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170 lines
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<title>07 December, 2023</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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<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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</ul>
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<h1 data-aos="fade-right" id="from-preprints">From Preprints</h1>
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<li><strong>Ribosomal frameshifting and misreading of mRNA in COVID-19 vaccines produces “off-target” proteins and immune responses eliciting safety concerns: Comment on UK study by Mulroney et al.</strong> -
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<div>
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We comment on the study by Mulroney et al.(1) entitled: “N1-methylpseudouridylation of mRNA causes +1 ribosomal frameshifting.” The study found evidence in mice and humans for the misreading of the modRNA contained within the Pfizer COVID-19 vaccine to inadvertently produce “off-target” proteins capable of eliciting “off-target” immune responses. The authors propose that these novel proteins are the result of ribosomal frameshifting occasioned by the substitution of N1-methyl pseudouridine. The authors state that the “error prone” code is a safety concern with a “huge potential to be harmful” and that “it is essential that these therapeutics are designed to be free from unintended side-effects.” The findings reveal a developmental and regulatory failure to ask fundamental questions that could affect the safety and effectiveness of these products. According to WHO guidelines for mRNA vaccines, (2) manufacturers should provide details of “unexpected ORFs”(Open Reading Frames). The formation of these off-target proteins is not disclosed in the package insert for COMIRNATY. The finding that unintended proteins may be produced as a result of vaccination is sufficient cause for regulators to conduct full risk assessments of past or future harms that may have ensued. Given that this study was conducted under the auspices of the United Kingdom Government, we must assume UK regulators, manufacturers, and international regulatory agencies, including FDA, were apprised of the data many months ago. We await their account of what steps they have taken to investigate why the formation of off-target proteins was not discovered sooner, what toxic effects they may have caused and what steps they are taken to prevent harm in the future and to inform the public of these findings.
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://osf.io/nt8jh/" target="_blank">Ribosomal frameshifting and misreading of mRNA in COVID-19 vaccines produces “off-target” proteins and immune responses eliciting safety concerns: Comment on UK study by Mulroney et al.</a>
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</div></li>
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<li><strong>GotGlycans: Role of N343 Glycosylation on the SARS-CoV-2 S RBD Structure and Co-Receptor Binding Across Variants of Concern</strong> -
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<div>
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Glycosylation of the SARS-CoV-2 spike (S) protein represents a key target for viral evolution because it affects both viral evasion and fitness. Successful variations in the glycan shield are difficult to achieve though, as protein glycosylation is also critical to folding and to structural stability. Within this framework, the identification of glycosylation sites that are structurally dispensable can provide insight into the evolutionary mechanisms of the shield and inform immune surveillance. In this work we show through over 45 s of cumulative sampling from conventional and enhanced molecular dynamics (MD) simulations, how the structure of the immunodominant S receptor binding domain (RBD) is regulated by N-glycosylation at N343 and how the structural role of this glycan changes from WHu-1, alpha (B.1.1.7), and beta (B.1.351), to the delta (B.1.617.2) and omicron (BA.1 and BA.2.86) variants. More specifically, we find that the amphipathic nature of the N-glycan is instrumental to preserve the structural integrity of the RBD hydrophobic core and that loss of glycosylation at N343 triggers a specific and consistent conformational change. We show how this change allosterically regulates the conformation of the receptor binding motif (RBM) in the WHu-1, alpha and beta RBDs, but not in the delta and omicron variants, due to mutations that reinforce the RBD architecture. In support of these findings, we show that the binding of the RBD to monosialylated ganglioside co-receptors is highly dependent on N343 glycosylation in the WHu-1, but not in the delta RBD, and that affinity changes significantly across VoCs. Ultimately, the molecular and functional insight we provide in this work reinforces our understanding of the role of glycosylation in protein structure and function and it also allows us to identify the structural constraints within which the glycosylation site at N343 can become a hotspot for mutations in the SARS-CoV-2 S glycan shield.
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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/10.1101/2023.12.05.570076v1" target="_blank">GotGlycans: Role of N343 Glycosylation on the SARS-CoV-2 S RBD Structure and Co-Receptor Binding Across Variants of Concern</a>
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</div></li>
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<li><strong>High throughput screening identifies broad-spectrum Coronavirus entry inhibitors</strong> -
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<div>
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The Covid-19 pandemic highlighted the pressing need for antiviral therapeutics capable of mitigating infection and spread of emerging coronaviruses (CoVs). A promising therapeutic strategy lies in inhibiting viral entry mediated by the Spike (S) glycoprotein. To identify small molecule inhibitors that block entry downstream of receptor binding, we established a high-throughput screening (HTS) platform based on pseudoviruses. We employed a three-step process to screen nearly 200,000 small molecules. First, we identified potential inhibitors by assessing their ability to inhibit pseudoviruses bearing the SARS-CoV-2 S glycoprotein. Subsequent counter-screening against pseudoviruses with the Vesicular Stomatitis Virus spike glycoprotein (VSV-G), yielding sixty-five SARS-CoV-2 S-specific inhibitors. These were further tested against pseudoviruses bearing the MERS-CoV S glycoprotein, which uses a different receptor. Out of these, five compounds including the known broad-spectrum inhibitor Nafamostat, were subjected to further validation and tested them against pseudoviruses bearing the S glycoprotein of the alpha, delta, and omicron variants as well as against bona fide SARS-CoV-2 in vitro. This rigorous approach revealed a novel inhibitor and its derivative as a potential broad-spectrum antiviral. These results validate the HTS platform and set the stage for lead optimization and future pre-clinical, in vivo studies.
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</div>
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.12.04.569985v1" target="_blank">High throughput screening identifies broad-spectrum Coronavirus entry inhibitors</a>
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</div></li>
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<li><strong>Identification and Analysis of SARS-CoV-2 Mutation and Subtype using 2x tiled Primer Set with Oxford Nanopore Technologies Sequencing for Enhanced Variant Detection and Surveillance in Seoul, Korea</strong> -
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<div>
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a respiratory virus that contains RNA as its genetic material and has caused a global pandemic since its outbreak in 2020. This virus has many mutations, some of which can reduce the effectiveness of existing vaccines. Therefore, next-generation sequencing (NGS) is necessary to accurately identify new mutations. Current NGS analysis of SARS-CoV-2 uses the amplicon analysis method through a multiplex polymerase chain reaction. This study collected and validated RNA samples from patients who tested positive for SARS-CoV-2 from April to July 2022, and selected 613 samples for sequencing. The findings demonstrate the importance of long-read-based NGS analysis and 2x tiled primer set for identifying full SARS-CoV-2 genome sequence with new mutations and understanding the correlation between viral genotypes and patient characteristics for the effective management of SARS-CoV-2.
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</div>
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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/10.1101/2023.12.03.569831v1" target="_blank">Identification and Analysis of SARS-CoV-2 Mutation and Subtype using 2x tiled Primer Set with Oxford Nanopore Technologies Sequencing for Enhanced Variant Detection and Surveillance in Seoul, Korea</a>
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</div></li>
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<li><strong>Multi-variate statistical and machine learning reveals the interplay between sex and age in antibody responses to de novo SARS-CoV-2 infection and vaccination</strong> -
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<div>
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Prevention of negative COVID19 infection outcomes and infection/vaccine-acquired immunity is associated with the quality of antibody responses, whose variance by age and sex are poorly understood. Integrated, network approaches, identified sex and age effects in antibody responses and neutralization potential of de novo infection and vaccination throughout the Covid-19 pandemic. Cluster analysis found neutralization values followed SARS-CoV-2 specific receptor binding RIgG, spike SIgG and S and RIgA levels based on COVID19 status. Stochastic behavior tests and other analytical methods revealed sex differences only in persons <40y.o. Serum IgA antibody titers correlated with neutralization only in females 40-60y.o. Network analysis found males could improve IgA responses after vaccination dose 2, unlike >60 y.o. females. Complex correlation analyses found vaccination induced less antibody isotype switching and neutralization in older persons, especially in females. Sex dependent antibody & neutralization behavior decayed fastest in older males and with vaccination. Such sex and age characterization by machine learning can direct studies integrating cell mediated responses to define yet elusive correlates of protection and inform age and sex precision-focused vaccine design.
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</div>
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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/10.1101/2023.12.05.569965v1" target="_blank">Multi-variate statistical and machine learning reveals the interplay between sex and age in antibody responses to de novo SARS-CoV-2 infection and vaccination</a>
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</div></li>
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<li><strong>Identification of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir</strong> -
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<div>
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The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an epidemic, zoonotically emerging pathogen initially reported in Saudi Arabia in 2012. MERS-CoV has the potential to mutate or recombine with other coronaviruses, thus acquiring the ability to efficiently spread among humans and become pandemic. Its high mortality rate of up to 35 % and the absence of effective targeted therapies call for the development of antiviral drugs for this pathogen. Since the beginning of the SARS-CoV-2 pandemic, extensive research has focused on identifying protease inhibitors for the treatment of SARS-CoV-2. Our intention was therefore to assess whether these protease inhibitors are viable options for combating MERS-CoV. To that end, we used previously established protease assays to quantify inhibition of the SARS-CoV-2 and MERS-CoV main proteases. Furthermore, we selected MERS-CoV-Mpro mutants resistant against nirmatrelvir, the most effective inhibitor of this protease, with a safe, surrogate virus-based system, and suggest putative resistance mechanisms. Notably, nirmatrelvir demonstrated effectiveness against various viral proteases, illustrating its potential as a broad-spectrum coronavirus inhibitor. To adress the inherent resistance of MERS-CoV-Mpro to ensitrelvir, we applied directed mutagenesis to a key ensitrelvir-interacting residue and provided structural models.
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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/10.1101/2023.12.04.569917v1" target="_blank">Identification of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir</a>
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</div></li>
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<li><strong>Sex-Specific Systemic Inflammatory Responses in Mice Infected with a SARS-CoV-2-like Virus and Femur Fracture</strong> -
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This study investigates the systemic inflammatory response in mice infected with a murine coronavirus (MHV), which shares a common genus with SARS-CoV-2, and sustaining a fracture. The study reveals that the combined inflammatory incidents of MHV infection and fracture disrupt the systemic immune response in both female and male mice, likely leading to immune dysregulation, altered cell recruitment, and disruption of the typical inflammatory cascade. Notably, the study uncovers sex-specific responses that modulate circulating immune factors. Females exhibit elevated levels of inflammatory factors, whereas males demonstrate a diminished response. This divergence is mirrored in cell populations, suggesting that the quantity of immune factors released may contribute to these discrepancies. The findings suggest that an overproduction of proinflammatory cytokines may induce a dysregulated immune response, contributing to the observed poorer prognosis in comorbid cases. These insights could pave the way for therapeutic advancements and treatment strategies aimed at reducing mortality rates in COVID-19 patients with fractures.
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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/10.1101/2023.12.04.567060v1" target="_blank">Sex-Specific Systemic Inflammatory Responses in Mice Infected with a SARS-CoV-2-like Virus and Femur Fracture</a>
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</div></li>
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<li><strong>In field use of water samples for genomic surveillance of ISKNV infecting tilapia fish in Lake Volta, Ghana</strong> -
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<div>
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Viral outbreaks are a constant threat to aquaculture, limiting production for better global food security. A lack of diagnostic testing and monitoring in resource-limited areas hinders the capacity to respond rapidly to disease outbreaks and to prevent viral pathogens becoming endemic in fisheries productive waters. Recent developments in diagnostic testing for emerging viruses, however, offers a solution for rapid in situ monitoring of viral outbreaks. Genomic epidemiology has furthermore proven highly effective in detecting viral mutations involved in pathogenesis and assisting in resolving chains of transmission. Here, we demonstrate the application of an in-field epidemiological tool kit to track viral outbreaks in aquaculture on farms with reduced access to diagnostic labs, and with non-destructive sampling. Inspired by the "lab in a suitcase" approach used for genomic surveillance of human viral pathogens and wastewater monitoring of COVID19, we evaluated the feasibility of real-time genome sequencing surveillance of the fish pathogen, Infectious spleen and kidney necrosis virus (ISKNV) in Lake Volta. Viral fractions from water samples collected from cages holding Nile tilapia (Oreochromis niloticus) with suspected ongoing ISKNV infections were concentrated and used as a template for whole genome sequencing, using a previously developed tiled PCR method for ISKNV. Mutations in ISKNV in samples collected from the water surrounding the cages matched those collected from infected caged fish, illustrating that water samples can be used for detecting predominant ISKNV variants in an ongoing outbreak. This approach allows for the detection of ISKNV and tracking of the dynamics of variant frequencies, and may thus assist in guiding control measures for the rapid isolation and quarantine of infected farms and facilities.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.12.02.569710v1" target="_blank">In field use of water samples for genomic surveillance of ISKNV infecting tilapia fish in Lake Volta, Ghana</a>
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</div></li>
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<li><strong>Towards ultra-low-cost smartphone microscopy</strong> -
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The outbreak of COVID-19 exposed the inadequacy of our technical tools for home health surveillance, and recent studies have shown the potential of smartphones as a universal optical microscopic imaging platform for such applications. However, most of them use laboratory-grade optomechanical components and transmitted illuminations to ensure focus tuning capability and imaging quality, which keeps the cost of the equipment high. Here we propose an ultra-low-cost solution for smartphone microscopy. To realize focus tunability, we designed a seesaw-like structure capable of converting large displacements on one side into small displacements on the other (reduced to [~]9.1%), which leverages the intrinsic flexibility of 3D printing materials. We achieved a focus-tuning accuracy of [~] 5 m, which is 40 times higher than the machining accuracy of the 3D-printed lens holder itself. For microscopic imaging, we use an off-the-shelf smartphone camera lens as the objective and the built-in flashlight as the illumination. To compensate for the resulting image quality degradation, we developed a learning-based image enhancement method. We use the CycleGAN architecture to establish the mapping from smartphone microscope images to benchtop microscope images without pairing. We verified the imaging performance on different biomedical samples. Except for the smartphone, we kept the full costs of the device under 4 USD. We think these efforts to lower the costs of smartphone microscopes will benefit their applications in various scenarios, such as point-of-care testing, on-site diagnosis, and home health surveillance.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.12.01.569689v1" target="_blank">Towards ultra-low-cost smartphone microscopy</a>
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<li><strong>Social isolation, mental health, and use of digital interventions in youth during the COVID-19 pandemic: a nationally representative survey</strong> -
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Summary Background: Public health measures to curb SARS-CoV-2 transmission rates may have negative psychosocial consequences in youth. Digital interventions may help to mitigate these effects. We investigated the associations between social isolation, cognitive preoccupation, worries, and anxiety, objective social risk indicators, psychological distress as well as use of, and attitude towards, mobile health (mHealth) interventions in youth during the COVID-19 pandemic. Methods: Data were collected as part of the ‘Mental Health And Innovation During COVID-19 Survey’ —a cross-sectional panel study including a representative sample of individuals aged 16 to 25 years (N=666; Mage 21·3) (assessment period: 07.05.-16.05.2020). Outcomes: Overall, 38% of youth met criteria for moderate psychological distress and 30% felt ‘often’ or ‘very often’ socially isolated, even after most restrictive infection control measures had been lifted. Social isolation, COVID-19-related worries and anxiety, and objective risk indicators were associated with psychological distress, with evidence of dose-response relationships for some of these associations. For instance, psychological distress was progressively more likely to occur as levels of social isolation increased (reporting ‘never’ as reference group: ‘occasionally’: adjusted odds ratio [aOR] 9·1, 95% confidence interval [CI] 4·3 – 19·1, p<0·001; ‘often’: aOR 22·2, CI 9·8 – 50·2, p<0·001;’very often’: aOR 42·3, CI 14·1 – 126·8, p<0·001). There was evidence that psychological distress, worries, and anxiety were associated with a positive attitude towards using digital interventions, whereas high levels of psychological distress, worries, and anxiety were associated with actual use. Interpretation: Public health measures during pandemics may be associated with poor mental health in youth. Digital interventions may help mitigate the negative psychosocial impact given there is an objective need and subjective demand.
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🖺 Full Text HTML: <a href="https://osf.io/preprints/psyarxiv/v64hf/" target="_blank">Social isolation, mental health, and use of digital interventions in youth during the COVID-19 pandemic: a nationally representative survey</a>
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<li><strong>Zheln.com: A protocol for a universal living overview of health-related systematic reviews</strong> -
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BACKGROUND Objectives. 1. Identify and monitor most of published systematic reviews. 2. Tag the identified systematic records with medical specialties. 3. Select or crowdfund reviews for further appraisal. 4. Critically appraise and replicate the selected systematic reviews. 5. Disseminate practice implications of positively appraised reviews to both the public and evidence-based practitioners in health care and other fields associated with intervention into a human life, such as education, business, policy, or ecology. METHODS Eligibility criteria. Record eligibility is assessed by checking the record title and, if the title failed, abstract against the ‘true positive criteria’ for systematic reviews taken from the publication by Shojania & Bero, 2001 (PMID 11525102). The record/study flow is as follows: All eligible records are amenable for tagging, selection, and crowdfunding process; Only those eligible records that have been selected or crowdfunded are subject to critical appraisal; For all records that have been selected, all relevant reports are collected; Reports are grouped into studies; Only for the studies appraised positively, practical implications are summarized and disseminated. COVID-19 publications are not selected. Crowdfunding an appraisal of any eligible record is possible for any individual or organization. Information sources. MEDLINE via PubMed. Adding other search sources, such as Scopus, OSF, and medRxiv, is planned in the future when more appraisers become available. The Replicated Version of the PubMed Systematic Review Subset Query Zheln Edition (DOI 10.17605/OSF.IO/Z3JU7) will be used. The searches are run daily. Risk of bias. Critical appraisal will feature: Duplication assessment; Replication; Assessment against the MECIR conduct standards; ROB-ME assessment; GRADE assessment. Synthesis of results. No across-studies synthesis is planned. Within-studies, I will formulate explicit practice-relevant statements based on the extracted health outcomes and quality-of-conduct assessment. Also, the process of each critical appraisal is video-recorded and published on YouTube daily. OTHER Funding. The review is crowdfunded; the details are available from the Zheln website (https://zheln.com). Crowd funders had no role in the design of the protocol. They will be able to request critical appraisal and additional critical appraisal (with new data provided) of any eligible record but will not influence the review process otherwise. Registration. The project is hosted on GitHub. Also, there is an umbrella Open Science Framework project that links repositories and preprints (DOI 10.17605/OSF.IO/EJKFC). The protocol for this overview of systematic reviews has been submitted for registration in PROSPERO.
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🖺 Full Text HTML: <a href="https://osf.io/preprints/metaarxiv/y2nrb/" target="_blank">Zheln.com: A protocol for a universal living overview of health-related systematic reviews</a>
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<li><strong>Failure to protect: COVID infection control policy privileges poor-quality evidence</strong> -
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The failure to immediately recognize the urgent need to control airborne spread of COVID-19, including use of adequate personal protective equipment for an airborne pathogen, represents a major medical error that cost “an enormous number of lives”. Made in the face of significant scientific evidence and a clear requirement to adhere to a precautionary approach, it has still not been fully remedied. To understand the substantial, ongoing gap between science and policy, we carried out an in-depth investigation of an illustrative publication authored by prominent authorities in the fields of Public Health and Infection Prevention and Control, describing a trial of medical masks and N95 respirators for the prevention of COVID-19. Although it was portrayed as among the highest quality evidence available within the Evidence-Based Medicine decision-making paradigm, we found this work to be deeply flawed to the extent that it does not meet basic standards of scientific rigour. Extensive prior work in the respiratory protection field – sufficiently well-established to be incorporated into both national standards and specific recommendations made to address infection control failures in SARS – was ignored. Randomization was compromised, with a statistically significant correlation between female sex and allocation to the higher-risk arm of the trial. Significant conflicts of interest in favour of the reported finding that medical masks are noninferior to N95 respirators in preventing COVID-19 transmission were not disclosed. Prespecified analyses were omitted, and the finding of noninferiority is entirely a product of inappropriate alterations to the trial that were not prospectively registered. Despite numerous flaws biasing the outcome towards a finding of noninferiority, re-analysis using the prespecified approach and noninferiority criterion unambiguously reverses the reported outcome of the trial.
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🖺 Full Text HTML: <a href="https://osf.io/preprints/metaarxiv/ey7bj/" target="_blank">Failure to protect: COVID infection control policy privileges poor-quality evidence</a>
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<li><strong>The Last Confirmed Case is Not the Last Infection and Catastrophic Outbreaks do Not Require Transmission</strong> -
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Efforts to prevent transmission of the infectious agent that causes an infectious disease in its capacity as a pathogen are praised and victory is declared after the last case of the expected outcomes of the event in which this disease occurs is confirmed. After all, it is assumed that such expected outcomes of the event in which the pathogen causes the infectious disease are manifestations of this disease and therefore that the last confirmed case in which such outcomes are observed is the last case of infection. But the results obtained while forging the path to immunological concepts which have eluded us since the birth of the repeatedly proven germ theory with the method by which Einstein approximated astronomical reality conceptually while developing General Relativity reveal that outcomes of the event in which the pathogen causes the infectious disease are not manifestations of this disease but rather consequences of the comanifestation of different diseases in the spectrum of the infectious disease. These results enable us to account for the differences between such outcomes which, for instance, in patients with COVID-19 that the current theory of infectious disease pathogenesis expects to produce outcomes that affect the upper respiratory disease, include unexpected conditions such as the chronic ones seen in Long COVID patients and in patients with mpox, which this theory logically deduced to be a skin-affecting disease, include deadly conditions like encephalitis with the consequence that outcomes with such deadly conditions are attributed to underlying conditions even after Spain’s health ministry reported deaths from such outcomes in healthy individuals. And the consequence of the same results is that the last cases of expected outcomes such as those that affect the skin of individuals who are infected with the mpox virus are not the last cases of infection but rather the last cases in which such outcomes appear as the sterile causes of the non-infectious diseases that co-manifest with the infectious disease for the emergence of such outcomes disappear from the population in which undetected spread of the infectious agent occurred long before the widespread appearance of such expected outcomes that called attention to this pathogen or an earlier form of the pathogen, such as the smallpox virus, which is assumed to have been eradicated. It follows in the reality which was visualized to obtain these results that even as the disappearance of such outcomes is being celebrated, the sterile causes of non-infectious diseases which co-manifest with the infectious disease for the emergence of unexpected deadly outcomes, such as those with encephalitis and toxic shock, may be appearing in the population which is already harboring the pathogen silently. And without exciting cause or warning, such deadly outcomes will become widespread in our populations and will decimate them if the only treatments available at the time are still those that reduce viral replication which are unable to bring about the remission of such outcomes. Instead of celebrating the disappearance of cases when the sterile causes of the non-infectious diseases that co-manifest with mpox for the emergence of those expected skin-affecting outcomes disappear, we ought to quickly elucidate the conditions that permit the immunological mechanisms of infection and vaccination to bring about uneventful exposure to such sterile causes even after deadly outcomes of such events have already appeared as achieved, in some cases, by the vaccines of William Coley and Julius Wagner-Jauregg even at a time when nothing was known about the nature of such immunological mechanisms and the remission that followed therapeutic infection in such cases was attributed to fever.
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🖺 Full Text HTML: <a href="https://osf.io/gb7ky/" target="_blank">The Last Confirmed Case is Not the Last Infection and Catastrophic Outbreaks do Not Require Transmission</a>
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<li><strong>Genome-wide Bioinformatics Analysis of Human Protease Capacity for Proteolytic Cleavage of the SARS-CoV-2 Spike Glycoprotein</strong> -
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The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) primarily enters the cell by binding the virus’s spike (S) glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor on the cell surface, followed by proteolytic cleavage by host proteases. Studies have identified furin and TMPRSS2 proteases in priming and triggering cleavages of the S glycoprotein, converting it into a fusion-competent form and initiating membrane fusion, respectively. Alternatively, SARS-CoV-2 can enter the cell through the endocytic pathway, where activation is triggered by lysosomal cathepsin L. However, other proteases are also suspected to be involved in both entry routes. In this study, we conducted a genome-wide bioinformatics analysis to explore the capacity of human proteases in hydrolyzing peptide bonds of the S glycoprotein. Predictive models of sequence specificity for 169 human proteases were constructed and applied to the S glycoprotein together with the method for predicting structural susceptibility to proteolysis of protein regions. After validating our approach on extensively studied S2’ and S1/S2 cleavage sites, we applied our method to each peptide bond of the S glycoprotein across all 169 proteases. Our results indicate that various members of the PCSK, TTSP, and kallikrein families, as well as specific coagulation factors, are capable of cleaving S2’ or S1/S2 sites. We have also identified a potential cleavage site of cathepsin L at the K790 position within the S2’ loop. Structural analysis suggests that cleavage of this site induces conformational changes similar to the cleavage at the R815 (S2’) position, leading to the exposure of the fusion peptide and subsequent fusion with the membrane. Other potential cleavage sites and the influence of mutations in common SARS-CoV-2 variants on proteolytic efficiency are discussed.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.08.19.553950v2" target="_blank">Genome-wide Bioinformatics Analysis of Human Protease Capacity for Proteolytic Cleavage of the SARS-CoV-2 Spike Glycoprotein</a>
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<li><strong>Murine Alveolar Macrophages Rapidly Accumulate Intranasally Administered SARS-CoV-2 Spike Protein leading to Neutrophil Recruitment and Damage</strong> -
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The trimeric SARS-CoV-2 Spike protein mediates viral attachment facilitating cell entry. Most COVID-19 vaccines direct mammalian cells to express the Spike protein or deliver it directly via inoculation to engender a protective immune response. The trafficking and cellular tropism of the Spike protein in vivo and its impact on immune cells remains incompletely elucidated. In this study we inoculated mice intranasally, intravenously, and subcutaneously with fluorescently labeled recombinant SARS-CoV-2 Spike protein. Using flow cytometry and imaging techniques we analyzed its localization, immune cell tropism, and acute functional impact. Intranasal administration led to rapid lung alveolar macrophage uptake, pulmonary vascular leakage, and neutrophil recruitment and damage. When injected near the inguinal lymph node medullary, but not subcapsular macrophages, captured the protein, while scrotal injection recruited and fragmented neutrophils. Wide-spread endothelial and liver Kupffer cell uptake followed intravenous administration. Human peripheral blood cells B cells, neutrophils, monocytes, and myeloid dendritic cells all efficiently bound Spike protein. Exposure to the Spike protein enhanced neutrophil NETosis and augmented human macrophage TNF- and IL-6 production. Human and murine immune cells employed C-type lectin receptors and Siglecs to help capture the Spike protein. This study highlights the potential toxicity of the SARS-CoV-2 Spike protein for mammalian cells and illustrates the central role for alveolar macrophage in pathogenic protein uptake.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.03.13.532446v2" target="_blank">Murine Alveolar Macrophages Rapidly Accumulate Intranasally Administered SARS-CoV-2 Spike Protein leading to Neutrophil Recruitment and Damage</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>Intravenous Immunoglobulin Replacement Therapy for Persistent COVID-19 in Patients With B-cell Impairment</strong> - <b>Conditions</b>: COVID-19 <br/><b>Interventions</b>: Drug: Immunoglobulins <br/><b>Sponsors</b>: Jaehoon Ko <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 Inhaled Hydroxy Gas on Long COVID Symptoms</strong> - <b>Conditions</b>: Post-Acute COVID-19 Syndrome <br/><b>Interventions</b>: Device: Hydroxy gas <br/><b>Sponsors</b>: Oxford Brookes University <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>Community Care Intervention to Decrease COVID-19 Vaccination Inequities</strong> - <b>Conditions</b>: COVID-19 Vaccination <br/><b>Interventions</b>: Behavioral: Community Health Worker Intervention to Enhance Vaccination Behavior (CHW-VB) <br/><b>Sponsors</b>: RAND; Clinical Directors Network; 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>Stem Cell Study for Long COVID-19 Neurological Symptoms</strong> - <b>Conditions</b>: Post-Acute COVID-19 Syndrome <br/><b>Interventions</b>: Biological: Stem Cell <br/><b>Sponsors</b>: Charles Cox; CBR Systems, Inc. <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>Multilevel Intervention of COVID-19 Vaccine Uptake Among Latinos</strong> - <b>Conditions</b>: Vaccine Hesitancy <br/><b>Interventions</b>: Behavioral: Multilevel Intervention <br/><b>Sponsors</b>: San Diego State University <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>PROmotion of COVID-19 BOOSTer VA(X)Ccination in the Emergency Department - PROBOOSTVAXED</strong> - <b>Conditions</b>: COVID-19 <br/><b>Interventions</b>: Behavioral: Vaccine Messaging; Behavioral: Vaccine Acceptance Question <br/><b>Sponsors</b>: University of California, San Francisco; National Institute of Allergy and Infectious Diseases (NIAID); Pfizer; Duke University; Baylor College of Medicine; Thomas Jefferson University <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>Evaluating a Comprehensive Multimodal Outpatient Rehabilitation Program for PASC Program to Improve Functioning of Persons Suffering From Post-COVID Syndrome: A Randomized Controlled Trial</strong> - <b>Conditions</b>: Post-Acute COVID-19; Post-Acute COVID-19 Syndrome; Post-Acute COVID-19 Infection; Long COVID; Long Covid19; Dyspnea; Orthostasis; Cognitive Impairment <br/><b>Interventions</b>: Other: Comprehensive Rehabilitation; Other: Augmented Usual Care <br/><b>Sponsors</b>: University of Pennsylvania; Medical College of Wisconsin; National Institutes of Health (NIH) <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>Pursuing Reduction in Fatigue After COVID-19 Via Exercise and Rehabilitation (PREFACER): A Randomized Feasibility Trial</strong> - <b>Conditions</b>: Long-COVID; Long Covid19; Post-COVID-19 Syndrome; Post-COVID Syndrome; Fatigue <br/><b>Interventions</b>: Other: COVIDEx <br/><b>Sponsors</b>: Lawson Health Research Institute; Western University <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 Metformin in Reducing Fatigue in Long COVID in Adolescents</strong> - <b>Conditions</b>: Long COVID <br/><b>Interventions</b>: Drug: Metformin; Other: Placebo <br/><b>Sponsors</b>: Trust for Vaccines and Immunization, Pakistan <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 Randomized Trial Evaluating a mRNA VLP Vaccine’s Immunogenicity and Safety for COVID-19</strong> - <b>Conditions</b>: COVID-19; SARS-CoV-2 Infection <br/><b>Interventions</b>: Biological: AZD9838; Biological: Licensed mRNA vaccine <br/><b>Sponsors</b>: AstraZeneca <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>Vale+Tú Salud: Corner-Based Randomized Trial to Test a Latino Day Laborer Program Adapted to Prevent COVID-19</strong> - <b>Conditions</b>: COVID-19 <br/><b>Interventions</b>: Behavioral: COVID-19 Group Problem Solving; Behavioral: Standard of Care; Behavioral: Booster session <br/><b>Sponsors</b>: The University of Texas Health Science Center, Houston; 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>“The Effect of Aerobic Exercise and Strength Training on Physical Activity Level, Quality of Life and Anxiety-Stress Disorder in Young Adults With and Without Covid-19”</strong> - <b>Conditions</b>: COVID-19 <br/><b>Interventions</b>: Behavioral: Aerobic Exercise and Strength Training <br/><b>Sponsors</b>: Pamukkale University <br/><b>Active, not 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 Study of SLV213 for the Treatment of COVID-19.</strong> - <b>Conditions</b>: COVID-19 <br/><b>Interventions</b>: Other: Placebo for SLV213; Drug: SLV213 <br/><b>Sponsors</b>: National Institute of Allergy and Infectious Diseases (NIAID) <br/><b>Not yet recruiting</b></p></li>
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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>Unraveling antiviral efficacy of multifunctional immunomodulatory triterpenoids against SARS-COV-2 targeting main protease and papain-like protease</strong> - The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be over, but its variants continue to emerge, and patients with mild symptoms having long COVID is still under investigation. SARS-CoV-2 infection leading to elevated cytokine levels and suppressed immune responses set off cytokine storm, fatal systemic inflammation, tissue damage, and multi-organ failure. Thus, drug molecules targeting the SARS-CoV-2 virus-specific…</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>Strategies to Mitigate the Drug-Drug Interaction between Nirmatrelvir/Ritonavir and Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplant Recipients on Azole Antifungals: Results of a Case Series</strong> - CONCLUSION: NIM/r-tacrolimus is a serious drug-drug interaction which can be mitigated by early discontinuation of tacrolimus and azole antifungals, close monitoring, and reinitiation of tacrolimus and antifungal 48-72 h after completion of therapy.</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>Patterns of physical activity among nursing home residents before and during the Covid 19 pandemic-a systematic observation</strong> - CONCLUSIONS: Nursing homes constitute highly sedentary places-an issue exacerbated by access restrictions for external activity experts and significant others as well as behavioural restrictions for residents during the Covid-19 pandemic. Staff could not compensate due to existing time restraints and lack of training in PA promotion. Based on our findings, we recommend future studies to develop feasible and resource-low activities to be integrated into the daily routines of nursing homes.</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 natural product YSK-A blocks SARS-CoV-2 propagation by targeting multiple host genes</strong> - Natural products and herbal medicine have been widely used in drug discovery for treating infectious diseases. Recent outbreak of COVID-19 requires various therapeutic strategies. Here, we used YSK-A, a mixture of three herbal components Boswellia serrata, Commiphora myrrha, and propolis, to evaluate potential antiviral activity against SARS-CoV-2. We showed that YSK-A inhibited SARS-CoV-2 propagation with an IC(50) values of 12.5 µg/ml and 15.42 µg/ml in Vero E6 and Calu-3 cells, respectively….</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>Validation of nuclear receptor RORγ isoform 1 as a novel host-directed antiviral target based on the modulation of cholesterol levels</strong> - Currently, the clinically approved repertoire of antiviral drugs predominantly comprises direct-acting antivirals (DAAs). However, the use of DAAs is frequently limited by adverse effects, restriction to individual virus species, or the induction of viral drug resistance. These issues will likely be resolved by the introduction of host-directed antivirals (HDAs) targeting cellular proteins crucial for viral replication. However, experiences with the development of antiviral HDAs and clinical…</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>Inhibition of non-muscular myosin light chain kinase accelerates the clearance of inflammatory cells by promoting the lysosome-mediated cell death</strong> - Infections like COVID-19 are the primary cause of death around the world because they can cause acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and sepsis. Inflammatory cells serve as crucial protective barriers in these diseases. However, excessive accumulation of inflammatory cells is also one of the major causes of organ damage. The non-muscular myosin light chain kinase (nmMLCK) plays crucial of cytoskeletal components involved in endothelial cell-matrix and cell-cell…</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>Crystal structure of SARS-CoV-2 main protease (M<sup>pro</sup>) mutants in complex with the non-covalent inhibitor CCF0058981</strong> - SARS-CoV-2 constantly circulates and evolves worldwide, generating many variants and posing a menace to global health. It is urgently needed to discover effective medicines to treat the disease caused by SARS-CoV-2 and its variants. An established target for anti-SARS-CoV-2 drug discovery is the main protease (M^(pro)), since it exerts an irreplaceable action in viral life cycle. CCF0058981, derived from ML300, is a non-covalent inhibitor that exhibits low nanomolar potency against 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>USP2 inhibition prevents infection with ACE2-dependent coronaviruses in vitro and is protective against SARS-CoV-2 in mice</strong> - Targeting angiotensin-converting enzyme 2 (ACE2) represents a promising and effective approach to combat not only the COVID-19 pandemic but also potential future pandemics arising from coronaviruses that depend on ACE2 for infection. Here, we report ubiquitin specific peptidase 2 (USP2) as a host-directed antiviral target; we further describe the development of MS102, an orally available USP2 inhibitor with viable antiviral activity against ACE2-dependent coronaviruses. Mechanistically, USP2…</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 Molecular Generative Model of COVID-19 Main Protease Inhibitors Using Long Short-Term Memory-Based Recurrent Neural Network</strong> - The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a serious threat to public health and prompted researchers to find anti-coronavirus 2019 (COVID-19) compounds. In this study, the long short-term memory-based recurrent neural network was used to generate new inhibitors for the coronavirus. First, the model was trained to generate drug compounds in the form of valid simplified molecular-input line-entry system strings. Then, the structures of COVID-19 main protease…</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>Phase II study of bemnifosbuvir in high-risk participants in a hospital setting with moderate COVID-19</strong> - CONCLUSION: Our results suggest a potential role for bemnifosbuvir in blunting COVID-19 progression.</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>Molecular mechanisms of dexamethasone actions in COVID-19: Ion channels and airway surface liquid dynamics</strong> - The COVID-19 pandemic has been a global health crisis of unprecedented magnitude. In the battle against the SARS-CoV-2 coronavirus, dexamethasone, a widely used corticosteroid with potent anti-inflammatory properties, has emerged as a promising therapy in the fight against severe COVID-19. Dexamethasone is a synthetic glucocorticoid that exerts its therapeutic effects by suppressing the immune system and reducing inflammation. In the context of COVID-19, the severe form of the disease is often…</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>Pilot Study of High-Dose Pemetrexed in Patients with Progressive Chordoma</strong> - CONCLUSIONS: High-dose pemetrexed appears tolerable and shows objective antitumor activity in patients with chordoma. Phase II studies of high-dose pemetrexed are warranted.</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>Antiviral Effects of Pyrroloquinoline Quinone through Redox Catalysis To Prevent Coronavirus Infection</strong> - The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus disease (COVID-19) is ongoing. Therefore, effective prevention of virus infection is required. Pyrroloquinoline quinone (PQQ), a natural compound found in various foods and human breast milk, plays a role in various physiological processes and is associated with health benefits. In this study, we aimed to determine the effects of PQQ on preventing coronavirus infections using a proxy Feline Infectious…</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>Dobrava hantavirus and coinciding SARS-CoV-2 infection mimicking thrombotic microangiopathy and responding to a single dose of eculizumab</strong> - The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has refocused scientific interest on gaining insight into the pathophysiology of systemic viral diseases. Complement activation has been characterized as a driver of endothelial injury and microvascular thrombosis in acute respiratory distress syndrome as well as hantavirus hemorrhagic fever with renal syndrome. On this occasion, we wish to report a case of severe hantavirus disease with coinciding 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>Cardiovascular safety pharmacology of ivermectin assessed using the isoflurane-anesthetized beagle dogs: ICH S7B follow-up study</strong> - Antiparasitic ivermectin has been reported to induce cardiovascular adverse events, including orthostatic hypotension, tachycardia and cardiopulmonary arrest, of which the underlying pathophysiology remains unknown. Since its drug repurposing as an antiviral agent is underway at higher doses than those for antiparasitic, we evaluated the cardiovascular safety pharmacology of ivermectin using isoflurane-anesthetized beagle dogs (n=4). Ivermectin in doses of 0.1 followed by 1 mg/kg was…</p></li>
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<h1 data-aos="fade-right" id="from-patent-search">From Patent Search</h1>
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