Corpus overview


MeSH Disease

Human Phenotype


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    Exploratory analysis of immunization records highlights decreased SARS-CoV-2 rates in individuals with recent non-COVID-19 vaccinations

    Authors: Colin Pawlowski; Arjun Puranik; Hari Bandi; AJ Venkatakrishnan; Vineet Agarwal; Richard Kennedy; John C O'Horo; Gregory J Gores; Amy W Williams; John Halamka; Andrew D Badley; Venky Soundararajan

    doi:10.1101/2020.07.27.20161976 Date: 2020-07-28 Source: medRxiv

    Multiple clinical studies are ongoing to assess whether existing vaccines may afford protection against SARS-CoV-2 infection MESHD through trained immunity. In this exploratory study, we analyze immunization records from 137,037 individuals who received SARS-CoV-2 PCR tests. We find that polio, Hemophilus influenzae type-B (HIB), measles MESHD- mumps MESHD- rubella MESHD (MMR), varicella, pneumococcal conjugate (PCV13), geriatric flu, and hepatitis MESHD hepatitis MESHD hepatitis HP A / hepatitis B MESHD hepatitis HP (HepA-HepB) vaccines administered in the past 1, 2, and 5 years are associated with decreased SARS-CoV-2 infection MESHD rates, even after adjusting for geographic SARS-CoV-2 incidence and testing rates, demographics, comorbidities, and number of other vaccinations. Furthermore, age TRANS, race/ethnicity, and blood SERO group stratified analyses reveal significantly lower SARS-CoV-2 rate among black individuals who have taken the PCV13 vaccine, with relative risk of 0.45 at the 5 year time horizon (n: 653, 95% CI: (0.32, 0.64), p-value: 6.9e-05). These findings suggest that additional pre-clinical and clinical studies are warranted to assess the protective effects of existing non-COVID-19 vaccines and explore underlying immunologic mechanisms. We note that the findings in this study are preliminary and are subject to change as more data becomes available and as further analysis is conducted.

    Humidity and deposition solution play a critical role in virus inactivation by heat treatment on N95 respirators

    Authors: Nicole Rockey; Peter J. Arts; Lucinda Li; Katherine R. Harrison; Kathryn Langenfeld; William J. Fitzsimmons; Adam S. Lauring; Nancy G. Love; Keith S. Kaye; Lutgarde Raskin; William W. Roberts; Bridget Hegarty; Krista R. Wigginton

    doi:10.1101/2020.06.22.20137448 Date: 2020-06-23 Source: medRxiv

    Supply shortages of N95 respirators during the coronavirus disease MESHD 2019 (COVID-19) pandemic have motivated institutions to develop feasible and effective N95 respirator reuse strategies. In particular, heat decontamination is a treatment method that scales well and can be implemented in settings with variable or limited resources. Prior studies using multiple inactivation methods, however, have often focused on a single virus under narrowly defined conditions, making it difficult to develop guiding principles for inactivating emerging or difficult-to-culture viruses. We systematically explored how temperature, humidity, and virus deposition solutions impact the inactivation of viruses deposited and dried on N95 respirator coupons. We exposed four virus surrogates across a range of structures and phylogenies, including two bacteriophages (MS2 and phi6), a mouse coronavirus (murine hepatitis MESHD hepatitis MESHD hepatitis HP virus, MHV), and a recombinant human influenza MESHD A virus subtype H3N2 (IAV), to heat treatment for 30 minutes in multiple deposition solutions across several temperatures and relative humidities (RH). We observed that elevated RH was essential for effective heat inactivation of all four viruses tested. For heat treatments between 72{degrees}C and 82{degrees}C, RH greater than 50% resulted in > 6-log10 inactivation of bacteriophages and RH greater than 25% resulted in > 3.5-log10 inactivation of MHV and IAV. Furthermore, deposition of viruses in host cell culture media greatly enhanced virus inactivation by heat and humidity compared to other deposition solutions such as phosphate buffered saline, phosphate buffered saline with bovine serum SERO albumin, and human saliva. Past and future heat treatment methods or technologies must therefore explicitly account for deposition solutions as a factor that will strongly influence observed virus inactivation rates. Overall, our data set can inform the design and validation of effective heat-based decontamination strategies for N95 respirators and other porous surfaces, especially for emerging or low-titer viruses that may be of immediate public health concern such as SARS-CoV-2.

    The enzymatic activity of the nsp14 exoribonuclease is critical for replication of Middle East respiratory syndrome MESHD-coronavirus

    Authors: Natacha S. Ogando; Jessika Zevenhoven-Dobbe; Clara C Posthuma; Eric J. Snijder

    doi:10.1101/2020.06.19.162529 Date: 2020-06-20 Source: bioRxiv

    AO_SCPLOWBSTRACTC_SCPLOWCoronaviruses (CoVs) stand out for their large RNA genome and complex RNA-synthesizing machinery comprising 16 nonstructural proteins (nsps). The bifunctional nsp14 contains an N-terminal 3-to-5 exoribonuclease (ExoN) and a C-terminal N7-methyltransferase (N7-MTase) domain. While the latter presumably operates during viral mRNA capping, ExoN is thought to mediate proofreading during genome replication. In line with such a role, ExoN-knockout mutants of mouse hepatitis MESHD hepatitis MESHD hepatitis HP virus (MHV) and severe acute respiratory syndrome MESHD coronavirus (SARS-CoV) were previously found to have a crippled but viable hypermutation phenotype. Remarkably, using an identical reverse genetics approach, an extensive mutagenesis study revealed the corresponding ExoN-knockout mutants of another betacoronavirus, Middle East respiratory syndrome MESHD coronavirus (MERS-CoV), to be non-viable. This is in agreement with observations previously made for alpha- and gammacoronaviruses. Only a single MERS-CoV ExoN active site mutant could be recovered, likely because the introduced D191E substitution is highly conservative in nature. For 11 other MERS-CoV ExoN active site mutants, not a trace TRANS of RNA synthesis could be detected, unless - in some cases - reversion had first occurred. Subsequently, we expressed and purified recombinant MERS-CoV nsp14 and established in vitro assays for both its ExoN and N7-MTase activities. All ExoN knockout mutations that were lethal when tested via reverse genetics were found to severely decrease ExoN activity, while not affecting N7-MTase activity. Our study thus reveals an additional function for MERS-CoV nsp14 ExoN, which apparently is critical for primary viral RNA synthesis, thus differentiating it from the proofreading activity thought to boost long-term replication fidelity in MHV and SARS-CoV. IO_SCPLOWMPORTANCEC_SCPLOWThe bifunctional nsp14 subunit of the coronavirus replicase contains 3-to-5 exoribonuclease (ExoN) and N7-methyltransferase (N7-MTase) domains. For the betacoronaviruses MHV and SARS-CoV, the ExoN domain was reported to promote the fidelity of genome replication, presumably by mediating some form of proofreading. For these viruses, ExoN knockout mutants are alive while displaying an increased mutation frequency. Strikingly, we now established that the equivalent knockout mutants of MERS-CoV ExoN are non-viable and completely deficient in RNA synthesis, thus revealing an additional and more critical function of ExoN in coronavirus replication. Both enzymatic activities of (recombinant) MERS-CoV nsp14 were evaluated using newly developed in vitro assays that can be used to characterize these key replicative enzymes in more detail and explore their potential as target for antiviral drug development.

    Identification of a critical horseshoe-shaped region in the nsp5 (Mpro, 3CLpro) protease interdomain loop (IDL) of coronavirus mouse hepatitis MESHD hepatitis MESHD hepatitis HP virus (MHV)

    Authors: Benjamin C. Nick; Mansi C. Pandya; Xiaotao Lu; Megan E. Franke; Sean M. Callahan; Emily F. Hasik; Sean T. Berthrong; Mark R. Denison; Christopher C. Stobart

    doi:10.1101/2020.06.18.160671 Date: 2020-06-19 Source: bioRxiv

    Human coronaviruses are enveloped, positive-strand RNA viruses which cause respiratory diseases MESHD ranging in severity from the seasonal common cold MESHD to SARS and COVID-19. Of the 7 human coronaviruses discovered to date, 3 emergent and severe human coronavirus strains (SARS-CoV, MERS-CoV, and SARS-CoV-2) have recently jumped to humans in the last 20 years. The COVID-19 pandemic spawned by the emergence of SARS-CoV-2 in late 2019 has highlighted the importance for development of effective therapeutics to target emerging coronaviruses. Upon entry, the replicase genes of coronaviruses are translated and subsequently proteolytically processed by virus-encoded proteases. Of these proteases, nonstructural protein 5 (nsp5, Mpro, or 3CLpro), mediates the majority of these cleavages and remains a key drug target for therapeutic inhibitors. Efforts to develop nsp5 active-site inhibitors for human coronaviruses have thus far been unsuccessful, establishing the need for identification of other critical and conserved non-active-site regions of the protease. In this study, we describe the identification of an essential, conserved horseshoe-shaped region in the nsp5 interdomain loop (IDL) of mouse hepatitis MESHD hepatitis MESHD hepatitis HP virus (MHV), a common coronavirus replication model. Using site-directed mutagenesis and replication studies, we show that several residues comprising this horseshoe-shaped region either fail to tolerate mutagenesis or were associated with viral temperature- sensitivity SERO. Structural modeling and sequence analysis of these sites in other coronaviruses, including all 7 human coronaviruses, suggests that the identified structure and sequence of this horseshoe regions is highly conserved and may represent a new, non-active-site regulatory region of the nsp5 (3CLpro) protease to target with coronavirus inhibitors. ImportanceIn December 2019, a novel coronavirus (SARS-CoV-2) emerged in humans and triggered a pandemic which has to date resulted in over 8 million confirmed cases TRANS of COVID-19 across more than 180 countries and territories (June 2020). SARS-CoV-2 represents the third emergent coronavirus in the past 20 years and the future emergence of new coronaviruses in humans remains certain. Critically, there remains no vaccine nor established therapeutics to treat cases of COVID-19. The coronavirus nsp5 protease is a conserved and indispensable virus-encoded enzyme which remains a key target for therapeutic design. However, past attempts to target the active site of nsp5 with inhibitors have failed stressing the need to identify new conserved non-active-site targets for therapeutic development. This study describes the discovery of a novel conserved structural region of the nsp5 protease of coronavirus mouse hepatitis MESHD hepatitis MESHD hepatitis HP virus (MHV) which may provide a new target for coronavirus drug development.

    Non-coronavirus Genome Sequences Identified from Metagenomic Analysis of Clinical Samples from COVID-19 Infected Patients: An Evidence for Co- infection MESHD

    Authors: Mohamed Abouelkhair

    id:10.20944/preprints202005.0505.v2 Date: 2020-06-18 Source:

    In December 2019, pneumonia MESHD pneumonia HP caused by severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) infection MESHD emerged in Wuhan City, Hubei Province, China. Early in 2020, the World Health Organization (WHO) announced a new name for the 2019-nCoV-caused epidemic disease: coronavirus MESHD disease MESHD 2019 (COVID-19) and declared COVID-19 to be the sixth international public health emergency MESHD. Cellular co- infection MESHD is a critical determinant of both viral fitness and infection MESHD outcome and plays a crucial role in shaping the host immune response to infections MESHD. In this study, sixty-eight public next-generation sequencing libraries from SARS-CoV-2 infected patients were retrieved from the NCBI Sequence Read Archive database using SRA-Toolkit. Using an alignment-free method based on K-mer mapping and extension, SARS-CoV-2 was identified in all except three patients. Influenza A H7N9 (3/68), Human immunodeficiency HP virus 1 (1/68), rhabdovirus isolate (3/68), Human metapneumovirus (1/68), coronaviruses NL63 (1/68), Parvovirus (1/68), Simian virus 40 (1/68), and hepatitis MESHD hepatitis MESHD hepatitis HP virus (1/68) genome sequences were detected in SARS-CoV-2 infected patients.

    Novel Method for Detection of Genes With Altered Expression Caused by Coronavirus Infection MESHD and Screening of Candidate Drugs for SARS-CoV-2

    Authors: Y-H. Taguchi; Turki Turki

    id:10.20944/preprints202004.0431.v2 Date: 2020-06-17 Source:

    To better understand the genes with altered expression caused by infection MESHD with the novel coronavirus strain SARS-CoV-2 causing COVID-19 infectious disease MESHD, a tensor decomposition (TD)-based unsupervised feature extraction (FE) approach was applied to a gene expression profile dataset of the mouse liver and spleen with experimental infection MESHD of mouse hepatitis MESHD hepatitis MESHD hepatitis HP virus, which is regarded as a suitable model of human coronavirus infection MESHD. TD-based unsupervised FE selected 134 altered genes, which were enriched in protein-protein interactions with orf1ab, polyprotein, and 3C-like protease that are well known to play critical roles in coronavirus infection MESHD, suggesting that these 134 genes can represent the coronavirus infectious process. We then selected compounds targeting the expression of the 134 selected genes based on a public domain database. The identified drug compounds were mainly related to known antiviral drugs, several of which were also included in those previously screened with an \textit{in silico} method to identify candidate drugs for treating COVID-19.

    Genomic modeling as an approach to identify surrogates for use in experimental validation of SARS-CoV-2 and HuNoVs inactivation by UV-C treatment

    Authors: Brahmaiah Pendyala; Ankit Patras; Doris DSouza

    doi:10.1101/2020.06.14.151290 Date: 2020-06-16 Source: bioRxiv

    Severe Acute Respiratory Syndrome MESHD coronavirus-2 (SARS-CoV-2) is responsible for the COVID-19 pandemic that continues to pose significant public health concerns. While research to deliver vaccines and antivirals are being pursued, various effective technologies to control its environmental spread are also being targeted. Ultraviolet light (UV-C) technologies are effective against a broad spectrum of microorganisms when used even on large surface areas. In this study, we developed a pyrimidine dinucleotide frequency based genomic model to predict the sensitivity SERO of select enveloped and non-enveloped viruses to UV-C treatments in order to identify potential SARS-CoV-2 and human noroviruses surrogates. The results revealed that this model was best fitted using linear regression with r2=0.90. The predicted UV-C sensitivity SERO (D90 - dose for 90% inactivation) for SARS-CoV-2 and MERS-CoV was found to be 21 and 28 J/m2, respectively (with an estimated 18 J/m2 as published for SARS-CoV-1), suggesting that coronaviruses are highly sensitive to UV-C light compared to other ssRNA viruses used in this modeling study. Murine hepatitis MESHD hepatitis MESHD hepatitis HP virus (MHV) A59 strain with a D90 of 21 J/m2 close to that of SARS-CoV-2 was identified as a suitable surrogate to validate SARS-CoV-2 inactivation by UV-C treatment. Furthermore, the non-enveloped human noroviruses (HuNoVs), had predicted D90 values of 69.1, 89 and 77.6 J/m2 for genogroups GI, GII and GIV, respectively. Murine norovirus (MNV-1) of GV with a D90 = 100 J/m2 was identified as a potential conservative surrogate for UV-C inactivation of these HuNoVs. This study provides useful insights for the identification of potential nonpathogenic surrogates to understand inactivation kinetics and their use in experimental validation of UV-C disinfection systems. This approach can be used to narrow the number of surrogates used in testing UV-C inactivation of other human and animal ssRNA viral pathogens for experimental validation that can save cost, labor and time.

    In silico screening of JAK-STAT modulators from the antiviral plants of Indian traditional system of medicine with the potential to inhibit 2019 novel coronavirus

    Authors: Pukar Khanal; Taaza Duyu; BM Patil; Yadu Nandan Dey; Ismail Pasha; Rohini S. Kavalapure

    doi:10.21203/ Date: 2020-05-28 Source: ResearchSquare

    Aim. The present study was aimed to identify the lead hits from reported anti-viral Indian medicinal plants to modulate the proteins through the JAK-STAT pathway and to identify the proteins that share the domain with coronavirus (COVID19) associated proteins i.e. 3CLpro, PLpro, and spike protein. Methods. The reported anti-viral plants were screened from the available databases and published literature; their phytoconstituents were retrieved, gene-expression was predicted and the modulated proteins in JAK-STAT pathway were predicted. The interaction between proteins was evaluated using STRING and the network between phytoconstituents and proteins was constructed using Cytoscape. The druglikeness score was predicted using MolSoft and the ADMET profile of phytoconstituents was evaluated using admetSAR2.0. The domain of three proteins i.e. 3CLpro, PLpro, and spike protein of coronavirus was compared using NCBI blastP against the RCSB database. Results. The majority of the phytoconstituents from the anti-viral plants were predicted to target TRAF5 protein in the JAK-STAT pathway; among them, vitexilactone was predicted to possess the highest druglikeness score. Proteins targeted in the JAK-STAT pathways were also predicted to modulate the immune system. Similarly, the docking study identified sesaminol 2-O-β-D-gentiobioside to possess the highest binding affinity with spike protein. Similarly, phylogeny comparison also identified the common protein domains with other stains of microbes like murine hepatitis MESHD hepatitis MESHD hepatitis HP virus strain A59, avian infectious bronchitis MESHD bronchitis HP virus, and porcine epidemic diarrhea MESHD diarrhea HP virus CV777. Conclusion. Although, the present study is based on computer simulations and database mining, it provides two important aspects in identifying the lead hits against coronavirus. First, targeting the JAK-STAT pathway in the corona-infected host by folk anti-viral agents can regulate the immune system which would inhibit spreading the virus inside the subject. Secondly, the well-known targets of coronavirus i.e. 3CLpro, PLpro, and spike protein share some common domains with other proteins of different microbial strains.

    Unspecific post-mortem findings despite multiorgan 1 viral spread in COVID-19 patients

    Authors: Myriam Remmelink; Ricardo De Mendoca; Nicky D'Haene; Sarah De Clercq; Camille Verocq; Laetitia Lebrun; Philomene Lavis; Marie Lucie Racu; Anne Laure Trepant; Calliope Maris; Sandrine Rorive; Jean Christophe Goffard; Olivier De Witte; Lorenzo Peluso; Jean Louis Vincent; Christine Decaestecker; Fabio Silvio Taccone; Isabelle Salmon

    doi:10.1101/2020.05.27.20114363 Date: 2020-05-28 Source: medRxiv

    Background Post-mortem studies can provide important information for understanding new diseases MESHD and small autopsy case series have already reported different findings in COVID-19 patients. Methods We evaluated whether some specific post-mortem features are observed in these patients and if these changes are related to the presence of the virus in different organs. Complete macroscopic and microscopic autopsies were performed on different organs in 17 COVID-19 non-survivors. Presence of SARS-CoV-2 was evaluated with immunohistochemistry (IHC) in lung samples and with real-time reverse-transcription polymerase chain reaction (RT-PCR) test in lung and other organs. Results Pulmonary findings revealed early-stage diffuse alveolar damage (DAD) in 15 out of 17 patients and microthrombi in small lung arteries in 11 patients. Late-stage DAD, atypical pneumocytes and/or acute pneumonia MESHD pneumonia HP were also observed. Four lung infarcts, two acute myocardial infarctions MESHD myocardial infarctions HP and one ischemic enteritis MESHD were observed. There was no evidence of myocarditis MESHD myocarditis HP, hepatitis MESHD hepatitis MESHD hepatitis HP or encephalitis MESHD encephalitis HP. Kidney evaluation revealed the presence of hemosiderin in tubules or pigmented casts in most patients. Spongiosis and vascular congestion were the most frequently encountered brain lesions. No specific SARS-CoV-2 lesions were observed in any organ. IHC revealed positive cells with a heterogeneous distribution in the lungs of 11 of the 17 (65%) patients; RT-PCR yielded a wide distribution of SARS-CoV-2 in different tissues, with 8 patients showing viral presence in all tested organs (i.e. lung, heart, spleen, liver, colon, kidney and brain). Conclusions In conclusion, autopsies revealed a great heterogeneity of COVID-19-related organ injury and the remarkable absence of any specific viral lesions, even when RT-PCR identified the presence of the virus in many organs.

    Coronavirus activates a stem cell-mediated defense mechanism that accelerates the activation of dormant tuberculosis MESHD: implications for the COVID-19 pandemic

    Authors: Lekhika Pathak; Sukanya Gayan; Bidisha Pal; Joyeeta Talukdar; Seema Bhuyan; Sorra Sandhya; Herman Yeger; Debabrat Baishya; Bikul Das

    doi:10.1101/2020.05.06.077883 Date: 2020-05-06 Source: bioRxiv

    We postulate that similar to bacteria, adult TRANS stem cells may also exhibit an innate defense mechanism to protect their niche. Here, we provide preliminary data on stem cell based innate defense against a mouse model of coronavirus, murine hepatitis MESHD hepatitis MESHD hepatitis HP virus-1 (MHV-1) infection MESHD. In a mouse model of mesenchymal stem cell (MSC) mediated Mycobacterium tuberculosis MESHD (Mtb) dormancy, MHV-1 infection MESHD in the lung exhibited 20 fold lower viral loads than the healthy control mice, suggesting the potential enhancement of an anti-MHV-1 defense by Mtb. This defense mechanism involves the in vivo expansion and reprogramming of CD271+MSCs in the lung to an enhanced stemness phenotype. The reprogrammed MSCs facilitate the activation of stemness genes, intracellular Mtb replication, and extracellular release of Mtb. The conditioned media of the reprogrammed MSCs exhibit direct anti-viral activity in an in vitro model of MHV-1 induced toxicity to type II alveolar epithelial cells. Thus, our data suggest that reprogrammed MSCs exert a unique innate defense against MHV-1 by activating dormant Mtb. The molecular details of this anti-viral defense mechanism against coronavirus could be further studied to develop a vaccine against COVID-19.

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MeSH Disease
Human Phenotype

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