Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 46
Filter
Add filters

Year range
2.
Signal Transduct Target Ther ; 6(1): 155, 2021 04 15.
Article in English | MEDLINE | ID: covidwho-1189204

ABSTRACT

Disease progression prediction and therapeutic drug target discovery for Coronavirus disease 2019 (COVID-19) are particularly important, as there is still no effective strategy for severe COVID-19 patient treatment. Herein, we performed multi-platform omics analysis of serial plasma and urine samples collected from patients during the course of COVID-19. Integrative analyses of these omics data revealed several potential therapeutic targets, such as ANXA1 and CLEC3B. Molecular changes in plasma indicated dysregulation of macrophage and suppression of T cell functions in severe patients compared to those in non-severe patients. Further, we chose 25 important molecular signatures as potential biomarkers for the prediction of disease severity. The prediction power was validated using corresponding urine samples and plasma samples from new COVID-19 patient cohort, with AUC reached to 0.904 and 0.988, respectively. In conclusion, our omics data proposed not only potential therapeutic targets, but also biomarkers for understanding the pathogenesis of severe COVID-19.


Subject(s)
/blood , Drug Discovery , Lipidomics , Proteomics , /metabolism , Biomarkers/blood , Female , Humans , Male
3.
Cell Rep ; 35(3): 109017, 2021 04 20.
Article in English | MEDLINE | ID: covidwho-1163486

ABSTRACT

Transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from humans to farmed mink has been observed in Europe and the US. In the infected animals, viral variants arose that harbored mutations in the spike (S) protein, the target of neutralizing antibodies, and these variants were transmitted back to humans. This raised concerns that mink might become a constant source of human infection with SARS-CoV-2 variants associated with an increased threat to human health and resulted in mass culling of mink. Here, we report that mutations frequently found in the S proteins of SARS-CoV-2 from mink are mostly compatible with efficient entry into human cells and its inhibition by soluble angiotensin-converting enzyme 2 (ACE2). In contrast, mutation Y453F reduces neutralization by an antibody with emergency use authorization for coronavirus disease 2019 (COVID-19) therapy and sera/plasma from COVID-19 patients. These results suggest that antibody responses induced upon infection or certain antibodies used for treatment might offer insufficient protection against SARS-CoV-2 variants from mink.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Mink , Spike Glycoprotein, Coronavirus , A549 Cells , Animals , /immunology , Chlorocebus aethiops , Cricetinae , Humans , Mink/immunology , Mink/virology , /immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vero Cells
4.
PLoS Comput Biol ; 17(3): e1008837, 2021 03.
Article in English | MEDLINE | ID: covidwho-1156074

ABSTRACT

Predictions of COVID-19 case growth and mortality are critical to the decisions of political leaders, businesses, and individuals grappling with the pandemic. This predictive task is challenging due to the novelty of the virus, limited data, and dynamic political and societal responses. We embed a Bayesian time series model and a random forest algorithm within an epidemiological compartmental model for empirically grounded COVID-19 predictions. The Bayesian case model fits a location-specific curve to the velocity (first derivative) of the log transformed cumulative case count, borrowing strength across geographic locations and incorporating prior information to obtain a posterior distribution for case trajectories. The compartmental model uses this distribution and predicts deaths using a random forest algorithm trained on COVID-19 data and population-level characteristics, yielding daily projections and interval estimates for cases and deaths in U.S. states. We evaluated the model by training it on progressively longer periods of the pandemic and computing its predictive accuracy over 21-day forecasts. The substantial variation in predicted trajectories and associated uncertainty between states is illustrated by comparing three unique locations: New York, Colorado, and West Virginia. The sophistication and accuracy of this COVID-19 model offer reliable predictions and uncertainty estimates for the current trajectory of the pandemic in the U.S. and provide a platform for future predictions as shifting political and societal responses alter its course.


Subject(s)
/epidemiology , Forecasting/methods , Models, Statistical , Pandemics/statistics & numerical data , Algorithms , Bayes Theorem , Computational Biology , Humans , Machine Learning , United States/epidemiology
5.
Front Pharmacol ; 11: 1071, 2020.
Article in English | MEDLINE | ID: covidwho-726004

ABSTRACT

Background: Currently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally, causing an unprecedented pandemic. However, there is no specific antiviral therapy for coronavirus disease 2019 (COVID-19). We conducted a clinical trial to compare the effectiveness of three antiviral treatment regimens in patients with mild to moderate COVID-19. Methods: This was a single-center, randomized, open-labeled, prospective clinical trial. Eligible patients with mild to moderate COVID-19 were randomized into three groups: ribavirin (RBV) plus interferon-α (IFN-α), lopinavir/ritonavir (LPV/r) plus IFN-α, and RBV plus LPV/r plus IFN-α at a 1:1:1 ratio. Each patient was invited to participate in a 28-d follow-up after initiation of an antiviral regimen. The outcomes include the difference in median interval to SARS-CoV-2 nucleic acid negativity, the proportion of patients with SARS-CoV-2 nucleic acid negativity at day 14, the mortality at day 28, the proportion of patients re-classified as severe cases, and adverse events during the study period. Results: In total, we enrolled 101 patients in this study. Baseline clinical and laboratory characteristics of patients were comparable among the three groups. In the analysis of intention-to-treat data, the median interval from baseline to SARS-CoV-2 nucleic acid negativity was 12 d in the LPV/r+IFN-α-treated group, as compared with 13 and 15 d in the RBV+IFN-α-treated group and in the RBV+LPV/r+ IFN-α-treated group, respectively (p=0.23). The proportion of patients with SARS-CoV-2 nucleic acid negativity in the LPV/r+IFN-α-treated group (61.1%) was higher than the RBV+ IFN-α-treated group (51.5%) and the RBV+LPV/r+IFN-α-treated group (46.9%) at day 14; however, the difference between these groups was calculated to be statistically insignificant. The RBV+LPV/r+IFN-α-treated group developed a significantly higher incidence of gastrointestinal adverse events than the LPV/r+ IFN-α-treated group and the RBV+ IFN-α-treated group. Conclusions: Our results indicate that there are no significant differences among the three regimens in terms of antiviral effectiveness in patients with mild to moderate COVID-19. Furthermore, the combination of RBV and LPV/r is associated with a significant increase in gastrointestinal adverse events, suggesting that RBV and LPV/r should not be co-administered to COVID-19 patients simultaneously. Clinical Trial Registration: www.ClinicalTrials.gov, ID: ChiCTR2000029387. Registered on January 28, 2019.

6.
Phys Chem Chem Phys ; 23(10): 5852-5863, 2021 Mar 14.
Article in English | MEDLINE | ID: covidwho-1125003

ABSTRACT

COVID-19 has recently caused a global health crisis and an effective interventional therapy is urgently needed. Remdesivir is one effective inhibitor for SARS-CoV-2 viral RNA replication. It supersedes other NTP analogues because it not only terminates the polymerization activity of RNA-dependent RNA polymerase (RdRp), but also inhibits the proofreading activity of intrinsic exoribonuclease (ExoN). Even though the static structure of Remdesivir binding to RdRp has been solved and biochemical experiments have suggested it to be a "delayed chain terminator", the underlying molecular mechanisms is not fully understood. Here, we performed all-atom molecular dynamics (MD) simulations with an accumulated simulation time of 24 microseconds to elucidate the inhibitory mechanism of Remdesivir on nucleotide addition and proofreading. We found that when Remdesivir locates at an upstream site in RdRp, the 1'-cyano group experiences electrostatic interactions with a salt bridge (Asp865-Lys593), which subsequently halts translocation. Our findings can supplement the current understanding of the delayed chain termination exerted by Remdesivir and provide an alternative molecular explanation about Remdesivir's inhibitory mechanism. Such inhibition also reduces the likelihood of Remdesivir to be cleaved by ExoN acting on 3'-terminal nucleotides. Furthermore, our study also suggests that Remdesivir's 1'-cyano group can disrupt the cleavage site of ExoN via steric interactions, leading to a further reduction in the cleavage efficiency. Our work provides plausible and novel mechanisms at the molecular level of how Remdesivir inhibits viral RNA replication, and our findings may guide rational design for new treatments of COVID-19 targeting viral replication.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Cyanides/chemistry , Nucleotides/metabolism , /physiology , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/chemistry , Alanine/metabolism , Alanine/pharmacology , Alanine/therapeutic use , /pathology , Catalytic Domain , Humans , Molecular Dynamics Simulation , Ribose/chemistry , /metabolism , Static Electricity , Virus Replication/drug effects
7.
Genome Med ; 13(1): 30, 2021 02 22.
Article in English | MEDLINE | ID: covidwho-1097198

ABSTRACT

BACKGROUND: Since early February 2021, the causative agent of COVID-19, SARS-CoV-2, has infected over 104 million people with more than 2 million deaths according to official reports. The key to understanding the biology and virus-host interactions of SARS-CoV-2 requires the knowledge of mutation and evolution of this virus at both inter- and intra-host levels. However, despite quite a few polymorphic sites identified among SARS-CoV-2 populations, intra-host variant spectra and their evolutionary dynamics remain mostly unknown. METHODS: Using high-throughput sequencing of metatranscriptomic and hybrid captured libraries, we characterized consensus genomes and intra-host single nucleotide variations (iSNVs) of serial samples collected from eight patients with COVID-19. The distribution of iSNVs along the SARS-CoV-2 genome was analyzed and co-occurring iSNVs among COVID-19 patients were identified. We also compared the evolutionary dynamics of SARS-CoV-2 population in the respiratory tract (RT) and gastrointestinal tract (GIT). RESULTS: The 32 consensus genomes revealed the co-existence of different genotypes within the same patient. We further identified 40 intra-host single nucleotide variants (iSNVs). Most (30/40) iSNVs presented in a single patient, while ten iSNVs were found in at least two patients or identical to consensus variants. Comparing allele frequencies of the iSNVs revealed a clear genetic differentiation between intra-host populations from the respiratory tract (RT) and gastrointestinal tract (GIT), mostly driven by bottleneck events during intra-host migrations. Compared to RT populations, the GIT populations showed a better maintenance and rapid development of viral genetic diversity following the suspected intra-host bottlenecks. CONCLUSIONS: Our findings here illustrate the intra-host bottlenecks and evolutionary dynamics of SARS-CoV-2 in different anatomic sites and may provide new insights to understand the virus-host interactions of coronaviruses and other RNA viruses.


Subject(s)
/prevention & control , Genome, Viral/genetics , High-Throughput Nucleotide Sequencing/methods , Polymorphism, Single Nucleotide , /genetics , /virology , Gene Frequency , Genotype , Haplotypes , Host-Pathogen Interactions , Humans , Phylogeny , /physiology
8.
Atmospheric Pollution Research ; 2021.
Article in English | WHO COVID | ID: covidwho-1064817

ABSTRACT

Lockdowns implemented in response to COVID-19 have caused an unprecedented reduction in global economic and transport activity In this study, variation in the concentration of health-threatening air pollutants (PM2 5, NO2, and O3) pre- and post-lockdown was investigated at global, continental, and national scales We analyzed ground-based data from >10,000 monitoring stations in 380 cities across the globe Global-scale results during lockdown (March to May 2020) showed that concentrations of PM2 5 and NO2 decreased by 16 1% and 45 8%, respectively, compared to the baseline period (2015–2019) However, O3 concentration increased by 5 4% At the continental scale, concentrations of PM2 5 and NO2 substantially dropped in 2020 across all continents during lockdown compared to the baseline, with a maximum reduction of 20 4% for PM2 5 in East Asia and 42 5% for NO2 in Europe The maximum reduction in O3 was observed in North America (7 8%), followed by Asia (0 7%), while small increases were found in other continents At the national scale, PM2 5 and NO2 concentrations decreased significantly during lockdown, but O3 concentration showed varying patterns among countries We found maximum reductions of 50 8% for PM2 5 in India and 103 5% for NO2 in Spain The maximum reduction in O3 (22 5%) was found in India Improvements in air quality were temporary as pollution levels increased in cities since lockdowns were lifted We posit that these unprecedented changes in air pollutants were mainly attributable to reductions in traffic and industrial activities Column reductions could also be explained by meteorological variability and a decline in emissions caused by environmental policy regulations Our results have implications for the continued implementation of strict air quality policies and emission control strategies to improve environmental and human health

9.
Epidemics ; 33(28), 2020.
Article in English | WHO COVID | ID: covidwho-1044758

ABSTRACT

In emerging epidemics, early estimates of key epidemiological characteristics of the disease are critical for guiding public policy In particular, identifying high-risk population subgroups aids policymakers and health officials in combating the epidemic This has been challenging during the coronavirus disease 2019 (COVID-19) pandemic because governmental agencies typically release aggregate COVID-19 data as summary statistics of patient demographics These data may identify disparities in COVID-19 outcomes between broad population subgroups, but do not provide comparisons between more granular population subgroups defined by combinations of multiple demographics We introduce a method that helps to overcome the limitations of aggregated summary statistics and yields estimates of COVID-19 infection and case fatality rates - key quantities for guiding public policy related to the control and prevention of COVID-19 - for population subgroups across combinations of demographic characteristics Our approach uses pseudo-likelihood based logistic regression to combine aggregate COVID-19 case and fatality data with population-level demographic survey data to estimate infection and case fatality rates for population subgroups across combinations of demographic characteristics We illustrate our method on California COVID-19 data to estimate test-based infection and case fatality rates for population subgroups defined by gender, age, and race/ethnicity Our analysis indicates that in California, males have higher test-based infection rates and test-based case fatality rates across age and race/ethnicity groups, with the gender gap widening with increasing age Although elderly infected with COVID-19 are at an elevated risk of mortality, the test-based infection rates do not increase monotonically with age The workforce population, especially, has a higher test-based infection rate than children, adolescents, and other elderly people in their 60-80 LatinX and African Americans have higher test-based infection rates than other race/ethnicity groups The subgroups with the highest 5 test-based case fatality rates are all-male groups with race as African American, Asian, Multi-race, LatinX, and White, followed by African American females, indicating that African Americans are an especially vulnerable California subpopulation

11.
Preprint | SciFinder | ID: ppcovidwho-5327

ABSTRACT

A review Novel coronavirus pneumonia (COVID-19) refers to viral pneumonia caused mainly by fever, cough, headache, fatigue, and dyspnea caused by the new coronavirus (2019-nCoV) The earliest patient with COVID-19 was found in Wuhan The infection is usually with in 14 days The virus is highly contagious As of Feb 23, 2020, a total of 77,049 COVID-19 patients were confirmed diagnosis, resulting in no less than 2445 patients death Compared with SARS, COVID-19 progresses faster, and critically ill patients often have lung injury, liver dysfunction, acute respiratory distress syndrome, and eventually develop multiple organ failure and shock The pathol mechanism of critically ill patient swith COVID-19 is still unclear, and some scholars have revealed abnormal liver function in patients with COVID-19 from the waterfall of inflammation caused by the 2019-nCoV The pathol development of COVID-19 needs to be confirmed by detailed anat and pathol studies The damage caused by COVID-19 to our country is no less than that of the outbreak of SARS in China in 2003 In the current COVID-19 prevention and treatment work, there is still no globally accepted treatment guideline for the best curative effect, and traditional Chinese medicine and modern medicine measures have been reported This article summarizes the latest traditional Chinese medicine and modern medicine prevention methods and measures for COVID-19, and provides support for the prevention and treatment of COVID-19

12.
J Clin Invest ; 130(10): 5235-5244, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-969923

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for coronavirus 2019 (COVID-19) pneumonia. Little is known about the kinetics, tissue distribution, cross-reactivity, and neutralization antibody response in patients with COVID-19. Two groups of patients with RT-PCR-confirmed COVID-19 were enrolled in this study: 12 severely ill patients in intensive care units who needed mechanical ventilation and 11 mildly ill patients in isolation wards. Serial clinical samples were collected for laboratory detection. Results showed that most of the severely ill patients had viral shedding in a variety of tissues for 20-40 days after onset of disease (8/12, 66.7%), while the majority of mildly ill patients had viral shedding restricted to the respiratory tract and had no detectable virus RNA 10 days after onset (9/11, 81.8%). Mildly ill patients showed significantly lower IgM response compared with that of the severe group. IgG responses were detected in most patients in both the severe and mild groups at 9 days after onset, and remained at a high level throughout the study. Antibodies cross-reactive to SARS-CoV and SARS-CoV-2 were detected in patients with COVID-19 but not in patients with MERS. High levels of neutralizing antibodies were induced after about 10 days after onset in both severely and mildly ill patients which were higher in the severe group. SARS-CoV-2 pseudotype neutralization test and focus reduction neutralization test with authentic virus showed consistent results. Sera from patients with COVID-19 inhibited SARS-CoV-2 entry. Sera from convalescent patients with SARS or Middle East respiratory syndrome (MERS) did not. Anti-SARS-CoV-2 S and N IgG levels exhibited a moderate correlation with neutralization titers in patients' plasma. This study improves our understanding of immune response in humans after SARS-CoV-2 infection.


Subject(s)
Antibodies, Viral/blood , Betacoronavirus/metabolism , Coronavirus Infections/blood , Pneumonia, Viral/blood , Viral Load , Virus Shedding , Adult , Aged , Antibody Specificity , Cross Reactions , Female , Humans , Kinetics , Male , Middle Aged , Pandemics , Severity of Illness Index
13.
Aging (Albany NY) ; 12(22): 22370-22389, 2020 Nov 20.
Article in English | MEDLINE | ID: covidwho-967740

ABSTRACT

SARS-coronavirus 2 (SARS-CoV-2) has been spreading widely and posing an international challenge for both healthcare and society. At present, cancer has been identified as an individual risk factor for COVID-19. Angiotensin converting enzyme 2 (ACE2) and Cathepsin L/Cathepsin B (CTSL/B), which act as the receptor and entry-associated proteases of SARS-CoV-2 respectively, are pivotal for SARS-CoV-2 infection. To investigate the possible SARS-CoV-2 infection risk of pan-cancer, we analyzed the genetic alterations, RNA expression, DNA methylation, and the association with immune subtypes of ACE2 and CTSL/B with the prognosis in pan-cancer. Results showed the upregulation of CTSL/B and ACE2 in Pancreatic adenocarcinoma (PAAD) and Stomach adenocarcinoma (STAD) and demonstrated a positive correlation between copy number alteration (CNA) and gene expression for CTSB in PAAD and STAD. Hypomethylation and a negative correlation of gene expression and methylation for CTSB were detected in PAAD. In addition, ACE2 and CTSL/B are overexpressed in the IFN-gamma immune subtype of ovarian serous Cystadenocarcinoma (OV), Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), and Bladder urothelial carcinoma (BLCA). Our study presents a bioinformatics assessment for the potential risk of SARS-CoV-2 infection in pan-cancer.

15.
Angewandte Chemie ; 59(47), 2020.
Article in English | WHO COVID | ID: covidwho-915118

ABSTRACT

Asymmetric Synthesis The first catalytic asymmetric synthesis of remdesivir by the coupling of the P‐racemic phosphoryl chloride with protected nucleoside GS441524 is described by W Zhang et al in their Communication on page 20814

16.
Angewandte Chemie ; 132(47), 2020.
Article in English | WHO COVID | ID: covidwho-915115

ABSTRACT

Asymmetrische Synthese Die erste katalytische asymmetrische Synthese von Remdesivir durch die Kupplung von P‐racemischem Phosphorylchlorid mit dem geschützten Nukleosid GS441524 wird von W Zhang et al in der Zuschrift auf S  21000 vorgestellt

17.
J Aerosol Sci ; : 105693, 2020 Oct 15.
Article in English | MEDLINE | ID: covidwho-880521

ABSTRACT

The COVID-19 pandemic has brought an unprecedented crisis to the global health sector. When discharging COVID-19 patients in accordance with throat or nasal swab protocols using RT-PCR, the potential risk of reintroducing the infection source to humans and the environment must be resolved. Here, 14 patients including 10 COVID-19 subjects were recruited; exhaled breath condensate (EBC), air samples and surface swabs were collected and analyzed for SARS-CoV-2 using reverse transcription-polymerase chain reaction (RT-PCR) in four hospitals with applied natural ventilation and disinfection practices in Wuhan. Here we discovered that 22.2% of COVID-19 patients (n = 9), who were ready for hospital discharge based on current guidelines, had SARS-CoV-2 in their exhaled breath (~105 RNA copies/m3). Although fewer surface swabs (3.1%, n = 318) tested positive, medical equipment such as face shield frequently contacted/used by healthcare workers and the work shift floor were contaminated by SARS-CoV-2 (3-8 viruses/cm2). Three of the air samples (n = 44) including those collected using a robot-assisted sampler were detected positive by a digital PCR with a concentration level of 9-219 viruses/m3. RT-PCR diagnosis using throat swab specimens had a failure rate of more than 22% in safely discharging COVID-19 patients who were otherwise still exhaling the SARS-CoV-2 by a rate of estimated ~1400 RNA copies per minute into the air. Direct surface contact might not represent a major transmission route, and lower positive rate of air sample (6.8%) was likely due to natural ventilation (1.6-3.3 m/s) and regular disinfection practices. While there is a critical need for strengthening hospital discharge standards in preventing re-emergence of COVID-19 spread, use of breath sample as a supplement specimen could further guard the hospital discharge to ensure the safety of the public and minimize the pandemic re-emergence risk.

18.
Microbiol Resour Announc ; 9(8)2020 Feb 20.
Article in English | MEDLINE | ID: covidwho-833422

ABSTRACT

We report the complete genome sequences of five human coronavirus NL63 (HCoV-NL63) strains obtained using next-generation sequencing. The five HCoV-NL63 strains were obtained from hospitalized children with severe acute respiratory infection detected in Guangdong, China. This study provides several complete genomes of HCoV-NL63 and improves our understanding of HCoV-NL63 evolution in China.

19.
Sci China Chem ; : 1-9, 2020 Jul 27.
Article in English | MEDLINE | ID: covidwho-832162

ABSTRACT

The outbreak of virus-induced infectious diseases poses a global public-health challenge. Nucleic acid amplification testing (NAAT) enables early detection of pandemic viruses and plays a vital role in preventing onward transmission. However, the requirement of skilled operators, expensive instrumentation, and biosafety laboratories has hindered the use of NAAT for screening and diagnosis of suspected patients. Here we report development of a fully automated centrifugal microfluidic system with sample-in-answer-out capability for sensitive, specific, and rapid viral nucleic acid testing. The release of nucleic acids and the subsequent reverse transcription loop-mediated isothermal amplification (RT-LAMP) were integrated into the reaction units of a microfluidic disc. The whole processing steps such as injection of reagents, fluid actuation by rotation, heating and temperature control, and detection of fluorescence signals were carried out automatically by a customized instrument. We validate the centrifugal microfluidic system using oropharyngeal swab samples spiked with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) armored RNA particles. The estimated limit of detection for armored RNA particles is 2 copies per reaction, the throughput is 21 reactions per disc, and the assay sample-to-answer time is approximately 70 min. This enclosed and automated microfluidic system efficiently avoids viral contamination of aerosol, and can be readily adapted for virus detection outside the diagnostic laboratory. Electronic Supplementary Material: Supplementary material is available for this article at 10.1007/s11426-020-9800-6 and is accessible for authorized users.

SELECTION OF CITATIONS
SEARCH DETAIL