limits of detection of 0.594 ng/mL for FSH and 19.1 ng/mL for PdG. This architecture is inherently scalable to tens of hormone targets on a millimetre-scale chip (a >10x multiplexing improvement over typical lateral-flow immunoassays) enabling future low-cost, quantitative at-home hormone panels that could transform research, diagnostics, and treatment in women's health.

bioengineering↗

bioRxiv2026

No objective evidence of neuropsychological deficits in people with subjective cognitive changes following COVID-19 infection

Abstract/SummaryO_ST_ABSBackgroundC_ST_ABSAmong those who develop Long COVID, many experience persistent cognitive "brain fog." The degree to which these subjective complaints reflect measurable neuropsychological deficits remains unclear. Prior work suggests that subjective cognitive impairment may be more closely associated with affective symptoms than objective performance. This study examines the relationship between subjective and objective cognitive function in adults with post-COVID cognitive complaints, and assesses the association between self-reported deficits and biological markers of dementia risk and inflammation. MethodsEighty-six adults with prior COVID-19 infection (mean age 41.5 years) completed neuropsychological testing (MATRICS; CVLT-III) and self-report measures of depression and anxiety (Beck Inventories). Participants were classified as Cases (n=47) if they endorsed worsening memory or concentration since infection or Controls (n=38) if they did not. Objective cognitive impairment was defined as performance <1 SD below normative means on at least one test. APOE-{varepsilon}4 status and soluble CD14 (sCD14) levels were assessed. ResultsCases reported higher depression and anxiety symptoms than Controls (both p<0.001), but groups did not differ on objective cognitive performance (p=0.39). Cases were more likely to be APOE-{varepsilon}4 carriers (p=0.01) and had higher sCD14 levels (p=0.01). Neither marker was associated with objective performance. ConclusionsSubjective cognitive complaints following COVID-19 were not accompanied by measurable neuropsychological deficits but were linked to elevated affective symptoms and biological risk markers. Findings highlight a dissociation between perceived and objective cognition and suggest that inflammatory, genetic, and affective factors may shape self-perceived decline. Longitudinal studies are needed to determine whether these markers confer vulnerability to cognitive decline.

neuroscience↗

bioRxiv2025

Molecular profiling of glioblastoma-derived extracellular vesicles identifies small nucleolar RNAs as candidate liquid biomarkers for radiation-induced senescence

Radiation-induced senescence (RIS) in glioblastoma (GBM) is an undesirable cell fate that reduces tumor cell death and supports resistance and outgrowth. While senescence-targeting drugs are promising adjuvants, their clinical application will require proper patient selection based on post-treatment RIS burden. Current methods to evaluate senescence, however, are tissue-based, and given GBMs difficult anatomical location, post-treatment biopsies are impractical. Innovative and less invasive biomarkers for RIS are urgently needed. To this end, we aimed to identify candidate extracellular vesicle (EV) liquid biomarkers for RIS by profiling senescence-associated cargo changes within GBM EVs. Using a panel of GBM patient-derived cell cultures, we show that RIS is the primary functional state following radiation exposure and is associated with significant alterations in the cargo of senescent-derived EVs (senEVs). In particular, senEV transcriptomes have an increased abundance of senescence-associated RNA genes and gene sets. Most striking, however, was that senEVs are most differentiated by the significant enrichment of a panel of snoRNAs. This signature was conserved in 4/5 GBM models of RIS and was validated by qRT-PCR. We further confirmed snoRNA enrichment in the senEVs of a breast cancer cell line, as well as the lack of snoRNA enrichment following senescence-independent drug exposure. Analysis by mass spectrometry revealed that snoRNAs are likely co-packaged with their associating proteins, as senEVs had concurrent increases in these binding partners. We examined whether packaging is associated with nucleolar stress during RIS, but found that upregulation in senEVs is likely due to a tightly controlled cellular abundance rather than nucleoli fragmentation and release of nucleolar components to the cytoplasm. Finally, using a preliminary cohort of longitudinal plasma samples from four GBM patients, we determined the feasibility of detecting senescence-associated and snoRNA species in the extracellular vesicles of patient biofluids. Of interest, post-treatment EVs had increased senescence-associated RNAs like CDKN2B and GLB1 and the snoRNA SNORA49. Altogether, this data suggests that senEV RNA species, and particularly snoRNAs, are a promising analyte for RIS-biomarker development. With further study, this work may open avenues for a companion diagnostic for senotherapeutics.

cancer biology↗

bioRxiv2025

Missense Mutation ADNP p.C687R Disrupts Chromatin Regulation and GABAergic Differentiation in HVDAS

Activity-dependent neuroprotective protein (ADNP) is a key regulator of neurodevelopment and a high-risk gene for autism spectrum disorder (ASD). Most pathogenic variants cause loss-of-function in Helsmoortel-Van der Aa syndrome (HVDAS), yet the impact of missense mutations remains unclear. Here, we characterized a ADNP missense mutation (p.C687R) identified from a HVDAS patient, predicted to disrupt its ninth zinc finger domain. Overexpression of p.C687R altered subnuclear localization and affected wild-type ADNP distribution. In utero electroporation revealed impaired neuronal migration and cortical branching. CUT&Tag profiling showed mutant- specific chromatin binding, preferentially targeting histone modification genes through both direct and distal interactions. Patient-derived iPSCs carrying p.C687R exhibited upregulated bivalent histone marks (H3K4me3 and H3K27me3) on neurodevelopmental genes, including regulators of GABAergic differentiation, which became transcriptionally activated in neural progenitors. These findings reveal a gain-of-function mechanism by which ADNP p.C687R perturbs chromatin regulation and disrupts GABAergic lineage specification, expanding the molecular framework of ADNP pathogenesis. The Paper Explained ProblemMutations in the gene ADNP cause Helsmoortel-Van der Aa syndrome (HVDAS), a severe neurodevelopmental disorder, and also increase the risk for autism spectrum disorder (ASD). While most known ADNP mutations lead to loss of protein function, many missense mutations that alter a single amino acid remain poorly understood regarding their effects on brain development and disease contribution. ResultsWe characterized a specific missense mutation, ADNP p.C687R, from a patient diagnosed with HVDAS, and found that it does not simply inactivate the protein but instead confers a disruptive new function. Across multiple models, from cells to mice, the p.C687R mutant exhibits abnormal chromatin binding, altered subnuclear localization, and impaired neuronal migration and differentiation. Importantly, in patient-derived iPSCs, it marks distinct neurodevelopmental genes with bivalent histone modifications, which become aberrantly activated during differentiation into GABAergic neural progenitor cells. ImpactThese findings confirm the pathogenicity of the missense mutation ADNP p.C687R in HVDAS, reveal a gain-of-function mechanism whereby the mutant disrupts chromatin regulation and GABAergic lineage specification, and advance our understanding of ADNP-related neurodevelopmental disorders.

neuroscience↗

bioRxiv2025

Within-subject rhythmicity and stability of hunger, satiety, and physiological markers: insights from a five-day laboratory study in time-isolation conditions

Hunger and satiety are interoceptions involved in the control of food intake. How they change across the day and from one day to the next, as well as their relationships with physiological parameters, remain poorly understood. In a five-day laboratory study, twenty healthy male participants (24.2 {+/-} 3.3 years) were given three meals per day (breakfast, lunch, dinner), at times based on each individuals internal time. Subjects had an 8-h sleep opportunity at night recorded by polysomnography, during which time they were exposed to 4 different light intensities (0, 3, 8, or 20 lux). Hunger and satiety were assessed before and after each meal. Heart rate was measured continuously and glucose levels were sampled every 15 minutes. We found that: 1) Hunger and satiety varied dynamically with the lowest levels at breakfast and the highest at lunch and dinner (p < 0.01); 2) the intensity of hunger and satiety remained stable across the five experimental days, and were subject-dependent; 3) Heart rate was higher after than before meals (p < 0.0001), and higher around breakfast than dinner; 4) Glycemia before and after meals was respectively stable throughout the day and over the study period; 5) Interoception was correlated with fluctuations in heart rate, glucose levels and sleep duration. Overall, our results reveal that hunger and satiety perception are individual characteristics. To better understand the role of interoception in food intake control, both hunger and satiety should be measured, but separately in their respective states.

physiology↗

bioRxiv2025

Cell-Free DNA Reveals the Longitudinal Effects of Temozolomide Treatment and Host Co-Culture in Glioblastoma Models

Glioblastoma (GBM) is a highly aggressive brain tumor with limited options for longitudinal monitoring. We evaluated the potential of cell-free DNA (cfDNA) as a real-time biomarker of tumor burden under tightly controlled conditions. We measured the cfDNA release dynamics, fragmentation sizes, and variant allele frequencies (VAF) in patient-derived GBM cell cultures. Time series of cfDNA were collected and analyzed in treatment-naive monocultures, during temozolomide (TMZ) treatment, and in co-culture with normal human astrocyte (NHA) cells. Longitudinal collection of media from individual cultures demonstrated that cfDNA yield increased, indicating the ability to use cfDNA to track tumor burden over time. Using a co-culture system, we deconvoluted cfDNA admixtures by analyzing yield, fragment size patterns, and cell line-specific variants. The exclusive detection of NHA- and GBM-specific mutations confirmed the distinct contributions of each cell type. Finally, TMZ treatment of GBM cells prompted an increase in cfDNA yield and VAF, suggesting that the effects of therapy could be measured using cfDNA. These findings support cfDNA as a non-invasive biomarker for real-time monitoring of GBM progression and treatment response, with clinical potential as a liquid biopsy tool in glioblastoma management. KEY POINTSO_LIcfDNA yield and variant allele frequencies (VAFs) correlate with GBM tumor burden. C_LIO_LIcfDNA properties can be used to differentiate between cell types in a mixed population. C_LIO_LITMZ treatment increases cfDNA yield and VAFs, reflecting treatment response. C_LI IMPORTANCE OF THE STUDYThis study highlights the potential of cell-free DNA (cfDNA) as a non-invasive biomarker for monitoring glioblastoma (GBM) progression and treatment response. By utilizing in-vitro models, we demonstrate that cfDNA yield, fragmentation patterns, and variant allele frequencies (VAFs) can effectively identify treatment-induced changes, such as those induced by temozolomide (TMZ) treatment, providing insights into therapeutic response. These results have significant translational implications, as cfDNA could serve as a real-time liquid biopsy tool for monitoring GBM progression, assessing treatment efficacy, and identifying early signs of treatment resistance in clinical settings. The ability to track tumor dynamics non-invasively holds great promise for improving GBM patient management and guiding personalized therapeutic approaches.

cancer biology↗

bioRxiv2025

Tenotomized Achilles tendons of MRL/MpJ mice show scar-mediated healing, but have superior recovery of biomechanical properties

Tendon healing in Murphy Ross Large (MRL/MpJ) mice was examined using an Achilles tendon tenotomy model, a full transection model, compared to a patella focal injury model in which tendons in MRL/MpJ mice showed regenerative healing. After complete transection, the Achilles tendons of MRL/MpJ mice healed via scar formation, regardless of sex, as did C57BL/6J mice. Tensile testing found that mechanical properties of injured tendons of both MRL/MpJ female and male mice exhibited comparable levels to those of C57BL/6J female and male mice, respectively after 4 weeks of healing, which is during the remodeling phase. After 10 weeks of healing, injured tendons of MRL/MpJ mice possessed smaller heterotopic ossification volumes than those of C57BL/6J mice. Proteomics analysis revealed similar alterations to signaling pathways in injured tendons of MRL/MpJ and C57BL/6J male mice after 4 weeks of healing. However, among the altered pathways, actin cytoskeleton and integrin signaling pathways were two of the top pathways that were more prominently activated in C57BL/6J males than in MRL/MpJ males. These findings indicate that MRL/MpJ mice possess limited capacity to regenerate injured tendons after complete rupture, and that tenotomized Achilles tendons of MRL/MpJ male mice have lesser induction of heterotopic ossification and lower activation of the signaling pathways also induced with injury in C57BL/6J male mice.

pathology↗

bioRxiv2025

AI-driven discovery of host thioredoxin as a CRISPR enhancer of phage-encoded miniature Cas12 hacker nuclease

The evolutionary arms race between bacteriophages and their bacterial hosts has driven the evolution of sophisticated adaptive immune systems, such as CRISPR-Cas, as a crucial defense mechanism. While bacteriophages have developed various anti-CRISPR strategies to counteract these immune systems, the role of bacterial host factors in enhancing CRISPR-Cas functions has been relatively unexplored. In this study, we employ an artificial intelligence (AI)-driven approach to systematically analyze potential interactions between Escherichia coli (E. coli) proteins and fifteen previously uncharacterized Cas12 proteins, generating 65,715 predicted binary complex structures. Our findings reveal a previously unknown dimension of CRISPR immunity, demonstrating that the hosts ubiquitous redox enzyme, thioredoxin (TrxA), significantly enhances the DNA cleavage efficiency of a phage-encoded, miniature Cas12 nuclease (termed Cas12 hacker). This synergistic relationship represents a strategic inversion, where a bacteriophage hijacks a host protein to reinforce its own genome degradation machinery, possibly targeting rival nucleic acids. Through comprehensive biochemical characterizations, structural analyses of the Cas12 hacker-TrxA-sgRNA-dsDNA quaternary complex, and in vivo bacterial defense assays, we uncover an intricate association in which thioredoxin binds to and activates the Cas12 hacker nuclease, intensifying its DNA cleavage capacity and bolstering CRISPR immunity. Our findings expand the understanding of the molecular interactions underlying host-phage conflicts and highlight the potential for harnessing endogenous host factors to enhance the capabilities of CRISPR-based genetic engineering tools.

microbiology↗

bioRxiv2024

Retinoid-impregnated nanoparticles enable control of bone growth by site-specific modulation of endochondral ossification in mice

Growth-plate (GP) injures in limbs and other sites can impair GP function and cause deceleration of bone growth, leading to progressive bone lengthening imbalance, deformities and/or physical discomfort, decreased motion and pain. At present, surgical interventions are the only means available to correct these conditions by suppressing the GP activity in the unaffected limb and/or other bones in the ipsilateral region. Here, we aimed to develop a pharmacologic treatment of GP growth imbalance that involves local application of nanoparticles-based controlled release of a selective retinoic acid nuclear receptor gamma (RAR{gamma}) agonist drug. When RAR{gamma} agonist-loaded nanoparticles were implanted near the medial and lateral sides of proximal tibial growth plate in juvenile C57BL/6j mice, the GP underwent involution and closure. Overall tibia length was shortened compared to the contralateral element implanted with drug-free control nanoparticles. Importantly, when the RAR{gamma} agonist nanoparticles were implanted on the lateral side only, the adjacent epiphysis tilted toward the lateral site, leading to apical angulation of the tibia. In contrast to the local selectivity of these responses, systemic administration of RAR{gamma} agonists led to GP closure at many sites, inhibiting skeletal growth over time. Agonists for RAR and RAR{beta} elicited no obvious responses over parallel regimens. Our findings provide novel evidence that RAR{gamma} agonist-loaded nanoparticles can control activity, function and directionality of a targeted GP, offering a potential and clinically-relevant alternative or supplementation to surgical correction of limb length discrepancy and angular deformities. Lay summaryGrowth-plates (physes), which are cartilage tissues near the ends of bones, support normal bone growth in children. Growth plate injures in limbs and other sites can impair growth plate function, leading to inhibited or imbalanced bone growth, skeletal deformities, decreased motion, discomfort or pain. At present, surgical interventions are the only means available to correct these conditions. Here, we aimed to develop a pharmacologic treatment for bone growth imbalance. Nanoparticles loaded with a selective agonist for the retinoic acid nuclear receptor gamma were prepared and implanted near the tibial growth plate in juvenile mice. The growth plate underwent involution and closure, and overall tibia length was shortened compared to the contralateral element implanted with drug-free control nanoparticles. Importantly, when the same drug nanoparticles were implanted in only one side of the tibia, the tibia was tilted toward the injection site. Our findings provide novel evidence that retinoic acid receptor gamma agonist-loaded nanoparticles can control activity, function and directionality of a targeted growth plate, offering a potential and clinically-relevant alternative or supplementation to surgical correction of limb length imbalances and deformities.

pharmacology and toxicology↗

bioRxiv2024

Alzheimer Disease Knowledge Graph Enhances Knowledge Discovery and Disease Prediction

BackgroundAlzheimers disease (AD), a progressive neurodegenerative disorder, continues to increase in prevalence without any effective treatments to date. In this context, knowledge graphs (KGs) have emerged as a pivotal tool in biomedical research, offering new perspectives on drug repurposing and biomarker discovery by analyzing intricate network structures. Our study seeks to build an AD-specific knowledge graph, highlighting interactions among AD, genes, variants, chemicals, drugs, and other diseases. The goal is to shed light on existing treatments, potential targets, and diagnostic methods for AD, thereby aiding in drug repurposing and the identification of biomarkers. ResultsWe annotated 800 PubMed abstracts and leveraged GPT-4 for text augmentation to enrich our training data for named entity recognition (NER) and relation classification. A comprehensive data mining model, integrating NER and relationship classification, was trained on the annotated corpus. This model was subsequently applied to extract relation triplets from unannotated abstracts. To enhance entity linking, we utilized a suite of reference biomedical databases and refine the linking accuracy through abbreviation resolution. As a result, we successfully identified 3,199,276 entity mentions and 633,733 triplets, elucidating connections between 5,000 unique entities. These connections were pivotal in constructing a comprehensive Alzheimers Disease Knowledge Graph (ADKG). We also integrated the ADKG constructed after entity linking with other biomedical databases. The ADKG served as a training ground for Knowledge Graph Embedding models with the high-ranking predicted triplets supported by evidence, underscoring the utility of ADKG in generating testable scientific hypotheses. Further application of ADKG in predictive modeling using the UK Biobank data revealed models based on ADKG outperforming others, as evidenced by higher values in the areas under the receiver operating characteristic (ROC) curves. ConclusionThe ADKG is a valuable resource for generating hypotheses and enhancing predictive models, highlighting its potential to advance ADs disease research and treatment strategies.

bioinformatics↗

bioRxiv2023

TCM-CMap: A Novel Computational Methodology to Link Gene Perturbation to Therapeutic Targets in Complex TCM Prescriptions

Herbal medicine, especially Traditional Chinese medicine (TCM), is a valuable resource of natural products for drug discovery with obvious therapeutic effects. However, the mechanisms of action (MOAs) of herbal medicine are often unknown due to limited target information and the complexity of multiple ingredients and targets. This study developed a Herb-CMap algorithm to prioritize active ingredients and targets within herbal medicine by integrating transcriptomics- based gene perturbation data with a random walk algorithm. This methodology bridges the gap between gene perturbation of herbal medicine and its therapeutic target. Using the Suhuang antitussive capsule (Suhuang) for treating cough variant asthma (CVA) as a case study, we identify and experimentally verify that quercetin and luteolin directly interact with Il17a, Pik3cb, Pik3cd, Akt1, and Tnf. These interactions inhibit the IL-17 signaling pathway and inactivate PI3K, Akt, and NF- {kappa}B, preventing lung inflammation and treating CVA. Our findings demonstrate the potential of the Herb-CMap methodology to provide insights into the molecular MOAs of herbal medicine, thereby advancing drug discovery from herbal medicine.

systems biology↗

bioRxiv2022

A cocktail containing two synergetic antibodies broadly neutralizes SARS-CoV-2 and its variants including Omicron BA.1 and BA.2

Neutralizing antibodies (NAbs) can prevent and treat infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, continuously emerging variants, such as Omicron, have significantly reduced the potency of most known NAbs. The selection of NAbs with broad neutralizing activities and the identification of conserved critical epitopes are still urgently needed. Here, we identified an extremely potent antibody (55A8) by single B-cell sorting from convalescent SARS-CoV-2-infected patients that recognized the receptor-binding domain (RBD) in the SARS-CoV-2 spike (S) protein. 55A8 could bind to wild-type SARS-CoV-2, Omicron BA.1 and Omicron BA.2 simultaneously with 58G6, a NAb previously identified by our group. Importantly, an antibody cocktail containing 55A8 and 58G6 (2-cocktail) showed synergetic neutralizing activity with a half-maximal inhibitory concentration (IC50) in the picomolar range in vitro and prophylactic efficacy in hamsters challenged with Omicron (BA.1) through intranasal delivery at an extraordinarily low dosage (25 g of each antibody daily) at 3 days post-infection. Structural analysis by cryo-electron microscopy (cryo-EM) revealed that 55A8 is a Class III NAb that recognizes a highly conserved epitope. It could block angiotensin-converting enzyme 2 (ACE2) binding to the RBD in the S protein trimer via steric hindrance. The epitopes in the RBD recognized by 55A8 and 58G6 were found to be different and complementary, which could explain the synergetic mechanism of these two NAbs. Our findings not only provide a potential antibody cocktail for clinical use against infection with current SARS-CoV-2 strains and future variants but also identify critical epitope information for the development of better antiviral agents.

immunology↗

bioRxiv2022

Extensive neutralization against SARS-CoV-2 variants elicited by Omicron-specific subunit vaccine booster

The currently dominant variant of SARS-CoV-2 Omicron, carrying a great number of mutations, has been verified its strong capacity of immune escape in COVID-19 convalescents and vaccinated individuals. An increased risk of SARS-CoV-2 reinfection or breakthrough infection should be concerned. Here we reported higher humoral immune response elicited by Delta and Omicron variants after breaking through previous infection and cross-neutralization against VOCs, compared to the ancestral wild-type (WT) virus infection. To overcome the immune escape of Omicron, Omicron-specific vaccine was considered as a novel and potential strategy. Mouse models were used to verify whether Omicron-specific RBD subunit boost immune response by immunizing Omicron-RBD recombinant proteins. Three doses of Omicron-RBD immunization elicit comparable neutralizing antibody (NAb) titers with three doses of WT-RBD immunization, but the neutralizing activity was not cross-active. By contrast, two doses of WT-RBD with an Omicron-RBD booster increased the NAb geometric mean titers against Omicron by 9 folds. Moreover, an additional boost vaccination with Omicron-RBD protein could increase humoral immune response against both WT and current VOCs. These results suggest that the Omicron-specific subunit booster shows its advantages in the immune protection from both WT and current VOCs, and that SARS-CoV-2 vaccines administration using two or more virus lineages as antigens might improve the NAb response.

microbiology↗

bioRxiv2021

Reduced infectivity but increased immune escape of the new SARS-CoV-2 variant of concern Omicron

A new detected SARS-CoV-2 variant Omicron (B.1.1.529) had reported from more than 80 countries. In the past few weeks, a new wave of infection driven by Omicron is in progress. Omicron Spike (S) protein pseudotyped virus was used to determine the effect of S mutations on its capacity of infectivity and immune evasion. Our results showed the lower entry efficiency and less cleavage ability of Omicron than D614G variant. Pseudotype-based neutralizing assay was performed to analyze neutralizing antibodies elicited by previously infection or the RBD-based protein subunit vaccine ZF2001 against the Omicron variant. Sera sampled at around one month after symptom onset from 12 convalescents who were previously infected by SARS-CoV-2 original strain shows a more than 20-fold decrease of neutralizing activity against Omicron variant, when compared to D614G variant. Among 12 individuals vaccinated by RBD subunit vaccine, 58.3% (7/12) sera sampled at 15-60 days after 3rd-dose vaccination did not neutralize Omicron. Geometric mean titers (GMTs, 50% inhibitory dose [ID50]) of these sera against Omicron were 9.4-fold lower than against D614G. These results suggested a higher risk of Omicron breakthrough infections and reduced efficiency of the protective immunity elicited by existing vaccines. There are important implications about the modification and optimization of the current epidemic prevention and control including vaccine strategies and therapeutic antibodies against Omicron variant.

microbiology↗

bioRxiv2021

Reduced neutralization of SARS-CoV-2 B.1.617 variant by inactivated and RBD-subunit vaccine

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The Spike protein that mediates coronavirus entry into host cells is a major target for COVID-19 vaccines and antibody therapeutics. However, multiple variants of SARS-CoV-2 have emerged, which may potentially compromise vaccine effectiveness. Using a pseudovirus-based assay, we evaluated SARS-CoV-2 cell entry mediated by the viral Spike B.1.617 and B.1.1.7 variants. We also compared the neutralization ability of monoclonal antibodies from convalescent sera and neutralizing antibodies (NAbs) elicited by CoronaVac (inactivated vaccine) and ZF2001 (RBD-subunit vaccine) against B.1.617 and B.1.1.7 variants. Our results showed that, compared to D614G and B.1.1.7 variants, B.1.617 shows enhanced viral entry and membrane fusion, as well as more resistant to antibody neutralization. These findings have important implications for understanding viral infectivity and for immunization policy against SARS-CoV-2 variants.

microbiology↗

bioRxiv2021

Ultrapotent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus displayed remarkable efficacy against authentic B.1.351 virus. Each of these 3 mAbs in combination with one neutralizing Ab recognizing non-competing epitope exhibited synergistic effect against authentic SARS-CoV-2 virus. Surprisingly, structural analysis revealed that 58G6 and 13G9, encoded by the IGHV1-58 and the IGKV3-20 germline genes, both recognized the steric region S470-495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly bound to another region S450-458 in the RBD. Significantly, 58G6 and 510A5 both demonstrated prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. These 2 ultrapotent neutralizing Abs can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.

immunology↗

bioRxiv2021

Decoding regulatory specificity of human ribosomal proteins on global gene expression

Human ribosomes, made of around 80 ribosomal proteins (RPs) and four ribosomal RNAs, have long been thought as uniform passive protein-making factories with little regulatory function. Recently, accumulating evidence showed heterogeneity of RP composition in ribosomes responsible for regulating gene expression in development and tumorigenesis. However, a comprehensive understanding of regulatory spectrum of RPs is still lacking. In this study, we conducted a systematic survey of regulatory specificity of human RPs on global gene expression. We quantified translational and transcriptional changes of gene expression upon deficiency of 75 RPs, including 44 from the large subunit (60S) and 31 from the small subunit (40S), by ribosomal profiling and RNA sequencing analysis. We showed that RP deficiency induced diverse expression changes, particularly at the translational level. RPs were subjected to co-translational regulation under ribosomal stress where deficiency of the 60S and the 40S RPs had opposite effects on the two subunits. RP deficiency perturbed expression of genes related to cell cycle, cellular metabolism, signal transduction and development. Deficiency of RPs from the 60S led to a greater repression effect on cell growth than that from the 40S by perturbing P53 signaling and cell cycle pathways. To demonstrate functional specificity of RPs, we showed that RPS8 deficiency stimulated cellular apoptosis and RPL13 or RPL18 deficiency promoted cellular senescence. We also showed that RPL11 and RPL15 played important roles in retina development and angiogenesis, respectively. Overall, our study demonstrated a widespread regulatory role of RPs in controlling cellular activity, providing an important resource which can offer novel insights into ribosome regulation in human diseases and cancer.

cell biology↗