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1.
Genet Res (Camb) ; 2021: 9952620, 2021.
Article in English | MEDLINE | ID: covidwho-1775004

ABSTRACT

Purpose: Herbal medicine is one of crucial symbols of Chinese national medicine. Investigation on molecular responses of different herbal strategies against viral myocarditis is immeasurably conducive to targeting drug development in the current international absence of miracle treatment. Methods: Literature retrieval platforms were applied in the collection of existing empirical evidences for viral myocarditis-related single-herbal strategies. SwissTargetPrediction, Metascape, and Discovery Studio coordinating with multidatabases investigated underlying target genes, interactive proteins, and docking molecules in turn. Results: Six single-herbal medicines consisting of Huangqi (Hedysarum Multijugum Maxim), Yuganzi (Phyllanthi Fructus), Kushen (Sophorae Flavescentis Radix), Jianghuang (Curcumaelongae Rhizoma), Chaihu (Radix Bupleuri), and Jixueteng (Spatholobus Suberectus Dunn) meet the requirement. There were 11 overlapped and 73 unique natural components detected in these herbs. SLC6A2, SLC6A4, NOS2, PPARA, PPARG, ACHE, CYP2C19, CYP51A1, and CHRM2 were equally targeted by six herbs and identified as viral myocarditis-associated symbols. MCODE algorithm exposed the hub role of SRC and EGFR in strategies without Jianghuang. Subsequently, we learned intermolecular interactions of herbal components and their targeting heart-tissue-specific CHRM2, FABP3, TNNC1, TNNI3, TNNT2, and SCN5A and cardiac-myocytes-specific IL6, MMP1, and PLAT coupled with viral myocarditis. Ten interactive characteristics such as π-alkyl and van der Waals were modeled in which ARG111, LYS253, ILE114, and VAL11 on cardiac troponin (TNNC1-TNNI3-TNNT2) and ARG208, ASN106, and ALA258 on MMP1 fulfilled potential communicating anchor with ellagic acid, 5α, 9α-dihydroxymatrine, and leachianone g via hydrogen bond and hydrophobic interaction, respectively. Conclusions: The comprehensive outcomes uncover differences and linkages between six herbs against viral myocarditis through component and target analysis, fostering development of drugs.


Subject(s)
Cardiovascular Infections , Drugs, Chinese Herbal , Myocarditis , Plants, Medicinal , Virus Diseases , Drugs, Chinese Herbal/therapeutic use , Humans , Myocarditis/drug therapy , Phytotherapy , Serotonin Plasma Membrane Transport Proteins , Virus Diseases/drug therapy
2.
Emerg Microbes Infect ; : 1-33, 2022 Apr 04.
Article in English | MEDLINE | ID: covidwho-1774287

ABSTRACT

It is important to know the safety and efficacy of vaccination in immunocompromised people living with HIV (PLWH), but currently, there is limited data on the inactivated SARS-CoV-2 vaccines' safety and immune responses in PLWH. In this prospective observational study, 139 PLWH and 120 healthy controls were enrolled and monitored for 21-105 days after a two-dose vaccination. The safety, anti-receptor binding domain IgG (anti-RBD-IgG) and anti-spike-IgG responses, and RBD-specific memory B cell (MBC) responses were evaluated. The overall adverse events within seven days were reported in 12.9% (18/139) of PLWH and 13.3% (16/120) of healthy controls. No serious adverse events occurred in both groups. Overall, the seroprevalence of anti-RBD-IgG in PLWH was significantly decreased (87.1% vs. 99.2%; p < 0.001). The geometric mean end-point titer (GMT) of anti-RBD-IgG in PLWH was also reduced, especially in patients with CD4 counts <200 cells/µL, regardless of age, gender, or HIV viral load. GMTs of anti-RBD-IgG in both PLWH and healthy controls declined gradually over time. Similar results were also observed in the anti-spike-IgG response. The frequency of RBD-specific MBCs in PLWH decreased (p < 0.05), and then remained stable over time. Lastly, through multivariate analysis, we found the factors that predicted a less robust response to inactivated vaccines in PLWH were a low CD4 count and long time interval after vaccination. In conclusion, inactivated vaccines are well-tolerated in PLWH but with low immunogenicity. Therefore, SARS-CoV-2 vaccines and booster doses should be given priority in PLWH, especially in patients with low CD4 counts.Trial registration: ClinicalTrials.gov identifier: NCT05043129..

4.
Emerg Microbes Infect ; 11(1): 749-752, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1699338

ABSTRACT

The immunity potency upon natural infection or vaccination is the main concern for the vaccine strategy of severe acute respiratory syndrome coronavirus 2 (SARS COV-2 variant), especially the recently reported Omicron variant (B.1.1.529). In this study, 200 recipients immunized with three doses of a COVID-19-inactivated vaccine were enrolled, whose serum samples were collected within 2 months after the third immunization. The neutralizing activity of sera against the pseudotyped Omicron variant, prototype, and Delta variant was determined. Our results demonstrated that the positive neutralization activity was 95.5% for the Omicron variant, 99.5% for the prototype, and 98.5% for the Delta variant. The geometric mean titers (GMT) for the Omicron variant was 49 and maintained sustained immune levels for 2 months, which decreased by 4.9-fold and 3.0-fold compared with the prototype (GMT, 239) and Delta variant (GMT, 148), respectively. In summary, our study demonstrated that three doses of a COVID-19-inactivated vaccine effectively yielded potent cross-neutralizing activity against the Omicron variant at 2 months after the third vaccination.


Subject(s)
COVID-19 Vaccines , COVID-19 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Humans , SARS-CoV-2/genetics
5.
J Relig Health ; 61(2): 1671-1683, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1669904

ABSTRACT

The present studies investigated how particular religious beliefs shape compliance with preventive measures in adherents of Gelug and Nyingma schools of Tibetan Buddhism. In Study 1, Gelug and Nyingma monks were asked to report their compliance with various infection prevention measures surrounding COVID-19. Results showed that the former group showed higher compliance with public health guidelines than the latter. Extending beyond self-report measures, Study 2 added a behavioral outcome measure and observed the same effect. Together, our results provide the first empirical evidence that various Tibetan Buddhist traditions are related to different degrees of compliance with precautionary measures against COVID-19.


Subject(s)
COVID-19 , Monks , Buddhism , COVID-19/prevention & control , Humans , Public Health , Tibet
6.
Curr Psychol ; : 1-8, 2022 Feb 04.
Article in English | MEDLINE | ID: covidwho-1664511

ABSTRACT

Vaccination plays a crucial role in containing the spread of the COVID-19 pandemic. However, a significant fraction of the global population is reluctant to take a coronavirus vaccine. A burgeoning literature has considered mainly adaptive personality traits as antecedents of vaccine hesitancy (i.e., Big Five and HEXACO), while maladaptive personality traits (i.e., "Dark Tetrad" of personality) are often a comparatively neglected area. In this research, we examined the relationship between everyday sadism and intention to get vaccinated against COVID-19. We theorized that driven by antisocial tendencies and social indifference, individuals with higher sadism may be less willing to obtain a vaccine. Employing a bug-killing paradigm to capture everyday sadism, we tested this prediction in a Chinese sample of non-student adults (N = 188). Support for this proposition was found in the lab task, which demonstrates that sadism was associated with more vaccine refusal spanning the self-report and behavioral domains. In addition, we showed that the sadistic behavioral choices can be predicted with self-report measure of sadistic personality. These findings highlight the important role of maladaptive personality traits in predicting vaccination attitudes and intentions.

7.
BMC Med ; 20(1): 13, 2022 01 18.
Article in English | MEDLINE | ID: covidwho-1639199

ABSTRACT

BACKGROUND: Recaticimab (SHR-1209, a humanized monoclonal antibody against PCSK9) showed robust LDL-C reduction in healthy volunteers. This study aimed to further assess the efficacy and safety of recaticimab in patients with hypercholesterolemia. METHODS: In this randomized, double-blind, placebo-controlled phase 1b/2 trial, patients receiving stable dose of atorvastatin with an LDL-C level of 2.6 mmol/L or higher were randomized in a ratio of 5:1 to subcutaneous injections of recaticimab or placebo at different doses and schedules. Patients were recruited in the order of 75 mg every 4 weeks (75Q4W), 150Q8W, 300Q12W, 150Q4W, 300Q8W, and 450Q12W. The primary endpoint was percentage change in LDL-C from the baseline to end of treatment (i.e., at week 16 for Q4W and Q8W schedule and at week 24 for Q12W schedule). RESULTS: A total of 91 patients were enrolled and received recaticimab and 19 received placebo. The dose of background atorvastatin in all 110 patients was 10 or 20 mg/day. The main baseline LDL-C ranged from 3.360 to 3.759 mmol/L. The least-squares mean percentage reductions in LDL-C from baseline to end of treatment relative to placebo for recaticimab groups at different doses and schedules ranged from -48.37 to -59.51%. No serious treatment-emergent adverse events (TEAEs) occurred. The most common TEAEs included upper respiratory tract infection, increased alanine aminotransferase, increased blood glucose, and increased gamma-glutamyltransferase. CONCLUSION: Recaticimab as add-on to moderate-intensity statin therapy significantly and substantially reduced the LDL-C level with an infrequent administration schedule (even given once every 12 weeks), compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov , number NCT03944109.


Subject(s)
Hypercholesterolemia , Antibodies, Monoclonal, Humanized/adverse effects , Double-Blind Method , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Hypercholesterolemia/drug therapy , Treatment Outcome
8.
Pers Individ Dif ; 188: 111447, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1562006

ABSTRACT

What influences people's vaccine attitudes and intentions in the combat against the COVID-19 pandemic? Extending beyond health factors, the present research examines whether non-health-specific factors-such as one's self-control ability-influence individual attitudes toward vaccination. Drawing on the social psychology literature, we propose that self-control, which is often associated with adherence to social norms and with engagement in socially desirable behaviors, can lead to more favorable attitudes toward vaccines. Study 1 provided correlational evidence for our theoretical perspective that students scoring high on trait self-control expressed less vaccine hesitancy than students scoring low on self-control. Employing a more representative population, Study 2 examined the relationship with behaviors. It was found that non-student adults with higher self-control strength levels were more likely to accept vaccine appointments opportunities than those with lower self-control strength levels. Using an experimental design, Study 3 found that participants exerting a high level of effort for attentional self-control in the incongruent Stroop task condition showed lower COVID-19 vaccine acceptance than participants in the congruent condition. In sum, our research provides the first experimental evidence that high self-control can have a reliable impact on individual perceptions of vaccination.

9.
Psychol Rep ; : 332941211051985, 2021 Dec 07.
Article in English | MEDLINE | ID: covidwho-1555686

ABSTRACT

Following preventive measures is crucial for slowing the rate of COVID-19 spread. To date, most research has focused on the role of individual differences and personality in compliance with preventive measures to COVID-19. Building on findings that interpersonal touch instills a feeling of security, we propose that interpersonal touching behavior, an underexplored factor tied to social interaction, leads to more breaches of coronavirus restrictions by inducing security feelings. In a lab experiment (Experiment 1) and a field study (Experiment 2), we demonstrated that a female experimenter's fleeting and comforting pat on the shoulder made people less willing to abide by preventive measures in their self-report and actual behavior. Further, we excluded a potential alternative explanation that touch intervention by the experimenter presents the defiance of COVID-19 rules because the effect cannot be observed when the touch consists of a handshake rather than a comforting pat on the shoulder (Experiment 3). Finally, consistent with our theoretical perspective, the results revealed that sense of security mediated the effect of interpersonal touch on violation of instructions to follow coronavirus precautions. Taken together, interpersonal touch not only enhances trust and security, but also can push people away from health guidelines.

10.
Journal of Medical Imaging and Health Informatics ; 11(11):2722-2732, 2021.
Article in English | ProQuest Central | ID: covidwho-1495787

ABSTRACT

The outbreak of 2019 novel coronavirus (COVID-19) has caused more than 176 million confirmed cases by June 14, 2021, and this number will continue to grow. Automatic and accurate COVID-19 detection/evaluation from the computed tomography (CT) scans is of great significance for COVID-19 diagnosis and treatment. Due to individual variations of patients and the influx of a large number of patients, the current clinical practices remain subject to shortcomings of potential high-risk and time-consumption issues from radiologists. In this paper, we propose a computer aided detection system to relieve the clinical physicians from tediously reading the CT images of COVID-19 patients. Particularly, a COVID-19 detection network (COVIDNet) is proposed using deep convolutional neural networks (DCNNs) for patient-level COVID-19 detection to distinguish infected and non-infected patients. The underlying method complementarily and comprehensively extract multi-level interplane volumetric correlation features of typical ground glass opacities (GGOs) lesions using 3D multi-Scale Network (MSN). To cover more GGO lesion features and reduce intra-class differences, a Phase Ensemble (PE) is proposed for aggregation of different phases in one CT scan. The proposed method is evaluated on a clinically established COVID-19 database with five-fold cross-validation. Experimental results show that the proposed framework achieves classification performance with the specificity of 1.0000, sensitivity of 0.9700, accuracy of 0.9850, precision of 1.0000, and Area Under the Curve (AUC) of 0.9980. All of these indicate that our method enables an efficient, accurate and reliable patient-level COVID-19 detection for clinical diagnosis. This can significantly improve the work efficiency of clinical physicians on COVID-19 patient diagnosis and evaluation in hospitals and clinics. Impact statement—The proposed method can automatically and accurately distinguish the COVID-19 patients from patient-level CT scan images. On a clinically established large-scale COVID-19 database with five-fold cross-validation, the experimental results show that the proposed framework achieves a classification performance with the specificity of 1.0000, sensitivity of 0.9700, accuracy of 0.9850, precision of 1.0000, and Area Under the Curve (AUC) of 0.9980. It can relieve the clinical physicians from tediously reading the CT images of COVID-19 patients. Thus, it can significantly improve the work efficiency of clinical physicians on COVID-19 patient diagnosis and evaluation in hospitals and clinics, particularly in the pandemic period of COVID-19.

11.
PLoS One ; 16(6): e0252803, 2021.
Article in English | MEDLINE | ID: covidwho-1453123

ABSTRACT

A variety of infectious diseases occur in mainland China every year. Cyclic oscillation is a widespread attribute of most viral human infections. Understanding the outbreak cycle of infectious diseases can be conducive for public health management and disease surveillance. In this study, we collected time-series data for 23 class B notifiable infectious diseases from 2004 to 2020 using public datasets from the National Health Commission of China. Oscillatory properties were explored using power spectrum analysis. We found that the 23 class B diseases from the dataset have obvious oscillatory patterns (seasonal or sporadic), which could be divided into three categories according to their oscillatory power in different frequencies each year. These diseases were found to have different preferred outbreak months and infection selectivity. Diseases that break out in autumn and winter are more selective. Furthermore, we calculated the oscillation power and the average number of infected cases of all 23 diseases in the first eight years (2004 to 2012) and the next eight years (2012 to 2020) since the update of the surveillance system. A strong positive correlation was found between the change of oscillation power and the change in the number of infected cases, which was consistent with the simulation results using a conceptual hybrid model. The establishment of reliable and effective analytical methods contributes to a better understanding of infectious diseases' oscillation cycle characteristics. Our research has certain guiding significance for the effective prevention and control of class B infectious diseases.


Subject(s)
Algorithms , Communicable Diseases/epidemiology , Disease Outbreaks , Models, Theoretical , Seasons , China/epidemiology , Communicable Diseases/classification , Communicable Diseases/diagnosis , Humans , Incidence , Infection Control/methods , Infection Control/statistics & numerical data , Population Surveillance/methods , Public Health/methods , Public Health/statistics & numerical data
12.
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
13.
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
14.
Biotechnol J ; 16(11): e2100207, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1351201

ABSTRACT

BACKGROUND: The emergence of COVID-19 pandemic resulted in an urgent need for the development of therapeutic interventions. Of which, neutralizing antibodies play a crucial role in the prevention and resolution of viral infection. METHODS: We generated antibody libraries from 18 different COVID-19 recovered patients and screened neutralizing antibodies to SARS-CoV-2 and its mutants. After 3 rounds of panning, 456 positive phage clones were obtained with high affinity to RBD (receptor binding domain). Clones were then reconstituted into whole human IgG for epitope binning assay and all 19 IgG were classified into 6 different epitope groups or Bins. RESULTS: Although all antibodies were found to bind RBD, the antibodies in Bin2 had superior inhibitory ability of the interaction between spike protein and angiotensin converting enzyme 2 receptor (ACE2). Most importantly, the antibodies from Bin2 showed stronger binding affinity or ability to mutant RBDs (N501Y, W463R, R408I, N354D, V367F, and N354D/D364Y) derived from different SARS-CoV-2 strains as well, suggesting the great potential of these antibodies in preventing infection of SARS-CoV-2 and its mutations. Furthermore, such neutralizing antibodies strongly restricted the binding of RBD to hACE2 overexpressed 293T cells. Consistently, these antibodies effectively neutralized wildtype and more transmissible mutant pseudovirus entry into hACE2 overexpressed 293T cells. In Vero-E6 cells, one of these antibodies can even block the entry of live SARS-CoV-2 into cells at 12.5 nM. CONCLUSIONS: These results indicate that the neutralizing human antibodies from the patient-derived antibody libraries have the potential to fight SARS-CoV-2 and its mutants in this global pandemic.


Subject(s)
Antibodies, Viral/immunology , COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , COVID-19/therapy , Humans , Immunization, Passive , Pandemics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
15.
Asian Pacific Journal of Tropical Medicine ; 14(6):241-253, 2021.
Article in English | GIM | ID: covidwho-1310155

ABSTRACT

Background: Cardiopulmonary resuscitation (CPR) strategies in COVID-19 patients differ from those in patients suffering from cardiogenic cardiac arrest. During CPR, both healthcare and non-healthcare workers who provide resuscitation are at risk of infection. The Working Group for Expert Consensus on Prevention and Cardiopulmonary Resuscitation for Cardiac Arrest in COVID-19 has developed this Chinese Expert Consensus to guide clinical practice of CPR in COVID-19 patients. Main recommendations: (1) A medical team should be assigned to evaluate severe and critical COVID-19 for early monitoring of cardiac-arrest warning signs. (2) Psychological counseling and treatment are highly recommended, since sympathetic and vagal abnormalities induced by psychological stress from the COVID-19 pandemic can induce cardiac arrest. (3) Healthcare workers should wear personal protective equipment (PPE). (4) Mouth-to-mouth ventilation should be avoided on patients suspected of having or diagnosed with COVID-19. (5) Hands-only chest compression and mechanical chest compression are recommended. (6) Tracheal-intubation procedures should be optimized and tracheal-intubation strategies should be implemented early. (7) CPR should be provided for 20-30 min. (8) Various factors should be taken into consideration such as the interests of patients and family members, ethics, transmission risks, and laws and regulations governing infectious disease control. Changes in management: The following changes or modifications to CPR strategy in COVID-19 patients are proposed: (1) Healthcare workers should wear PPE. (2) Hands-only chest compression and mechanical chest compression can be implemented to reduce or avoid the spread of viruses by aerosols. (3) Both the benefits to patients and the risk of infection should be considered. (4) Hhealthcare workers should be fully aware of and trained in CPR strategies and procedures specifically for patients with COVID-19.

16.
Front Psychiatry ; 12: 566990, 2021.
Article in English | MEDLINE | ID: covidwho-1291006

ABSTRACT

Chinese emergency department (ED) staff encountered significant mental stress while fighting the coronavirus disease 2019 (COVID-19) pandemic. We sought to investigate the prevalence and associated factors for depressive symptoms among ED staff (including physicians, nurses, allied health, and auxiliary ED staff). A cross-sectional national survey of ED staff who were on duty and participated in combating the COVID-19 pandemic was conducted March 1-15, 2020. A total of 6,588 emergency medical personnel from 1,060 hospitals responded to this survey. A majority of respondents scored above 10 points on the PHQ-9 standardized test, which is associated with depressive symptoms. Those aged 31-45, those working in the COVID-19 isolation unit, and those with relatives ≤ 16 or ≥70 years old at home all had statistically significant associations with scoring >10 points. Depressive symptoms among Chinese emergency medical staff were likely quite common during the response to the COVID-19 pandemic and reinforce the importance of targeted ED staff support during future outbreaks.

17.
Nature ; 595(7869): 718-723, 2021 07.
Article in English | MEDLINE | ID: covidwho-1253950

ABSTRACT

Resistance represents a major challenge for antibody-based therapy for COVID-191-4. Here we engineered an immunoglobulin M (IgM) neutralizing antibody (IgM-14) to overcome the resistance encountered by immunoglobulin G (IgG)-based therapeutics. IgM-14 is over 230-fold more potent than its parental IgG-14 in neutralizing SARS-CoV-2. IgM-14 potently neutralizes the resistant virus raised by its corresponding IgG-14, three variants of concern-B.1.1.7 (Alpha, which first emerged in the UK), P.1 (Gamma, which first emerged in Brazil) and B.1.351 (Beta, which first emerged in South Africa)-and 21 other receptor-binding domain mutants, many of which are resistant to the IgG antibodies that have been authorized for emergency use. Although engineering IgG into IgM enhances antibody potency in general, selection of an optimal epitope is critical for identifying the most effective IgM that can overcome resistance. In mice, a single intranasal dose of IgM-14 at 0.044 mg per kg body weight confers prophylactic efficacy and a single dose at 0.4 mg per kg confers therapeutic efficacy against SARS-CoV-2. IgM-14, but not IgG-14, also confers potent therapeutic protection against the P.1 and B.1.351 variants. IgM-14 exhibits desirable pharmacokinetics and safety profiles when administered intranasally in rodents. Our results show that intranasal administration of an engineered IgM can improve efficacy, reduce resistance and simplify the prophylactic and therapeutic treatment of COVID-19.


Subject(s)
COVID-19/prevention & control , COVID-19/virology , Immunoglobulin M/administration & dosage , Immunoglobulin M/immunology , SARS-CoV-2/classification , SARS-CoV-2/immunology , Administration, Intranasal , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/adverse effects , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/immunology , Apoptosis Regulatory Proteins/chemistry , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/immunology , Apoptosis Regulatory Proteins/metabolism , COVID-19/drug therapy , COVID-19/immunology , Dose-Response Relationship, Immunologic , Female , Humans , Immunoglobulin A/genetics , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Immunoglobulin M/adverse effects , Immunoglobulin M/therapeutic use , Mice , Mice, Inbred BALB C , Protein Engineering , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/metabolism , SARS-CoV-2/genetics
18.
Int J Cardiol ; 336: 123-129, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1230514

ABSTRACT

BACKGROUND: Angiotensin converting enzyme 2 (ACE2) has recently been identified as the functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent response for novel coronavirus disease 2019 (COVID-19). This study aimed to explore the roles of ACE2, apelin and sodium-glucose cotransporter 2 (SGLT2) in SARS-CoV-2-mediated cardiorenal damage. METHODS AND RESULTS: The published RNA-sequencing datasets of cardiomyocytes infected with SARS-CoV-2 and COVID-19 patients were used. String, UMAP plots and single cell RNA sequencing data were analyzed to show the close relationship and distinct cardiorenal distribution patterns of ACE2, apelin and SGLT2. Intriguingly, there were decreases in ACE2 and apelin expression as well as marked increases in SGLT2 and endothelin-1 levels in SARS-CoV-2-infected cardiomyocytes, animal models with diabetes, acute kidney injury, heart failure and COVID-19 patients. These changes were linked with downregulated levels of interleukin (IL)-10, superoxide dismutase 2 and catalase as well as upregulated expression of profibrotic genes and pro-inflammatory cytokines/chemokines. Genetic ACE2 deletion resulted in upregulation of pro-inflammatory cytokines containing IL-1ß, IL-6, IL-17 and tumor necrosis factor α. More importantly, dapagliflozin strikingly alleviated cardiorenal fibrosis in diabetic db/db mice by suppressing SGLT2 levels and potentiating the apelin-ACE2 signaling. CONCLUSION: Downregulation of apelin and ACE2 and upregulation of SGLT2, endothelin-1 and pro-inflammatory cytokines contribute to SARS-CoV-2-mediated cardiorenal injury, indicating that the apelin-ACE2 signaling and SGLT2 inhibitors are potential therapeutic targets for COVID-19 patients.


Subject(s)
COVID-19 , Angiotensin-Converting Enzyme 2 , Animals , Apelin , Humans , Mice , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2 , Sodium-Glucose Transporter 2
19.
Nucleic Acids Res ; 49(9): 5382-5392, 2021 05 21.
Article in English | MEDLINE | ID: covidwho-1217861

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
20.
Air Qual Atmos Health ; 14(7): 1049-1061, 2021.
Article in English | MEDLINE | ID: covidwho-1147619

ABSTRACT

Hospitalisation risks for chronic obstructive pulmonary disease (COPD) have been attributed to ambient air pollution worldwide. However, a rise in COPD hospitalisations may indicate a considerable increase in fatality rate in public health. The current study focuses on the association between consecutive ambient air pollution (CAAP) and COPD hospitalisation to offer predictable early guidance towards estimates of COPD hospital admissions in the event of consecutive exposure to air pollution. Big data analytics were collected from 3-year time series recordings (from 2015 to 2017) of both air data and COPD hospitalisation data in the Chengdu region in China. Based on the combined effects of CAAP and unit increase in air pollutant concentrations, a quasi-Poisson regression model was established, which revealed the association between CAAP and estimated COPD admissions. The results show the dynamics and outbreaks in the variations in COPD admissions in response to CAAP. Cross-validation and mean squared error (MSE) are applied to validate the goodness of fit. In both short-term and long-term air pollution exposures, Z test outcomes show that the COPD hospitalisation risk is greater for men than for women; similarly, the occurrence of COPD hospital admissions in the group of elderly people (> 65 years old) is significantly larger than that in lower age groups. The time lag between the air quality and COPD hospitalisation is also investigated, and a peak of COPD hospitalisation risk is found to lag 2 days for air quality index (AQI) and PM10, and 1 day for PM2.5. The big data-based predictive paradigm would be a measure for the early detection of a public health event in post-COVID-19. The study findings can also provide guidance for COPD admissions in the event of consecutive exposure to air pollution in the Chengdu region.

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