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178 lines
48 KiB
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<meta content="width=device-width, initial-scale=1.0, user-scalable=yes" name="viewport"/>
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<title>02 August, 2022</title>
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<title>Covid-19 Sentry</title><meta content="width=device-width, initial-scale=1.0" name="viewport"/><link href="styles/simple.css" rel="stylesheet"/><link href="../styles/simple.css" rel="stylesheet"/><link href="https://unpkg.com/aos@2.3.1/dist/aos.css" rel="stylesheet"/><script src="https://unpkg.com/aos@2.3.1/dist/aos.js"></script></head>
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<h1 data-aos="fade-down" id="covid-19-sentry">Covid-19 Sentry</h1>
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<h1 data-aos="fade-right" data-aos-anchor-placement="top-bottom" id="contents">Contents</h1>
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<ul>
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<li><a href="#from-preprints">From Preprints</a></li>
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<li><a href="#from-clinical-trials">From Clinical Trials</a></li>
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<li><a href="#from-pubmed">From PubMed</a></li>
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<li><a href="#from-patent-search">From Patent Search</a></li>
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<h1 data-aos="fade-right" id="from-preprints">From Preprints</h1>
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<li><strong>H172Y mutation perturbs the S1 pocket and nirmatrelvir binding of SARS CoV-2 main protease through a nonnative hydrogen bond</strong> -
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Nirmatrelvir is an orally available inhibitor of SARS-CoV-2 main protease (Mpro) and the main ingredient of PAXLOVID, a drug approved by FDA for high-risk COVID-19 patients. Although the prevalent Mpro mutants in the SARS-CoV-2 Variants of Concern (e.g., Omicron) are still susceptible to nirmatrelvir, a rare natural mutation, H172Y, was found to significantly reduce nirmatrelvir’s inhibitory activity. As the selective pressure of antiviral therapy may favor resistance mutations, there is an urgent need to understand the effect of the H172Y mutation on Mpro’s structure, function, and drug resistance. Here we report the molecular dynamics (MD) simulations as well as the measurements of stability, enzyme kinetics of H172Y Mpro, and IC50 value of nirmatrelvir. Simulations showed that mutation disrupts the interactions between the S1 pocket and N terminus of the opposite protomer. Intriguingly, a native hydrogen bond (H-bond) between Phe140 and the N terminus is replaced by a transient H-bond between Phe140 and Tyr172. In the ligand-free simulations, strengthening of this nonnative H-bond is correlated with disruption of the conserved aromatic stacking between Phe140 and His163, leading to a partial collapse of the oxyanion loop. In the nirmatrelvir-bound simulations, the nonnative H-bond is correlated with the loss of an important H-bond between Glu166 and nirmatrelvir’s lactam nitrogen at P1 position. These results are consistent with the newly reported X-ray structures of H172Y Mpro and suggest a mechanism by which the H172Y substitution perturbs the S1 pocket, leading to the decreased structural stability and binding affinity, which in turn explains the drastic reduction in catalytic activity and antiviral susceptibility.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.07.31.502215v1" target="_blank">H172Y mutation perturbs the S1 pocket and nirmatrelvir binding of SARS CoV-2 main protease through a nonnative hydrogen bond</a>
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<li><strong>Free energy perturbation calculations of mutation effects on SARS-CoV-2 RBD::ACE2 binding affinity</strong> -
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The strength of binding between human angiotensin converting enzyme 2 (ACE2) and the receptor binding domain (RBD) of viral spike protein plays a role in the transmissibility of the SARS-CoV-2 virus. In this study we focus on a subset of RBD mutations that have been frequently observed in sequenced samples from infected individuals and probe binding affinity changes to ACE2 using surface plasmon resonance (SPR) measurements and free energy perturbation (FEP) calculations. We find that FEP performance is significantly better than that of other computational approaches examined here, in part due to its ability to account for protein structure relaxation resulting from the mutation of interfacial residues. Moreover, analysis of FEP trajectories offers physical insights not available from other methods. Notably, FEP calculations successfully predict the observed cooperative stabilization of binding by the Q498R N501Y double mutant present in the Omicron variant and offer a physical explanation for the underlying mechanism. Our results furthermore suggest a strategy as to how to effectively deploy FEP methods in the optimization of neutralizing antibodies.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.08.01.502301v1" target="_blank">Free energy perturbation calculations of mutation effects on SARS-CoV-2 RBD::ACE2 binding affinity</a>
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<li><strong>SARS-CoV-2-specific CD4+ and CD8+ T cell responses can originate from cross-reactive CMV-specific T cells</strong> -
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Detection of SARS-coronavirus-2 (SARS-CoV-2) specific CD4+ and CD8+ T cells in SARS-CoV-2- unexposed donors has been explained by the presence of T cells primed by other coronaviruses. However, based on the relative high frequency and prevalence of cross-reactive T cells, we hypothesized CMV may induce these cross-reactive T cells. Stimulation of pre-pandemic cryo-reserved PBMCs with SARS-CoV-2 peptides revealed that frequencies of SARS-CoV-2-specific T cells were higher in CMV-seropositive donors. Characterization of these T cells demonstrated that membrane-specific CD4+ and spike-specific CD8+ T cells originate from cross-reactive CMV-specific T cells. Spike-specific CD8+ T cells recognize SARS-CoV-2 spike peptide FVSNGTHWF (FVS) and dissimilar CMV pp65 peptide IPSINVHHY (IPS) presented by HLA-B*35:01. These dual IPS/FVS-reactive CD8+ T cells were found in multiple donors and shared a common T cell receptor (TCR), illustrating that IPS/FVS-cross-reactivity is caused by a public TCR. Importantly, these cross-reactive T cells reduced spreading of SARS-CoV-2 in airway epithelial Calu-3 cells yet they were not phenotypically activated during late-stage COVID-19, indicating that cross-reactive T cells may more likely play a role during early stage of infection. In conclusion, CMV-specific T cells cross-react with SARS-CoV-2, despite low sequence homology between the two viruses, and may contribute to the pre-existing immunity against SARS-CoV-2.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.07.31.502203v1" target="_blank">SARS-CoV-2-specific CD4+ and CD8+ T cell responses can originate from cross-reactive CMV-specific T cells</a>
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<li><strong>InterClone: Store, Search and Cluster Adaptive Immune Receptor Repertoires</strong> -
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B and T cell receptor repertoire data has the potential to fundamentally change the way we diagnose and treat a wide range of diseases. However, there are few resources for storing or analyzing repertoire data. InterClone provides tools for storing, searching, and clustering repertoire datasets. Efficiency is achieved by encoding the complementarity-determining regions of sequences as mmseqs2 databases. Single chain search or cluster results can be merged into paired (alpha-beta or heavy-light) results for analysis of single-cell sequencing data. We illustrate the use of InterClone with two recently reported examples: 1) searching for SARS-CoV-2 infection-enhancing antibodies in bulk COVID-19 and healthy donor repertoires; 2) identification of SARS-CoV-2 specific TCRs by clustering paired and bulk sequences from COVID-19, BNT162b2 vaccinated and healthy unvaccinated donors. The core functions of InterClone have been implemented as a web server and integrated database (https://sysimm.org/interclone). All source code is available upon request.
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.07.31.501809v1" target="_blank">InterClone: Store, Search and Cluster Adaptive Immune Receptor Repertoires</a>
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<li><strong>Use of a Self-Care and Educational Mobile App to Improve Outcomes of Patients with Acute Decompensated Heart Failure during the COVID-19 Pandemic</strong> -
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Introduction Expansion in digital health using mobile phone health applications has increased recently. We developed a mobile phone application (Aintree Heart Failure Passport AHFP APP) for heart failure (HF) patient education, self-care and improved medication adherence. Methods This was a prospective observational study of patients with acute decompensated HF managed with day-case intravenous diuretics in a HF specialist nurse delivered Ambulatory Acute Heart Failure Unit (AAHFU) in a British university hospital during the ongoing COVID19 pandemic (March 2020 to July 2021). We assessed self-care behaviour (European Heart Failure Self-care Behaviour scale EHFSBs-9) and medication adherence (Medication Adherence Report Scale MARS-5) at 2 weeks post-presentation in patients who utilised the AHFP APP and compared 30 day HF re-admissions with annual hospital HF data. Results 148 out of 221 consecutive ADHF patients treated in the AAHFU downloaded the AHFP Mobile APP. 45% were women and mean age of the cohort 62 +/- 6.1 years. 55% patients had HF with reduced ejection fraction (HFrEF), 34% had HF with preserved EF (HFpEF) and 11% had HF with mildly reduced EF. Mean EHFSBs-9 was 19.1 +/ -6.7; mean MARS-5 score 23.3 +/- 1.HF 30 day re-hospitalisation incidence significantly lower (11%) in the APP cohort compared to the incidence of 19% amongst all patients with ADHF during the study period (p=0.02). Conclusions Our pilot feasibility study suggests that use of a HF educational self-care mobile phone APP in ADHF patients during the COVID pandemic, leads to high quality self-care behaviour, high medication adherence and also lower levels of 30 day HF re-hospitalisation. These results will need to be validated in a randomised controlled trial.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.07.28.22270513v1" target="_blank">Use of a Self-Care and Educational Mobile App to Improve Outcomes of Patients with Acute Decompensated Heart Failure during the COVID-19 Pandemic</a>
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<li><strong>Recombinant Human ACE2-Fc : A promising therapy for SARS-CoV2 infection</strong> -
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SARS-CoV2 entry is mediated by binding of viral spike-protein(S) to the transmembrane Angiotensin-Converting Enzyme-2 (ACE2) of the host cell. Thus, to prevent transmission of disease, strategies to abrogate the interaction are important. However, ACE2 cannot be blocked since its normal function is to convert the Angiotensin II peptide to Angiotensin(1-7) to reduce hypertension. This work reports a recombinant cell line secreting soluble ACE2-ectopic domain (MFcS2), modified to increase binding and production efficacy and fused to human immunoglobulin-Fc. While maintaining its enzymatic activity, the molecule trapped and neutralized SARS CoV2 virus in vitro with an IC50 of 64 nM. In vivo, with no pathology in the vital organs, it inhibited the viral load in lungs in SARS-CoV2 infected Golden-Syrian-hamster. The Intravenous pharmacokinetic profiling of MFcS2 in hamster at a dose of 5 mg/Kg presented a maximum serum concentration of 23.45 microgram/mL with a half-life of 29.5 hrs. These results suggest that MFcS2 could be used as an effective decoy based therapeutic strategy to treat COVID19. This work also reports usage of a novel oral-cancer cell line as in vitro model of SARS-Cov2 infection, validated by over expressing viral-defence pathways upon RNA-seq analysis and over-expression of ACE2 and TMPRSS upon growth in hyperglycaemic condition.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.07.30.501940v1" target="_blank">Recombinant Human ACE2-Fc : A promising therapy for SARS-CoV2 infection</a>
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<li><strong>SARS-CoV-2 ORF8 is a viral cytokine regulating immune responses</strong> -
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Many patients with severe COVID-19 suffer from pneumonia, and thus elucidation of the mechanisms underlying the development of such severe pneumonia is important. The ORF8 protein is a secreted protein of SARS-CoV-2, whose in vivo function is not well understood. Here, we analyzed the function of ORF8 protein by generating ORF8-knockout SARS-CoV-2. We found that the lung inflammation observed in wild-type SARS-CoV-2-infected hamsters was decreased in ORF8-knockout SARS-CoV-2-infected hamsters. Administration of recombinant ORF8 protein to hamsters also induced lymphocyte infiltration into the lungs. Similar pro-inflammatory cytokine production was observed in primary human monocytes treated with recombinant ORF8 protein. Furthermore, we demonstrate that the serum ORF8 protein levels are correlated well with clinical markers of inflammation. These results demonstrated that the ORF8 protein is a viral cytokine of SARS-CoV-2 involved in the in the immune dysregulation observed in COVID-19 patients, and that the ORF8 protein could be a novel therapeutic target in severe COVID-19 patients.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.08.01.502275v1" target="_blank">SARS-CoV-2 ORF8 is a viral cytokine regulating immune responses</a>
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<li><strong>Epitranscriptomic N6-methyladenosine profile of SARS-CoV-2-infected human lung epithelial cells</strong> -
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N6-methyladenosine (m6A) is a dynamic post-transcriptional RNA modification that plays an important role in determining transcript fate. Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has caused the global pandemic of coronavirus disease 2019 (COVID-19) and the virus has been extensively studied. However, how m6A modification of host cell RNAs change during SARS-CoV-2 infection has not been reported. Here we define the epitranscriptomic m6A profile of SARS-CoV-2-infected human lung epithelial cells compared to uninfected controls. Biological pathway analyses revealed that differentially methylated transcripts were significantly associated with cancer-related pathways, protein processing in the endoplasmic reticulum, cell death and proliferation. Upstream regulators predicted to be associated with the proteins encoded by differentially methylated mRNAs include proteins involved in the type I interferon response, inflammation, and cytokine signaling. These data suggest that m6A modification of cellular RNA is an important mechanism of regulating host gene expression during SARS-CoV-2 infection of lung epithelial cells.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.08.01.502311v1" target="_blank">Epitranscriptomic N6-methyladenosine profile of SARS-CoV-2-infected human lung epithelial cells</a>
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<li><strong>Coronaviruses using different strategies to antagonize antiviral responses and pyroptosis</strong> -
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Viral infection triggers inflammasome-mediated caspase-1 activation. However, less is known about how viruses use the active caspase-1 to evade host immune response. Here, we use porcine epidemic diarrhea virus (PEDV) as a model of coronaviruses (CoVs) to illustrate the sophisticated regulation of CoVs to counteract IFN-I signaling and pyroptosis. We show that PEDV infection stabilizes caspase-1 expression via papain-like protease PLP2’s deubiquitinase activity and the enhanced stabilization of caspase-1 disrupts IFN-I signaling by cleaving RIG-I at D189 residue. Meanwhile, PLP2 can degrade GSDMD-p30 by removing its K27-linked ubiquitin chain at K275 to restrain pyroptosis. Papain-like proteases from other genera of CoVs (PDCoV and SARS-CoV-2) have the similar activity to degrade GSDMD-p30. We further demonstrate that SARS-CoV-2 N protein induced NLRP3 inflammasome activation also uses the active caspase-1 to counter IFN-I signaling by cleaving RIG-I. Therefore, our work unravels a novel antagonistic mechanism employed by CoVs to evade host antiviral response.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.07.29.502014v1" target="_blank">Coronaviruses using different strategies to antagonize antiviral responses and pyroptosis</a>
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<li><strong>Evolution to increased positive charge on the viral spike protein may be part of the adaptation of SARS-CoV-2 to human transmission</strong> -
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) epidemic, continues to evolve and infect individuals. The physical properties of the surface proteins of the virus such as charge, size, hydrophobicity and folding may influence survival and promoting movement through the environment and within the human airway to reach target cells to bind, enter and establish the next round of infection. The exterior surface of the SARS-CoV-2 virion is dominated by the spike protein and the current work examined spike protein biochemical features that have changed during the 2 years that SARS-CoV-2 has infected humans. In addition to selective pressure to avoid immune recognition of viral proteins, we hypothesised that SARS-CoV-2 emerged from an animal reservoir capable of human infection and transmission but in a sub-optimum state and a second level of selective pressure acts on these biochemical features. Our analysis identified a striking change in spike protein charge occurring across the 2 years of human host evolution of SARS-CoV-2.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.07.30.502143v1" target="_blank">Evolution to increased positive charge on the viral spike protein may be part of the adaptation of SARS-CoV-2 to human transmission</a>
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<li><strong>Memory B cells and memory T cells induced by SARS-CoV-2 booster vaccination or infection show different dynamics and efficacy to the Omicron variant.</strong> -
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Although BNT162b2 vaccination was shown to prevent infection and reduce COVID-19 severity, and the persistence of immunological memory generated by the vaccination has not been well elucidated. We evaluated memory B and T cell responses to the SARS-CoV-2 spike protein before and after the third BNT162b2 booster. Although the antibody titer against the spike receptor-binding domain (RBD) decreased significantly 8 months after the second vaccination, the number of memory B cells continued to increase, while the number of memory T cells decreased slowly. Memory B and T cells from unvaccinated infected patients showed similar kinetics. After the third vaccination, the antibody titer increased to the level of the second vaccination, and memory B cells increased at significantly higher levels before the booster, while memory T cells recovered close to the second vaccination levels. In memory T cells, the frequency of CXCR5+CXCR3+CCR6- cTfh1 was positively correlated with RBD-specific antibody-secreting B cells. Furthermore, T cell-dependent antibody production from reactivated memory B cells in vitro was correlated to the Tfh-like cytokine levels. For the response to variant RBDs, although 60%-80% of memory B cells could bind to the Omicron RBD, their binding affinity was low, while memory T cells show an equal response to the Omicron spike. Thus, the persistent presence of memory B and T cells will quickly upregulate antibody production and T cell responses after Omicron strain infection, which prevents severe illness and death due to COVID-19.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.07.31.500554v1" target="_blank">Memory B cells and memory T cells induced by SARS-CoV-2 booster vaccination or infection show different dynamics and efficacy to the Omicron variant.</a>
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<li><strong>Antigenic characterization of the SARS-CoV-2 Omicron subvariant BA.2.75</strong> -
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The SARS-CoV-2 Omicron subvariant BA.2.75 emerged recently and appears to be spreading rapidly. It has nine mutations in its spike compared to BA.2, raising concerns it may further evade vaccine-elicited and therapeutic antibodies. Here, we found BA.2.75 to be moderately more neutralization resistant to sera from vaccinated/boosted individuals than BA.2 (1.8-fold), similar to BA.2.12.1 (1.1-fold), but more neutralization sensitive than BA.4/5 (0.6-fold). Relative to BA.2, BA.2.75 showed heightened resistance to class 1 and class 3 monoclonal antibodies to the receptor-binding domain, while gaining sensitivity to class 2 antibodies. The resistance was largely conferred by the G446S and R460K mutations. Of note, BA.2.75 was slightly resistant (3.7-fold) to bebtelovimab, the only therapeutic antibody with potent activity against all Omicron subvariants. BA.2.75 also exhibited higher receptor binding affinity than other Omicron subvariants. BA.2.75 provides yet another example of the ongoing evolution of SARS-CoV-2 as it gains transmissibility while incrementally evading antibody neutralization.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.07.31.502235v1" target="_blank">Antigenic characterization of the SARS-CoV-2 Omicron subvariant BA.2.75</a>
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<li><strong>Estimating the time-varying reproduction number for COVID-19 in South Africa during the first four waves using multiple measures of incidence for public and private sectors across four waves</strong> -
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Objectives We aimed to quantify transmission trends in South Africa during the first four waves of the COVID-19 pandemic using estimates of the time-varying reproduction number (R) and to compare the robustness of R estimates based on three different data sources and using data from public and private sector service providers. Methods We estimated R from March 2020 through April 2022, nationally and by province, based on time series of rt-PCR-confirmed cases, hospitalizations, and hospital-associated deaths, using a method which models daily incidence as a weighted sum of past incidence. We also estimated R separately using public and private sector data. Results Nationally, the maximum case-based R following the introduction of lockdown measures was 1.55 (CI: 1.43-1.66), 1.56 (CI: 1.47-1.64), 1.46 (CI: 1.38-1.53) and 3.33 (CI: 2.84-3.97) during the first (Wuhan-Hu), second (Beta), third (Delta), and fourth (Omicron) waves respectively. Estimates based on the three data sources (cases, hospitalisations, deaths) were generally similar during the first three waves but cases-based estimates were higher during the fourth wave. Public and private sector R estimates were generally similar except during the initial lockdowns and in case-based estimates during the fourth wave. Discussion Agreement between R estimates using different data sources during the first three waves suggests data from any of these sources could be used in early stages of a future pandemic. High R estimates for Omicron relative to earlier waves is interesting given a high level of exposure pre-Omicron. The agreement between public and private sector R estimates highlights the fact that clients of the public and private sectors did not experience two separate epidemics, except perhaps to a limited extent during the strictest lockdowns during the first wave.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.07.22.22277932v2" target="_blank">Estimating the time-varying reproduction number for COVID-19 in South Africa during the first four waves using multiple measures of incidence for public and private sectors across four waves</a>
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<li><strong>Impact of age-structure and vaccine prioritization on COVID-19 in West Africa</strong> -
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The ongoing COVID-19 pandemic has been a major global health challenge since its emergence in 2019. Contrary to early predictions that sub-Saharan Africa (SSA) would bear a disproportionate share of the burden of COVID-19 due to the region9s vulnerability to other infectious diseases, weak healthcare systems, and socioeconomic conditions, the pandemic9s effects in SSA have been very mild in comparison to other regions. Interestingly, the number of cases, hospitalizations, and disease-induced deaths in SSA remain low, despite the loose implementation of non-pharmaceutical interventions (NPIs) and the low availability and administration of vaccines. Possible explanations for this low burden include epidemiological disparities, under-reporting (due to limited testing), climatic factors, population structure, and government policy initiatives. In this study, we formulate a model framework consisting of a basic model (in which only susceptible individuals are vaccinated), a vaccine-structured model, and a hybrid vaccine-age-structured model to reflect the dynamics of COVID-19 in West Africa (WA). The framework is trained with a portion of the confirmed daily COVID-19 case data for 16 West African countries, validated with the remaining portion of the data, and used to (i) assess the effect of age structure on the incidence of COVID-19 in WA, (ii) evaluate the impact of vaccination and vaccine prioritization based on age brackets on the burden of COVID-19 in the sub-region, and (iii) explore plausible reasons for the low burden of COVID-19 in WA compared to other parts of the world. Calibration of the model parameters and global sensitivity analysis show that asymptomatic youths are the primary drivers of the pandemic in WA. Also, the basic and control reproduction numbers of the hybrid vaccine-age-structured model are smaller than those of the other two models indicating that the disease burden is overestimated in the models which do not account for age-structure. This result is also confirmed through the vaccine-derived herd immunity thresholds. In particular, a comprehensive analysis of the basic (vaccine-structured) model reveals that if 84% (73%) of the West African populace is fully immunized with the vaccines authorized for use in WA, vaccine-derived herd immunity can be achieved. This herd immunity threshold is lower (68%) for the hybrid model. Also, all three thresholds are lower (60% for the basic model, 51% for the vaccine structured model, and 48% for the hybrid model) if vaccines of higher efficacies (e.g., the Pfizer or Moderna vaccine) are prioritized, and higher if vaccines of lower efficacy are prioritized. Simulations of the models show that controlling the COVID-19 pandemic in WA (by reducing transmission) requires a proactive approach, including prioritizing vaccination of more youths or vaccination of more youths and elderly simultaneously. Moreover, complementing vaccination with a higher level of mask compliance will improve the prospects of containing the pandemic. Additionally, simulations of the model predict another COVID-19 wave (with a smaller peak size compared to the Omicron wave) by mid-July 2022. Furthermore, the emergence of a more transmissible variant or easing the existing measures that are effective in reducing transmission will result in more devastating COVID-19 waves in the future. To conclude, accounting for age-structure is important in understanding why the burden of COVID-19 has been low in WA and sustaining the current vaccination level, complemented with the WHO recommended NPIs is critical in curbing the spread of the disease in WA.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.07.03.22277195v2" target="_blank">Impact of age-structure and vaccine prioritization on COVID-19 in West Africa</a>
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<li><strong>Role of Error Catastrophe in Transmission Ability of Virus</strong> -
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The role played by “error catastrophe” is explicitly taken into account in the mathematical formulation to analyze the COVID-19 data. The idea is to combine the mathematical genetics formalism of the error catastrophe of mutations in the virus gene loci with the standard model of epidemics which lacks the explicit incorporation of the mutation effect on the spreading of the viruses. We apply the formalism to the case of SARS-CoV-2 virus. We assume the “universality” of the error catastrophe in the process of analyzing the data. This means that some basic parameter to describe the error catastrophe is independent of which group (country or city) we deal with. Concretely, we analyze the omicron data of South Africa and then analyze the cases of Japan using the same value of the basic parameter derived in the South Africa analysis. The result shows the validity of our universality assumption.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.06.28.22276997v2" target="_blank">Role of Error Catastrophe in Transmission Ability of Virus</a>
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<h1 data-aos="fade-right" id="from-clinical-trials">From Clinical Trials</h1>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Puerto Rico COVID-19 Vaccine Uptake Study</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Other: Educational intervention<br/><b>Sponsors</b>: University of Puerto Rico; National Institutes of Health (NIH); National Institute on Minority Health and Health Disparities (NIMHD)<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Study to Learn About a New COVID-19 RNA Vaccine Candidate as a Booster Dose in COVID-19 Vaccine-Experienced Healthy Adults</strong> - <b>Conditions</b>: SARS-CoV-2 Infection; COVID-19<br/><b>Interventions</b>: Biological: BNT162b5 Bivalent (WT/OMI BA.2); Biological: BNT162b2 Bivalent (WT/OMI BA.1)<br/><b>Sponsors</b>: BioNTech SE; Pfizer<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Monitoring the Efficacy of a Probiotic Dietary Supplement SmartProbio C in Patients With Severe COVID-19 Infection</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Dietary Supplement: SmartProbio C; Dietary Supplement: Placebo<br/><b>Sponsors</b>: Medi Pharma Vision; Veterinary Research Institute; Brno University Hospital<br/><b>Completed</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Beta-glucans for Hospitalised Patients With COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: MC 3x3; Drug: Placebo<br/><b>Sponsors</b>: Concentra Educacion e Investigación Biomédica; Wohlstand Pharmaceutical<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>An Observer-blind, Cohort Randomized, Exploratory Phase 3 Study to Evaluate the Safety and Immunogenicity of Recombinant Covid-19 Vaccine, mRNA Covid-19 Vaccine and Recombinant SARS-CoV-2 Trimeric S-protein Subunit Vaccine as 4th Dose in Individuals Primed/ Boosted With Various Regimens</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: AstraZeneca/Fiocruz; Biological: Pfizer/Wyeth; Biological: Clover SCB-2019<br/><b>Sponsors</b>: D’Or Institute for Research and Education; Bill and Melinda Gates Foundation; University of Oxford<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Safety and Immunogenicity of Recombinant COVID-19 Vaccine (Sf9 Cell) as a Booster</strong> - <b>Conditions</b>: COVID-19; SARS-CoV-2 Infection<br/><b>Interventions</b>: Biological: Recombinant COVID-19 Vaccine (Sf9 Cell); Biological: COVID-19 Vaccine (Vero Cell), Inactivated<br/><b>Sponsor</b>: WestVac Biopharma Co., Ltd.<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Safety and Immunogenicity of Recombinant COVID-19 Variant Vaccine (Sf9 Cell) as a Booster</strong> - <b>Conditions</b>: COVID-19; SARS-CoV-2 Infection<br/><b>Interventions</b>: Biological: Recombinant COVID-19 variant Vaccine (Sf9 Cell); Biological: COVID-19 Vaccine (Vero Cell), Inactivated; Biological: mRNA COVID-19 vaccine (Moderna); Biological: Viral Vector COVID-19 vaccine (AstraZeneca)<br/><b>Sponsor</b>: WestVac Biopharma Co., Ltd.<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Effect of Pulmonary Rehabilitation Program on Post Hospitalization Severe COVID- 19 Patients</strong> - <b>Condition</b>: Post COVID-19 Condition<br/><b>Intervention</b>: Combination Product: respiratory exercises - incentive spirometer - walking<br/><b>Sponsor</b>: Fayoum University Hospital<br/><b>Completed</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Physiotherapy in Post COVID-19 Syndrome Patients</strong> - <b>Condition</b>: Post-COVID-19 Syndrome<br/><b>Interventions</b>: Other: Cognitive behavioral principles-based treatment program; Other: Control intervention<br/><b>Sponsor</b>: Universidad de Granada<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Rehabilitation for People With Post COVID-19 Syndrome</strong> - <b>Condition</b>: Post-COVID-19 Syndrome<br/><b>Interventions</b>: Other: Multidimensional intervention; Other: Control intervention<br/><b>Sponsor</b>: Universidad de Granada<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Xanthohumol as an Adjuvant Therapy in Critically Ill COVID-19 Patients</strong> - <b>Condition</b>: COVID-19 Respiratory Infection<br/><b>Intervention</b>: Biological: Xanthohumol - prenylated chalcone extracted from female inflorescences of hop cones (Humulus lupus). Hop-RXn™, BioActive-Tech Ltd, Lublin, Poland; http://xanthohumol.com.pl/<br/><b>Sponsor</b>: Medical University of Lublin<br/><b>Suspended</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Clinical Trial of Immuno-bridging Between Different Manufacture Scales of Recombinant COVID-19 Vaccine (Sf9 Cell)</strong> - <b>Conditions</b>: COVID-19; SARS-CoV-2 Pneumonia<br/><b>Intervention</b>: Biological: Recombinant COVID-19 vaccine (Sf9 cell)<br/><b>Sponsor</b>: WestVac Biopharma Co., Ltd.<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A CHW Intervention to Identify and Decrease Barriers to COVID 19 Testing & Vaccination</strong> - <b>Conditions</b>: Vaccine Hesitancy; COVID-19 Testing; Community Health Workers<br/><b>Intervention</b>: Behavioral: Community Health Worker led curriculum<br/><b>Sponsors</b>: Charles Drew University of Medicine and Science; Los Angeles County Department of Public Health; National Library of Medicine (NLM)<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Study to Evaluate Safety and Immunogenicity of COVID-19 Vaccine in Children 6 Months to < 12 Years</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: Biological/Vaccine: SARS-CoV-2 rS/Matrix-M1 Adjuvant (Initial Vaccination Period); Biological: SARS-CoV-2 rS/Matrix-M1 Adjuvant (Open Label Crossover Vaccination period); Biological: SARS-CoV-2 rS/Matrix-M1 Adjuvant (Booster Vaccination); Other: Placebo<br/><b>Sponsor</b>: Novavax<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Phase II/III Study of PIKA Recombinant SARS-CoV-2 Vaccine as a Booster Dose.</strong> - <b>Condition</b>: Covid-19 Vaccine<br/><b>Intervention</b>: Biological: PIKA COVID-19 vaccine<br/><b>Sponsor</b>: Yisheng Biopharma (Singapore) Pte. Ltd.<br/><b>Not yet recruiting</b></p></li>
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</ul>
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<h1 data-aos="fade-right" id="from-pubmed">From PubMed</h1>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>“Intention to receive COVID-19 vaccine among healthcare workers: a comparison between two surveys”</strong> - CONCLUSIONS: Present study showed an undesirable rate of intention to receive COVID-19 vaccine among healthcare workers, especially decreasing over the time, emphasize the need of interventions to promote healthcare workers’ intention to receive the vaccine and reduce the spread of COVID-19 disease.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>APOE interacts with ACE2 inhibiting SARS-CoV-2 cellular entry and inflammation in COVID-19 patients</strong> - Apolipoprotein E (APOE) plays a pivotal role in lipid including cholesterol metabolism. The APOE ε4 (APOE4) allele is a major genetic risk factor for Alzheimer’s and cardiovascular diseases. Although APOE has recently been associated with increased susceptibility to infections of several viruses, whether and how APOE and its isoforms affect SARS-CoV-2 infection remains unclear. Here, we show that serum concentrations of APOE correlate inversely with levels of cytokine/chemokine in 73 COVID-19…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Bovine coronavirus nucleocapsid suppresses IFN-β production by inhibiting RIG-I-like receptors pathway in host cells</strong> - The present study aimed to explore if bovine coronavirus nucleocapsid (BCoV N) impacts IFN-β production in the host cells and to reveal further molecular mechanism of BCoV pathogenesis. Human embryonic kidney (HEK) 293 T cells were transiently transfected with pMyc-BCoV-N recombinant plasmids, then infected with the vesicular stomatitis virus (VSV). Expression levels of beta interferon (IFN-β) mRNA were detected using RT-qPCR. The results showed that BCoV N gene was 1347 bp that was consistent…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Human TMPRSS2 non-catalytic ectodomain and SARS-CoV-2 S2’ subunit interaction mediated SARS-CoV-2 endocytosis: a model proposal with virtual screening for potential drug molecules to inhibit this interaction</strong> - This study proposes a novel model for integration of SARS-CoV-2 into host cell via endocytosis as a possible alternative to the prevailing direct fusion model. It is known that the SARS-CoV-2 spike protein undergoes proteolytic cleavage at S1-S2 cleavage site and the cleaved S2 domain is primed by the activated serine protease domain (SPD) of humanTMPRSS2 to become S2’. The activated SPD of TMPRSS2 is formed after it is cleaved by autocatalysis from the membrane bound non-catalytic ectodomain…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Ion channel inhibition with amiodarone or verapamil in symptomatic hospitalized nonintensive-care COVID-19 patients: The ReCOVery-SIRIO randomized trial</strong> - CONCLUSIONS: In this randomized trial, neither amiodarone nor verapamil were found to significantly accelerate short-term clinical improvement. Peak CRP and nadir platelet counts were associated with increased mortality both in isolation and by cluster analysis.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Unveiling the “Template-Dependent” Inhibition on the Viral Transcription of SARS-CoV-2</strong> - Remdesivir is one nucleotide analogue prodrug capable to terminate RNA synthesis in SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) by two distinct mechanisms. Although the “delayed chain termination” mechanism has been extensively investigated, the “template-dependent” inhibitory mechanism remains elusive. In this study, we have demonstrated that remdesivir embedded in the template strand seldom directly disrupted the complementary NTP incorporation at the active site. Instead, the translocation…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Tackling medical misinformation in allergy and immunology practice</strong> - SummaryWhen Dictionary.com named “misinformation” the word of the year, it stated that “The rampant spread of misinformation poses new challenges for navigating life …”. That was in 2018, two years before the global COVID-19 pandemic fundamentally changed the manner in which misinformation inhibited public health efforts unlike any other time in human history. Our patients are continually seeking information pertaining to their health. When we see them for new patient consultations or follow up…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Antimicrobial Alkaloids from Marine-Derived Fungi as Drug Leads versus COVID-19 Infection: A Computational Approach to Explore their Anti-COVID-19 Activity and ADMET Properties</strong> - Therapeutic strategies based upon enzyme inhibition have recently gained higher attention in treating hazardous ailments. Herein, the potential use of seventy-two antimicrobial alkaloids isolated from marine-derived fungi to fight COVID-19 infection via inhibition of SARS-CoV-2 lethal virus was performed using in silico analyses. Molecular modelling was performed to assess their enzyme inhibitory potential on the main protease SARS-CoV-2 M^(Pro), 3-chymotrypsin-like protease SARS-CoV-2…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Access to Health Care for Migrants Along the Mexico-United States Border: Applying a Framework to Assess Barriers to Care in Mexico</strong> - CONCLUSIONS: While Mexico’s health regulations are inclusive of migrants, in practice there are major barriers to access public health services, which might inhibit migrants from seeking those services. In order to comply with its commitment to guarantee the right to health of all persons, the Mexican health authorities should address the implementation gap between an inclusive policy, and the barriers to access that still remain.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>DNA aptamers inhibit SARS-CoV-2 spike-protein binding to hACE2 by an RBD- independent or dependent approach</strong> - Objective: Nobody knows when the COVID-19 pandemic will end or when and where the next coronavirus will outbreak. Therefore, it is still necessary to develop SARS-CoV-2 inhibitors for different variants or even the new coronavirus. Since SARS-CoV-2 uses its surface spike-protein to recognize hACE2, mediating its entry into cells, ligands that can specifically recognize the spike-protein have the potential to prevent infection. Methods: We have recently discovered DNA aptamers against the…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Non-Targeted Metabolomic Analysis of Chicken Kidneys in Response to Coronavirus IBV Infection Under Stress Induced by Dexamethasone</strong> - Stress in poultry can lead to changes in body metabolism and immunity, which can increase susceptibility to infectious diseases. However, knowledge regarding chicken responses to viral infection under stress is limited. Dexamethasone (Dex) is a synthetic glucocorticoid similar to that secreted by animals under stress conditions, and has been widely used to induce stress in chickens. Herein, we established a stress model in 7-day-old chickens injected with Dex to elucidate the effects of stress…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Repurposing Metformin for Vascular Disease</strong> - Metformin has seen use as an oral anti-hyperglycaemic drug since the late 1950s; however, following the release in 1998 of the findings of the 20-year United Kingdom Prospective Diabetes Study (UKPDS) metformin use rapidly increased and today is the first-choice anti-hyperglycaemic drug for patients with type 2 diabetes (T2D). Metformin is in daily use by an estimated 150 million people worldwide. Historically, the benefits of metformin as an anti-diabetic and cardiovascular-protective drug have…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Theaflavin 3-gallate inhibits the main protease (M<sup>pro</sup>) of SARS-CoV-2 and reduces its count in vitro</strong> - The main protease (M^(pro)) of SARS-CoV-2 has been recognized as an attractive drug target because of its central role in viral replication. Our previous preliminary molecular docking studies showed that theaflavin 3-gallate (a natural bioactive molecule derived from theaflavin and found in high abundance in black tea) exhibited better docking scores than repurposed drugs (Atazanavir, Darunavir, Lopinavir). In this study, conventional and steered MD-simulations analyses revealed stronger…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Behavioral activation / inhibition systems and lifestyle as predictors of mental disorders in adolescent athletes during Covid19 pandemic</strong> - CONCLUSIONS: Analyzing the data, it can thus be concluded that whilst behavioral inhibition and activation systems seem to work together to significantly predict mental disorders, lifestyle cannot.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>SARS-CoV-2 VOC type and biological sex affect molnupiravir efficacy in severe COVID-19 dwarf hamster model</strong> - SARS-CoV-2 variants of concern (VOC) have triggered infection waves. Oral antivirals such as molnupiravir promise to improve disease management, but efficacy against VOC delta was questioned and potency against omicron is unknown. This study evaluates molnupiravir against VOC in human airway epithelium organoids, ferrets, and a lethal Roborovski dwarf hamster model of severe COVID-19-like lung injury. VOC were equally inhibited by molnupiravir in cells and organoids. Treatment reduced shedding…</p></li>
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<h1 data-aos="fade-right" id="from-patent-search">From Patent Search</h1>
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