Corpus overview


Overview

MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (1850)

ProteinN (502)

NSP5 (400)

ComplexRdRp (232)

ProteinE (133)


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SARS-CoV-2 Proteins
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    A novel, multiplexed RT-qPCR assay to distinguish lineage B.1.1.7 from the remaining SARS-CoV-2 lineages

    Authors: Viera Kovacova; Kristína Boršová; Evan D Paul; Monika Radvanszka; Roman Hajdu; Viktória Čabanová; Monika Sláviková; Martina Ličková; Ľubomíra Lukáčiková; Andrej Belak; Lucia Roussier; Michaela Kostičová; Anna Líšková; Lucia Maďarová; Mária Štefkovičová; Lenka Reizigová; Elena Nováková; Peter Sabaka; Alena Koščálová; Broňa Brejová; Tomas Vinar; Jozef Nosek; Pavol Cekan; Boris Klempa

    doi:10.1101/2021.02.09.21251168 Date: 2021-03-03 Source: medRxiv

    The emergence of a novel SARS-CoV-2 variant called lineage B.1.1.7 sparked global alarm due to evidence of increased transmissibility, mortality, and uncertainty about vaccine efficacy, thus accelerating efforts to detect and track the variant. Current approaches to detect lineage B.1.1.7 include sequencing and RT-qPCR tests containing a target assay that fails or results in reduced sensitivity towards the B.1.1.7 variant. Since many countries lack robust genomic surveillance programs and failed assays detect multiple unrelated variants containing similar mutations as B.1.1.7, we sought to develop an RT-qPCR test that can accurately and rapidly differentiate the B.1.1.7 variant from other SARS-CoV-2 variants. We used bioinformatics, allele-specific PCR, and judicious placement of LNA-modified nucleotides to develop a test that differentiates B.1.1.7 from other SARS-CoV-2 variants. We validated the test on 106 clinical samples with lineage status confirmed by sequencing. Our room temperature-stable, multiplexed RT-qPCR test consists of two assays that target either the common SARS-CoV-2 spike PROTEIN gene or spike gene deletions specific to lineage B.1.1.7. A simple relative comparison of the Ct values of the two assays permits not only identification of the B.1.1.7 variant but also its differentiation from other variants that harbor only the {Delta}H69/{Delta}V70 deletion. The test showed 97% clinical sensitivity at detecting lineage B.1.1.7. This test can easily be implemented in labs to rapidly scale B.1.1.7 surveillance efforts and is particularly useful in countries with high prevalence of variants possessing only the {Delta}H69/{Delta}V70 deletion because current strategies using target failure assays incorrectly identify these as putative B.1.1.7 variants.

    Modeling University Reopening in Low Risk Countries During COVID-19 MESHD

    Authors: Jing Yang (Sunny) Xi; Wai Kin (Victor) Chan

    doi:10.1101/2021.03.02.21250607 Date: 2021-03-03 Source: medRxiv

    The safety of students worldwide remains a key issue during COVID-19 MESHD. The reopening of universities in high risk countries during Fall 2020 resulted in numerous outbreaks. While regular screening and testing on campus can prevent the transmission of SARS-CoV-2, they are extremely challenging to implement due to various reasons such as cost and logistics. However, for low risk countries, our study suggests that universities can fully reopen without testing, if students self-quarantine for 14 days on arrival and adopt proper nonpharmaceutical interventions (NPIs). We adopt agent-based simulation to model virus transmission on campus and test the effectiveness of several NPIs when school reopens. Assuming one initially infected student, results indicate that transmission between roommates causes the most infections with visitors, ground floors, and elevators, being the next main contributors. Limiting density and/or population are not impactful at flattening the curve. However, adopting masks, minimizing movement, and increasing the frequency of cleaning can effectively minimize infection and prevent outbreak, allowing for classes and activities to resume as normal.

    Impact of COVID-19 pandemic MESHD on Black, Asian and Minority Ethnic (BAME) communities: a qualitative study on the perspectives of BAME community leaders

    Authors: Fesani Mahmood; Dev Acharya; Kanta Kumar; Vibhu Paudyal

    doi:10.1101/2021.03.03.21252286 Date: 2021-03-03 Source: medRxiv

    Objectives: The aim of this study was to explore the perspectives of BAME community leaders in relation to - the impact of the COVID-19 pandemic MESHD on their communities; and BAME community perceptions, understanding and adherence to Government guidelines on COVID-19 MESHD public health measures. Design: A phenomenological approach was adopted using qualitative semi-structured interviews. Settings: Community organisations and places of worships in the West Midlands region of England. Participants: Community leaders were recruited through organisations representing BAME communities and religious places of worship. Results: A total of 19 participants took part. Participants alluded to historical and structural differences for the observed disparities in COVID-19 MESHD morbidity and mortality. Many struggled with lockdown measures which impeded cultural and religious gatherings that were deemed to be integral to the community. Cultural and social practices led to many suffering on their own as discussion of mental health was still deemed a taboo within many communities. Many expressed their community reluctance to report symptoms for the fear of financial and physical health implications. They reported increase in hate crime which was deemed to be exacerbated due to perceived insensitive messaging from authority officials and historical structural biases. Access and adherence to government guidelines was an issue for many due to language and digital barriers. Reinforcement from trusted community and religious leaders encouraged adherence. Points of support such as food banks were vital in ensuring essential supplies during the pandemic. Many could not afford masks and sanitisers. Conclusion: The study highlights the perceived impact of COVID-19 pandemic MESHD on BAME communities. Government agencies and public health agencies need to integrate with the community, and community leaders to penetrate the key messages and deliver targeted yet sensitive public health advice which incorporates cultural and religious practices. Addressing route cause of disparities is imperative to mitigate current and future pandemics.

    A pharmacophore model for SARS-CoV-2 3CLpro PROTEIN small molecule inhibitors and in vitro experimental validation of computationally screened inhibitors

    Authors: Enrico Glaab; Ganesh Babu Manoharan; Daniel Abankwa

    doi:10.1101/2021.03.02.433618 Date: 2021-03-03 Source: bioRxiv

    Among the biomedical efforts in response to the current coronavirus ( COVID-19 MESHD) pandemic, pharmacological strategies to reduce viral load in patients with severe forms of the disease are being studied intensively. One of the main drug target proteins proposed so far is the SARS-CoV-2 viral protease 3CLpro PROTEIN (also called Mpro PROTEIN), an essential component for viral replication. Ongoing ligand- and receptor-based computational screening efforts would be facilitated by an improved understanding of the electrostatic, hydrophobic and steric features that characterize small molecule inhibitors binding stably to 3CLpro PROTEIN, as well as by an extended collection of known binders. Here, we present combined virtual screening, molecular dynamics simulation, machine learning and in vitro experimental validation analyses which have led to the identification of small molecule inhibitors of 3CLpro PROTEIN with micromolar activity, and to a pharmacophore model that describes functional chemical groups associated with the molecular recognition of ligands by the 3CLpro PROTEIN binding pocket. Experimentally validated inhibitors using a ligand activity assay include natural compounds with available prior knowledge on safety and bioavailability properties, such as the natural compound rottlerin (IC50 = 37 mcM), and synthetic compounds previously not characterized (e.g. compound CID 46897844, IC50 = 31 mcM). In combination with the developed pharmacophore model, these and other confirmed 3CLpro PROTEIN inhibitors may provide a basis for further similarity-based screening in independent compound databases and structural design optimization efforts, to identify 3CLpro PROTEIN ligands with improved potency and selectivity. Overall, this study suggests that the integration of virtual screening, molecular dynamics simulations and machine learning can facilitate 3CLpro PROTEIN-targeted small molecule screening investigations. Different receptor-, ligand- and machine learning-based screening strategies provided complementary information, helping to increase the number and diversity of identified active compounds. Finally, the resulting pharmacophore model and experimentally validated small molecule inhibitors for 3CLpro PROTEIN provide resources to support follow-up computational screening efforts for this drug target.

    Blockade of SARS-CoV-2 infection MESHD in-vitro by highly potent PI3K-α/ mTOR HGNC/ BRD4 HGNC inhibitor

    Authors: Arpan Acharya; Kabita Pandey; Michellie Thurman; Kishore B Challagundla; Kendra R Vann; Tatiana G Kutateladze; Guillermo A Morales; Donald L Durden; Siddappa N Byrareddy

    doi:10.1101/2021.03.02.433604 Date: 2021-03-03 Source: bioRxiv

    Pathogenic viruses like SARS-CoV-2 and HIV hijack the host MESHD molecular machinery to establish infection and survival in infected cells. This has led the scientific community to explore the molecular mechanisms by which SARS-CoV-2 infects MESHD host cells, establishes productive infection, and causes life-threatening pathophysiology. Very few targeted therapeutics for COVID-19 MESHD currently exist, such as remdesivir. Recently, a proteomic approach explored the interactions of 26 of 29 SARS-CoV-2 proteins with cellular targets in human cells and identified 67 interactions as potential targets for drug development. Two of the critical targets, the bromodomain and extra-terminal domain proteins (BETs): BRD2 HGNC/ BRD4 HGNC and mTOR HGNC, are inhibited by the dual inhibitory small molecule SF2523 at nanomolar potency. SF2523 is the only known mTOR HGNC PI3K-/( BRD2 HGNC/ BRD4 HGNC) inhibitor with potential to block two orthogonal pathways necessary for SARS-CoV-2 pathogenesis in human cells. Our results demonstrate that SF2523 effectively blocks SARS-CoV-2 replication in lung bronchial epithelial cells in vitro, showing an IC50 value of 1.5 uM, comparable to IC50 value of remdesivir (1.1 uM). Further, we demonstrated that the combination of doses of SF2523 and remdesivir is highly synergistic: it allows for the reduction of doses of SF2523 and remdesivir by 25-fold and 4-fold, respectively, to achieve the same potency observed for a single inhibitor. Because SF2523 inhibits two SARS-CoV-2 driven pathogenesis mechanisms involving BRD2 HGNC/ BRD4 HGNC and mTOR HGNC signaling, our data suggest that SF2523 alone or in combination with remdesivir could be a novel and efficient therapeutic strategy to block SARS-CoV-2 infection MESHD and hence be beneficial in preventing severe COVID-19 MESHD disease evolution.

    Neutralizing IFNL3 HGNC Autoantibodies in Severe COVID-19 MESHD Identified Using Molecular Indexing of Proteins by Self-Assembly

    Authors: Joel J. Credle; Jonathan Gunn; Puwanat Sangkhapreecha; Daniel R. Monaco; Xuwen Alice Zheng; Hung-Ji Tsai; Azaan Wilbon; William R. Morgenlander; Yi Dong; Sahana Jayaraman; Lorenzo Tosi; Biju Parekkadan; Alan N. Baer; Mario Roederer; Evan M. Bloch; Aaron A. R. Tobian; Israel Zyskind; Jonathan I. Silverberg; Avi Z. Rosenberg; Andrea L. Cox; Tom Lloyd; Andrew L. Mammen; H. Benjamin Larman

    doi:10.1101/2021.03.02.432977 Date: 2021-03-03 Source: bioRxiv

    Unbiased antibody profiling can identify the targets of an immune reaction. A number of likely pathogenic autoreactive antibodies have been associated with life-threatening SARS-CoV-2 infection MESHD; yet, many additional autoantibodies likely remain unknown. Here we present Molecular Indexing of Proteins by Self Assembly (MIPSA), a technique that produces ORFeome-scale libraries of proteins covalently coupled to uniquely identifying DNA barcodes for analysis by sequencing. We used MIPSA to profile circulating autoantibodies from 55 patients with severe COVID-19 MESHD against 11,076 DNA-barcoded proteins of the human ORFeome library. MIPSA identified previously known autoreactivities, and also detected undescribed neutralizing interferon lambda 3 HGNC ( IFNL3 HGNC) autoantibodies. At-risk individuals with anti- IFNL3 HGNC antibodies may benefit from interferon supplementation therapies, such as those currently undergoing clinical evaluation.

    Low-dose lung radiotherapy for COVID-19 MESHD lung disease MESHD: a pre-clinical efficacy study in a bleomycin model of pneumonitis MESHD.

    Authors: Mark R Jackson; Katrina Stevenson; Sandeep K Chahal; Emer Curley; George Finney; Rodrigo Gutierrez-Quintana; Evarest Onwubiko; Angelika F Rupp; Karen Strathdee; Megan KL MacLeod; Charles McSharry; Anthony J Chalmers

    doi:10.1101/2021.03.03.433704 Date: 2021-03-03 Source: bioRxiv

    Purpose: Low-dose whole lung radiotherapy ( LDLR HGNC) has been proposed as a treatment for patients with acute respiratory distress syndrome MESHD associated with SARS-CoV-2 infection MESHD and clinical trials are underway. There is an urgent need for preclinical evidence to justify this approach and inform dose, scheduling and mechanisms of action. Materials and methods: Female C57BL/6 mice were treated with intranasal bleomycin sulphate (7.5 or 11.25 units/kg, day 0) then exposed to whole lung radiation therapy (0.5, 1.0, 1.5 Gy or sham, day 3). Bodyweight was measured daily and lung tissue harvested for histology and flow cytometry on day 10. Computed tomography (CT) lung imaging was performed pre-radiation (day 3) and pre-endpoint (day 10). Results: Bleomycin caused pneumonitis MESHD of variable severity which correlated with weight loss MESHD. LDLR at 1.0 Gy was associated with a significant increase in the proportion of mice recovering to 98% of initial bodyweight; many of these mice exhibited less severe histopathological lung changes. Mice experiencing moderate initial weight loss MESHD were more likely to respond to LDLR than those experiencing severe initial weight loss MESHD. LDLR (1.0 Gy) significantly reduced bleomycin induced increases in interstitial macrophages, CD103+ dendritic cells and neutrophil-DC hybrids. Pre-radiation, bleomycin treated mice exhibited significantly higher percentages of non-aerated lung in left than right lungs; LDLR (1.0 Gy) prevented further reductions in aerated lung volume in right but not left lungs. LDLR doses of 0.5 and 1.5 Gy did not modulate bodyweight or flow cytometric readouts of bleomycin pneumonitis MESHD. Conclusions: Our data support the concept that LDLR can ameliorate acute inflammatory lung injury MESHD, identify 1.0 Gy as the most effective dose and provide preliminary evidence that it is more effective in the context of moderate than severe pneumonitis MESHD. Mechanistically, LDLR significantly suppressed bleomycin induced accumulation of interstitial macrophages, CD103+ dendritic cells and neutrophil-DC hybrids in the lung.

    Altered Sub-Genomic RNA Expression in SARS-CoV-2 B.1.1.7 Infections

    Authors: Matthew D Parker; Benjamin B Lindsey; Dhruv R Shah; Sharon Hsu; Alexander James Keeley; David G Partridge; Shay Leary; Alison Cope; Amy State; Katie Johnson; Nasar Ali; Rasha Raghei; Joe Heffer; Nikki Smith; Peijun Zhang; Marta Gallis; Stavroula F Louka; Max Whiteley; Benjamin H Foulkes; Stella Christou; Paige Wolverson; Manoj Pohare; Sam E Hansford; Luke R Green; Cariad Evans; Mohammad Raza; Dennis Wang; Silvana Gaudieri; Simon Mallal; - The COVID-19 Genomics UK (COG-UK) consortium; Thushan I de Silva

    doi:10.1101/2021.03.02.433156 Date: 2021-03-03 Source: bioRxiv

    SARS-CoV-2 lineage B.1.1.7 viruses are more transmissible, may lead to greater clinical severity, and result in modest reductions in antibody neutralization. subgenomic RNA (sgRNA) is produced by discontinuous transcription of the SARS-CoV-2 genome and is a crucial step in the SARS-CoV-2 life cycle. Applying our tool (periscope) to ARTIC Network Oxford Nanopore genomic sequencing data from 4400 SARS-CoV-2 positive clinical samples, we show that normalised sgRNA expression profiles are significantly increased in B.1.1.7 infections (n=879). This increase is seen over the previous dominant circulating lineage in the UK, B.1.177 (n=943), which is independent of genomic reads, E gene PROTEIN cycle threshold and day of illness when sampling occurred. A noncanonical subgenomic RNA which could represent ORF9b PROTEIN is significantly enriched in B.1.1.7 SARS-CoV-2 infections MESHD, potentially as a result of a triple nucleotide mutation leading to amino acid substitution D3L in nucleocapsid in this lineage which increases complementarity with the genomic leader sequence. These findings provide a unique insight into the biology of B.1.1.7 and support monitoring of sgRNA profiles in sequence data to evaluate emerging potential variants of concern.

    Recombinant protein subunit SARS-CoV-2 vaccines formulated with CoVaccine HT adjuvant induce broad, Th1 biased, humoral and cellular immune responses in mice

    Authors: Chih-Yun Lai; Albert To; Teri Ann S Wong; Michael M Lieberman; David E Clements; James T Senda; Aquena H Ball; Laurent Pessaint; Hanne Andersen; Oreola Donini; Axel T Lehrer

    doi:10.1101/2021.03.02.433614 Date: 2021-03-03 Source: bioRxiv

    The speed at which several COVID-19 MESHD vaccines went from conception to receiving FDA and EMA approval for emergency use is an achievement unrivaled in the history of vaccine development. Mass vaccination efforts using the highly effective vaccines are currently underway to generate sufficient herd immunity and reduce transmission of the SARS-CoV-2 virus. Despite the most advanced vaccine technology, global recipient coverage, especially in resource-poor areas remains a challenge as genetic drift in naive population pockets threatens overall vaccine efficacy. In this study, we described the production of insect-cell expressed SARS-CoV-2 spike PROTEIN protein ectodomain and examined its immunogenicity in mice. We demonstrated that, when formulated with CoVaccine HTTM adjuvant, an oil-in-water nanoemulsion compatible with lyophilization, our vaccine candidates elicit a broad spectrum IgG response, high neutralizing antibody titers, and a robust, antigen-specific IFN-{gamma}; secreting response from immune splenocytes in outbred mice. Our findings lay the foundation for the development of a dry-thermostabilized vaccine that is deployable without refrigeration.

    Identification and quantification of SARS-CoV-2 leader subgenomic mRNA gene junctions in nasopharyngeal samples shows phasic transcription in animal models of COVID-19 MESHD and aberrant pattens in humans

    Authors: Rebekah Penrice-Randal; Hannah Goldswain; Tessa Prince; Nadine Randle; Javier Salguero; Julia Tree; Ecaterina Vamos; Charlotte Nelson; - ISARIC-4C Investigators; - COG-UK Consortium; James P Stewart; David A Matthews; Miles Carroll; Alistair Darby; Julian Alexander Hiscox

    doi:10.1101/2021.03.03.433753 Date: 2021-03-03 Source: bioRxiv

    Introduction: SARS-CoV-2 has a complex strategy for the transcription of viral subgenomic mRNAs (sgmRNAs), which are targets for nucleic acid diagnostics. Each of these sgRNAs has a unique 5 sequence, the leader-transcriptional regulatory sequence gene junction (leader-TRS-junction), that can be identified using sequencing. Results: High resolution sequencing has been used to investigate the biology of SARS-CoV-2 and the host response in cell culture models and from clinical samples. LeTRS, a bioinformatics tool, was developed to identify leader-TRS-junctions and be used as a proxy to quantify sgmRNAs for understanding virus biology. This was tested on published datasets and clinical samples from patients and longitudinal samples from animal models with COVID-19 MESHD. Discussion: LeTRS identified known leader-TRS-junctions and identified novel species that were common across different species. The data indicated multi-phasic abundance of sgmRNAs in two different animal models, with spikes in sgmRNA abundance reflected in human samples, and therefore has implications for transmission models and nucleic acid-based diagnostics.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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