04 December, 2021

The effect of the Pandemic on European Narratives on Smart Cities and Surveillance -

This paper presents the analysis of European smart city narratives and how they evolved under the pressure of the COVID-19 pandemic. We approach the smart city concept from the critical perspective of surveillance capitalism, as proposed by Zuboff, to highlight the growing privacy concerns related to technological development. We have collected and analysed 184 articles regarding smart city solutions, published on social media by five European journals between 2017 and 2021. We adopted both human and machine coding processes for qualitative and quantitative analysis of our data. As a result, we identified the main actors and four dominant narratives: regulation of AI and facial recognition, technological fight with the climate emergency, contact tracing apps, and the potential of 5G technology to boost the digitalisation processes. Our analysis shows the growing number of positive narratives underlining the importance of technology in fighting the pandemic and mitigating the climate emergency. Although the discourse on surveillance is often accompanied by the consideration of the right to privacy, those types of concerns are central for only two topics out of the four we discovered. We found that the main rationale for the development of surveillance technologies relates to the competitiveness of the EU in the global technological rivalry, rather than increasing societal wellbeing or safeguarding the transparency of new policies.

🖺 Full Text HTML: The effect of the Pandemic on European Narratives on Smart Cities and Surveillance

SARS-CoV-2 wildlife surveillance in Ontario and Quebec, Canada -

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the COVID-19 pandemic, is capable of infecting a variety of wildlife species. Wildlife living in close contact with humans are at an increased risk of SARS-CoV-2 exposure and if infected have the potential to become a reservoir for the pathogen, making control and management more difficult. Objective: To conduct SARS-CoV-2 surveillance in urban wildlife from Ontario and Quebec, Canada, increasing our knowledge of the epidemiology of the virus and our chances of detecting spillover from humans into wildlife. Methods: Using a One Health approach, we leveraged activities of existing research, surveillance, and rehabilitation programs among multiple agencies to collect samples from 776 animals from 17 different wildlife species between June 2020 and May 2021. Samples from all animals were tested for the presence of SARS-CoV-2 viral RNA, and a subset of samples from 219 animals across 3 species (raccoons, Procyon lotor; striped skunks, Mephitis mephitis; and mink, Neovison vison) were also tested for the presence of neutralizing antibodies. Results: No evidence of SARS- CoV-2 viral RNA or neutralizing antibodies was detected in any of the tested samples. Conclusion: Although we were unable to identify positive SARS-CoV-2 cases in wildlife, continued research and surveillance activities are critical to better understand the rapidly changing landscape of susceptible animal species. Collaboration between academic, public and animal health sectors should include experts from relevant fields to build coordinated surveillance and response capacity.

🖺 Full Text HTML: SARS-CoV-2 wildlife surveillance in Ontario and Quebec, Canada

Drug repurposing screening identified tropifexor as a SARS-CoV-2 papain-like protease inhibitor -

The global COVID-19 pandemic underscores the dire need of effective antivirals. Encouraging progress has been made in developing small molecule inhibitors targeting the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and main protease (Mpro). However, the development of papain-like protease (PLpro) inhibitors faces several obstacles. Nevertheless, PLpro represents a high-profile drug target given its multifaceted roles in viral replication. PLpro is involved in not only the cleavage of viral polyprotein but also modulation of host immune response. In this study, we conducted a drug- repurposing screening of PLpro against the MedChemExpress bioactive compound library and identified three hits, EACC, KY-226, and tropifexor, as potent PLpro inhibitors with IC50 values ranging from 3.39 to 8.28 micromolar. The three hits showed dose-dependent binding to PLpro in the thermal shift assay. In addition, tropifexor inhibited the cellular PLpro activity in the FlipGFP assay with an IC50 of 10.6 micromolar. Gratifyingly, tropifexor showed antiviral activity against SARS-CoV-2 in Calu-3 cells with an EC50 of 4.03 micromolar, a 7.8-fold increase compared to GRL0617 (EC50 = 31.4 micromolar). Overall, tropifexor represents a novel PLpro inhibitor that can be further developed as SARS-CoV-2 antivirals.

🖺 Full Text HTML: Drug repurposing screening identified tropifexor as a SARS-CoV-2 papain-like protease inhibitor

Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection -

Coronavirus disease 2019 is a respiratory infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence on the pathogenesis of SARS-CoV-2 is accumulating rapidly. In addition to structural proteins such as Spike and Envelope, the functional roles of non-structural and accessory proteins in regulating viral life cycle and host immune responses remain to be understood. Here, we show that open reading frame 8 (ORF8) acts as messenger for inter-cellular communication between alveolar epithelial cells and macrophages during SARS- CoV-2 infection. Mechanistically, ORF8 is a secretory protein that can be secreted by infected epithelial cells via both conventional and unconventional secretory pathways. The unconventionally secreted ORF8 recognizes the IL17RA receptor of macrophages and induces cytokine release. However, conventionally secreted ORF8 cannot bind to IL17RA due to N-linked glycosylation. Furthermore, we found that Yip1 interacting factor homolog B (YIF1B) is a channel protein that translocates unglycosylated ORF8 into vesicles for unconventional secretion. Blocking the unconventional secretion of ORF8 via a YIF1B knockout in hACE2 mice attenuates inflammation and yields delayed mortality following SARS-CoV-2 challenge.

🖺 Full Text HTML: Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection

Secreted ORF8 is a pathogenic cause of severe Covid-19 and potentially targetable with select NLRP3 inhibitors -

Despite extensive research, the specific factor associated with SARS-CoV-2 infection that mediates the life- threatening inflammatory cytokine response in patients with severe Covid-19 remains unidentified. Herein we demonstrate that the virus-encoded Open Reading Frame 8 (ORF8) protein is abundantly secreted as a glycoprotein in vitro and in patients with newly diagnosed Covid-19. ORF8 specifically binds to the NOD-like receptor family pyrin domain-containing 3 (NLRP3) in CD14+/CD16+ monocytes to induce an inflammasomal cytokine response. The levels of ORF8 protein in the blood correlate with disease mortality in patients with acute infection, and the disease trajectory in patients with severe Covid-19. Furthermore, in vitro the ORF8-induced inflammasome response can be readily inhibited by the select NLRP3 inhibitor MCC950. Our results identify the pathogenic cause and mechanism of severe disease, and a potential new treatment of severe Covid-19.

🖺 Full Text HTML: Secreted ORF8 is a pathogenic cause of severe Covid-19 and potentially targetable with select NLRP3 inhibitors

Systems immune profiling of variant-specific vaccination against SARS-CoV-2 -

Lipid-nanoparticle(LNP)-mRNA vaccines offer protection against COVID-19. However, multiple variant lineages caused widespread breakthrough infections. There is no report on variant-specific vaccines to date. Here, we generated LNP- mRNAs specifically encoding wildtype, B.1.351 and B.1.617 SARS-CoV-2 spikes, and systematically studied their immune responses in animal models. All three LNP-mRNAs induced potent antibody responses in mice. However, WT-LNP-mRNA vaccination showed reduced neutralization against B.1.351 and B.1.617; and B.1.617-specific vaccination showed differential neutralization. All three vaccine candidates elicited antigen-specific CD8 and CD4 T cell responses. Single cell transcriptomics of B.1.351-LNP-mRNA and B.1.617-LNP-mRNA vaccinated animals revealed a systematic landscape of immune cell populations and global gene expression. Variant-specific vaccination induced a systemic increase in reactive CD8 T cell population, with a strong signature of transcriptional and translational machineries in lymphocytes. BCR-seq and TCR-seq unveiled repertoire diversity and clonal expansions in vaccinated animals. These data provide direct systems immune profiling of variant-specific LNP-mRNA vaccination in vivo.

🖺 Full Text HTML: Systems immune profiling of variant-specific vaccination against SARS-CoV-2

Internal Tremors and Vibration Symptoms Among People with Post-Acute Sequelae of SARS-CoV-2: A narrative review of patient reports -

To introduce the perspective of patients who have PASC with vibrations and tremors as a prominent component, we leveraged the efforts by Survivor Corps, a grassroots COVID-19 patient advocacy group, to gather information from people in their Facebook group suffering from vibrations and tremors. Survivor Corps collected 140 emails and 450 Facebook comments from members. From the emails, we identified 22 themes and 7 broader domains based on common coding techniques for qualitative data and the constant comparative method of qualitative data analysis. Facebook comments were analyzed using Word Clouds to visualize frequency of terms. The respondent emails reflected 7 domains that formed the basis of characterizing their experience with vibrations and tremors. These domains were: (1) symptom experience, description, and anatomic location; (2) initial symptom onset; (3) symptom timing; (4) symptom triggers or alleviators; (5) change from baseline health status; (6) experience with medical establishment; and (7) impact on lives and livelihood. There were 22 themes total, each corresponding to one of the broader domains. The Facebook comments Word Cloud revealed that the 10 most common words used in comments were: tremors (64), covid (55), pain (51), vibrations (43), months (36), burning (29), feet (24), hands (22), legs (21), back (20). Overall, these patient narratives described intense suffering, and there is still no diagnosis or treatment available.

🖺 Full Text HTML: Internal Tremors and Vibration Symptoms Among People with Post-Acute Sequelae of SARS-CoV-2: A narrative review of patient reports

A population framework for predicting the proportion of people infected by the far-field airborne transmission of SARS-CoV-2 indoors -

The number of occupants in a space influences the risk of far-field airborne transmission of the SARS-CoV-2 virus because the likelihood of having infectious and susceptible people both scale with the number of occupants. Mass- balance and dose-response models determine far-field transmission risks for an individual person and a population of people after sub-dividing a large reference space into 10 identical comparator spaces. For a single infected person when the per capita ventilation rate is preserved, the dose received by an individual person in the comparator space is 10-times higher because the equivalent ventilation rate per infected person is lower. However, accounting for population dispersion, such as the community infection rate, the probability of an infected person being present and uncertainty in their viral load, shows the probability of transmission increases with occupancy. Also, far-field transmission is likely to be a rare event that requires a set of Goldilocks conditions that are just right, when mitigation measures have limited effect. Therefore, resilient buildings should deliver the equivalent ventilation rate required by standards and increase the space volume per person, but also require reductions in the viral loads and the infection rate of the wider population.

🖺 Full Text HTML: A population framework for predicting the proportion of people infected by the far-field airborne transmission of SARS-CoV-2 indoors

A public antibody class recognizes a novel S2 epitope exposed on open conformations of SARS-CoV-2 spike -

Delineating the origins and properties of antibodies elicited by SARS-CoV-2 infection and vaccination is critical for understanding their benefits and potential shortcomings. Therefore, we investigated the SARS-CoV-2 spike (S)-reactive B cell repertoire in unexposed individuals by flow cytometry and single-cell sequencing. We found that ~82% of SARS-CoV-2 S-reactive B cells show a naive phenotype, which represents an unusually high fraction of total human naive B cells (~0.1%). Approximately 10% of these naive S-reactive B cells shared an IGHV1-69/IGKV3-11 B cell receptor pairing, an enrichment of 18-fold compared to the complete naive repertoire. A proportion of memory B cells, comprising switched (~0.05%) and unswitched B cells (~0.04%), was also reactive with S and some of these cells were reactive with ADAMTS13, which is associated with thrombotic thrombocytopenia. Following SARS-CoV-2 infection, we report an average 37-fold enrichment of IGHV1-69/IGKV3-11 B cell receptor pairing in the S-reactive memory B cells compared to the unselected memory repertoire. This class of B cells targets a previously undefined non-neutralizing epitope on the S2 subunit that becomes exposed on S proteins used in approved vaccines when they transition away from the native pre- fusion state because of instability. These findings can help guide the improvement of SARS-CoV-2 vaccines.

🖺 Full Text HTML: A public antibody class recognizes a novel S2 epitope exposed on open conformations of SARS-CoV-2 spike

ScRNA-Seq study of neutrophils reveals vast heterogeneity and breadth of inflammatory responses in severe COVID-19 patients -

Neutrophils are considered as a primary driver of the pathogenesis of acute respiratory distress syndrome (ARDS) and have been implicated in the pathophysiology of severe COVID-19. While single-cell RNA sequencing (scRNA-seq) analysis has provided insights into immune cell heterogeneity and dysregulation during COVID-19, the challenges of isolating neutrophils and their inability to survive cryopreservation have resulted in a poor understanding of their genomic and phenotypic heterogeneity on a single cell level during COVID-19 infection. Here, we report for the first time a dedicated study of neutrophil responses using scRNA seq of fresh leukocytes from 11 hospitalized adult patients with mild and severe COVID-19 disease and 5 healthy controls. We observed that neutrophils display a pronounced inflammatory profile, with dramatic disruption of predicted cell-cell interactions as the severity of the disease increases. We also identified unique mature and immature neutrophil subpopulations based on transcriptomic profiling, including an antiviral phenotype, and changes in the proportion of each population linked to the severity of the disease. Finally, pathway analysis revealed increased markers of oxidative phosphorylation and ribosomal genes, along with downregulation of many antiviral and host defense pathway genes during severe disease compared to mild infections. Collectively, our findings indicate that neutrophils are capable of mounting effective antiviral defenses but in patients with more severe disease, adopt a form of immune dysregulation characterized by excess cellular stress, thereby contributing to the pathogenesis of severe COVID-19.

🖺 Full Text HTML: ScRNA-Seq study of neutrophils reveals vast heterogeneity and breadth of inflammatory responses in severe COVID-19 patients

Macaque-human differences in SARS-CoV-2 Spike antibody response elicited by vaccination or infection -

Macaques are a commonly used model for studying immunity to human viruses, including for studies of SARS-CoV-2 infection and vaccination. However, it is unknown whether macaque antibody responses recapitulate, and thus appropriately model, the response in humans. To answer this question, we employed a phage-based deep mutational scanning approach (Phage-DMS) to compare which linear epitopes are targeted on the SARS-CoV-2 Spike protein in humans and macaques following either vaccination or infection. We also used Phage-DMS to determine antibody escape pathways within each epitope, enabling a granular comparison of antibody binding specificities at the locus level. Overall, we identified some common epitope targets in both macaques and humans, including in the fusion peptide (FP) and stem helix- heptad repeat 2 (SH-H) regions. Differences between groups included a response to epitopes in the N-terminal domain (NTD) and C-terminal domain (CTD) in vaccinated humans but not vaccinated macaques, as well as recognition of a CTD epitope and epitopes flanking the FP in convalescent macaques but not convalescent humans. There was also considerable variability in the escape pathways among individuals within each group. Sera from convalescent macaques showed the least variability in escape overall and converged on a common response with vaccinated humans in the SH-H epitope region, suggesting highly similar antibodies were elicited. Collectively, these findings suggest that the antibody response to SARS-CoV-2 in macaques shares many features with humans, but with substantial differences in the recognition of certain epitopes and considerable individual variability in antibody escape profiles, suggesting a diverse repertoire of antibodies that can respond to major epitopes in both humans and macaques.

🖺 Full Text HTML: Macaque- human differences in SARS-CoV-2 Spike antibody response elicited by vaccination or infection

Investigating the mutational landscape of the SARS-CoV-2 Omicron variant via ab initio quantum mechanical modeling -

SARS-CoV-2 variant “Omicron” B1.1.529 was first identified in South Africa in November 2021. Given the large number of mutations in Omicron’s spike protein compared to the original Wuhan strain, its binding efficacy to the ACE2 receptor and its potential to escape antibodies are in the spotlight. Recently, we presented an ab initio quantum mechanical model to characterize the interactions of spike protein’s Receptor Binding Domain (RBD) with select antibodies and ACE2 variants. The model identified weak links among the residues constituting interactions with the human ACE2 receptor (hACE2), and also enabled us to characterize in silico mutated RBDs to identify potential Variants of Concern (VOC). In particular, we focused on the role of RBD residue 484 in the interaction of the Delta variant with ACE2 and neutralizing antibodies (nAbs). In this report, we apply our model to the Omicron VOC, and characterize its interaction pattern with hACE2. Our results show that (i) binding affinity with hACE2, compared to Delta, is considerably increased, possibly contributing to increased infectivity. (ii) The interaction pattern between B1.1.529 and hACE2 differs from previous variants by shifting the hot-spot interaction residues on hACE2, and potentially affecting nAbs efficacy. (iii) A K mutation in the RBD residue 484 can further improve Omicron’s binding of hACE2 and evasion of nAbs. Finally, we argue that a library of hot-spots for point-mutations can predict binding interaction energies of complex variants.

🖺 Full Text HTML: Investigating the mutational landscape of the SARS-CoV-2 Omicron variant via ab initio quantum mechanical modeling

Thermal Analysis of Protein Stability and Ligand Binding in Complex Media -

Screening of ligands that can bind to biologic products of in vitro expression systems typically requires some purification of the expressed biologic target. Such purification is often laborious and time consuming and a limiting challenge. What is required, that could represent an enormous advantage, is the ability to screen expressed proteins in the crude lysate stage without purification. For that purpose, we explore here the utility of differential scanning calorimetry (DSC) measurements for detecting the presence of specific proteins and their interactions with ligands in the complex media where they were prepared, i.e. crude lysates. Model systems were designed to mimic analogous conditions comparable to those that might be encountered in actual in vitro expression systems. Results are reported for several examples where DSC measurements distinctly showed differences in the thermal denaturation behaviors of the crude lysate alone, proteins and proteins plus binding ligands added to the crude lysate. Results were obtained for Streptavidin/Biotin binding in E. coli lysate, and binding of Angiotensin Converting Enzyme 2 (ACE2) by captopril or lisinopril in the lysate supernatant derived from cultured Human Kidney cells (HEK293). ACE2 binding by the reactive binding domain (RBC) of SARS-CoV-2 was also examined. Binding of ACE2 by RBC and lisinopril were similar and consistent with the reported ACE2 inhibitory activity of lisinopril.

🖺 Full Text HTML: Thermal Analysis of Protein Stability and Ligand Binding in Complex Media

Delta variant with P681R critical mutation revealed by ultra-large atomic-scale ab initio simulation: Implications for the fundamentals of biomolecular interactions -

SARS-CoV-2 Delta variant is emerging as a globally dominant strain. Its rapid spread and high infection rate are attributed to a mutation in the spike protein of SARS-CoV-2 allowing the virus to invade human cells much faster and with increased efficiency. Particularly, an especially dangerous mutation P681R close to the furin cleavage site has been identified as responsible for increasing the infection rate. Together with the earlier reported mutation D614G in the same domain, it offers an excellent instance to investigate the nature of mutations and how they affect the interatomic interactions in the spike protein. Here, using ultra large-scale ab initio computational modeling, we study the P681R and D614G mutations in the SD2-FP domain including the effect of double mutation and compare the results with the wild type. We have recently developed a method of calculating the amino acid-amino acid bond pairs (AABP) to quantitatively characterize the details of the interatomic interactions, enabling us to explain the nature of mutation at the atomic resolution. Our most significant find is that the mutations reduce the AABP value, implying a reduced bonding cohesion between interacting residues and increasing the flexibility of these amino acids to cause the damage. The possibility of using this unique mutation quantifiers in a machine learning protocol could lead to the prediction of emerging mutations.

🖺 Full Text HTML: Delta variant with P681R critical mutation revealed by ultra-large atomic-scale ab initio simulation: Implications for the fundamentals of biomolecular interactions

Safety, tolerability, and immunogenicity of a SARS-CoV-2 recombinant spike protein vaccine: a randomised, double- blind, placebo-controlled, phase 1-2 clinical trial (ABDALA Study). -

Aim: To evaluate the safety and immunogenicity of a SARS-CoV-2 recombinant spike protein vaccine (Abdala), administered intramuscularly in different strengths and vaccination schedules. Method: A phase 1-2, randomized, double- blind, placebo-controlled trial was done. Subjects were randomly distributed in 3 groups: placebo, 25 and 50 μg RBD. The product was applied intramuscularly, 0.5 mL in the deltoid region. During the first phase, two immunization schedules were studied: short (0-14-28 days) and long (0-28-56 days). In phase 2, only the short scheme was evaluated. The main endpoints were: safety and proportion of subjects with seroconversion of anti-RBD IgG antibodies to SARS-CoV-2. Blood samples were collected in several points according to the corresponding vaccination schedule to determine the level of RBD-specific IgG antibodies (seroconversion rates and geometric mean of the titers), the percentage of inhibition of RBD-ACE-2 binding and levels of neutralizing antibodies. Results: The product was well tolerated. Severe adverse events were not reported. Adverse reactions were minimal, mostly mild and local (from the injection site), resolved in the first 24-48 hours without medication. In phase 1, at day 56 (28 days after the third dose of the short vaccination schedule, 0-14-28 days) seroconversion of anti-RBD IgG was seen in 95.2 % of the participants (20/21) for the 50 μg group and 81 % of the participants (17/21) for the 25 μg group, and none in the placebo group (0/22); whereas neutralizing antibodies to SARS-CoV-2 were seen in 80 % of the participants (8/10) for the 50 μg group and 94.7% of the participants (18/19) for the 25 μg group. For the long schedule, at day 70 (14 days after the third dose) seroconversion of anti-RBD IgG was seen in 100% of the participants (21/21) for the 50 μg group and 94.7% of the participants (18/19) for the 25 μg group, and none in the placebo group (0/22); whereas neutralizing antibodies to SARS-CoV-2 were seen in 95 % of the participants (19/20) for the 50 μg group and 93.8% of the participants (15/16) for the 25 μg group In phase 2, at day 56 seroconversion of anti-RBD IgG was seen in 89.2% of the participants (214/240) for the 50 μg group, 77.7% of the participants (185/238) for the 25 μg group, and 4.6% in the placebo group (11/239); whereas neutralizing antibodies to SARS-CoV-2 were seen in 97.3% of the participants (146/150) for the 50 μg group and 95.1% of the participants (58/61) for the 25 μg group. Conclusion: Abdala vaccine against SARS-CoV-2 was safe, well tolerated and induced humoral immune responses against SARS-CoV-2 among adults from 19 to 80 years of age.

🖺 Full Text HTML: Safety, tolerability, and immunogenicity of a SARS-CoV-2 recombinant spike protein vaccine: a randomised, double-blind, placebo- controlled, phase 1-2 clinical trial (ABDALA Study).

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