Spike substitution T813S increases Sarbecovirus fusogenicity by enhancing the usage of TMPRSS2.

SARS-CoV Spike (S) protein shares considerable homology with SARS-CoV-2 S, especially in the conserved S2 subunit (S2). S protein mediates coronavirus receptor binding and membrane fusion, and the latter activity can greatly influence coronavirus infection. We observed that SARS-CoV S is less effective in inducing membrane fusion compared with SARS-CoV-2 S. We identify that S813T mutation is sufficient in S2 interfering with the cleavage of SARS-CoV-2 S by TMPRSS2, reducing spike fusogenicity and pseudoparticle entry. Conversely, the mutation of T813S in SARS-CoV S increased fusion ability and viral replication. Our data suggested that residue 813 in the S was critical for the proteolytic activation, and the change from threonine to serine at 813 position might be an evolutionary feature adopted by SARS-2-related viruses. This finding deepened the understanding of Spike fusogenicity and could provide a new perspective for exploring Sarbecovirus' evolution.

Comparative global B cell receptor repertoire difference induced by SARS-CoV-2 infection or vaccination via single-cell V(D)J sequencing.

Dynamic changes of the paired heavy and light chain B cell receptor (BCR) repertoire provide an essential insight into understanding the humoral immune response post-SARS-CoV-2 infection and vaccination. However, differences between the endogenous paired BCR repertoire kinetics in SARS-CoV-2 infection and previously recovered/naïve subjects treated with the inactivated vaccine remain largely unknown. We performed single-cell V(D)J sequencing of B cells from six healthy donors with three shots of inactivated SARS-CoV-2 vaccine (BBIBP-CorV), five people who received the BBIBP-CorV vaccine after having recovered from COVID-19, five unvaccinated COVID-19 recovered patients and then integrated with public data of B cells from four SARS-CoV-2-infected subjects. We discovered that BCR variable (V) genes were more prominently used in the SARS-CoV-2 exposed groups (both in the group with active infection and in the group that had recovered) than in the vaccinated groups. The VH gene that expanded the most after SARS-CoV-2 infection was IGHV3-33, while IGHV3-23 in the vaccinated groups. SARS-CoV-2-infected group enhanced more BCR clonal expansion and somatic hypermutation than the vaccinated healthy group. A small proportion of public clonotypes were shared between the SARS-CoV-2 infected, vaccinated healthy, and recovered groups. Moreover, several public antibodies had been identified against SARS-CoV-2 spike protein. We comprehensively characterize the paired heavy and light chain BCR repertoire from SARS-CoV-2 infection to vaccination, providing further guidance for the development of the next-generation precision vaccine.

Stationary distribution and long-time behavior of COVID-19 model with stochastic effect

The coronavirus disease (COVID-19) is a dangerous pandemic and it spreads to many people in most of the world. In this paper, we propose a COVID-19 model with the assumption that it is affected by randomness. For positivity, we prove the global existence of positive solution and the system exhibits extinction under certain parametric restrictions. Moreover, we establish the stability region for the stochastic model under the behavior of stationary distribution. The stationary distribution gives the guarantee of the appearance of infection in the population. Besides that, we find the reproduction ratio R0S for prevail and disappear of infection within the human population. From the graphical representation, we have validated the threshold conditions that define in our theoretical findings. [ FROM AUTHOR] Copyright of International Journal of Biomathematics is the property of World Scientific Publishing Company and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

ORF8 protein of SARS-CoV-2 reduces male fertility in mice.

As one of the most rapidly evolving proteins of the genus Betacoronavirus, open reading frames (ORF8's) function and potential pathological consequence in vivo are still obscure. In this study, we show that the secretion of ORF8 is dependent on its N-terminal signal peptide sequence and can be inhibited by reactive oxygen species scavenger and endoplasmic reticulum-Golgi transportation inhibitor in cultured cells. To trace the effect of its possible in vivo secretion, we examined the plasma samples of coronavirus disease 2019 (COVID-19) convalescent patients and found that the patients aged from 40 to 60 had higher antibody titers than those under 40. To explore ORF8's in vivo function, we administered the mice with ORF8 via tail-vein injection to simulate the circulating ORF8 in the patient. Although no apparent difference in body weight, food intake, and vitality was detected between vehicle- and ORF8-treated mice, the latter displayed morphological abnormalities of testes and epididymides, as indicated by the loss of the central ductal lumen accompanied by a decreased fertility in 5-week-old male mice. Furthermore, the analysis of gene expression in the testes between vehicle- and ORF8-treated mice identified a decreased expression of Col1a1, the loss of which is known to be associated with mice's infertility. Although whether our observation in mice could be translated to humans remains unclear, our study provides a potential mouse model that can be used to investigate the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the human reproductive system.

Interaction Context-Aware Network Behavior Anomaly Detection for Discovering Unknown Attacks

Network behavior anomaly detection is an effective approach to discover unknown attacks, where generating high-efficacy network behavior representation is one of the most crucial parts. Nowadays, complicated network environments and advancing attack techniques make it more challenging. Existing methods cannot yield satisfied representations that express the semantics of network behaviors comprehensively. To tackle this problem, we propose XNBAD, a novel unsupervised network behavior anomaly detection framework, in this work. It integrates the timely high-order host states under the dynamic interaction context with the conversation patterns between hosts for behavior representation. High-order states can better summarize latent interaction patterns, but they are hard to be obtained directly. Therefore, XNBAD utilizes a graph neural network (GNN) to automatically generate high-order features from series of extracted base ones. We evaluated the detection performance of XNBAD in a publicly available benchmark dataset ISCX-2012. To report detailed and precise experimental results, we carefully refined the dataset before evaluation. The results show that XNBAD discovered various attack behaviors more effectively, and it significantly outperformed the existing representative methods by at least 3.8% relative improvement in terms of the overall weighted AUC.

Challenges in simulating and modeling the airborne virus transmission: A state-of-the-art review.

Recently, the COVID-19 virus pandemic has led to many studies on the airborne transmission of expiratory droplets. While limited experiments and on-site measurements offer qualitative indication of potential virus spread rates and the level of transmission risk, the quantitative understanding and mechanistic insights also indispensably come from careful theoretical modeling and numerical simulation efforts around which a surge of research papers has emerged. However, due to the highly interdisciplinary nature of the topic, numerical simulations of the airborne spread of expiratory droplets face serious challenges. It is essential to examine the assumptions and simplifications made in the existing modeling and simulations, which will be reviewed carefully here to better advance the fidelity of numerical results when compared to the reality. So far, existing review papers have focused on discussing the simulation results without questioning or comparing the model assumptions. This review paper focuses instead on the details of the model simplifications used in the numerical methods and how to properly incorporate important processes associated with respiratory droplet transmission. Specifically, the critical issues reviewed here include modeling of the respiratory droplet evaporation, droplet size distribution, and time-dependent velocity profile of air exhaled from coughing and sneezing. According to the literature review, another problem in numerical simulations is that the virus decay rate and suspended viable viral dose are often not incorporated; therefore here, empirical relationships for the bioactivity of coronavirus are presented. It is hoped that this paper can assist researchers to significantly improve their model fidelity when simulating respiratory droplet transmission.

Rapid isolation and immune profiling of SARS-CoV-2 specific memory B cell in convalescent COVID-19 patients via LIBRA-seq.

B cell response plays a critical role against SARS-CoV-2 infection. However, little is known about the diversity and frequency of the paired SARS-CoV-2 antigen-specific BCR repertoire after SARS-CoV-2 infection. Here, we performed single-cell RNA sequencing and VDJ sequencing using the memory and plasma B cells isolated from five convalescent COVID-19 patients, and analyzed the spectrum and transcriptional heterogeneity of antibody immune responses. Via linking BCR to antigen specificity through sequencing (LIBRA-seq), we identified a distinct activated memory B cell subgroup (CD11chigh CD95high) had a higher proportion of SARS-CoV-2 antigen-labeled cells compared with memory B cells. Our results revealed the diversity of paired BCR repertoire and the non-stochastic pairing of SARS-CoV-2 antigen-specific immunoglobulin heavy and light chains after SARS-CoV-2 infection. The public antibody clonotypes were shared by distinct convalescent individuals. Moreover, several antibodies isolated by LIBRA-seq showed high binding affinity against SARS-CoV-2 receptor-binding domain (RBD) or nucleoprotein (NP) via ELISA assay. Two RBD-reactive antibodies C14646P3S and C2767P3S isolated by LIBRA-seq exhibited high neutralizing activities against both pseudotyped and authentic SARS-CoV-2 viruses in vitro. Our study provides fundamental insights into B cell response following SARS-CoV-2 infection at the single-cell level.