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1.
Frontiers in immunology ; 13, 2022.
Article in English | EuropePMC | ID: covidwho-1871974

ABSTRACT

The continuous spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) around the world has raised unprecedented challenges to the human society. Antibodies and nanobodies possessing neutralization activity represent promising drug candidates. In this study, we report the identification and characterization of a potent SARS-CoV-2 neutralizing nanobody that targets the viral spike receptor-binding domain (S-RBD). The nanobody, termed as Nb-007, engages SARS-CoV-2 S-RBD with the two-digit picomolar binding affinity and shows outstanding virus entry-inhibition activity. The complex structure of Nb-007 bound to SARS-CoV-2 S-RBD reveals an epitope that is partially overlapping with the binding site for the human receptor of angiotensin-converting enzyme 2 (ACE2). The nanobody therefore exerts neutralization by competing with ACE2 for S-RBD binding, which is further ascertained by our in-vitro biochemical analyses. Finally, we also show that Nb-007 reserves promising, though compromised, neutralization activity against the currently-circulating Delta variant and that fusion of the nanobody with Fc dramatically increases its entry-inhibition capacity. Taken together, these data have paved the way of developing Nb-007 as a drug-reserve for potential treatment of SARS-CoV-2 related diseases.

2.
Sci China Life Sci ; 2022 Apr 28.
Article in English | MEDLINE | ID: covidwho-1826874

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by a strong production of inflammatory cytokines such as TNF and IL-6, which underlie the severity of the disease. However, the molecular mechanisms responsible for such a strong immune response remains unclear. Here, utilizing targeted tandem mass spectrometry to analyze serum metabolome and lipidome in COVID-19 patients at different temporal stages, we identified that 611 metabolites (of 1,039) were significantly altered in COVID-19 patients. Among them, two metabolites, agmatine and putrescine, were prominently elevated in the serum of patients; and 2-quinolinecarboxylate was changed in a biphasic manner, elevated during early COVID-19 infection but levelled off. When tested in mouse embryonic fibroblasts (MEFs) and macrophages, these 3 metabolites were found to activate the NF-κB pathway that plays a pivotal role in governing cytokine production. Importantly, these metabolites were each able to cause strong increase of TNF and IL-6 levels when administered to wildtype mice, but not in the mice lacking NF-κB. Intriguingly, these metabolites have little effects on the activation of interferon regulatory factors (IRFs) for the production of type I interferons (IFNs) for antiviral defenses. These data suggest that circulating metabolites resulting from COVID-19 infection may act as effectors to elicit the peculiar systemic inflammatory responses, exhibiting severely strong proinflammatory cytokine production with limited induction of the interferons. Our study may provide a rationale for development of drugs to alleviate inflammation in COVID-19 patients.

3.
Pathogens ; 11(4)2022 Apr 09.
Article in English | MEDLINE | ID: covidwho-1785868

ABSTRACT

Noroviruses (NoVs) are one of the emerging and rapidly spreading groups of pathogens threatening human health. A reduction in sporadic NoV infections was noted following the start of the COVID-19 pandemic, but the return of NoV gastroenteritis during the COVID-19 pandemic has been noted recently. Research in recent years has shown that different virus strains are associated with different clinical characteristics; moreover, there is a paucity of research into extraintestinal or unusual complications that may be associated with NoV. The genomic diversity of circulating NoVs is also complex and may vary significantly. Therefore, this short narrative review focuses on sharing the Taiwan experience of NoV infection including epidemiology, clinical features, and complications following suboptimal rotavirus immunization in Taiwan (after October 2006). We also highlight the unusual complications associated with NoV infections and the impacts of NoV infection during the COVID-19 pandemic in the literature for possible future research directions. To conclude, further research is needed to quantify the burden of NoV across the spectrum of disease severity in Taiwan. The evidence of the connection between NoV and the unusual complications is still lacking.

4.
Frontiers in cellular and infection microbiology ; 12, 2022.
Article in English | EuropePMC | ID: covidwho-1762433

ABSTRACT

Objective To evaluate the necessity of Covid-19 vaccination in children aged < 12 y by comparing the clinical characteristics between unvaccinated children aged < 12 y and vaccinated patients aged ≥ 12y during the Delta surge (B.1.617.2) in Putian, Fujian, China. Methods A total of 226 patients with SARS-Cov-2 Delta variant (B.1.167.2;confirmed by Real-time PCR positivity and sequencing) were enrolled from Sep 10th to Oct 20th, 2021, including 77 unvaccinated children (aged < 12y) and 149 people aged ≥ 12y, mostly vaccinated. The transmission route was explored and the clinical data of two groups were compared;The effect factors for the time of the nucleic acid negativization (NAN) were examined by R statistical analysis. Results The Delta surge in Putian spread from children in schools to factories, mostly through family contact. Compared with those aged ≥ 12y, patients aged < 12y accounted for 34.07% of the total and showed milder fever, less cough and fatigue;they reported higher peripheral blood lymphocyte counts [1.84 (1.32, 2.71)×10

5.
Clin Infect Dis ; 2021 Nov 12.
Article in English | MEDLINE | ID: covidwho-1758700

ABSTRACT

BACKGROUND: To combat the COVID-19 pandemic, nonpharmaceutical interventions (NPI) were implemented worldwide, which impacted a broad spectrum of acute respiratory infections (ARI). METHODS: Etiologically diagnostic data from 142 559 cases with ARIs, who were tested for eight viral pathogens (influenza virus, IFV; respiratory syncytial virus, RSV; human parainfluenza virus, HPIV; human adenovirus; human metapneumovirus; human coronavirus, HCoV; human bocavirus, HBoV, and human rhinovirus, HRV) between 2012 and 2021, were analyzed to assess the changes of respiratory infections in China during the first COVID-19 pandemic year compared to pre-pandemic years. RESULTS: Test positive rates of all respiratory viruses decreased during 2020, compared to the average levels during 2012-2019, with changes ranging from -17·2% for RSV to -87·6% for IFV. Sharp decreases mostly occurred between February and August when massive NPIs remained active, although HRV rebounded to the historical level during the summer. While IFV and HMPV were consistently suppressed year round, RSV, HPIV, HCoV, HRV HBov resurged and went beyond historical levels during September, 2020-January, 2021, after NPIs were largely relaxed and schools reopened. Resurgence was more prominent among children younger than 18 years and in Northern China. These observations remain valid after accounting for seasonality and long-term trend of each virus. CONCLUSIONS: Activities of respiratory viral infections were reduced substantially in the early phases of the COVID-19 pandemic, and massive NPIs were likely the main driver. Lifting of NPIs can lead to resurgence of viral infections, particularly in children.

6.
J Pers Med ; 12(3)2022 Mar 12.
Article in English | MEDLINE | ID: covidwho-1742521

ABSTRACT

(1) Background: Our study investigated whether monocyte distribution width (MDW) could be used in emergency department (ED) settings as a predictor of prolonged length of stay (LOS) for patients with COVID-19. (2) Methods: A retrospective cohort study was conducted; patients presenting to the ED of an academic hospital with confirmed COVID-19 were enrolled. Multivariable logistic regression models were used to obtain the odds ratios (ORs) for predictors of an LOS of >14 days. A validation study for the association between MDW and cycle of threshold (Ct) value was performed. (3) Results: Fever > 38 °C (OR: 2.82, 95% CI, 1.13-7.02, p = 0.0259), tachypnea (OR: 4.76, 95% CI, 1.67-13.55, p = 0.0034), and MDW ≥ 21 (OR: 5.67, 95% CI, 1.19-27.10, p = 0.0269) were robust significant predictors of an LOS of >14 days. We developed a new scoring system in which patients were assigned 1 point for fever > 38 °C, 2 points for tachypnea > 20 breath/min, and 3 points for MDW ≥ 21. The optimal cutoff was a score of ≥2. MDW was negatively associated with Ct value (ß: -0.32 per day, standard error = 0.12, p = 0.0099). (4) Conclusions: Elevated MDW was associated with a prolonged LOS.

7.
BMC Infect Dis ; 22(1): 240, 2022 Mar 10.
Article in English | MEDLINE | ID: covidwho-1736349

ABSTRACT

BACKGROUND: The duration of antibodies against SARS-CoV-2 in Covid-19 patients remains uncertain. Longitudinal serological studies are needed to prevent disease and transmission of the virus. METHODS: In 2020, 414 blood samples were tested, obtained from 157 confirmed Covid-19 patients, in a prospective cohort study in Shanghai. RESULTS: The seropositive rate of IgM peaked at 40.5% (17/42) within 1 month after illness onset and then declined. The seropositive rate of IgG was 90.6% (58/64) after 2 months, remained above 85% from 2 to 9 months and was 90.9% (40/44) after 9 months. Generalized estimating equations models suggested that IgM (P < 0.001) but not IgG significantly decreased over time. Age ≥ 40 years (adjusted odds ratio [aOR] 4.531; 95% confidence interval [CI] 1.879-10.932), and cigarette smoking (aOR 0.344; 95% CI 0.124-0.951) were associated with IgG, and age ≥ 40 years (aOR 2.820; 95% CI 1.579-5.036) was associated with IgM. After seroconversion, over 90% and 75.1% of subjects were estimated to remain IgG-positive 220 and 254 days, respectively. Of 1420 self-reported symptoms questionnaires, only 5% reported symptoms 9 months after onset. CONCLUSIONS: In patients with a history of natural infection, anti-SARS-CoV-2 IgG is long-lived, being present for at least 9 months after illness onset. The long duration of natural immunity can mitigate and eliminate Covid-19 and the ongoing pandemic.


Subject(s)
COVID-19 , Adult , COVID-19/epidemiology , China/epidemiology , Humans , Immunity , Immunoglobulin M , Prospective Studies , SARS-CoV-2
8.
Front Bioeng Biotechnol ; 10: 796996, 2022.
Article in English | MEDLINE | ID: covidwho-1731753

ABSTRACT

The COVID-19 pandemic has had a globally devastating impact. This highly contagious virus has significantly overburdened and undermined medical systems. While most infected patients experience only mild symptoms, those who are severely affect require urgent medical interventions and some develop acute respiratory failure and require mechanical ventilation. The broad and potentially deadly impact of infection underscores the critical need for early recognition, especially for those at risk for respiratory failure. Those who are severely impacted and at high risk for respiratory failure have been found to present high levels of serum cytokines, such as interleukin-6 (IL-6). Timely diagnosis and management of those at risk for respiratory failure is crucial. Measurement of IL-6 may provide a means for distinguishing such patients. Currently, most serum IL-6 detection relies on the use of laboratory-based conventional enzyme-linked immunosorbent assays. Although some rapid assays have been developed recently, they need to be conducted by specific technicians in central laboratory settings with advanced and expensive equipment. In this study, we propose an IL-6 test strip combined with a spectrum-based optical reader for early recognition of COVID-19-infected patients at imminent risk of acute respiratory failure requiring mechanical ventilator support. For our analyses, clinical demographic data and sera samples were obtained from three medical centers, and test strip specificity and detection performance were analyzed. This would help healthcare personnel stratify the risk of respiratory failure and provide prompt, and suitable management.

9.
Diagnostics (Basel) ; 12(2)2022 Feb 16.
Article in English | MEDLINE | ID: covidwho-1707948

ABSTRACT

As the COVID-19 (Coronavirus disease 19) pandemic spreads worldwide, the massive numbers of COVID-19 patients have created a considerable healthcare burden for every country. The clinical spectrum of SARS-CoV-2 infection is broad, ranging from asymptomatic to mild, moderate, severe, and critical. Most COVID-19 patients present with no or mild symptoms, but nearly one-fifth of all patients develop severe or life-threatening complications. In addition to localized respiratory manifestations, severe COVID-19 cases also show extra-pulmonary complications or induce multiorgan failure. Identifying, triaging, and treating patients at risk early is essential and urgent. This article reviews the potential prognostic value of various biomarkers at different clinical spectrum stages of COVID-19 infection and includes information on fundamental prognostic mechanisms as well as potential clinical implications. Biomarkers are measurable biochemical substances used to recognize and indicate disease severity or response to therapeutic interventions. The information they provide is objective and suitable for delivering healthcare providers with a means of stratifying disease state in COVID-19 patients. This, in turn, can be used to help select and guide intervention efforts as well as gauge the efficacy of therapeutic approaches. Here, we review a number of potential biomarkers that may be used to guide treatment, monitor treatment efficacy, and form individualized therapeutic guidance based on patient response. Implementation of the COVID-19 biomarkers discussed here may lead to significantly improved quality of care and patient outcomes for those infected with SARS-CoV-2 worldwide.

11.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-314400

ABSTRACT

Background: Little is known about the characteristics of those who transmit SARS-CoV-2 infection vs those who do not, but this information could inform disease control policies. This study described the features of clusters in the first wave of COVID-19 in Shanghai and compared contagiousness by clinical and health care risk factors. Methods: : In this retrospective cohort study of cases in Shanghai in January and February 2020, cases with successive generations were considered to be “contagious.” Characteristics of contagious and non-contagious cases were compared in log-binomial models that also adjusted for age and sex. Results: : Between January 21 and February 17, 2020, 333 cases of COVID-19 were reported in Shanghai across 28 known infection chains. Contagiousness was higher among cases with a sore throat (risk ratio [RR]: 3.41, 95% CI: 1.59, 7.35, P=0.0051), and those with heart disease (RR: 2.06, 95% CI: 0.72, 5.90). Delays in diagnosis were also associated with higher risk of contagiousness. Having ≥2 medical visits before diagnosis was associated with 4.46 times higher risk of contagiousness (95% CI: 2.03, 9.83, P=0.0002), and there was a non-significant increase in risk with increasing numbers of days between disease onset and isolation (for each day, RR: 1.08, 95% CI: 1.01, 1.16, P=0.1734). Conclusions: : Individuals with mild COVID-19 symptoms in the upper respiratory tract may still be contagious, and such individuals should be prioritized for early diagnosis and isolation to limit further chains of transmission.

12.
Viruses ; 14(2)2022 01 28.
Article in English | MEDLINE | ID: covidwho-1662709

ABSTRACT

The human body is colonized by a wide range of microorganisms. The field of viromics has expanded since the first reports on the detection of viruses via metagenomic sequencing in 2002. With the continued development of reference materials and databases, viral metagenomic approaches have been used to explore known components of the virome and discover new viruses from various types of samples. The virome has attracted substantial interest since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic. Increasing numbers of studies and review articles have documented the diverse virome in various sites in the human body, as well as interactions between the human host and the virome with regard to health and disease. However, there have been few studies of direct causal relationships. Viral metagenomic analyses often lack standard references and are potentially subject to bias. Moreover, most virome-related review articles have focused on the gut virome and did not investigate the roles of the virome in other sites of the body in human disease. This review presents an overview of viral metagenomics, with updates regarding the relations between alterations in the human virome and the pathogenesis of human diseases, recent findings related to COVID-19, and therapeutic applications related to the human virome.


Subject(s)
Gastrointestinal Microbiome/genetics , Metagenome , Metagenomics/methods , Virome/genetics , Virus Diseases/drug therapy , Animals , COVID-19/therapy , Humans , Mice , Obesity/complications , SARS-CoV-2/genetics , Virus Diseases/therapy , Viruses/classification , Viruses/genetics
13.
Infect Dis Poverty ; 10(1): 140, 2021 Dec 28.
Article in English | MEDLINE | ID: covidwho-1639437

ABSTRACT

BACKGROUND: Reaching optimal vaccination rates is an essential public health strategy to control the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to simulate the optimal vaccination strategy to control the disease by developing an age-specific model based on the current transmission patterns of COVID-19 in Wuhan City, China. METHODS: We collected two indicators of COVID-19, including illness onset data and age of confirmed case in Wuhan City, from December 2, 2019, to March 16, 2020. The reported cases were divided into four age groups: group 1, ≤ 14 years old; group 2, 15 to 44 years old; group 3, 44 to 64 years old; and group 4, ≥ 65 years old. An age-specific susceptible-exposed-symptomatic-asymptomatic-recovered/removed model was developed to estimate the transmissibility and simulate the optimal vaccination strategy. The effective reproduction number (Reff) was used to estimate the transmission interaction in different age groups. RESULTS: A total of 47 722 new cases were reported in Wuhan City from December 2, 2019, to March 16, 2020. Before the travel ban of Wuhan City, the highest transmissibility was observed among age group 2 (Reff = 4.28), followed by group 2 to 3 (Reff = 2.61), and group 2 to 4 (Reff = 1.69). China should vaccinate at least 85% of the total population to interrupt transmission. The priority for controlling transmission should be to vaccinate 5% to 8% of individuals in age group 2 per day (ultimately vaccinated 90% of age group 2), followed by 10% of age group 3 per day (ultimately vaccinated 90% age group 3). However, the optimal vaccination strategy for reducing the disease severity identified individuals ≥ 65 years old as a priority group, followed by those 45-64 years old. CONCLUSIONS: Approximately 85% of the total population (nearly 1.2 billion people) should be vaccinated to build an immune barrier in China to safely consider removing border restrictions. Based on these results, we concluded that 90% of adults aged 15-64 years should first be vaccinated to prevent transmission in China.


Subject(s)
COVID-19 , Adolescent , Adult , Aged , China , Cities , Humans , Middle Aged , SARS-CoV-2 , Vaccination , Young Adult
14.
Clin Infect Dis ; 2021 Nov 12.
Article in English | MEDLINE | ID: covidwho-1522157

ABSTRACT

BACKGROUND: To combat the COVID-19 pandemic, nonpharmaceutical interventions (NPI) were implemented worldwide, which impacted a broad spectrum of acute respiratory infections (ARI). METHODS: Etiologically diagnostic data from 142 559 cases with ARIs, who were tested for eight viral pathogens (influenza virus, IFV; respiratory syncytial virus, RSV; human parainfluenza virus, HPIV; human adenovirus; human metapneumovirus; human coronavirus, HCoV; human bocavirus, HBoV, and human rhinovirus, HRV) between 2012 and 2021, were analyzed to assess the changes of respiratory infections in China during the first COVID-19 pandemic year compared to pre-pandemic years. RESULTS: Test positive rates of all respiratory viruses decreased during 2020, compared to the average levels during 2012-2019, with changes ranging from -17·2% for RSV to -87·6% for IFV. Sharp decreases mostly occurred between February and August when massive NPIs remained active, although HRV rebounded to the historical level during the summer. While IFV and HMPV were consistently suppressed year round, RSV, HPIV, HCoV, HRV HBov resurged and went beyond historical levels during September, 2020-January, 2021, after NPIs were largely relaxed and schools reopened. Resurgence was more prominent among children younger than 18 years and in Northern China. These observations remain valid after accounting for seasonality and long-term trend of each virus. CONCLUSIONS: Activities of respiratory viral infections were reduced substantially in the early phases of the COVID-19 pandemic, and massive NPIs were likely the main driver. Lifting of NPIs can lead to resurgence of viral infections, particularly in children.

15.
Nat Commun ; 12(1): 5026, 2021 08 18.
Article in English | MEDLINE | ID: covidwho-1363491

ABSTRACT

Nationwide prospective surveillance of all-age patients with acute respiratory infections was conducted in China between 2009‒2019. Here we report the etiological and epidemiological features of the 231,107 eligible patients enrolled in this analysis. Children <5 years old and school-age children have the highest viral positivity rate (46.9%) and bacterial positivity rate (30.9%). Influenza virus, respiratory syncytial virus and human rhinovirus are the three leading viral pathogens with proportions of 28.5%, 16.8% and 16.7%, and Streptococcus pneumoniae, Mycoplasma pneumoniae and Klebsiella pneumoniae are the three leading bacterial pathogens (29.9%, 18.6% and 15.8%). Negative interactions between viruses and positive interactions between viral and bacterial pathogens are common. A Join-Point analysis reveals the age-specific positivity rate and how this varied for individual pathogens. These data indicate that differential priorities for diagnosis, prevention and control should be highlighted in terms of acute respiratory tract infection patients' demography, geographic locations and season of illness in China.


Subject(s)
Bacteria/isolation & purification , Bacterial Infections/microbiology , Respiratory Tract Infections/microbiology , Respiratory Tract Infections/virology , Virus Diseases/virology , Viruses/isolation & purification , Adolescent , Adult , Bacteria/classification , Bacteria/genetics , Bacterial Infections/epidemiology , Child , Child, Preschool , China/epidemiology , Female , Humans , Infant , Male , Prospective Studies , Respiratory Tract Infections/epidemiology , Seasons , Virus Diseases/epidemiology , Viruses/classification , Viruses/genetics , Young Adult
16.
Signal Transduct Target Ther ; 6(1): 343, 2021 09 16.
Article in English | MEDLINE | ID: covidwho-1415924

ABSTRACT

SARS-CoV-2 recognizes, via its spike receptor-binding domain (S-RBD), human angiotensin-converting enzyme 2 (ACE2) to initiate infection. Ecto-domain protein of ACE2 can therefore function as a decoy. Here we show that mutations of S19W, T27W, and N330Y in ACE2 could individually enhance SARS-CoV-2 S-RBD binding. Y330 could be synergistically combined with either W19 or W27, whereas W19 and W27 are mutually unbeneficial. The structures of SARS-CoV-2 S-RBD bound to the ACE2 mutants reveal that the enhanced binding is mainly contributed by the van der Waals interactions mediated by the aromatic side-chains from W19, W27, and Y330. While Y330 and W19/W27 are distantly located and devoid of any steric interference, W19 and W27 are shown to orient their side-chains toward each other and to cause steric conflicts, explaining their incompatibility. Finally, using pseudotyped SARS-CoV-2 viruses, we demonstrate that these residue substitutions are associated with dramatically improved entry-inhibition efficacy toward both wild-type and antibody-resistant viruses. Taken together, our biochemical and structural data have delineated the basis for the elevated S-RBD binding associated with S19W, T27W, and N330Y mutations in ACE2, paving the way for potential application of these mutants in clinical treatment of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , COVID-19 , Molecular Dynamics Simulation , Mutation, Missense , SARS-CoV-2/chemistry , Amino Acid Substitution , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Viral/chemistry , Antibodies, Viral/metabolism , Humans , SARS-CoV-2/genetics , SARS-CoV-2/metabolism
17.
Lancet Reg Health West Pac ; 16: 100268, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1415636

ABSTRACT

BACKGROUND: Non pharmaceutical interventions (NPI) including hand washing directives were implemented in China and worldwide to combat the COVID-19 pandemic, which are likely to have had impacted a broad spectrum of enteric pathogen infections. METHODS: Etiologically diagnostic data from 45 937 and 67 395 patients with acute diarrhea between 2012 and 2020, who were tested for seven viral pathogens and 13 bacteria respectively, were analyzed to assess the changes of enteric pathogen infections in China during the first COVID-19 pandemic year compared to pre-pandemic years. FINDINGS: Test positive rates of all enteric viruses decreased during 2020, compared to the average levels during 2012-2019, with a relative decrease of 71•75% for adenovirus, 58•76% for norovirus, 53•50% for rotavirus A, and 72•07% for the combination of other four uncommon viruses. In general, a larger reduction of positive rate in viruses was seen among adults than pediatric patients. A rebound of rotavirus A was seen after September 2020 in North China rather than South China. Test positive rates of bacteria decreased during 2020, compared to the average levels during 2012-2019, excepting for nontyphoidal Salmonella and Campylobacter coli with 66•53% and 90•48% increase respectively. This increase was larger for pediatric patients than for adult patients. INTERPRETATION: The activity of enteric pathogens changed profoundly alongside the NPIs implemented during the COVID-19 pandemic in China. Greater reductions of the test positive rates were found for almost all enteric viruses than for bacteria among acute diarrhea patients, with further large differences by age and geography. Lifting of NPIs will lead to resurgence of enteric pathogen infections, particularly in children whose immunity may not have been developed and/or waned. FUNDING: China Mega-Project on Infectious Disease Prevention; National Natural Science Funds.

18.
Nucleic Acids Res ; 49(9): 5382-5392, 2021 05 21.
Article in English | MEDLINE | ID: covidwho-1387965

ABSTRACT

The emergence of SARS-CoV-2 infection has posed unprecedented threat to global public health. The virus-encoded non-structural protein 14 (nsp14) is a bi-functional enzyme consisting of an exoribonuclease (ExoN) domain and a methyltransferase (MTase) domain and plays a pivotal role in viral replication. Here, we report the structure of SARS-CoV-2 nsp14-ExoN domain bound to its co-factor nsp10 and show that, compared to the SARS-CoV nsp10/nsp14-full-length complex, SARS-CoV-2 nsp14-ExoN retains an integral exoribonuclease fold and preserves an active configuration in the catalytic center. Analysis of the nsp10/nsp14-ExoN interface reveals a footprint in nsp10 extensively overlapping with that observed in the nsp10/nsp16 structure. A marked difference in the co-factor when engaging nsp14 and nsp16 lies in helix-α1', which is further experimentally ascertained to be involved in nsp14-binding but not in nsp16-engagement. Finally, we also show that nsp10/nsp14-ExoN is enzymatically active despite the absence of nsp14-MTase domain. These data demonstrate that SARS-CoV-2 nsp10/nsp14-ExoN functions as an exoribonuclease with both structural and functional integrity.


Subject(s)
Biocatalysis , Exoribonucleases/chemistry , Exoribonucleases/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/enzymology , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Viral Regulatory and Accessory Proteins/chemistry , Viral Regulatory and Accessory Proteins/metabolism , Binding Sites , Crystallography, X-Ray , Exoribonucleases/genetics , Guanine , Methyltransferases/chemistry , Methyltransferases/deficiency , Methyltransferases/genetics , Methyltransferases/metabolism , Models, Molecular , Protein Domains/genetics , SARS-CoV-2/genetics , Viral Nonstructural Proteins/genetics , Viral Regulatory and Accessory Proteins/genetics
19.
J Pers Med ; 11(8)2021 Jul 28.
Article in English | MEDLINE | ID: covidwho-1376869

ABSTRACT

(1) Background: Sepsis is a life-threatening condition, and most patients with sepsis first present to the emergency department (ED) where early identification of sepsis is challenging due to the unavailability of an effective diagnostic model. (2) Methods: In this retrospective study, patients aged ≥20 years who presented to the ED of an academic hospital with systemic inflammatory response syndrome (SIRS) were included. The SIRS, sequential organ failure assessment (SOFA), and quick SOFA (qSOFA) scores were obtained for all patients. Routine complete blood cell testing in conjugation with the examination of new inflammatory biomarkers, namely monocyte distribution width (MDW), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), was performed at the ED. Propensity score matching was performed between patients with and without sepsis. Logistic regression was used for constructing models for early sepsis prediction. (3) Results: We included 296 patients with sepsis and 1184 without sepsis. A SIRS score of >2, a SOFA score of >2, and a qSOFA score of >1 showed low sensitivity, moderate specificity, and limited diagnostic accuracy for predicting early sepsis infection (c-statistics of 0.660, 0.576, and 0.536, respectively). MDW > 20, PLR > 9, and PLR > 210 showed higher sensitivity and moderate specificity. When we combined these biomarkers and scoring systems, we observed a significant improvement in diagnostic performance (c-statistics of 0.796 for a SIRS score of >2, 0.761 for a SOFA score of >2, and 0.757 for a qSOFA score of >1); (4) Conclusions: The new biomarkers MDW, NLR, and PLR can be used for the early detection of sepsis in the current sepsis scoring systems.

20.
Journal of Loss Prevention in the Process Industries ; : 104583, 2021.
Article in English | ScienceDirect | ID: covidwho-1284226

ABSTRACT

The COVID-19 epidemic has caused a lack of data on highway transportation accidents involving dangerous goods in China in the first quarter of 2020, and this lack of data has seriously affected research on highway transportation accidents involving dangerous goods. This study strives to compensate for this lack to a certain extent and reduce the impact of missing data on research of dangerous goods transportation accidents. Data pertaining to 2340 dangerous goods accidents in the process of highway transportation in China from 2013 to 2019 are obtained with webpage crawling software. In this paper, the number of monthly highway transportation accidents involving dangerous goods from 2013 to 2019 is determined, and the time series of transportation accidents and an autoregressive moving average (ARMA) prediction model are established. The prediction accuracy of the model is evaluated based on the actual number of dangerous goods highway transportation accidents in China from 2017 to 2019. The results indicate that the mean absolute percentage error (MAPE) between the actual and predicted values of dangerous goods highway transportation accidents from 2017 to 2019 is 0.147, 0.315 and 0.29. Therefore, the model meets the prediction accuracy requirements. Then, the prediction model is applied to predict the number of dangerous goods transportation accidents in the first quarter of 2020 in China. Twenty-two accidents are predicted in January, 23 accidents in February and 27 accidents in March. The results provide a reference for the study of dangerous goods transportation accidents and the formulation of accident prevention and emergency measures.

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