Clinical characteristics and host immunity responses of SARS-CoV-2 Omicron variant BA.2 with deletion of ORF7a, ORF7b and ORF8.

BACKGROUND: The pathogenicity and virulence of the Omicron strain have weakened significantly pathogenesis of Omicron variants. Accumulating data indicated accessory proteins play crucial roles in host immune evasion and virus pathogenesis of SARS-CoV-2. Therefore, the impact of simultaneous deletion of accessory protein ORF7a, ORF7b and ORF8 on the clinical characteristics and specific immunity in Omicron breakthrough infected patients (BIPs) need to be verified. METHODS: Herein, plasma cytokines were identified using a commercial Multi-cytokine detection kit. Enzyme-linked immunosorbent assay and pseudovirus neutralization assays were utilized to determine the titers of SARS-CoV-2 specific binding antibodies and neutralizing antibodies, respectively. In addition, an enzyme-linked immunospot assay was used to quantify SARS-CoV-2 specific T cells and memory B cells. RESULTS: A local COVID-19 outbreak was caused by the Omicron BA.2 variant, which featured a deletion of 871 base pairs (∆871 BA.2), resulting in the removal of ORF7a, ORF7b, and ORF8. We found that hospitalized patients with ∆871 BA.2 had significantly shorter hospital stays than those with wild-type (WT) BA.2. Plasma cytokine levels in both ∆871 BA.2 and WT BA.2 patients were within the normal range of reference, and there was no notable difference in the titers of SARS-CoV-2 ancestor or Omicron-specific binding IgG antibodies, neutralizing antibody titers, effector T cells, and memory B cells frequencies between ∆871 BA.2 and WT BA.2 infected adult patients. However, antibody titers in ∆871 BA.2 infected adolescents were higher than in adults. CONCLUSIONS: The simultaneous deletion of ORF7a, ORF7b, and ORF8 facilitates the rapid clearance of the BA.2 variant, without impacting cytokine levels or affecting SARS-CoV-2 specific humoral and cellular immunity in Omicron-infected individuals.

Interfacial water molecules contribute to antibody binding to the receptor-binding domain of SARS-CoV-2 spike protein.

Antibodies that recognize the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially the neutralizing antibodies, carry great hope in the treatment and final elimination of COVID-19. Driven by a synchronized global effort, thousands of antibodies against the spike protein have been identified during the past two years, with the structural information available at atomistic detail for hundreds of these antibodies. We developed an improved molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method including explicitly treated interfacial water to calculate the binding free energy between representative antibodies and the receptor binding domain (RBD) domain of SARS-COV-2 spike proteins. We discovered that explicit treatment of water molecules located at the interface between RBD and antibody effectively improves the results for the WT and variants of concern (VOC) systems. Interfacial water molecules, together with surface and internal water molecules, behave drastically from bulk water and exert peculiar impacts on protein dynamics and energy, and thus warrant explicit treatment to complement implicit solvent models. Our results illustrate the importance of including interfacial water molecules to approach efficient and reliable prediction of binding free energy.Communicated by Ramaswamy H. Sarma.

Inosine: a broad-spectrum anti-inflammatory against SARS-CoV-2 infection-induced acute lung injury via suppressing TBK1 phosphorylation.

SARS-CoV-2-induced cytokine storms constitute the primary cause of COVID-19 progression, severity, criticality, and death. Glucocorticoid and anti-cytokine therapies have been frequently administered to treat COVID-19 but have had limited clinical efficacy in severe and critical cases. Nevertheless, the weaknesses of these treatment modalities have prompted the development of anti-inflammatory therapy against this infection. We found that the broad-spectrum anti-inflammatory agent inosine downregulated proinflammatory IL-6, upregulated anti-inflammatory IL-10, and ameliorated acute inflammatory lung injury caused by multiple infectious agents. Inosine significantly improved survival in mice infected with SARS-CoV-2. It indirectly impeded TANK-binding kinase 1 (TBK1) phosphorylation by binding stimulator of interferon genes (STING) and glycogen synthase kinase-3ß (GSK3ß), inhibited the activation and nuclear translocation of the downstream transcription factors IRF3 and NF-κB, and downregulated IL-6 in the sera and lung tissues of mice infected with lipopolysaccharide (LPS), H1N1, or SARS-CoV-2. Thus, inosine administration is feasible for clinical anti-inflammatory therapy against severe and critical COVID-19. Moreover, targeting TBK1 is a promising strategy for inhibiting cytokine storms and mitigating acute inflammatory lung injury induced by SARS-CoV-2 and other infectious agents.

Targeted photodynamic neutralization of SARS-CoV-2 mediated by singlet oxygen.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has been on a rampage for more than two years. Vaccines in combination with neutralizing antibodies (NAbs) against SARS-CoV-2 carry great hope in the treatment and final elimination of coronavirus disease 2019 (COVID-19). However, the relentless emergence of variants of concern (VOC), including the most recent Omicron variants, presses for novel measures to counter these variants that often show immune evasion. Hereby we developed a targeted photodynamic approach to neutralize SARS-CoV-2 by engineering a genetically encoded photosensitizer (SOPP3) to a diverse list of antibodies targeting the wild-type (WT) spike protein, including human antibodies isolated from a 2003 Severe acute respiratory syndrome (SARS) patient, potent monomeric and multimeric nanobodies targeting receptor-binding domain (RBD), and non-neutralizing antibodies (non-NAbs) targeting the more conserved N-terminal domain (NTD). As confirmed by pseudovirus neutralization assay, this targeted photodynamic approach significantly increased the efficacy of these antibodies, especially that of non-NAbs, against not only the WT but also the Delta strain and the heavily immune escape Omicron strain (BA.1). Subsequent measurement of infrared phosphorescence at 1270 nm confirmed the generation of singlet oxygen (1O2) in the photodynamic process. Mass spectroscopy assay uncovered amino acids in the spike protein targeted by 1O2. Impressively, Y145 and H146 form an oxidization "hotspot", which overlaps with the antigenic "supersite" in NTD. Taken together, our study established a targeted photodynamic approach against the SARS-CoV-2 virus and provided mechanistic insights into the photodynamic modification of protein molecules mediated by 1O2.

Commercial dynamics in urban China during the COVID-19 recession: Vulnerability and short-term adaptation of commercial centers in Shanghai.

Studying the commercial dynamics during the COVID-19 recession could help deepen our understanding of how the pandemic damages the commercial economy and how to against the pandemic. This study aims to explore the vulnerability and adaptation of commercial centers using a weekly consumption data of UnionPay cards in Shanghai. A vulnerability index and multiscale geographically weighted regressions (MGWR) are employed. Our results suggest that retail, leisure, and entertainment sectors are less vulnerable to the pandemic at the early stage, when catering, life service, and wholesale sectors are more influenced. Catering, life service, and wholesale sectors were better adapted to the second wave of the pandemic, while the retail and entertainment sectors were even more vulnerable. Further analysis using MGWR models suggests that the commercial centers with higher consumption volume are better adapted to the shock. The diversity of commercial sectors mainly reduces low-level commercial centers' vulnerability to the pandemic. The commercial centers targeting high-end consumers with wider hinterland were less adapted to the pandemic. These research outcomes reveal the disparities in commercial centers' vulnerability against COVID-19 and highlight adaptation's role during the pandemic.

The persuasive role of the past: Policy feedback and citizens' acceptance of information communication technologies during the COVID‐19 pandemic in China

How can the enforcement of policies in the past influence a society's future adoption of information communication technologies (ICTs)? In this paper, we tackle this question by exploring how past e‐governance policies influence citizens' willingness to use the health QR code, which is a COVID‐19 tracing app widely used in China's pandemic control. Past policies regarding smart‐city development in China involve two aspects: the construction of electronic infrastructure and the applications of specific technologies. Empirical analysis based on a nationwide dataset in China suggests that past policies exhibit persuasive effects and influence citizens' acceptance of the health QR code. Specifically, e‐governance applications in cities significantly enhance citizens' acceptance through the demonstration of their usefulness. However, the construction of e‐governance infrastructure per se does not have the same impact on citizens' acceptance. By connecting citizens' acceptance of new technology with past e‐governance policies, the study illustrates a nuanced policy feedback mechanism through which past policies can substantially reshape public opinion by policy outcomes.

The persuasive role of the past: Policy feedback and citizens' acceptance of information communication technologies during the COVID-19 pandemic in China.

How can the enforcement of policies in the past influence a society's future adoption of information communication technologies (ICTs)? In this paper, we tackle this question by exploring how past e-governance policies influence citizens' willingness to use the health QR code, which is a COVID-19 tracing app widely used in China's pandemic control. Past policies regarding smart-city development in China involve two aspects: the construction of electronic infrastructure and the applications of specific technologies. Empirical analysis based on a nationwide dataset in China suggests that past policies exhibit persuasive effects and influence citizens' acceptance of the health QR code. Specifically, e-governance applications in cities significantly enhance citizens' acceptance through the demonstration of their usefulness. However, the construction of e-governance infrastructure per se does not have the same impact on citizens' acceptance. By connecting citizens' acceptance of new technology with past e-governance policies, the study illustrates a nuanced policy feedback mechanism through which past policies can substantially reshape public opinion by policy outcomes.

¿Cómo puede la aplicación de políticas en el pasado influir en la futura adopción de tecnologías de la información y la comunicación (TIC) en una sociedad? En este documento, abordamos esta pregunta explorando cómo las políticas de gobierno electrónico anteriores influyen en la voluntad de los ciudadanos de usar el código QR de salud, que es una aplicación de rastreo de COVID­19 ampliamente utilizada en el control de la pandemia en China. Las políticas anteriores con respecto al desarrollo de ciudades inteligentes en China involucran dos aspectos: la construcción de infraestructura electrónica y las aplicaciones de tecnologías específicas. El análisis empírico basado en un conjunto de datos a nivel nacional en China sugiere que las políticas anteriores exhiben efectos persuasivos e influyen en la aceptación del código QR de salud por parte de los ciudadanos. Específicamente, las aplicaciones de gobierno electrónico en las ciudades mejoran significativamente la aceptación de los ciudadanos a través de la demostración de su utilidad. Sin embargo, la construcción de infraestructura de gobierno electrónico per se no tiene el mismo impacto en la aceptación de los ciudadanos. Al conectar la aceptación de las nuevas tecnologías por parte de los ciudadanos con las políticas anteriores de gobierno electrónico, el estudio ilustra un mecanismo matizado de retroalimentación de políticas a través del cual las políticas anteriores pueden remodelar sustancialmente la opinión pública mediante los resultados de las políticas.

A nucleic acid detection assay combining reverse transcription recombinase-aided amplification with a lateral flow dipstick for the rapid visual detection of porcine deltacoronavirus.

Porcine deltacoronavirus (PDCoV) is an emerging enteropathogen causing severe diarrhoea, dehydration, and death in nursing piglets and enormous economic losses for the global swine industry. Furthermore, it can infect multiple animal species including humans. Therefore, a rapid, definitive diagnostic assay is required for the effective control of this zoonotic pathogen. To identify PDCoV, we developed a nucleic acid detection assay combining reverse transcription recombinase-aided amplification (RT-RAA) with a lateral flow dipstick (LFD) targeting the highly conserved genomic region in the ORF1b gene. The RT-RAA-LFD assay exhibited good PDCoV detection reproducibility and repeatability and could be completed within 11 min. Ten minutes at 40 °C was required for nucleic acid amplification and 1 min at room temperature was needed for the visual LFD readout. The assay specifically detected PDCoV and did not cross-react with any other major swine pathogens. The 95% limit of detection (LOD) was 3.97 median tissue culture infectious dose PDCoV RNA per reaction. This performance was comparable to that of a reference TaqMan-based real-time RT-PCR (trRT-PCR) assay for PDCoV. Of 149 swine small intestine, rectal swab, and serum samples, 71 and 75 tested positive for PDCoV according to RT-RAA-LFD and trRT-PCR, respectively. The diagnostic coincidence rate for both assays was 97.32% (145/149) and the kappa value was 0.946 (p < 0.001). Overall, the RT-RAA-LFD assay is a user-friendly diagnostic tool that can rapidly and visually detect PDCoV.

An extracellular matrix biosensing mimetic for evaluating cathepsin as a host target for COVID-19.

To combat the new virus currently ravaging the whole world, every possible anti-virus strategy should be explored. As the main strategy of targeting the virus itself is being frustrated by the rapid mutation of the virus, people are seeking an alternative "host targeting" strategy: neutralizing proteins in the human body that cooperate with the virus. The cathepsin family is such a group of promising host targets, the main biological function of which is to digest the extracellular matrix (ECM) to clear a path for virus spreading. To evaluate the potential of cathepsin as a host target, we have constructed a biosensing interface mimicking the ECM, which can detect cathepsin from 3.3 pM to 33 nM with the limit of detection of 1 pM. Based on our quantitative analysis enabled by this biosensing interface, it is clear that patients with background diseases such as chronic inflammation and tumor, tend to have higher cathepsin activity, confirming the potential of cathepsin to serve as a host target for combating COVID-19 virus.

Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial.

BACKGROUND: Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine-rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL. METHODS: We conducted an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0-2. A central interactive web response system randomly assigned patients without del(17)(p13·1) to zanubrutinib (group A) or bendamustine-rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13·1) were enrolled in group C and received zanubrutinib. Zanubrutinib was administered orally at 160 mg twice per day (28-day cycles); bendamustine at 90 mg/m2 of body surface area on days 1 and 2 for six cycles plus rituximab at 375 mg/m2 of body surface area the day before or on day 1 of cycle 1, and 500 mg/m2 of body surface area on day 1 of cycles 2-6, were administered intravenously. The primary endpoint was progression-free survival per independent review committee in the intention-to-treat population in groups A and B, with minimum two-sided α of 0·05 for superiority. Safety was analysed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT03336333, and is closed to recruitment. FINDINGS: Between Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13·1) were randomly assigned to zanubrutinib (group A; n=241) or bendamustine-rituximab (group B; n=238). At median follow-up of 26·2 months (IQR 23·7-29·6), median progression-free survival per independent review committee was not reached in either group (group A 95% CI not estimable [NE] to NE; group B 28·1 months to NE). Progression-free survival was significantly improved in group A versus group B (HR 0·42 [95% CI 0·28 to 0·63]; two-sided p<0·0001). The most common grade 3 or worse adverse event was neutropenia (27 [11%] of 240 patients in group A, 116 [51%] of 227 in group B, and 17 [15%] of 111 patients in group C). Serious adverse events occurred in 88 (37%) of 240 patients in group A, 113 (50%) of 227 patients in group B, and 45 (41%) of 111 patients in group C. Adverse events leading to death occurred in 11 (5%) of 240 patients in group A, 12 (5%) of 227 patients in group B, and three (3%) of 111 patients in group C, most commonly due to COVID-19 (four [2%] of 240 patients in group A), diarrhoea, and aspiration pneumonia (two each [1%] of 227 patients in group B). INTERPRETATION: Zanubrutinib significantly improved progression-free survival versus bendamustine-rituximab, with an acceptable safety profile consistent with previous studies. These data support zanubrutinib as a potential new treatment option for untreated CLL and SLL. FUNDING: BeiGene.

Risk Factors for Death Among the First 80 543 Coronavirus Disease 2019 (COVID-19) Cases in China: Relationships Between Age, Underlying Disease, Case Severity, and Region.

BACKGROUND: Knowledge of COVID-19 epidemiology remains incomplete and crucial questions persist. We aimed to examine risk factors for COVID-19 death. METHODS: A total of 80 543 COVID-19 cases reported in China, nationwide, through 8 April 2020 were included. Risk factors for death were investigated by Cox proportional hazards regression and stratified analyses. RESULTS: Overall national case-fatality ratio (CFR) was 5.64%. Risk factors for death were older age (≥80: adjusted hazard ratio, 12.58; 95% confidence interval, 6.78-23.33), presence of underlying disease (1.33; 1.19-1.49), worse case severity (severe: 3.86; 3.15-4.73; critical: 11.34; 9.22-13.95), and near-epicenter region (Hubei: 2.64; 2.11-3.30; Wuhan: 6.35; 5.04-8.00). CFR increased from 0.35% (30-39 years) to 18.21% (≥70 years) without underlying disease. Regardless of age, CFR increased from 2.50% for no underlying disease to 7.72% for 1, 13.99% for 2, and 21.99% for ≥3 underlying diseases. CFR increased with worse case severity from 2.80% (mild) to 12.51% (severe) and 48.60% (critical), regardless of region. Compared with other regions, CFR was much higher in Wuhan regardless of case severity (mild: 3.83% vs 0.14% in Hubei and 0.03% elsewhere; moderate: 4.60% vs 0.21% and 0.06%; severe: 15.92% vs 5.84% and 1.86%; and critical: 58.57% vs 49.80% and 18.39%). CONCLUSIONS: Older patients regardless of underlying disease and patients with underlying disease regardless of age were at elevated risk of death. Higher death rates near the outbreak epicenter and during the surge of cases reflect the deleterious effects of allowing health systems to become overwhelmed.

Molecular Mechanisms of Cardiac Injury Associated With Myocardial SARS-CoV-2 Infection.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread around the world. The development of cardiac injury is a common condition in patients with COVID-19, but the pathogenesis remains unclear. The RNA-Seq dataset (GSE150392) comparing expression profiling of mock human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and SARS-CoV-2-infected hiPSC-CMs was obtained from Gene Expression Omnibus (GEO). We identified 1,554 differentially expressed genes (DEGs) based on GSE150392. Gene set enrichment analysis (GSEA), Gene ontology (GO) analysis, and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis showed that immune-inflammatory responses were activated by SARS-CoV-2, while muscle contraction, cellular respiration, and cell cycle of hiPSC-CMs were inhibited. A total of 15 hub genes were identified according to protein-protein interaction (PPI), among which 11 upregulated genes were mainly involved in cytokine activation related to the excessive inflammatory response. Moreover, we identified potential drugs based on these hub genes. In conclusion, SARS-CoV-2 infection of cardiomyocytes caused a strong defensive response, leading to excessive immune inflammation, cell hypoxia, functional contractility reduction, and apoptosis, ultimately resulting in myocardial injury.

COVID-19 Disruption Strategy for Redesigning Global Supply Chain Network across TPP Countries

Background: COVID-19 has disrupted and adversely affected supply chains worldwide. A global supply chain network that considers disruptions is needed. This study strategically analyzes the economic and structural effects of disruption on a global supply chain network with customs duty and the trans-pacific partnership (TPP) agreement. Methods: We present a cost minimization model which helps in understanding the difficulty of supplying materials or products to factories or customers if the supplier’s cities are facing disruption. This enables us to model and evaluate simultaneous considerations of supplier disruption, customs duty, and TPP in redesigning a global supply chain network. This network is modeled and formulated using integer programming, disruption scenarios, and a sensitivity analysis for customs duty. Results: Regarding the impact of disruptions on suppliers, two patterns emerge in the reconfigured network: direct changes due to supplier disruptions and indirect changes due to factory relocation. The sensitivity analysis for customs duty shows that the TPP has a positive impact on cost maintained, even in the presence of disruptions. Conclusions: Suppliers should be switched depending on the scale of disruption;when many distant suppliers need to be switched, the factory should be relocated to the country where these suppliers are located.

A RFID Authentication Protocol for Epidemic Prevention and Epidemic Emergency Management Systems.

The outbreak of the novel coronavirus has exposed many problems in the auxiliary information system for epidemic prevention and control, which needs to be resolved by using methods such as the antitampering of logistics data and the management and control of epidemic materials. This article discusses the introduction of emerging technologies such as Radio Frequency Identification (RFID), which support privacy protection into the auxiliary information system for epidemic prevention and control. Recently, this paper found that Khwaja et al.'s protocol (RAPUS protocol) is susceptible to database impersonation attacks and reader impersonation attacks. Therefore, this article proposes the enhanced protocol, which not only perfectly solves the problems of the abovementioned protocols but also comprehensively compares multiple protocols. The enhanced protocol has higher efficiency and security. The security of the proposed protocol (RAPUS + protocol) is analyzed by GNY logic and the AVISPA model. The designed scheme can help realize the safety and traceability of epidemic prevention materials and improve the automation and decision-making efficiency of the epidemic prevention.

Infodemics: A new challenge for public health.

The COVID-19 information epidemic, or "infodemic," demonstrates how unlimited access to information may confuse and influence behaviors during a health emergency. However, the study of infodemics is relatively new, and little is known about their relationship with epidemics management. Here, we discuss unresolved issues and propose research directions to enhance preparedness for future health crises.

Cooperation for Win-Win Results: Healthy Community Planning

Introduction The 2020 Annual Meeting of the Housing and Community Planning Committee of the Urban Planning Society of China (UPSC) was successfully held in Xian on Sept. 4, 2020. Jointly supported by the UPSC, the Housing and Community Planning Committee of the UPSC, the School of Architecture of Tsinghua University, the Beijing Tsinghua Tongheng Urban Planning & Design Institute, and the Xian University of Architecture and Technology, this meeting took Cooperation for Win-Win Results: Healthy Community Planning as its theme, guided by the principle of strengthening and innovating social governance, building a social governance pattern ofjoint contribution, co-governance, and shared benefits proposed in the report of the 19th National Congress of the Communist Party of China (CPC). In both online and offline ways, it brought together experts and scholars from universities and scientific research institutes, heads of relevant departments, and representatives of the fields of housing studies and community planning, to jointly promote healthy and sustainable development of communities. The government is not the only decision maker any longer, instead multiple stakeholders are working together to deal with important matters based on the consensus, developing common action guidelines and working mechanisms, putting forward institutional arrangements. 2.Core principles of urban governance In this context, traditional planning, especially at the community level, faces a series of challenges, which may even trigger the restructuring of the knowledge system.