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1.
Procedia Comput Sci ; 199: 354-360, 2022.
Article in English | MEDLINE | ID: covidwho-1796212

ABSTRACT

Under the influence of COVID-19, the global economic and social development is facing great challenges. With the increase of government financial pressure and the decrease of debt paying ability, the problem of debt risk of local governments in China is attracting wide attention. In order to measure the level of China's local government debt risk under the influence of COVID-19, this paper takes China's Sichuan Province as an example, collects the core indicators data of measuring local government debt risk in 2017-2020 years, and uses AHP-TOPSIS method to make a comprehensive analysis of the local government debt risk situation in different periods before and after COVID-19. It is found that the local government debt risk in Sichuan Province is generally controllable. However, influenced by COVID-19, in 2020, the overall level of local government debt risk in Sichuan province expanded by 22.1% compared with 2019, this is mainly due to the further expansion of debt scale and slower economic growth. This paper suggests that the Chinese government should speed up the construction of comprehensive early warning and supervision system of local government debt risk, and prevent and resolve the debt risk of local government in advance.

2.
PLoS One ; 17(3): e0266036, 2022.
Article in English | MEDLINE | ID: covidwho-1770755

ABSTRACT

Under the condition of resource tolerance, engineering construction projects face the problem of labor force balance in the working face. Notably, a deviation occurs between the distribution and certain demand of the labor force in the limited working face, which affects the realization of an extremely short construction period. To address this problem, we first introduced the stochastic coefficient of labor force equilibrium to measure the degree of labor balance. Second, a labor force equilibrium model with the realization goal of an extremely short construction period was established. Then, the standard particle swarm optimization (PSO) algorithm was improved from two perspectives to solve the proposed model. The update equation was rounded to solve practical project problems, and a dynamic variable inertia weight was adopted to ensure the PSO algorithm accuracy and convergence speed. Finally, through case analysis, we determined the extremely short construction period and best labor force distribution scheme. Moreover, the case results revealed that the established model is simple, operable and practical and that the proposed algorithm achieves a high search accuracy and efficiency in the model solution process. Overall, under the condition of resource tolerance, this study provides scientific and effective references for managers to realize an extremely short construction period.


Subject(s)
Algorithms , Labor, Obstetric , Data Collection , Drug Tolerance , Female , Humans , Immune Tolerance , Pregnancy
3.
PLoS One ; 17(3): e0265087, 2022.
Article in English | MEDLINE | ID: covidwho-1742020

ABSTRACT

Under the condition of sufficient resources, there are many factors affecting the realization of extremely short construction period of engineering construction projects. Based on literature review and questionnaire survey, this paper firstly selected 17 influencing factors from the five dimensions of design, management, technology, policy and environment. And the factor analytic hierarchy process model was established based on Grey-DEMATEL-ISM. The model introduced the improved grey system theory and combined decision-making trial and evaluation laboratory (DEMATEL) with interpretative structural modeling method (ISM). In addition, the model can not only identify the critical factors in the system, but also present the internal logical relationship between the influencing factors through the multi-level hierarchical structure diagram. Finally, through the analysis of the influencing factors of extremely short construction period under the sufficient resources, it defined that the key factor is the natural environment and second is the structure type. The methodology implemented in this paper helps decision makers and managers of construction projects to understand the interrelationship and degree of influence among factors affecting the duration under the condition of sufficient resources, to effectively grasp key factors, and to effectively achieve project success.


Subject(s)
Health Services , Technology , Models, Structural
4.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-325326

ABSTRACT

Corona viruses hijack human enzymes to assembly sugar coat on Spike glycoproteins. The mechanism that human antibodies may uncover the antigenic viral peptide epitopes hidden by sugar coat are unknown. In this study, we analyzed recombinant SARS-CoV-2 Spike protein secreted from BTI-Tn-5B1-4 cells, by trypsin and chymotrypsin digestion followed by mass spectrometry analysis. We acquired MS/MS spectrums for glycopeptides of all 22 predicted N-glycosylated sites. We further analyzed the surface accessibility of Spike proteins according to Cryo-EM and homolog-modeled structures, and available antibodies that bind to SARS-CoV-1. The results showed that all 22 N-glycosylated sites of SARS-CoV-2 are modified by high-mannose type of N-glycans. MS/MS fragmentation clearly established the glycopeptide identities. Electron densities of glycans cover most of the Spike receptor binding domain of SARS-CoV-2, except YQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQ, similar to a region FSPDGKPCTPPALNCYWPLNDYGFYTTTGIGYQ in SARS-CoV-1. Other surface-exposed domains included those located on Central Helix, between amino acids 967 and 1016 of SARS-CoV-1, and 985 to 1034 of SARS-CoV-2 Spike protein. As the majority of antibody paratopes bind to peptide portion with or without sugar modification, we propose a snake-catcher model that a minimal length of peptide is first clamped by a paratope, and the binding is either strengthened by sugars close to peptide, or not interfered by sugar modification.

5.
Signal Transduct Target Ther ; 6(1): 378, 2021 11 03.
Article in English | MEDLINE | ID: covidwho-1500450

ABSTRACT

The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years. The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines and therapeutic antibodies that confer broad protection against SARS-CoV-2 variants. Here we show that the bivalency of an affinity maturated fully human single-domain antibody (n3113.1-Fc) exhibits exquisite neutralizing potency against SARS-CoV-2 pseudovirus, and confers effective prophylactic and therapeutic protection against authentic SARS-CoV-2 in the host cell receptor angiotensin-converting enzyme 2 (ACE2) humanized mice. The crystal structure of n3113 in complex with the receptor-binding domain (RBD) of SARS-CoV-2, combined with the cryo-EM structures of n3113 and spike ecto-domain, reveals that n3113 binds to the side surface of up-state RBD with no competition with ACE2. The binding of n3113 to this novel epitope stabilizes spike in up-state conformations but inhibits SARS-CoV-2 S mediated membrane fusion, expanding our recognition of neutralization by antibodies against SARS-CoV-2. Binding assay and pseudovirus neutralization assay show no evasion of recently prevalent SARS-CoV-2 lineages, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) for n3113.1-Fc with Y58L mutation, demonstrating the potential of n3113.1-Fc (Y58L) as a promising candidate for clinical development to treat COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Antibodies, Neutralizing/chemistry , Antibodies, Viral/chemistry , COVID-19 , SARS-CoV-2/chemistry , Single-Chain Antibodies/chemistry , Angiotensin-Converting Enzyme 2/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/immunology , Antibodies, Viral/therapeutic use , Crystallography, X-Ray , Epitopes/chemistry , Epitopes/immunology , Humans , Mice , SARS-CoV-2/immunology , Single-Chain Antibodies/immunology , Single-Chain Antibodies/therapeutic use
8.
Nat Commun ; 12(1): 4635, 2021 07 30.
Article in English | MEDLINE | ID: covidwho-1333940

ABSTRACT

SARS-CoV-2, the causative agent of COVID-191, features a receptor-binding domain (RBD) for binding to the host cell ACE2 protein1-6. Neutralizing antibodies that block RBD-ACE2 interaction are candidates for the development of targeted therapeutics7-17. Llama-derived single-domain antibodies (nanobodies, ~15 kDa) offer advantages in bioavailability, amenability, and production and storage owing to their small sizes and high stability. Here, we report the rapid selection of 99 synthetic nanobodies (sybodies) against RBD by in vitro selection using three libraries. The best sybody, MR3 binds to RBD with high affinity (KD = 1.0 nM) and displays high neutralization activity against SARS-CoV-2 pseudoviruses (IC50 = 0.42 µg mL-1). Structural, biochemical, and biological characterization suggests a common neutralizing mechanism, in which the RBD-ACE2 interaction is competitively inhibited by sybodies. Various forms of sybodies with improved potency have been generated by structure-based design, biparatopic construction, and divalent engineering. Two divalent forms of MR3 protect hamsters from clinical signs after live virus challenge and a single dose of the Fc-fusion construct of MR3 reduces viral RNA load by 6 Log10. Our results pave the way for the development of therapeutic nanobodies against COVID-19 and present a strategy for rapid development of targeted medical interventions during an outbreak.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Single-Domain Antibodies/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/pharmacology , Antibodies, Neutralizing/ultrastructure , Antibodies, Viral/pharmacology , Antibodies, Viral/ultrastructure , Binding Sites/immunology , COVID-19/prevention & control , COVID-19/virology , Cryoelectron Microscopy , Crystallography, X-Ray , Female , Humans , Mass Spectrometry/methods , Mesocricetus , Mice, Inbred C57BL , Neutralization Tests , Protein Binding/drug effects , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Single-Domain Antibodies/chemistry , Single-Domain Antibodies/metabolism
9.
Protein Cell ; 12(11): 877-888, 2021 11.
Article in English | MEDLINE | ID: covidwho-1188202

ABSTRACT

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (Mpro), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 µmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC50 value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three "hot" spots on PLpro, including the substrate-binding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.


Subject(s)
Coronavirus Papain-Like Proteases/chemistry , High-Throughput Screening Assays/methods , Protease Inhibitors/chemistry , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Coronavirus Papain-Like Proteases/genetics , Coronavirus Papain-Like Proteases/metabolism , Crystallography, X-Ray , Drug Evaluation, Preclinical , Drug Repositioning , Humans , Imidazoles/chemistry , Imidazoles/metabolism , Imidazoles/therapeutic use , Inhibitory Concentration 50 , Molecular Dynamics Simulation , Mutagenesis, Site-Directed , Naphthoquinones/chemistry , Naphthoquinones/metabolism , Naphthoquinones/therapeutic use , Protease Inhibitors/metabolism , Protease Inhibitors/therapeutic use , Protein Structure, Tertiary , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , SARS-CoV-2/isolation & purification
10.
Med (N Y) ; 2(1): 99-112.e7, 2021 01 15.
Article in English | MEDLINE | ID: covidwho-1036371

ABSTRACT

BACKGROUND: The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a global public health concern due to relatively easy person-to-person transmission and the current lack of effective antiviral therapy. However, the exact molecular mechanisms of SARS-CoV-2 pathogenesis remain largely unknown. METHODS: Genome-wide screening was used to establish intraviral and viral-host interactomes. Quantitative proteomics was used to investigate the peripheral blood mononuclear cell (PBMC) proteome signature in COVID-19. FINDINGS: We elucidated 286 host proteins targeted by SARS-CoV-2 and >350 host proteins that are significantly perturbed in COVID-19-derived PBMCs. This signature in severe COVID-19 PBMCs reveals a significant upregulation of cellular proteins related to neutrophil activation and blood coagulation, as well as a downregulation of proteins mediating T cell receptor signaling. From the interactome, we further identified that non-structural protein 10 interacts with NF-κB-repressing factor (NKRF) to facilitate interleukin-8 (IL-8) induction, which potentially contributes to IL-8-mediated chemotaxis of neutrophils and the overexuberant host inflammatory response observed in COVID-19 patients. CONCLUSIONS: Our study not only presents a systematic examination of SARS-CoV-2-induced perturbation of host targets and cellular networks but it also reveals insights into the mechanisms by which SARS-CoV-2 triggers cytokine storms, representing a powerful resource in the pursuit of therapeutic interventions. FUNDING: National Key Research and Development Project of China, National Natural Science Foundation of China, National Science and Technology Major Project, Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, Shanghai Science and Technology Commission, Shanghai Municipal Health Commission, Shanghai Municipal Key Clinical Specialty, Innovative Research Team of High-level Local Universities in Shanghai, Interdisciplinary Program of Shanghai Jiao Tong University, SII Challenge Fund for COVID-19 Research, Chinese Academy of Sciences (CAS) Large Research Infrastructure of Maintenance and Remolding Project, and Chinese Academy of Sciences Key Technology Talent Program.


Subject(s)
COVID-19 , SARS-CoV-2 , China/epidemiology , Humans , Interleukin-8 , Leukocytes, Mononuclear , Proteomics , Virulence Factors
11.
Sci Adv ; 6(33): eabb7238, 2020 08.
Article in English | MEDLINE | ID: covidwho-733188

ABSTRACT

Cigarette smoking, the leading cause of chronic obstructive pulmonary disease (COPD), has been implicated as a risk factor for severe disease in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we show that mice with lung epithelial cell-specific loss of function of Miz1, which we identified as a negative regulator of nuclear factor κB (NF-κB) signaling, spontaneously develop progressive age-related changes resembling COPD. Furthermore, loss of Miz1 up-regulates the expression of Ace2, the receptor for SARS-CoV-2. Concomitant partial loss of NF-κB/RelA prevented the development of COPD-like phenotype in Miz1-deficient mice. Miz1 protein levels are reduced in the lungs from patients with COPD, and in the lungs of mice exposed to chronic cigarette smoke. Our data suggest that Miz1 down-regulation-induced sustained activation of NF-κB-dependent inflammation in the lung epithelium is sufficient to induce progressive lung and airway destruction that recapitulates features of COPD, with implications for COVID-19.


Subject(s)
Epithelial Cells/metabolism , Kruppel-Like Transcription Factors/metabolism , Lung/metabolism , Peptidyl-Dipeptidase A/metabolism , Phenotype , Protein Inhibitors of Activated STAT/genetics , Pulmonary Disease, Chronic Obstructive/genetics , Ubiquitin-Protein Ligases/genetics , Up-Regulation/genetics , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus , COVID-19 , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Gene Knockout Techniques , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Protein Inhibitors of Activated STAT/metabolism , Pulmonary Disease, Chronic Obstructive/etiology , Pulmonary Disease, Chronic Obstructive/metabolism , SARS-CoV-2 , Signal Transduction/genetics , Smoking/adverse effects , Transcription Factor RelA/metabolism , Ubiquitin-Protein Ligases/metabolism
12.
Sci Total Environ ; 749: 141419, 2020 Dec 20.
Article in English | MEDLINE | ID: covidwho-693328

ABSTRACT

China has been performing nationwide social lockdown by releasing the Level 1 response to major public health emergencies (RMPHE) to struggle against the COVID-19 (SARS-CoV-2) outbreak since late January 2020. During the Level 1 RMPHE, social production and public transport were maintained at minimal levels, and residents stayed in and worked from home. The universal impact of anthropogenic activities on air pollution can be evaluated by comparing it with air quality under such extreme conditions. We investigated the concentration of both gaseous and particulate pollutants and aerosol light absorption at different levels of (RMPHE) in an urban area of southwestern China. During the lockdown, PM2.5, PM10, SO2, NOx, and BC decreased by 30-50%, compared to the pre-Level 1 RMPHE period. Meanwhile, the decrease of NOx caused the rise of O3 by up to 2.3 times due to the volatile organic compounds (VOCs) limitation. The aerosol light absorption coefficient at multiple wavelengths decreased by 50%, and AAE decreased by 20% during the Level 1 RMPHE. BrC played essential roles in light absorption after the RMPHE was announced, accounting for 54.0% of the aerosol absorption coefficient at 370 nm. Moreover, the lockdown down-weighted the fraction of fossil fuel in BC concentrations to 0.43 (minima). This study characterizes air pollution at the most basic level and can provide policymakers with references for the "baseline."


Subject(s)
Air Pollutants , Air Pollution , COVID-19 , Aerosols , Air Pollutants/analysis , Air Pollution/analysis , China , Communicable Disease Control , Environmental Monitoring , Humans , Pandemics , Particulate Matter/analysis , SARS-CoV-2
13.
Nature ; 582(7811): 289-293, 2020 06.
Article in English | MEDLINE | ID: covidwho-608904

ABSTRACT

A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)1-4. Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (Mpro) of SARS-CoV-2: Mpro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-25,6. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of Mpro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds-including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds-as inhibitors of Mpro. Six of these compounds inhibited Mpro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 µM. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.


Subject(s)
Betacoronavirus/chemistry , Cysteine Endopeptidases/chemistry , Drug Discovery/methods , Models, Molecular , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , COVID-19 , Cells, Cultured/virology , Coronavirus 3C Proteases , Coronavirus Infections/enzymology , Coronavirus Infections/virology , Drug Design , Drug Evaluation, Preclinical , Humans , Pandemics , Pneumonia, Viral/enzymology , Pneumonia, Viral/virology , Protease Inhibitors/pharmacology , Protein Structure, Tertiary , SARS-CoV-2
14.
Glycobiology ; 31(1): 69-80, 2021 01 09.
Article in English | MEDLINE | ID: covidwho-592209

ABSTRACT

Coronaviruses hijack human enzymes to assemble the sugar coat on their spike glycoproteins. The mechanisms by which human antibodies may recognize the antigenic viral peptide epitopes hidden by the sugar coat are unknown. Glycosylation by insect cells differs from the native form produced in human cells, but insect cell-derived influenza vaccines have been approved by the US Food and Drug Administration. In this study, we analyzed recombinant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein secreted from BTI-Tn-5B1-4 insect cells, by trypsin and chymotrypsin digestion followed by mass spectrometry analysis. We acquired tandem mass spectrometry (MS/MS) spectrums for glycopeptides of all 22 predicted N-glycosylated sites. We further analyzed the surface accessibility of spike proteins according to cryogenic electron microscopy and homolog-modeled structures and available antibodies that bind to SARS-CoV-1. All 22 N-glycosylated sites of SARS-CoV-2 are modified by high-mannose N-glycans. MS/MS fragmentation clearly established the glycopeptide identities. Electron densities of glycans cover most of the spike receptor-binding domain of SARS-CoV-2, except YQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQ, similar to a region FSPDGKPCTPPALNCYWPLNDYGFYTTTGIGYQ in SARS-CoV-1. Other surface-exposed domains include those located on central helix, connecting region, heptad repeats and N-terminal domain. Because the majority of antibody paratopes bind to the peptide portion with or without sugar modification, we propose a snake-catching model for predicted paratopes: a minimal length of peptide is first clamped by a paratope and sugar modifications close to the peptide either strengthen or do not hinder the binding.


Subject(s)
Antibodies, Viral , COVID-19 Vaccines , COVID-19/therapy , Glycopeptides , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Amino Acid Motifs , Antibodies, Viral/immunology , Antibodies, Viral/therapeutic use , COVID-19/immunology , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , Glycopeptides/chemistry , Glycopeptides/immunology , Humans , Immunization, Passive , SARS-CoV-2/chemistry , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
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