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1.
Optimization letters ; 16(5):1563-1586, 2022.
Article in English | EuropePMC | ID: covidwho-1837957

ABSTRACT

Mathematical approaches, such as compartmental models and agent-based models, have been utilized for modeling the spread of the infectious diseases in the computational epidemiology. However, the role of social network structure for transmission of diseases is not explicitly considered in these models. In this paper, the influence maximization problem, considering the diseases starting at some initial nodes with the potential to maximize the spreading in a social network, is adapted to model the spreading process. This approach includes the analysis of network structure and the modeling of connections among individuals with probabilities to be infected. Additionally, individual behaviors that change along the time and eventually influence the spreading process are also included. These considerations are formulated by integer optimization models. Simulation results, based on the randomly generated networks and a local community network under the COVID-19, are performed to validate the effectiveness of the proposed models, and their relationships to the classic compartmental models.

2.
Chemical Engineering Journal ; : 136864, 2022.
Article in English | ScienceDirect | ID: covidwho-1821170

ABSTRACT

Synthetic biology enabling technologies have been harnessed to create new diagnostic technologies. However, most strategies involve error-prone amplification steps and limitations of accuracy in RNA detection. Here, a cell-free synthetic biology-powered biosensing strategy, termed as SHARK (Synthetic Enzyme Shift RNA Signal Amplifier Related Cas13a Knockdown Reaction), could efficiently and accurately amplify RNA signal by leveraging the collateral cleavage of activated Cas13a to regulate cell-free enzyme synthesis. Based on cascade amplification and tailored enzyme output, SHARK behaves broad compatibility in different scenarios. The portable device based on SHARK was successfully used as SARS-CoV-2 biosensors with high sensitivity and selectivity, and the results were highly consistent with Ct values of qRT-PCR. In addition, when combined with machine learning, SHARK performs bio-computations and thus for cancer diagnosis and staging based on 64 clinical samples. SHARK shows characteristics of precise recognition, cascade amplification and tailored signal outputting comparisons with established assays, presenting significant potential in developing next-generation RNA detection technology.

3.
J Stat Plan Inference ; 221: 172-187, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1821396

ABSTRACT

Doubly censored data are very common in epidemiology studies. Ignoring censorship in the analysis may lead to biased parameter estimation. In this paper, we highlight that the publicly available COVID19 data may involve high percentage of double-censoring and point out the importance of dealing with such missing information in order to achieve better forecasting results. Existing statistical methods for doubly censored data may suffer from the convergence problems of the EM algorithms or may not be good enough for small sample sizes. This paper develops a new empirical likelihood method to analyze the recovery rate of COVID19 based on a doubly censored dataset. The efficient influence function of the parameter of interest is used to define the empirical likelihood (EL) ratio. We prove that - 2 log (EL-ratio) asymptotically follows a standard χ 2 distribution. This new method does not require any scale parameter adjustment for the log-likelihood ratio and thus does not suffer from the convergence problems involved in traditional EM-type algorithms. Finite sample simulation results show that this method provides much less biased estimate than existing methods, when censoring percentage is large. The application to COVID19 data will help researchers in other field to achieve better estimates and forecasting results.

4.
Biosens Bioelectron ; 209: 114226, 2022 Aug 01.
Article in English | MEDLINE | ID: covidwho-1767929

ABSTRACT

Protein sensors based on allosteric enzymes responding to target binding with rapid changes in enzymatic activity are potential tools for homogeneous assays. However, a high signal-to-noise ratio (S/N) is difficult to achieve in their construction. A high S/N is critical to discriminate signals from the background, a phenomenon that might largely vary among serum samples from different individuals. Herein, based on the modularized luciferase NanoLuc, we designed a novel biosensor called NanoSwitch. This sensor allows direct detection of antibodies in 1 µl serum in 45 min without washing steps. In the detection of Flag and HA antibodies, NanoSwitches respond to antibodies with S/N ratios of 33-fold and 42-fold, respectively. Further, we constructed a NanoSwitch for detecting SARS-CoV-2-specific antibodies, which showed over 200-fold S/N in serum samples. High S/N was achieved by a new working model, combining the turn-off of the sensor with human serum albumin and turn-on with a specific antibody. Also, we constructed NanoSwitches for detecting antibodies against the core protein of hepatitis C virus (HCV) and gp41 of the human immunodeficiency virus (HIV). Interestingly, these sensors demonstrated a high S/N and good performance in the assays of clinical samples; this was partly attributed to the combination of off-and-on models. In summary, we provide a novel type of protein sensor and a working model that potentially guides new sensor design with better performance.


Subject(s)
Biosensing Techniques , COVID-19 , Antibodies, Viral , COVID-19/diagnosis , Humans , Luciferases , SARS-CoV-2
7.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329675

ABSTRACT

With the development of COVID-19, even though increased global vaccination coverage, a super variant of SARS-CoV-2, Omicron, carrying a great number of mutations, has been verified its strong capacity of immune escape. An increased risk of SARS-CoV-2 reinfection or breakthrough infection should be concerned. We analyzed the humoral immune response of Omicron breakthrough infection and found its cross-neutralization against VOCs. We established mouse models to verify whether Omicron-specific RBD subunit boost immune response by immunizing Omicron-RBD recombinant proteins. The results suggest that an additional boost vaccination with Omicron-RBD protein could increase humoral immune response against both WT and current VOCs.

8.
Optim Lett ; 16(5): 1563-1586, 2022.
Article in English | MEDLINE | ID: covidwho-1699450

ABSTRACT

Mathematical approaches, such as compartmental models and agent-based models, have been utilized for modeling the spread of the infectious diseases in the computational epidemiology. However, the role of social network structure for transmission of diseases is not explicitly considered in these models. In this paper, the influence maximization problem, considering the diseases starting at some initial nodes with the potential to maximize the spreading in a social network, is adapted to model the spreading process. This approach includes the analysis of network structure and the modeling of connections among individuals with probabilities to be infected. Additionally, individual behaviors that change along the time and eventually influence the spreading process are also included. These considerations are formulated by integer optimization models. Simulation results, based on the randomly generated networks and a local community network under the COVID-19, are performed to validate the effectiveness of the proposed models, and their relationships to the classic compartmental models.

9.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-313429

ABSTRACT

Accumulating mutations on SARS-CoV-2 Spike (S) protein may increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, in a panel of receptor binding domain (S-RBD) specific monoclonal antibodies (mAbs) with high neutralizing potency against authentic SARS-CoV-2, at least 6 of them were found to efficiently block the pseudovirus of 501Y.V2, a highly transmissible SARS-CoV-2 variant with escape mutations. The top 3 neutralizing Abs (13G9, 58G6 and 510A5) exhibited comparative ultrapotency as those being actively pursued for clinical development. Interestingly, the antigenic sites for the majority of our neutralizing Abs overlapped with a single epitope (13G9e) on S-RBD. Further, the 3-dimensional structures of 2 ultrapotent neutralizing Abs 13G9 or 58G6 in complex with SARS-CoV-2 S trimer demonstrated that both Abs bound to a steric region within S 472–490 . Moreover, a specific linear region (S 450–457 ) was identified as an additional target for 58G6. Importantly, our cryo-electron microscopy (cryo-EM) analysis revealed a unique phenomenon that the S-RBDs interacting with the fragments of antigen binding (Fabs) of 13G9 or 58G6 encoded by the IGHV1-58 and the IGKV3-20 gene segments were universally in the ‘up’ conformation in all observed particles. The potent neutralizing Abs presented in the current study may be promising candidates to fulfill the urgent needs for the current pandemic of SARS-CoV-2, and may of fundamental value for the next-generation vaccine development.

10.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-311951

ABSTRACT

After the epidemic of COVID-19, neutralizing antibodies (NAbs) against SARS-CoV-2 has been developed for the preventative and therapeutic purposes. However, few methodologies are reported in detail on how to rapidly and efficiently generate NAbs of interest. Here, we present a strategically optimized screening method for NAbs, which has enabled us to obtain SARS-CoV-2 receptor-binding domain (RBD) specific monoclonal Abs within 4 days, followed by additional 2 days to evaluate their neutralizing activities. Using this method, we obtained 198 specific Abs against SARS-CoV-2 RBD from the blood samples of COVID-19 convalescent patients, and 96 of them showed neutralizing activity. At least 20% of these NAbs exhibited high neutralizing potency. The top 2 NAbs showed the half-maximal inhibitory concentration (IC50) to block authentic SARS-CoV-2 at 9.88 and 11.13 ng/ml, respectively. Altogether, our study provides a fundamental methodology for discovering NAbs with potential preventative and therapeutic value for emerging infectious diseases.

11.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-328767

ABSTRACT

This study explored circulating pneumoproteins in the diagnosis, severity, and prognosis of COVID-19 by meta-analysis. We searched six English databases until December 16, 2021. Standardised mean difference (SMD) and 95% confidence interval (CI) were the overall outcomes. RevMan 5.3, Stata 16, and Meta-DiSc 1.4 were utilised for pooled analyses. Totally, 2902 subjects from 29 studies were included. COVID-19 patients had higher circulating KL-6, SP-D, and SP-A levels (SMD=1.34, 95% CI [0.60, 2.08];SMD=1.74, 95% CI [0.64, 2.84];SMD=3.42, 95% CI [1.31, 5.53], respectively) than healthy individuals. Circulating KL-6 levels were lower in survivors than in non-survivors (SMD=-1.09, 95% CI [-1.63, -0.55]). Circulating KL-6, SP-D, and RAGEs levels in mild to moderate patients were significantly lower (SMD=-0.93, 95% CI [-1.22, -0.65];SMD=-1.67, 95% CI [-2.82, -0.52];SMD=-1.17, 95% CI [-2.06, -0.28], respectively) than severe patients. Subgroup analysis and meta-regression suggested that age may be responsible for the heterogeneity (P=0.071) when analysing KL-6 in mild to moderate vs. severe patients. The meta-analysis of diagnostic accuracy including KL-6 for severity and mortality, and SP-D for severity demonstrated that they all had limited diagnostic values. Therefore, circulating pneumoproteins (KL-6, SP-D, and RAGEs) may reflect the diagnosis, severity, and prognosis of COVID-19 to some extent.

12.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-325083

ABSTRACT

Aim: The hospitalized children with Mycoplasma pneumonia (M. pneumonia) infection caused by respiratory tract infection in Chengdu were studied and analysis of the epidemiological characteristics was carried out to provide a theoretical basis for clinical diagnosis and treatment. Method: 22882 hospitalized children with respiratory tract infections between January 2014 and December 2020 were collected M . pneumonia IgM antibody was detected by indirect immunofluorescence method and passive agglutination method. Demographic characteristics, clinical diagnose and laboratory data of these children were analyzed.retrospectively.. Result: : The 4213 specimens with M. pneumonia were tested positive, the total positive rate was18.41%(18.30% in male and 22.72% in female). Higher positive rates were found in female children,Look from the statistical analysis results, the consistency between the two sets of data is low(x 2 =198.078、P<0.01). The results of different age patients with contrast different M. pneumonia infection degree were statistically significant(F=162.7532、P<0.01),there was higher M. pneumonia positive rate in Preschoolers and school-age children ,33.98% and 32.98%, respectively.The incidence rate of M. pneumonia in 2017 and 2019 was significantly higher than average (F=538.95, P<0.01)The difference of incidence rate of M. pneumonia was not significant in different months in 2014, 2015 and 2020 (P>0.05). But the probability of M .pneumonia infection patients was much higher from April to May and September to October in2016,2017,2018 and 2019(P<0.05). There was no correlation about M. pneumonia infection with temperature and humidity( P>0.05),there was negative correlation with PM 2.5 (R=0.09362, P<0.01)and PM 10 .(R=0.1185, P<0.01).There was no difference about constituent ratio of case of M. pneumonia infection between 2014 and 2019 (F=32.34,P>0.05).The Common respiratory diseases of M. pneumonia infection , bronchopneumonia accounts for the highest proportion,followed the exacerbation of asthma and severe pneumonia . There was significantly difference about constituent ratio of case of M. pneumonia infection between in 2020 and in other years (F=159.35,P<0.01) . The Common respiratory diseases of M. pneumonia infection , bronchopneumonia accounts for the highest proportion,followed the acute bronchitis and exacerbation of asthma. Conclusion: The distribution and epidemiological trend of M. pneumonia in patients with respiratory tract infection showed the risk of inflammation was connected with the gender, age, year and month, no relationship with temperature and humidity in Chengdu,.Higher M. pneumonia positive rate was shown in the children with bronchial pneumonia and exacerbation of asthma.The prevention measures which controlled the COVID-19 disease had effectively controlled the infection rate of M. pneumonia .

13.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-325017

ABSTRACT

Synthetic biology has been harnessed to create new diagnostic technologies. However, most synthetic biosensors involve error-prone amplification steps and limitations of accuracy in RNA detection. Here, we report a cell-free synthetic biosensing platform, termed as SHARK ( S ynthetic Enzyme S h ift RNA Signal A mplifier R elated Cas13a K nockdown Reaction), to efficiently and accurately amplify RNA signal by leveraging the collateral cleavage of activated Cas13a to regulate cell-free enzyme synthesis. Based on cascade amplification and customized enzyme output, SHARK behaves a broad compatibility in different scenarios. Using a personal glucose meter, we detected 50 copies/μl SARS-CoV-2 on a SHARK-loaded paper. In addition, when combined with machine learning, SHARK can perform bio-computations and thus provide miRNA patterns for cancer diagnosis and staging. SHARK shows characteristics of precise recognition, cascade amplification and customizable signal outputting in one pot comparisons with established assays based on 64 clinical samples, presenting great potential in developing next-generation RNA detection technology.

14.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-324114

ABSTRACT

Background: The impact of corticosteroid therapy on outcomes of patients with Coronavirus disease-2019 (COVID-19) is highly controversial. We aimed to compare the risk of death between COVID-19-related ARDS patients with corticosteroid treatment and those without. Methods In this single-centre retrospective observational study, patients with ARDS caused by COVID-19 between 24 December 2019 and 24 February 2020 were enrolled. The primary outcome was 60-day in-hospital death. The exposure was prescribed systemic corticosteroids or not. Time-dependent Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for 60-day in-hospital mortality. Results A total of 382 patients including 226 (59.2%) patients who received systemic corticosteroids and 156 (40.8%) patients with standard treatment were analyzed. The maximum dose of corticosteroids was 80.0 (IQR 40.0–80.0) mg equivalent methylprednisolone per day, and duration of corticosteroid treatment was 7.0 (4.0–12.0) days in total. In Cox regression analysis using corticosteroid treatment as a time-varying variable, corticosteroid treatment was associated with a significant reduction in risk of in-hospital death within 60 days (HR, 0.48;95% CI, 0.25, 0.93;p  = 0.0285). The association remained significantly after adjusting for age, sex, Sequential Organ Failure Assessment score at hospital admission, propensity score of corticosteroid treatment, and comorbidities (HR: 0.51;CI: 0.27, 0.99;p  = 0.0471). Corticosteroids were not associated with delayed viral RNA clearance in our cohort. Conclusion In this clinical practice setting, low-to-moderate dose corticosteroid treatment was associated with reduced risk of death in COVID-19 patients who developed ARDS.

15.
Nat Med ; 26(6): 845-848, 2020 06.
Article in English | MEDLINE | ID: covidwho-1641979

ABSTRACT

We report acute antibody responses to SARS-CoV-2 in 285 patients with COVID-19. Within 19 days after symptom onset, 100% of patients tested positive for antiviral immunoglobulin-G (IgG). Seroconversion for IgG and IgM occurred simultaneously or sequentially. Both IgG and IgM titers plateaued within 6 days after seroconversion. Serological testing may be helpful for the diagnosis of suspected patients with negative RT-PCR results and for the identification of asymptomatic infections.


Subject(s)
Antibodies, Viral/blood , Antibody Formation/drug effects , Betacoronavirus/pathogenicity , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Adult , Aged , Antibody Formation/immunology , Antiviral Agents/therapeutic use , Betacoronavirus/genetics , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/immunology , Coronavirus Infections/virology , Female , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Male , Middle Aged , Pandemics/prevention & control , Pneumonia, Viral/blood , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2
17.
Genes Dis ; 2021 Dec 03.
Article in English | MEDLINE | ID: covidwho-1616497

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The Spike protein that mediates coronavirus entry into host cells is a major target for COVID-19 vaccines and antibody therapeutics. However, multiple variants of SARS-CoV-2 have emerged, which may potentially compromise vaccine effectiveness. Using a pseudovirus-based assay, we evaluated SARS-CoV-2 cell entry mediated by the viral Spike B.1.617 and B.1.1.7 variants. We also compared the neutralization ability of monoclonal antibodies from convalescent sera and neutralizing antibodies (NAbs) elicited by CoronaVac (inactivated vaccine) and ZF2001 (RBD-subunit vaccine) against B.1.617 and B.1.1.7 variants. Our results showed that, compared to D614G and B.1.1.7 variants, B.1.617 shows enhanced viral entry and membrane fusion, as well as more resistant to antibody neutralization. These findings have important implications for understanding viral infectivity and for immunization policy against SARS-CoV-2 variants.

18.
Emerg Microbes Infect ; 11(1): 483-497, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1606402

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has set off a global pandemic. There is an urgent unmet need for safe, affordable, and effective therapeutics against COVID-19. In this regard, drug repurposing is considered as a promising approach. We assessed the compounds that affect the endosomal acidic environment by applying human angiotensin-converting enzyme 2 (hACE2)- expressing cells infected with a SARS-CoV-2 spike (S) protein-pseudotyped HIV reporter virus and identified that obatoclax resulted in the strongest inhibition of S protein-mediated virus entry. The potent antiviral activity of obatoclax at nanomolar concentrations was confirmed in different human lung and intestinal cells infected with the SARS-CoV-2 pseudotype system as well as clinical virus isolates. Furthermore, we uncovered that obatoclax executes a double-strike against SARS-CoV-2. It prevented SARS-CoV-2 entry by blocking endocytosis of virions through diminished endosomal acidification and the corresponding inhibition of the enzymatic activity of the endosomal cysteine protease cathepsin L. Additionally, obatoclax impaired the SARS-CoV-2 S-mediated membrane fusion by targeting the MCL-1 protein and reducing furin protease activity. In accordance with these overarching mechanisms, obatoclax blocked the virus entry mediated by different S proteins derived from several SARS-CoV-2 variants of concern such as, Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2). Taken together, our results identified obatoclax as a novel effective antiviral compound that keeps SARS-CoV-2 at bay by blocking both endocytosis and membrane fusion. Our data suggested that obatoclax should be further explored as a clinical drug for the treatment of COVID-19.


Subject(s)
Cathepsins/metabolism , Furin/metabolism , Indoles/pharmacology , Pyrroles/pharmacology , SARS-CoV-2 , Virus Internalization/drug effects , COVID-19 , Humans , Hydrogen-Ion Concentration , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus
19.
Mol Biomed ; 1(1): 14, 2020 Nov 30.
Article in English | MEDLINE | ID: covidwho-1515460

ABSTRACT

The global pandemic of COVID-19 has attracted extensive drug searching interets for the new coronavirus SARS-CoV-2. Although currently several of clinically used "old" drugs have been repurposed to this new disease for the urgent clinical investigation, there is still great demand for more effective therapies for the anti-infections. Here we report the discovery that an "old" drug Emetine could potently inhibit SARS-CoV-2 virus replication and displayed virus entry blocking effect in Vero cells at low dose. In addition, Emetine could significantly reduce the lipopolysaccharide (LPS) induced interleukin-6 (IL-6) protein level and moderately reduce the tumor necrosis factor (TNF-α) protein level in the M1 polarized THP-1 macrophages. In vivo animal pharmacokinetics (PK) study revealed that Emetine was enriched in the lung tissue and had a long retention time (over 12 h). With 1 mg/kg single oral dose, the effective concentration of Emetine in lung was up to 1.8 µM (mice) and 1.6 µM (rats) at 12 h, which is over 200-fold higher than the EC50 of the drug. The potent in vitro antiviral replication efficacy and the high enrichment in target tissue, combining with the well documented safety profiles in human indicate that low dose of Emetine might be a potentially effective anti-SARS-CoV-2 infection therapy.

20.
Nat Commun ; 12(1): 6304, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1500462

ABSTRACT

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus display remarkable efficacy against authentic B.1.351 virus. Surprisingly, structural analysis has revealed that 58G6 and 13G9 both recognize the steric region S470-495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly binds to another region S450-458 in the RBD. Significantly, 58G6 and 510A5 both demonstrate prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. Together, we have evidenced 2 potent neutralizing Abs with unique mechanism targeting authentic SARS-CoV-2 mutants, which can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/chemistry , Antibodies, Viral/administration & dosage , Antibodies, Viral/chemistry , Binding Sites , COVID-19/pathology , COVID-19/virology , Epitopes , Humans , Mice , Mice, Transgenic , Mutation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Viral Load/drug effects , Weight Loss/drug effects
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