Corpus overview


MeSH Disease

Human Phenotype


    displaying 31 - 40 records in total 1342
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    Elovanoid-N32 or RvD6-isomer decrease ACE2 and binding of S protein RBD after injury or INFγ in the eye

    Authors: Thang L. Pham; Jiucheng He; Azucena H. Kakazu; Jorgelina Calandria; Khanh V. Do; Robert Nshimiyimana; Nicos A. Petasis; Haydee E.P. Bazan; Nicolas G. Bazan

    doi:10.21203/ Date: 2020-08-07 Source: ResearchSquare

    The severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) infection MESHD that causes coronavirus disease MESHD 2019 (COVID-19) has resulted in a pandemic affecting the most vulnerable in society, triggering a public health crisis and economic tall around the world. Effective treatments to mitigate this virus infection MESHD are needed. Since the eye is a route of virus entrance, we use an in vivo rat model of corneal inflammation MESHD as well as human corneal epithelial cells in culture challenged with IFNγ to study this issue. We explore ways to block the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein to angiotensin-converting enzyme 2 (ACE2). Elovanoid (ELV)-N32 or Resolvin D6-isomer (RvD6i), among the lipid mediators studied, consistently decreased the expression of the ACE2 receptor, furin, and integrins in damaged corneas or IFNγ stimulated human corneal epithelial cells (HCEC). There was also a concomitant decrease in the binding of spike RBD with the lipid treatments. Concurrently, we uncovered that the lipid mediators also attenuated the expression of cytokines that participate in the cytokine storm, hyper- inflammation MESHD and senescence programming. Thus, the bioactivity of these lipid mediators will contribute to opening therapeutic avenues for COVID-19 by counteracting virus attachment and entrance to the eye and other cells and the ensuing disruptions of homeostasis. 

    An improved methodology for estimating the prevalence SERO of SARS-CoV-2

    Authors: Virag Patel; Catherine McCarthy; Rachel A Taylor; Ruth Moir; Louise A Kelly; Emma L Snary

    doi:10.1101/2020.08.04.20168187 Date: 2020-08-06 Source: medRxiv

    Since the identification of Coronavirus disease MESHD 2019 (COVID-19) caused by severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) in China in December 2019, there have been more than 17 million cases of the disease MESHD in 216 countries worldwide. Comparisons of prevalence SERO estimates between different communities can inform policy decisions regarding safe travel TRANS between countries, help to assess when to implement (or remove) disease MESHD control measures and identify the risk of over-burdening healthcare providers. Estimating the true prevalence SERO can, however, be challenging because officially reported figures are likely to be significant underestimates of the true burden of COVID-19 within a community. Previous methods for estimating the prevalence SERO fail to incorporate differences between populations (such as younger populations having higher rates of asymptomatic TRANS cases) and so comparisons between, for example, countries, can be misleading. Here, we present an improved methodology for estimating COVID-19 prevalence SERO. We take the reported number of cases and deaths MESHD (together with population size) as raw prevalence SERO for the population. We then apply an age TRANS-adjustment to this which allows the age TRANS-distribution of that population to influence the case-fatality rate and the proportion of asymptomatic TRANS cases. Finally, we calculate the likely underreporting factor for the population and use this to adjust our prevalence SERO estimate further. We use our method to estimate the prevalence SERO for 166 countries (or the states of the United States of America, hereafter referred to as US state) where sufficient data were available. Our estimates show that as of the 30th July 2020, the top three countries with the highest estimated prevalence SERO are Brazil (1.26%, 95% CI: 0.96 - 1.37), Kyrgyzstan (1.10%, 95% CI: 0.82 - 1.19) and Suriname (0.58%, 95% CI: 0.44 - 0.63). Brazil is predicted to have the largest proportion of all the current global cases (30.41%, 95%CI: 27.52 - 30.84), followed by the USA (14.52%, 95%CI: 14.26 - 16.34) and India (11.23%, 95%CI: 11.11 - 11.24). Amongst the US states, the highest prevalence SERO is predicted to be in Louisiana (1.07%, 95% CI: 1.02 - 1.12), Florida (0.90%, 95% CI: 0.86 - 0.94) and Mississippi (0.77%, 95% CI: 0.74 - 0.81) whereas amongst European countries, the highest prevalence SERO is predicted to be in Montenegro (0.47%, 95% CI: 0.42 - 0.50), Kosovo (0.35%, 95% CI: 0.29 - 0.37) and Moldova (0.28%, 95% CI: 0.23 - 0.30). Our results suggest that Kyrgyzstan (0.04 tests per predicted case), Brazil (0.04 tests per predicted case) and Suriname (0.29 tests per predicted case) have the highest underreporting out of the countries in the top 25 prevalence SERO. In comparison, Israel (34.19 tests per predicted case), Bahrain (19.82 per predicted case) and Palestine (9.81 tests per predicted case) have the least underreporting. The results of this study may be used to understand the risk between different geographical areas and highlight regions where the prevalence SERO of COVID-19 is increasing most rapidly. The method described is quick and easy to implement. Prevalence SERO estimates should be updated on a regular basis to allow for rapid fluctuations in disease MESHD patterns.

    Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors

    Authors: Jerzy Osipiuk; Saara-Anne Azizi; Steve Dvorkin; Michael Endres; Robert Jedrzejczak; Krysten A. Jones; Rahul S. Kathayat; Vladislav G. Lisnyak; Samantha L. Maki; Soowon Kang; Youngchang Kim; Vlad Nicolaescu; Cooper A. Taylor; Christine Tesar; Yu-An Zhang; Zhiyao Zhou; Glenn Randall; Karolina Michalska; Scott A. Snyder; Bryan C. Dickinson; Andrzej Joachimiak

    doi:10.1101/2020.08.06.240192 Date: 2020-08-06 Source: bioRxiv

    The number of new cases world-wide for the COVID-19 disease MESHD is increasing dramatically, while efforts to contain Severe Acute Respiratory Syndrome MESHD Coronavirus 2 is producing varied results in different countries. There are three key SARS-CoV-2 enzymes potentially targetable with antivirals: papain-like protease (PLpro), main protease (Mpro), and RNA-dependent RNA polymerase. Of these, PLpro is an especially attractive target because it plays an essential role in several viral replication processes, including cleavage and maturation of viral polyproteins, assembly of the replicasetranscriptase complex (RTC), and disruption of host viral response machinery to facilitate viral proliferation and replication. Moreover, this enzyme is conserved across different coronaviruses and promising inhibitors have already been discovered for its SARS-CoV variant. Here we report a substantive body of structural, biochemical, and virus replication studies that identify several inhibitors of the enzyme from SARS-CoV-2 in both wild-type and mutant forms. These efforts include the first structures of wild-type PLpro, the active site C111S mutant, and their complexes with inhibitors, determined at 1.60-2.70 Angstroms. This collection of structures provides fundamental molecular and mechanistic insight to PLpro, and critically, illustrates details for inhibitors recognition and interactions. All presented compounds inhibit the peptidase activity of PLpro in vitro, and some molecules block SARS-CoV-2 replication in cell culture assays. These collated findings will accelerate further structure-based drug design efforts targeting PLpro, with the ultimate goal of identifying high-affinity inhibitors of clinical value for SARS-CoV-2.

    Antibody SERO Response and Therapy in COVID-19 Patients: Significance in Vaccine Development

    Authors: Ligong Lu; Hui Zhang; Meixiao Zhan; Jun Jiang; Hua Yin; Danielle J. Dauphars; Shi-You Li; Yong Li; You-Wen He

    id:10.20944/preprints202008.0166.v1 Date: 2020-08-06 Source:

    The newly emerged severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) has infected millions of people and caused tremendous morbidity and mortality worldwide. Effective treatment for coronavirus disease MESHD 2019 (COVID-19) due to SARS-CoV-2 infection MESHD is lacking and different therapeutic strategies are under testing. Host humoral and cellular immunity to SARS-CoV-2 infection MESHD is a critical determinant for patients’ outcome. SARS-CoV-2 infection MESHD results in seroconversion and production of anti- SARS-CoV-2 antibodies SERO. The antibodies SERO may suppress viral replication through neutralization but also might also participate in COVID-19 pathogenesis through a process termed antibody SERO-dependent enhancement. Rapid progress has been made in the research of antibody SERO response and therapy in COVID-19 patients including characterization of the clinical features of antibody SERO responses in different populations infected by SARS-CoV-2, treatment of COVID-19 patients with convalescent plasma SERO and intravenous immunoglobin products, isolation and characterization of a large panel of monoclonal neutralizing antibodies SERO, as well as preliminary clinical results from several COVID-19 vaccine candidates. In this review, we summarize the recent progress and discuss the implications of these findings in vaccine development.

    Signatures and mechanisms of efficacious therapeutic ribonucleotides against SARS-CoV-2 revealed by analysis of its replicase using magnetic tweezers

    Authors: Mona Seifert; Subhas C. Bera; Pauline van Nies; Robert N. Kirchdoerfer; Ashleigh Shannon; Thi-Tuyet-Nhung Le; Tyler L. Grove; Flavia S. Papini; Jamie J. Arnold; Steven C. Almo; Bruno Canard; Martin Depken; Craig E. Cameron; David Dulin

    doi:10.1101/2020.08.06.240325 Date: 2020-08-06 Source: bioRxiv

    Coronavirus Disease MESHD 2019 (COVID-19) results from an infection MESHD infection by the severe HP by the severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2), the third coronavirus outbreak to plague MESHD humanity this century. Currently, the most efficacious therapeutic against SARS-CoV-2 infection MESHD is the Remdesivir (RDV), an adenine-like ribonucleotide analogue that is very efficiently incorporated by the SARS-CoV-2 replicase. Understanding why RDV is so well incorporated will facilitate development of even more effective therapeutics. Here, we have applied a high-throughput, single-molecule, magnetic-tweezers platform to study thousands of cycles of nucleotide addition by the SARS-CoV-2 replicase in the absence and presence of RDV, a Favipiravir-related analog (T-1106), and the endogenously produced ddhCTP. Our data are consistent with two parallel catalytic pathways of the replicase: a high-fidelity catalytic (HFC) state and a low-fidelity catalytic (LFC) state, the latter allowing the slow incorporation of both cognate and non-cognate nucleotides. ddhCTP accesses HFC, T-1106 accesses LFC as a non-cognate nucleotide, while RDV efficiently accesses both LFC pathway. In contrast to previous reports, we provide unequivocal evidence against RDV functioning as a chain terminator. We show that RDV incorporation transiently stalls the replicase, only appearing as termination events when traditional, gel-based assays are used. The efficiency of ddhCTP utilization by the SARS-CoV-2 replicase suggests suppression of its synthesis during infection MESHD, inspiring new therapeutic strategies. Use of this experimental paradigm will be essential to the development of therapeutic nucleotide analogs targeting polymerases.

    Development of mass spectrometry-based targeted assay for direct detection of novel SARS-CoV-2 coronavirus from clinical specimens

    Authors: Santosh Renuse; Patrick M Vanderboom; Anthony D. Maus; Jennifer V. Kemp; Kari M. Gurtner; Anil K. Madugundu; Sandip Chavan; Jane A. Peterson; Benjamin J. Madden; Kiran K. Mangalaparthi; Dong-Gi Mun; Smrita Singh; Benjamin R. Kipp; Surendra Dasari; Ravinder J. Singh; Stefan K. Grebe; Akhilesh Pandey

    doi:10.1101/2020.08.05.20168948 Date: 2020-08-06 Source: medRxiv

    The COVID-19 pandemic caused by severe acute respiratory syndrome MESHD-coronavirus 2 (SARS-CoV-2) has overwhelmed health systems worldwide and highlighted limitations of diagnostic testing. Several types of diagnostics including RT-PCR-based assays, antigen detection by lateral flow assays and antibody SERO-based assays have been developed and deployed in a short time. However, many of these assays are lacking in sensitivity SERO and/or specificity. Here, we describe an immunoaffinity purification followed by high resolution mass spectrometry-based targeted assay capable of detecting viral antigen in nasopharyngeal swab samples of SARS-CoV-2 infected individuals. Based on our discovery experiments using purified virus, recombinant viral protein and nasopharyngeal swab samples from COVID-19 positive patients, nucleocapsid protein was selected as a target antigen. We then developed an automated antibody SERO capture-based workflow coupled to targeted high-field asymmetric ion mobility spectrometry (FAIMS) - parallel reaction monitoring (PRM) assays on an Orbitrap Exploris 480 mass spectrometer. An ensemble machine learning-based model for determining COVID-19 positive samples was created using fragment ion intensities in the PRM data. This resulted in 97.8% sensitivity SERO and 100% specificity with RT-PCR-based molecular testing as the gold standard. Our results demonstrate that direct detection of infectious agents from clinical samples by mass spectrometry-based assays have potential to be deployed as diagnostic assays in clinical laboratories.

    Serology assessment of antibody SERO response to SARS-CoV-2 in patients with COVID-19 by rapid IgM/IgG antibody test SERO

    Authors: Yang De Marinis; Torgny Sunnerhagen; Pradeep Bompada; Anna Blackberg; Runtao Yang; Joel Svensson; Ola Ekstrom; Karl-Fredrik Eriksson; Ola Hansson; Leif Groop; Isabel Goncalves; Magnus Rasmussen

    doi:10.1101/2020.08.05.20168815 Date: 2020-08-06 Source: medRxiv

    The coronavirus disease MESHD 2019 (COVID-19) pandemic has created a global health- and economic crisis. Lifting confinement restriction and resuming to normality depends greatly on COVID-19 immunity screening. Detection of antibodies SERO to severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) which causes COVID-19 by serological methods is important to diagnose a current or resolved infection MESHD. In this study, we applied a rapid COVID-19 IgM/IgG antibody test SERO and performed serology assessment of antibody SERO response to SARS-CoV-2. In PCR-confirmed COVID-19 patients (n=45), the total antibody SERO detection rate is 92% in hospitalized patients and 79% in non-hospitalized patients. We also studied antibody SERO response in relation to time after symptom onset TRANS and disease MESHD severity, and observed an increase in antibody SERO reactivity and distinct distribution patterns of IgM and IgG following disease progression MESHD. The total IgM and IgG detection is 63% in patients with < 2 weeks from disease MESHD onset; 85% in non-hospitalized patients with > 2 weeks disease MESHD duration; and 91% in hospitalized patients with > 2 weeks disease MESHD duration. We also compared different blood SERO sample types and suggest a potentially higher sensitivity SERO by serum SERO/ plasma SERO comparing with whole blood SERO measurement. To study the specificity of the test, we used 69 sera/ plasma SERO samples collected between 2016-2018 prior to the COVID-19 pandemic, and obtained a test specificity of 97%. In summary, our study provides a comprehensive validation of the rapid COVID-19 IgM/IgG serology test, and mapped antibody SERO detection patterns in association with disease MESHD progress and hospitalization. Our study supports that the rapid COVID-19 IgM/IgG test may be applied to assess the COVID-19 status both at the individual and at a population level.

    Clinical Mortality Review in a Large COVID-19 Cohort

    Authors: Mark P Jarrett; Susanne F Schultz; Julie S Lyall; Jason J Wang; Lori Stier; Marcella De Geronimo; Karen L Nelson

    doi:10.1101/2020.08.05.20168146 Date: 2020-08-06 Source: medRxiv

    Background: Northwell Health (Northwell), an integrated health system in New York, treated more than 15000 inpatients with coronavirus disease MESHD (COVID-19) at the US epicenter of the severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) pandemic. We describe the demographic characteristics of COVID-19 mortalities, observation of frequent rapid response teams (RRT)/ cardiac arrest HP (CA) calls for non-intensive care unit (ICU) patients, and factors that contributed to RRT/CA calls. Methods: A team of registered nurses reviewed medical records of inpatients who tested positive for SARS-CoV-2 via polymerase chain reaction (PCR) before or on admission and died between March 13 (first Northwell inpatient expiration) and April 30, 2020 at 15 Northwell hospitals. Findings for these patients were abstracted into a database and statistically analyzed. Findings: Of 2634 COVID-19 mortalities, 56.1% had oxygen saturation levels greater than or equal to 90% on presentation and required no respiratory support. At least one RRT/CA was called on 42.2% of patients at a non-ICU level of care. Before the RRT/CA call, the most recent oxygen saturation levels for 76.6% of non-ICU patients were at least 90%. At the time RRT/CA was called, 43.1% had an oxygen saturation less than 80%. Interpretation: This study represents one of the largest cohorts of reviewed mortalities that also captures data in non-structured fields. Approximately 50% of deaths MESHD occurred at a non-ICU level of care, despite admission to the appropriate care setting with normal staffing. The data imply a sudden, unexpected deterioration in respiratory status requiring RRT/CA in a large number of non-ICU patients. Patients admitted to a non-ICU level of care suffer rapid clinical deterioration MESHD, often with a sudden decrease in oxygen saturation. These patients could benefit from additional monitoring (eg, continuous central oxygenation saturation), although this approach warrants further study.

    Swab-Seq: A high-throughput platform for massively scaled up SARS-CoV-2 testing

    Authors: Joshua S. Bloom; Eric M. Jones; Molly Gasperini; Nathan B. Lubock; Laila Sathe; Chetan Munugala; A. Sina Booeshaghi; Oliver F. Brandenberg; Longhua Guo; Scott W. Simpkins; Isabella Lin; Nathan LaPierre; Duke Hong; Yi Zhang; Gabriel Oland; Bianca Judy Choe; Sukantha Chandrasekaran; Evann E. Hilt; Manish J. Butte; Robert Damoiseaux; Aaron R. Cooper; Yi Yin; Lior Pachter; Omai B. Garner; Jonathan Flint; Eleazar Eskin; Chongyuan Luo; Sriram Kosuri; Leonid Kruglyak; Valerie A. Arboleda

    doi:10.1101/2020.08.04.20167874 Date: 2020-08-06 Source: medRxiv

    The rapid spread of severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) is due to the high rates of transmission TRANS by individuals who are asymptomatic TRANS at the time of transmission TRANS. Frequent, widespread testing of the asymptomatic TRANS population for SARS-CoV-2 is essential to suppress viral transmission TRANS and is a key element in safely reopening society. Despite increases in testing capacity, multiple challenges remain in deploying traditional reverse transcription and quantitative PCR (RT-qPCR) tests at the scale required for population screening of asymptomatic TRANS individuals. We have developed SwabSeq, a high-throughput testing platform for SARS-CoV-2 that uses next-generation sequencing as a readout. SwabSeq employs sample-specific molecular barcodes to enable thousands of samples to be combined and simultaneously analyzed for the presence or absence of SARS-CoV-2 in a single run. Importantly, SwabSeq incorporates an in vitro RNA standard that mimics the viral amplicon, but can be distinguished by sequencing. This standard allows for end-point rather than quantitative PCR, improves quantitation, reduces requirements for automation and sample-to-sample normalization, enables purification-free detection, and gives better ability to call true negatives. We show that SwabSeq can test nasal and oral specimens for SARS-CoV-2 with or without RNA extraction while maintaining analytical sensitivity SERO better than or comparable to that of fluorescence-based RT-qPCR tests. SwabSeq is simple, sensitive, flexible, rapidly scalable, inexpensive enough to test widely and frequently, and can provide a turn around time of 12 to 24 hours.

    Structural analysis of full-length SARS-CoV-2 spike protein from an advanced vaccine candidate

    Authors: Sandhya Bangaru; Gabriel Ozorowski; Hannah L Turner; Aleksandar Antanasijevic; Deli Huang; Xiaoning Wang; Jonathan L Torres; Jolene K Diedrich; Jing-Hui Tian; Alyse D. Portnoff; Nita Patel; Michael J. Massare; John Robert Yates III; David Nemazee; James C. Paulson; Greg Glenn; Gale Smith; Andrew B. Ward

    doi:10.1101/2020.08.06.234674 Date: 2020-08-06 Source: bioRxiv

    Vaccine efforts against the severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) responsible for the current COVID-19 pandemic are focused on SARS-CoV-2 spike glycoprotein, the primary target for neutralizing antibodies SERO. Here, we performed cryo-EM and site-specific glycan analysis of one of the leading subunit vaccine candidates from Novavax based on a full-length spike protein formulated in polysorbate 80 (PS 80) detergent. Our studies reveal a stable prefusion conformation of the spike immunogen with slight differences in the S1 subunit compared to published spike ectodomain structures. Interestingly, we also observed novel interactions between the spike trimers allowing formation of higher order spike complexes. This study confirms the structural integrity of the full-length spike protein immunogen and provides a basis for interpreting immune responses to this multivalent nanoparticle immunogen.

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MeSH Disease
Human Phenotype

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