Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 25
Filter
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.
Prostate Cancer Prostatic Dis ; 2022 Mar 15.
Article in English | MEDLINE | ID: covidwho-1747251

ABSTRACT

BACKGROUND: Men with progressive neuroendocrine or aggressive-variant metastatic prostate cancer (NEPC/AVPC) have a poor prognosis and limited treatment options, and immunotherapy has not been tested in such patients. METHODS: We conducted an open label single center phase 2 trial (NCT03179410) of men with progressive NEPC/AVPC either defined by histology or AVPC criteria. Avelumab (10 mg/kg every 2 weeks) was administered until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Secondary endpoints included ORR, radiographic progression-free survival (rPFS), overall survival, and safety. Correlative studies included longitudinal peripheral blood immune phenotyping. The study was limited by the small number of patients enrolled and by the early termination due to COVID-19. RESULTS: A total of 15 men with AVPC/NEPC were enrolled. The median age was 71 (range 51-85 years), and men had received a median of two prior therapies (range 1-3). Median PSA was 54 ng/dl (range 0-393), and 73% of men had liver metastasis. The ORR with avelumab in this setting by iRECIST or RECIST 1.1 was 6.7%, including one patient (6.7%) with a complete remission (CR), 20% with stable disease, and 67% with progressive disease. The patient with the CR had an MSH2 somatic mutation and MSI-high NEPC with central nervous system metastases, and his CR remains durable off all therapy for 2 years. The median rPFS was 1.8 months (95% CI 1.6-3.6 months), and median overall survival was 7.4 months (85% CI 2.8-12.6 months). Safety was consistent with the known profile of avelumab. Phenotyping of peripheral immune subsets suggest enhanced CXCR2-dependent myeloid and T-cell responses in this extraordinary responder. CONCLUSIONS: While the study was terminated early due to slow enrollment at the onset of the COVID-19 pandemic and lower than anticipated objective response rate, PD-L1 inhibition with avelumab monotherapy showed poor efficacy in patients with microsatellite stable NEPC/AVPC. Immune profiling revealed enhanced CXCR2 positive immune cell activation in the one extraordinary responder, suggesting potential mechanisms for further immunotherapy development in this population.

3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-315306

ABSTRACT

The emergence of numerous variants of SARS-CoV-2, the causative agent of COVID-19, has presented new challenges to the global efforts to control the still ravaging COVID-19 pandemic. Here, we obtain two cross-neutralizing antibodies (7D6 and 6D6) that target Sarbecoviruses’ receptor binding domain (RBD) with sub-picomolar affinities and potently neutralize authentic SARS-CoV-2. Crystal structures show that both antibodies bind a cryptic site different from that recognized by existing antibodies and highly conserved across Sarbecovirus isolates. Binding of these two antibodies to the RBD clashes with the adjacent N-terminal domain and disrupts the viral spike. Significantly, both antibodies confer good mutation resistance to the currently circulating SARS-CoV-2 variants. Thus, our results have direct relevance to public health as options for passive antibody therapeutics and even active prophylactics, and can also inform the design of pan-sarbecovirus vaccines.

4.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-310229

ABSTRACT

Background: More than 230,000 cases of coronavirus disease (COVID-19) have been reported worldwide. We sought to discuss the impact of new electronic communication tools with patients in diagnosis and treatment of these cases. Methods: : We recruited adult patients from Jan 20 to Feb 26, 2020, with laboratory-confirmed SARS-CoV-2 infection from The Fifth Affiliated Hospital, Sun Yat-sen University, in Zhuhai, China. 47 eligible patients were enrolled and randomly classified into either a test or control group. All of them were treated with standard therapeutic regimen and routine ward-round. The test group was subdivided into three subgroups. The first subgroup was arranged an extra 5min on-line ward-round by WeChat voice call once daily for basic disease communication. The second subgroup was given an extra 10min voice call once daily for further detail, similarly, the third subgroup was given an extra 10min than the second group every three days. The main end point was the duration of positive-to-negative conversion of SARS-CoV-2 RNA. Results: : 47 patients were included in the final analysis. The median time from disease diagnosed to the endpoint of test group was 7.0 days (interquartile range, 3.8 to 10.8), whereas the control group was 10.0 days (interquartile range, 6.5 to 14.5). It showed significant reduced the duration time of virus from positive to negative by the NAT (nucleic acid testing) (P=0.032), especially compared the 10 minutes group (3.0 days, interquartile range, 3.0 to 7.5) to control group (P=0.0065). Conclusions: : The patients with SARS-CoV-2 infection might benefit from the use of the new electronic communication mode. It’s very valuable to reduce the shortage of medical protection resources and the risk of occupation.

5.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-309731

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a threat to global public health. Prompt patient identification and quarantine is the most effective way to control its rapid transmission, which can be facilitated by early detection of viral antigens. Here we present a platform to develop and optimize the fibronectin-based affinity-enhanced antibody mimetics (monobodies) for recognizing viral antigens. Specifically, we developed monobodies targeting SARS-CoV-2 nucleocapsid (N) protein. We showed that two monobodies, NN2 and NC2, bind to N protein’s N- and C-terminal domains respectively with a Kd in nM range.The specificity of the recognition was confirmed with co-immunoprecipitation and immunofluorescence assays. Furthermore, we demonstrated that one round of in vitro maturation using mRNA display can improve the binding affinity of monobodies. Machine learning algorithms were integrated with deep sequencing data for selecting candidates that improve the detection sensitivity of N. Using this pair of monobodies, we have developed an enzyme-linked immunosorbent assay (ELISA) for viral detection. We were able to detect recombinant N at 4 pg/ml and detect N in viral culture supernatant, with no cross-reactivity with other CoV. Integrating high-dense mutagenesis, mRNA display, deep sequencing and machine learning, this platform can be applied through iterations to identify and optimize monobodies against emerging viral antigens, potentiating point-of-care detection of communicable diseases in a cost-and time-sensitive manner.Authors Yushen Du, Tian-hao Zhang, Xiangzhi Meng, Yuan Shi, and Menglong Hu contributed equally to this work.

6.
Front Mol Neurosci ; 15: 812479, 2022.
Article in English | MEDLINE | ID: covidwho-1686515

ABSTRACT

The neuroprotective effect of electroacupuncture (EA) treatment has been well studied; growing evidence suggests that changes in lipid composition may be involved in the pathogenesis of post-traumatic stress disorder (PTSD) and may be a target for treatment. However, the influence of early EA intervention on brain lipid composition in patients with PTSD has never been investigated. Using a modified single prolonged stress (mSPS) model in mice, we assessed the anti-PTSD-like effects of early intervention using EA and evaluated changes in lipid composition in the hippocampus and prefrontal cortex (PFC) using a mass spectrometry-based lipidomic approach. mSPS induced changes in lipid composition in the hippocampus, notably in the content of sphingolipids, glycerolipids, and fatty acyls. These lipid changes were more robust than those observed in the PFC. Early intervention with EA after mSPS ameliorated PTSD-like behaviors and partly normalized mSPS-induced lipid changes, notably in the hippocampus. Cumulatively, our data suggest that EA may reverse mSPS-induced PTSD-like behaviors due to region-specific regulation of the brain lipidome, providing new insights into the therapeutic mechanism of EA.

7.
JAMA Netw Open ; 4(11): e2134330, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1513769

ABSTRACT

Importance: Androgen deprivation therapy (ADT) has been theorized to decrease the severity of SARS-CoV-2 infection in patients with prostate cancer owing to a potential decrease in the tissue-based expression of the SARS-CoV-2 coreceptor transmembrane protease, serine 2 (TMPRSS2). Objective: To examine whether ADT is associated with a decreased rate of 30-day mortality from SARS-CoV-2 infection among patients with prostate cancer. Design, Setting, and Participants: This cohort study analyzed patient data recorded in the COVID-19 and Cancer Consortium registry between March 17, 2020, and February 11, 2021. The consortium maintains a centralized multi-institution registry of patients with a current or past diagnosis of cancer who developed COVID-19. Data were collected and managed using REDCap software hosted at Vanderbilt University Medical Center in Nashville, Tennessee. Initially, 1228 patients aged 18 years or older with prostate cancer listed as their primary malignant neoplasm were included; 122 patients with a second malignant neoplasm, insufficient follow-up, or low-quality data were excluded. Propensity matching was performed using the nearest-neighbor method with a 1:3 ratio of treated units to control units, adjusted for age, body mass index, race and ethnicity, Eastern Cooperative Oncology Group performance status score, smoking status, comorbidities (cardiovascular, pulmonary, kidney disease, and diabetes), cancer status, baseline steroid use, COVID-19 treatment, and presence of metastatic disease. Exposures: Androgen deprivation therapy use was defined as prior bilateral orchiectomy or pharmacologic ADT administered within the prior 3 months of presentation with COVID-19. Main Outcomes and Measures: The primary outcome was the rate of all-cause 30-day mortality after COVID-19 diagnosis for patients receiving ADT compared with patients not receiving ADT after propensity matching. Results: After exclusions, 1106 patients with prostate cancer (before propensity score matching: median age, 73 years [IQR, 65-79 years]; 561 (51%) self-identified as non-Hispanic White) were included for analysis. Of these patients, 477 were included for propensity score matching (169 who received ADT and 308 who did not receive ADT). After propensity matching, there was no significant difference in the primary end point of the rate of all-cause 30-day mortality (OR, 0.77; 95% CI, 0.42-1.42). Conclusions and Relevance: Findings from this cohort study suggest that ADT use was not associated with decreased mortality from SARS-CoV-2 infection. However, large ongoing clinical trials will provide further evidence on the role of ADT or other androgen-targeted therapies in reducing COVID-19 infection severity.


Subject(s)
Androgen Antagonists/adverse effects , COVID-19/complications , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/mortality , Aged , Aged, 80 and over , Androgen Antagonists/therapeutic use , COVID-19/epidemiology , COVID-19/mortality , Cohort Studies , Humans , Male , Middle Aged , Prostatic Neoplasms/epidemiology , Risk Factors , Tennessee/epidemiology
8.
Chem Biol Interact ; 351: 109744, 2022 Jan 05.
Article in English | MEDLINE | ID: covidwho-1509623

ABSTRACT

Remdesivir, an intravenous nucleotide prodrug, has been approved for treating COVID-19 in hospitalized adults and pediatric patients. Upon administration, remdesivir can be readily hydrolyzed to form its active form GS-441524, while the cleavage of the carboxylic ester into GS-704277 is the first step for remdesivir activation. This study aims to assign the key enzymes responsible for remdesivir hydrolysis in humans, as well as to investigate the kinetics of remdesivir hydrolysis in various enzyme sources. The results showed that remdesivir could be hydrolyzed to form GS-704277 in human plasma and the microsomes from human liver (HLMs), lung (HLuMs) and kidney (HKMs), while the hydrolytic rate of remdesivir in HLMs was the fastest. Chemical inhibition and reaction phenotyping assays suggested that human carboxylesterase 1 (hCES1A) played a predominant role in remdesivir hydrolysis, while cathepsin A (CTSA), acetylcholinesterase (AchE) and butyrylcholinesterase (BchE) contributed to a lesser extent. Enzymatic kinetic analyses demonstrated that remdesivir hydrolysis in hCES1A (SHUTCM) and HLMs showed similar kinetic plots and much closed Km values to each other. Meanwhile, GS-704277 formation rates were strongly correlated with the CES1A activities in HLM samples from different individual donors. Further investigation revealed that simvastatin (a therapeutic agent for adjuvant treating COVID-19) strongly inhibited remdesivir hydrolysis in both recombinant hCES1A and HLMs. Collectively, our findings reveal that hCES1A plays a predominant role in remdesivir hydrolysis in humans, which are very helpful for predicting inter-individual variability in response to remdesivir and for guiding the rational use of this anti-COVID-19 agent in clinical settings.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Carboxylesterase/metabolism , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Alanine/chemistry , Alanine/metabolism , Butyrylcholinesterase/chemistry , Butyrylcholinesterase/metabolism , Carboxylesterase/chemistry , Cathepsin A/chemistry , Cathepsin A/metabolism , Humans , Hydrolysis/drug effects , Kinetics , Liver/metabolism , Microsomes, Liver/metabolism , Simvastatin/pharmacology
9.
Journal for Immunotherapy of Cancer ; 9(Suppl 2):A655, 2021.
Article in English | ProQuest Central | ID: covidwho-1511496

ABSTRACT

625 Table 1Baseline characteristics of ICI and control populations

10.
Int J Environ Res Public Health ; 18(21)2021 11 08.
Article in English | MEDLINE | ID: covidwho-1512321

ABSTRACT

This study aimed to examine the profile of COVID-19-related public stigma and its correlates in the general population of China. A cross-sectional online survey was conducted in China from 7 May to 25 May in 2020. A total of 1212 participants from the general population completed the survey measuring their stigmatizing attitudes towards COVID-19, as well as knowledge and causal attributions of COVID-19. Univariate and multivariate analyses were performed to examine the correlates of COVID-19-related public stigma. A total of 31.8% of participants endorsed stigmatization towards people with COVID-19. Those who were of older age (t = -3.97, p < 0.001), married (F = 3.04, p < 0.05), had a lower level of education (F = 8.11, p < 0.001), and a serious psychological response (F = 3.76, p < 0.05) reported significantly higher scores of public stigma. Dangerousness (B = 0.047, p < 0.001), fear (B = 0.059, p < 0.001), anger (B = 0.038, p < 0.01), and responsibility (B = 0.041, p < 0.001) were positively associated with public stigma. This study shows that public stigma related to COVID-19 is prevalent in the general population of China. Actions against public stigma need to contain the spread of misinformation about COVID-19, alter inappropriate attributions, alleviate unfavorable reactions, and provide psychosocial support for the public.


Subject(s)
COVID-19 , Aged , China , Cross-Sectional Studies , Humans , SARS-CoV-2 , Social Stigma , Surveys and Questionnaires
11.
Emerg Microbes Infect ; 10(1): 365-375, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1490458

ABSTRACT

Concerns about vaccine safety are an important reason for vaccine hesitancy, however, limited information is available on whether common adverse reactions following vaccination affect the immune response. Data from three clinical trials of recombinant vaccines were used in this post hoc analysis to assess the correlation between inflammation-related solicited adverse reactions (ISARs, including local pain, redness, swelling or induration and systematic fever) and immune responses after vaccination. In the phase III trial of the bivalent HPV-16/18 vaccine (Cecolin®), the geometric mean concentrations (GMCs) for IgG anti-HPV-16 and -18 (P<0.001) were significantly higher in participants with any ISAR following vaccination than in those without an ISAR. Local pain, induration, swelling and systemic fever were significantly correlated with higher GMCs for IgG anti-HPV-16 and/or anti-HPV-18, respectively. Furthermore, the analyses of the immunogenicity bridging study of Cecolin® and the phase III trial of a hepatitis E vaccine yielded similar results. Based on these results, we built a scoring model to quantify the inflammation reactions and found that the high score of ISAR indicates the strong vaccine-induced antibody level. In conclusion, this study suggests inflammation-related adverse reactions following vaccination potentially indicate a stronger immune response.


Subject(s)
Hepatitis E/immunology , Human papillomavirus 16/immunology , Human papillomavirus 18/immunology , Papillomavirus Infections/immunology , Papillomavirus Vaccines/immunology , Vaccines, Synthetic/immunology , Viral Hepatitis Vaccines/immunology , Adolescent , Adult , Aged , Antibodies, Viral/immunology , Female , Hepatitis E/prevention & control , Hepatitis E/virology , Human papillomavirus 16/genetics , Human papillomavirus 18/genetics , Humans , Immunity , Immunoglobulin G/immunology , Male , Middle Aged , Papillomavirus Infections/prevention & control , Papillomavirus Infections/virology , Papillomavirus Vaccines/administration & dosage , Papillomavirus Vaccines/adverse effects , Papillomavirus Vaccines/genetics , Vaccination/adverse effects , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/adverse effects , Vaccines, Synthetic/genetics , Viral Hepatitis Vaccines/administration & dosage , Viral Hepatitis Vaccines/adverse effects , Viral Hepatitis Vaccines/genetics , Young Adult
12.
Obesity (Silver Spring) ; 29(11): 1907-1915, 2021 11.
Article in English | MEDLINE | ID: covidwho-1439707

ABSTRACT

OBJECTIVE: The Chinese government decisively imposed nationwide confinement in response to the COVID-19 outbreak. This study aimed to evaluate the impact of the COVID-19 pandemic on the progression of obesity in children and adolescents in Changshu, China. METHODS: Based on the Health Promotion Program for Children and Adolescents (HPPCA), which is a prospective cross-sectional and school-based study, BMI assessed in seven consecutive years (2014 to 2020) among children and adolescents aged 6 to 17 years in Changshu city was extracted. The standardized BMI z scores (zBMI) and prevalence of obesity between 2020 (after COVID-19 home confinement) and the previous 6 years were compared among age-specific subgroups and between sexes. RESULTS: The mean number of participants per year was 29,648. The overall mean zBMI drastically increased from 0.29 in 2019 to 0.45 in 2020, resulting in a rise of 0.16 (95% CI: 0.14-0.18); the prevalence of obesity substantially elevated to 12.77% in 2020 (versus 10.38% in 2017), with an acceleration of 2.39% (95% CI: 1.88%-2.90%). Of note, these increases were more likely to be observed in boys and those 6 to 11 years old. CONCLUSIONS: The COVID-19 pandemic seemed to exacerbate the obesity epidemic among pediatric populations in Changshu, China.


Subject(s)
COVID-19 , Pandemics , Pediatric Obesity , Adolescent , COVID-19/epidemiology , Child , China/epidemiology , Cross-Sectional Studies , Female , Health Surveys , Humans , Male , Pediatric Obesity/epidemiology , Prevalence , Prospective Studies , Schools
13.
Mol Psychiatry ; 27(1): 19-33, 2022 01.
Article in English | MEDLINE | ID: covidwho-1440466

ABSTRACT

Infectious diseases, including COVID-19, are crucial public health issues and may lead to considerable fear among the general public and stigmatization of, and discrimination against, specific populations. This meta-analysis aimed to estimate the pooled prevalence of stigma in infectious disease epidemics. We systematically searched PubMed, PsycINFO, Embase, MEDLINE, Web of Science, and Cochrane databases since inception to June 08, 2021, and reported the prevalence of stigma towards people with infectious diseases including SARS, H1N1, MERS, Zika, Ebola, and COVID-19. A total of 50 eligible articles were included that contributed 51 estimates of prevalence in 92722 participants. The overall pooled prevalence of stigma across all populations was 34% [95% CI: 28-40%], including enacted stigma (36% [95% CI: 28-44%]) and perceived stigma (31% [95% CI: 22-40%]). The prevalence of stigma in patients, community population, and health care workers, was 38% [95% CI: 12- 65%], 36% [95% CI: 28-45%], and 30% [95% CI: 20-40%], respectively. The prevalence of stigma in participants from low- and middle-income countries was 37% [95% CI: 29-45%], which is higher than that from high-income countries (27% [95% CI: 18-36%]) though this difference was not statistically significant. A similar trend of prevalence of stigma was also observed in individuals with lower education (47% [95% CI: 23-71%]) compared to higher education level (33% [95% CI: 23-4%]). These findings indicate that stigma is a significant public health concern, and effective and comprehensive interventions are needed to counteract the damaging effects of the infodemics during infectious disease epidemics, including COVID-19, and reduce infectious disease-related stigma.


Subject(s)
COVID-19 , Communicable Diseases , Influenza A Virus, H1N1 Subtype , Zika Virus Infection , Zika Virus , Humans , Prevalence
14.
Acta Pharm Sin B ; 11(9): 2850-2858, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1415197

ABSTRACT

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development. No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections. We report herein that a macrolide antibiotic, carrimycin, potently inhibited the cytopathic effects (CPE) and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229E, OC43, and SARS-CoV-2. Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection. In support of this notion, metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA. Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.

15.
Journal of Advanced Research ; 2021.
Article in English | ScienceDirect | ID: covidwho-1330938

ABSTRACT

Introduction The SARS-CoV-2 pandemic has endangered global health, the world economy, and societal values. Despite intensive measures taken around the world, morbidity and mortality remain high as many countries face new waves of infection and the spread of new variants. Worryingly, more and more variants are now being identified, such as 501Y.V1 (B.1.1.7) in the UK, 501Y.V2 (B.1.351) in South Africa, 501Y.V3 in Manaus, Brazil, and B.1.617/B.1.618 in India, which could lead to a severe epidemic rebound. Moreover, some variants have a stronger immune escape ability. To control the new SARS-CoV-2 variant, we may need to develop and redesign new vaccines repeatedly. So it is important to investigate how our immune system combats and responds to SARS-CoV-2 infection to develop safe and effective medical interventions. Objectives In this study, we performed a longitudinal and proteome-wide analysis of antibodies in the COVID-19 patients to revealed some immune processes of COVID-19 patients against SARS-CoV-2 and found some dominant epitopes of a potential vaccine. Methods Microarray assay, Antibody depletion assays, Neutralization assay Results We profiled a B-cell linear epitope landscape of SARS-CoV-2 and identified the epitopes specifically recognized by either IgM, IgG, or IgA. We found that epitopes more frequently recognized by IgM are enriched in non-structural proteins. We further identified epitopes with different immune responses in severe and mild patients. Moreover, we identified 12 dominant epitopes eliciting antibodies in most COVID-19 patients and identified five key amino acids of epitopes. Furthermore, we found epitope S-82 and S-15 are perfect immunogenic peptides and should be considered in vaccine design. Conclusion This data provide useful information and rich resources for improving our understanding of viral infection and developing a novel vaccine/neutralizing antibodies for the treatment of SARS-CoV-2.

16.
Atmosphere ; 12(6):788, 2021.
Article in English | MDPI | ID: covidwho-1273383

ABSTRACT

In the context of the outbreak of coronavirus disease 2019 (COVID-19), strict lockdown policies were implemented to control nonessential human activities in Xi’an, northwest China, which greatly limited the spread of the pandemic and affected air quality. Compared with pre-lockdown, the air quality index and concentrations of PM2.5, PM10, SO2, and CO during the lockdown reduced, but the reductions were not very significant. NO2 levels exhibited the largest decrease (52%) during lockdown, owing to the remarkable decreased motor vehicle emissions. The highest K+ and lowest Ca2+ concentrations in PM2.5 samples could be attributed to the increase in household biomass fuel consumption in suburbs and rural areas around Xi’an and the decrease in human physical activities in Xi’an (e.g., human travel, vehicle emissions, construction activities), respectively, during the lockdown period. Secondary chemical reactions in the atmosphere increased in the lockdown period, as evidenced by the increased O3 level (increased by 160%) and OC/EC ratios in PM2.5 (increased by 26%), compared with pre-lockdown levels. The results, based on a natural experiment in this study, can be used as a reference for studying the formation and source of air pollution in Xi’an and provide evidence for establishing future long-term air pollution control policies.

17.
Nat Biomed Eng ; 5(8): 815-829, 2021 08.
Article in English | MEDLINE | ID: covidwho-1213929

ABSTRACT

The rapid repurposing of antivirals is particularly pressing during pandemics. However, rapid assays for assessing candidate drugs typically involve in vitro screens and cell lines that do not recapitulate human physiology at the tissue and organ levels. Here we show that a microfluidic bronchial-airway-on-a-chip lined by highly differentiated human bronchial-airway epithelium and pulmonary endothelium can model viral infection, strain-dependent virulence, cytokine production and the recruitment of circulating immune cells. In airway chips infected with influenza A, the co-administration of nafamostat with oseltamivir doubled the treatment-time window for oseltamivir. In chips infected with pseudotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), clinically relevant doses of the antimalarial drug amodiaquine inhibited infection but clinical doses of hydroxychloroquine and other antiviral drugs that inhibit the entry of pseudotyped SARS-CoV-2 in cell lines under static conditions did not. We also show that amodiaquine showed substantial prophylactic and therapeutic activities in hamsters challenged with native SARS-CoV-2. The human airway-on-a-chip may accelerate the identification of therapeutics and prophylactics with repurposing potential.


Subject(s)
Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19 Testing/methods , COVID-19/drug therapy , Lab-On-A-Chip Devices , Animals , COVID-19/diagnosis , COVID-19/virology , Cell Line , Cricetinae , Female , Green Fluorescent Proteins , Humans , Male , SARS-CoV-2/drug effects , Virus Internalization/drug effects
18.
mSystems ; 6(2)2021 Apr 13.
Article in English | MEDLINE | ID: covidwho-1183288

ABSTRACT

RNA viruses, such as hepatitis C virus (HCV), influenza virus, and SARS-CoV-2, are notorious for their ability to evolve rapidly under selection in novel environments. It is known that the high mutation rate of RNA viruses can generate huge genetic diversity to facilitate viral adaptation. However, less attention has been paid to the underlying fitness landscape that represents the selection forces on viral genomes, especially under different selection conditions. Here, we systematically quantified the distribution of fitness effects of about 1,600 single amino acid substitutions in the drug-targeted region of NS5A protein of HCV. We found that the majority of nonsynonymous substitutions incur large fitness costs, suggesting that NS5A protein is highly optimized. The replication fitness of viruses is correlated with the pattern of sequence conservation in nature, and viral evolution is constrained by the need to maintain protein stability. We characterized the adaptive potential of HCV by subjecting the mutant viruses to selection by the antiviral drug daclatasvir at multiple concentrations. Both the relative fitness values and the number of beneficial mutations were found to increase with the increasing concentrations of daclatasvir. The changes in the spectrum of beneficial mutations in NS5A protein can be explained by a pharmacodynamics model describing viral fitness as a function of drug concentration. Overall, our results show that the distribution of fitness effects of mutations is modulated by both the constraints on the biophysical properties of proteins (i.e., selection pressure for protein stability) and the level of environmental stress (i.e., selection pressure for drug resistance).IMPORTANCE Many viruses adapt rapidly to novel selection pressures, such as antiviral drugs. Understanding how pathogens evolve under drug selection is critical for the success of antiviral therapy against human pathogens. By combining deep sequencing with selection experiments in cell culture, we have quantified the distribution of fitness effects of mutations in hepatitis C virus (HCV) NS5A protein. Our results indicate that the majority of single amino acid substitutions in NS5A protein incur large fitness costs. Simulation of protein stability suggests viral evolution is constrained by the need to maintain protein stability. By subjecting the mutant viruses to selection under an antiviral drug, we find that the adaptive potential of viral proteins in a novel environment is modulated by the level of environmental stress, which can be explained by a pharmacodynamics model. Our comprehensive characterization of the fitness landscapes of NS5A can potentially guide the design of effective strategies to limit viral evolution.

19.
J Hematol Oncol ; 14(1): 38, 2021 02 27.
Article in English | MEDLINE | ID: covidwho-1105724

ABSTRACT

Less than a year since the start of the COVID-19 pandemic, ten vaccines against SARS-CoV-2 have been approved for at least limited use, with over sixty others in clinical trials. This swift achievement has generated excitement and arrives at a time of great need, as the number of COVID-19 cases worldwide continues to rapidly increase. Two vaccines are currently approved for full use, both built on mRNA and lipid nanotechnology platforms, a success story of mRNA technology 20 years in the making. For patients with cancer, questions arise around the safety and efficacy of these vaccines in the setting of immune alterations engendered by their malignancy and/or therapies. We summarize the current data on leading COVID-19 vaccine candidates and vaccination of patients undergoing immunomodulatory cancer treatments. Most current cancer therapeutics should not prevent the generation of protective immunity. We call for more research in this area and recommend that the majority of patients with cancer receive COVID vaccinations when possible.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/complications , COVID-19/prevention & control , Neoplasms/complications , Animals , Antineoplastic Agents/therapeutic use , COVID-19/immunology , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Humans , Immunotherapy , Neoplasms/immunology , Neoplasms/therapy , Pandemics/prevention & control
20.
Front Pharmacol ; 11: 609592, 2020.
Article in English | MEDLINE | ID: covidwho-1094200

ABSTRACT

To identify drugs that are potentially used for the treatment of COVID-19, the potency of 1403 FDA-approved drugs were evaluated using a robust pseudovirus assay and the candidates were further confirmed by authentic SARS-CoV-2 assay. Four compounds, Clomiphene (citrate), Vortioxetine, Vortioxetine (hydrobromide) and Asenapine (hydrochloride), showed potent inhibitory effects in both pseudovirus and authentic virus assay. The combination of Clomiphene (citrate), Vortioxetine and Asenapine (hydrochloride) is much more potent than used alone, with IC50 of 0.34 µM.

SELECTION OF CITATIONS
SEARCH DETAIL