Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 46
Filter
1.
Cell Discov ; 8(1): 53, 2022 Jun 06.
Article in English | MEDLINE | ID: covidwho-1878521

ABSTRACT

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important target for vaccine and drug development. However, the rapid emergence of variant strains with mutated S proteins has rendered many treatments ineffective. Cleavage of the S protein by host proteases is essential for viral infection. Here, we discovered that the S protein contains two previously unidentified Cathepsin L (CTSL) cleavage sites (CS-1 and CS-2). Both sites are highly conserved among all known SARS-CoV-2 variants. Our structural studies revealed that CTSL cleavage promoted S to adopt receptor-binding domain (RBD) "up" activated conformations, facilitating receptor-binding and membrane fusion. We confirmed that CTSL cleavage is essential during infection of all emerged SARS-CoV-2 variants (including the recently emerged Omicron variant) by pseudovirus (PsV) infection experiment. Furthermore, we found CTSL-specific inhibitors not only blocked infection of PsV/live virus in cells but also reduced live virus infection of ex vivo lung tissues of both human donors and human ACE2-transgenic mice. Finally, we showed that two CTSL-specific inhibitors exhibited excellent In vivo effects to prevent live virus infection in human ACE2-transgenic mice. Our work demonstrated that inhibition of CTSL cleavage of SARS-CoV-2 S protein is a promising approach for the development of future mutation-resistant therapy.

2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-336878

ABSTRACT

The global emergence of SARS-CoV-2 variants has led to increasing breakthrough infections in vaccinated populations, calling for an urgent need to develop more effective and broad-spectrum vaccines to combat COVID-19. Here we report the preclinical development of RQ3013, an mRNA vaccine candidate intended to bring broad protection against SARS-CoV-2 variants of concern (VOCs). RQ3013, which contains pseudouridine-modified mRNAs formulated in lipid nanoparticles, encodes the spike(S) protein harboring a combination of mutations responsible for immune evasion of VOCs. Here we characterized the expressed S immunogen and evaluated the immunogenicity, efficacy, and safety of RQ3013 in various animal models. RQ3013 elicited robust immune responses in mice, hamsters, and nonhuman primates (NHP). It can induce high titers of antibodies with broad cross-neutralizing ability against the Wild-type, B.1.1.7, B.1.351, B.1.617.2, and the omicron B.1.1.529 variants. In mice and NHP, two doses of RQ3013 protected the upper and lower respiratory tract against infection by SARS-CoV-2 and its variants. We also proved the safety of RQ3013 in NHP models. Our results provided key support for the evaluation of RQ3013 in clinical trials.

3.
Journal of Shandong University ; 58(4):65-70, 2020.
Article in English, Chinese | GIM | ID: covidwho-1812835

ABSTRACT

Objective: To investigate the clinical characteristics of corona virus disease 2019 (COVID-19) patients in Wuhan City, and the correlation between inflammatory factors and severity.

5.
Nanomaterials (Basel) ; 12(6)2022 Mar 17.
Article in English | MEDLINE | ID: covidwho-1753655

ABSTRACT

Coronavirus disease 2019 (COVID-19) has spread rapidly and led to over 5 million deaths to date globally. Due to the successively emerging mutant strains, therapeutics and prevention against the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are urgently needed. Prevention of SARS-CoV-2 infection in public and hospital areas is essential to reduce the frequency of infections. Silver nanoparticles (AgNPs) with virucidal effects have been reported. Therefore, we investigated the virucidal activity and safety of ten types of AgNPs with different surface modifications and particle sizes, in cells exposed to SARS-CoV-2 in vitro. The AgNPs could effectively inhibit the activity of SARS-CoV-2, and different surface modifications and particle sizes conferred different virucidal effects, of which 50-nm BPEI showed the strongest antiviral effect. We concluded that the efficacy of each type of AgNP type was positively correlated with the corresponding potential difference (R2 = 0.82). These in vitro experimental data provide scientific support for the development of therapeutics against COVID-19, as well as a research basis for the development of broad-spectrum virucides. Given the increasing acquired resistance of pathogens against conventional chemical and antibody-based drugs, AgNPs may well be a possible solution for cutting off the route of transmission, either as an external material or a potential medicine.

6.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-315303

ABSTRACT

We study the functioning of the municipal bond market during the COVID-19 pandemic. The average offering yield increases while the number of new issues drops when county-level COVID-19 case and death counts rise. Exploiting the differential timing of local policy actions, we find that emergency declarations lead to a 69 basis-point increase in offering yields and a significant drop in new issuance. Investors shun transportation and dedicated tax bonds or bonds issued in fiscally unhealthy states. The Federal Reserve's unprecedented interventions through two municipal liquidity facilities have calmed the market. The reopening of local economies has led to a significant drop in offering yields.

7.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-313366

ABSTRACT

Background: Blood laboratory tests are the most reliable methods for the diagnosis and assessment of vital organs’ functions and the body’s response to infection. Herein, we compared the results of dynamic blood tests between the survivor and non-survivor group of patients with coronavirus disease 2019 (COVID-19) and aimed to determine the predicted and tricky week for death and surveillance. Methods: : The survivor and non-survivor groups were compared using biochemical blood tests, routine blood tests, and coagulation blood tests over four weeks of investigation. Results: : Blood urea nitrogen, creatinine, high-sensitivity C-reactive protein, total bile acid, neutrophil count, white blood cell count, D-dimer, fibrin and fibrinogen degradation product, and prothrombin time showed significantly higher levels in the non-survivor group than the survivor group. Only pre-albumin, eosinophil count, lymphocyte count, red blood cell count, platelet count, hemoglobin, and prothrombin activity tests were significantly higher in the survivor group than the non-survivor group. Generally, the third week of the non-survivor’s group could be regarded as the predicted week for death based on all tests except for creatinine, pre-albumin, total bile acid, monocyte count, white blood cell count, and prothrombin activity. The tricky week in the non-survivor group was the second week in all tests except for pre-albumin, basophil count, eosinophil count, lymphocyte count, platelet count, D-dimer, and fibrin and fibrinogen degradation product. Conclusions: : Based on our study, specific attention should be given to some weeks with respect to their related tests as predicted or tricky for death or surveillance, respectively.

8.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327245

ABSTRACT

Importance: Early treatment of mild SARS-CoV-2 infection might lower the risk of clinical deterioration in COVID-19. Objective: To determine whether oral camostat mesylate would reduce upper respiratory SARS-CoV-2 viral load in newly diagnosed outpatients with mild COVID-19, and would lead to improvement in COVID-19 symptoms. Design: From June, 2020 to April, 2021, we conducted a randomized, double-blind, placebo-controlled phase 2 trial. Setting: Single site, academic medical center, outpatient setting in Connecticut, USA. Participants: Of 568 COVID-19 positive potential adult participants diagnosed within 3 days of study entry and assessed for eligibility, 70 were randomized and 498 were excluded (198 did not meet eligibility criteria, 37 were not interested, 265 were excluded for unknown or other reasons). The primary inclusion criteria were a positive SARS-CoV-2 nucleic acid amplification result in adults within 3 days of screening regardless of COVID-19 symptoms. Intervention: Treatment was 7 days of oral camostat mesylate, 200 mg po four times a day, or placebo. Main Outcomes and Measures: The primary outcome was reduction of 4-day log10 nasopharyngeal swab viral load by 0.5 log10 compared to placebo. The main prespecified secondary outcome was reduction in symptom scores as measured by a quantitative Likert scale instrument, Flu-PRO-Plus modified to measure changes in smell/taste measured using FLU-PRO-Plus. Results: Participants receiving camostat had statistically significant lower quantitative symptom scores (FLU-Pro-Plus) at day 6, accelerated overall symptom resolution and notably improved taste/smell, and fatigue beginning at onset of intervention in the camostat mesylate group compared to placebo. Intention-to-treat analysis demonstrated that camostat mesylate was not associated with a reduction in 4-day log10 NP viral load compared to placebo. Conclusions and relevance: The camostat group had more rapid resolution of COVID-19 symptoms and amelioration of the loss of taste and smell. Camostat compared to placebo was not associated with reduction in nasopharyngeal SARS-COV-2 viral load. Additional clinical trials are warranted to validate the role of camostat mesylate on SARS-CoV-2 infection in the treatment of mild COVID-19. Trial registration: Clinicaltrials.gov, NCT04353284 (04/20/20) (https://clinicaltrials.gov/ct2/show/ NCT04353284 ?term=camostat+%2C+yale&draw=2&rank=1)

9.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-325159

ABSTRACT

At least three months have been passed since the outbreak of the severe acute respiratory disease, COVID-19 in Wuhan city, China in December 2019, caused by the infection of a novel coronavirus, SARS-CoV-2. 1,2 . Due to its rapid spread throughout China and abroad, knowledge sharing for both its epidemiology and clinic manifestations is urgently need. Here we analyzed the clinical, molecular and immunological data from 326 confirmed cases of SARS-CoV-2 infection in Shanghai. Genomic sequences assembled from 112 quality samples together with uploaded sequences in Global Initiative on Sharing All Influenza Data (GISAID) showed a stable evolution and suggested two major lineages with differential exposure history during the earliest outbreak in Wuhan. Nevertheless, they exhibited similar virulence and clinical outcomes. Lymphocytopenia, especially the reduced CD4+ and CD8+ T cell counts upon admission, was predictive of disease progression. High level of IL-6 and IL-8 during treatment was observed in severe and critical patients and correlated with decreased lymphocyte count. The determinants of disease severity seemed to stem mostly from host factors such age, lymphocytopenia and its associated cytokine storm whereas viral genetic variation did not significantly affect the outcomes. This comprehensive analysis on the molecular, immunological and clinical data provides a panorama of the key determinants related to the disease outcomes which should be helpful for improving the current combat against this extremely aggressive pandemic.Authors Xiaonan Zhang, Yun Tan, Yun Ling, Gang Lu, Feng Liu, and Zhigang Yi contributed equally to this work.

10.
Sustainability ; 14(3):1806, 2022.
Article in English | MDPI | ID: covidwho-1674789

ABSTRACT

The Boeing 737 MAX crisis and COVID-19 pandemic have seriously influenced the development of China’s aircraft leasing industry in the past two years. This paper applies system dynamics theory to explore the sustainable development of China’s aircraft leasing industry. It analyses the dynamic mechanism and constructs a system dynamics model. Based on China’s macroeconomic data and historical data from the financial, aviation, and leasing industries, it aims to stimulate the development of China’s aircraft leasing industry in the next five years. Through sensitivity analysis, this research finds that changes in GDP growth have the most obvious impact on the sustainable development of China’s aircraft leasing industry. Reducing the average financing cost and the income tax rate of aircraft leasing companies, increasing their investment in talent, and controlling risk will increase the market share of China’s aircraft leasing companies and promote the development of the industry. However, increasing the number of aircraft leasing companies has little effect on market share. On this basis, this paper proposes policy recommendations to promote the sustainable development of China’s aircraft leasing industry.

11.
Nat Commun ; 13(1): 460, 2022 01 24.
Article in English | MEDLINE | ID: covidwho-1651070

ABSTRACT

The SARS-CoV-2 Delta variant has spread rapidly worldwide. To provide data on its virological profile, we here report the first local transmission of Delta in mainland China. All 167 infections could be traced back to the first index case. Daily sequential PCR testing of quarantined individuals indicated that the viral loads of Delta infections, when they first become PCR-positive, were on average ~1000 times greater compared to lineage A/B infections during the first epidemic wave in China in early 2020, suggesting potentially faster viral replication and greater infectiousness of Delta during early infection. The estimated transmission bottleneck size of the Delta variant was generally narrow, with 1-3 virions in 29 donor-recipient transmission pairs. However, the transmission of minor iSNVs resulted in at least 3 of the 34 substitutions that were identified in the outbreak, highlighting the contribution of intra-host variants to population-level viral diversity during rapid spread.


Subject(s)
COVID-19/transmission , Contact Tracing/methods , Disease Outbreaks/prevention & control , SARS-CoV-2/isolation & purification , Animals , COVID-19/epidemiology , COVID-19/virology , Chlorocebus aethiops , Humans , RNA-Seq/methods , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Time Factors , Vero Cells , Viral Load/genetics , Viral Load/physiology , Virus Replication/genetics , Virus Replication/physiology , Virus Shedding/genetics , Virus Shedding/physiology
12.
Pharmacological Research - Modern Chinese Medicine ; : 100049, 2022.
Article in English | ScienceDirect | ID: covidwho-1620970

ABSTRACT

A B S T R A C T Ethnopharmacological relevance Several studies have confirmed that intestinal microflora dysbiosis correlates with the severity of COVID-19 patients. Clinical meta-analysis and our data show that the circulating miRNAs like miRNA-146 and the levels of serum cytokines in the peripheral blood are closely related to mild to moderate COVID-19 patients. Despite the widespread use of traditional herbal medicine for COVID-19 in China, the mechanisms remain largely uncovered. Aim of the study We conducted an observational case-control study to verify the efficacy and safety of traditional Chinese herbal medicine Qushi Jianpi Hewei Decoction (QJHD) for mild to moderate COVID-19 patients, and investigated the potential biomolecular mechanisms through metagenomics and transcriptomic sequencing methods. Materials and methods QJHD was given orally twice a day individually for 14 to 28 days. A total of 10 patients were enrolled in the study and given QJHD. We observed advantages in clinical cure time rate, and the relief of gastrointestinal symptoms as compared with reports in the literature. The metagenomics sequencing data of fecal microflora and transcriptomic sequencing data of blood cell in patients with SARS-Cov-2 infection patients were selected compared to the healthy control donors. Results No serious adverse events were reported. Meanwhile, the transcriptome analysis showed a decrease of the hsa-miR-21-5p expression in peripheral blood without QJHD. The species composition analysis showed an increase in the expression of Faecalibacterium prausnitzii in the intestinal tract;The interleukin-10 (IL-10) expression also in COVID-19 patient decreased in peripheral blood compared with healthy control donors. And we found an improvement in these parameters in patients taking QJHD. Conclusions Our findings show that QJHD could improve clinical outcomes of mild to moderate COVID-19 patients, probably through beneficial immunomodulatory effects by regulating Faecalibacterium prausnitzii in the intestinal tract and hsa-miR-21 and IL-10 expression in peripheral blood. (chictr.org.cn, ChiCTR2000030305)

13.
Cell Death Differ ; 29(6): 1240-1254, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1612182

ABSTRACT

A recent mutation analysis suggested that Non-Structural Protein 6 (NSP6) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a key determinant of the viral pathogenicity. Here, by transcriptome analysis, we demonstrated that the inflammasome-related NOD-like receptor signaling was activated in SARS-CoV-2-infected lung epithelial cells and Coronavirus Disease 2019 (COVID-19) patients' lung tissues. The induction of inflammasomes/pyroptosis in patients with severe COVID-19 was confirmed by serological markers. Overexpression of NSP6 triggered NLRP3/ASC-dependent caspase-1 activation, interleukin-1ß/18 maturation, and pyroptosis of lung epithelial cells. Upstream, NSP6 impaired lysosome acidification to inhibit autophagic flux, whose restoration by 1α,25-dihydroxyvitamin D3, metformin or polydatin abrogated NSP6-induced pyroptosis. NSP6 directly interacted with ATP6AP1, a vacuolar ATPase proton pump component, and inhibited its cleavage-mediated activation. L37F NSP6 variant, which was associated with asymptomatic COVID-19, exhibited reduced binding to ATP6AP1 and weakened ability to impair lysosome acidification to induce pyroptosis. Consistently, infection of cultured lung epithelial cells with live SARS-CoV-2 resulted in autophagic flux stagnation, inflammasome activation, and pyroptosis. Overall, this work supports that NSP6 of SARS-CoV-2 could induce inflammatory cell death in lung epithelial cells, through which pharmacological rectification of autophagic flux might be therapeutically exploited.


Subject(s)
COVID-19 , Coronavirus Nucleocapsid Proteins , NLR Family, Pyrin Domain-Containing 3 Protein , SARS-CoV-2 , Vacuolar Proton-Translocating ATPases , COVID-19/metabolism , COVID-19/virology , Coronavirus Nucleocapsid Proteins/genetics , Coronavirus Nucleocapsid Proteins/metabolism , Humans , Inflammasomes/metabolism , Interleukin-1beta/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pyroptosis , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Vacuolar Proton-Translocating ATPases/metabolism
14.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-295289

ABSTRACT

Summary We report the first local transmission of the SARS-CoV-2 Delta variant in mainland China. All 167 infections could be traced back to the first index case. Daily sequential PCR testing of the quarantined subjects indicated that the viral loads of Delta infections, when they first become PCR+, were on average ∼1000 times greater compared to A/B lineage infections during initial epidemic wave in China in early 2020, suggesting potentially faster viral replication and greater infectiousness of Delta during early infection. We performed high-quality sequencing on samples from 126 individuals. Reliable epidemiological data meant that, for 111 transmission events, the donor and recipient cases were known. The estimated transmission bottleneck size was 1-3 virions with most minor intra-host single nucleotide variants (iSNVs) failing to transmit to the recipients. However, transmission heterogeneity of SARS-CoV-2 was also observed. The transmission of minor iSNVs resulted in at least 4 of the 30 substitutions identified in the outbreak, highlighting the contribution of intra-host variants to population level viral diversity during rapid spread. Disease control activities, such as the frequency of population testing, quarantine during pre-symptomatic infection, and level of virus genomic surveillance should be adjusted in order to account for the increasing prevalence of the Delta variant worldwide.

15.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-293892

ABSTRACT

Background: COVID-19 pandemic is underway. Some COVID-19 cases re-tested positive for SARS-CoV-2 RNA after discharge raising the public concern on their infectivity. Characterization of re-positive cases are urgently needed for designing intervention strategies. <br><br>Methods: Clinical data were obtained through Guangdong COVID-19 surveillance network. Neutralization antibody titre was determined using a microneutralization assay. Potential infectivity of clinical samples was evaluated after the cell inoculation. SARS-CoV-2 RNA was detected using three different RT-PCR kits and multiplex PCR with nanopore sequencing. <br><br>Findings: Among 619 discharged COVID-19 cases, 87 were re-tested as SARS-CoV-2 positive in circumstance of social isolation. All re-positive cases had mild or moderate symptoms in initial diagnosis and a younger age distribution (mean, 30·4). Re-positive cases (n=59) exhibited similar neutralization antibodies (NAbs) titre distributions to other COVID-19 cases (n=150) parallel-tested in this study. No infective viral strain could be obtained by culture and none full-length viral genomes could be sequenced for all re-positive cases. I<br><br>nterpretation: Re-positive SARS-CoV-2 was not caused by the secondary infection and was identified in around 14% of discharged cases. A robust Nabs response and a potential virus genome degradation were detected from nearly all re-positive cases suggesting a lower transmission risk, especially through a respiratory route. <br><br>Funding: This work was supported by grants from Guangdong Provincial Novel Coronavirus Scientific and Technological Project (2020111107001), Science and Technology Planning Project of Guangdong(2018B020207006), National Science and Technology Project(2020YFC0846800).<br><br>Declaration of Interests: All authors: No reported conflicts of interest.<br><br>Ethics Approval Statement: This study was reviewed and approved by the Medical Ethical Committee of Guangdong Provincial Center for Disease Control and Prevention. Data collection and analysis of cases were determined by the Health Commission of Guangdong province to be part of a continuing public health outbreak investigation during the emergency response and were thus considered exempt from institutional review board approval.

16.
Microbiol Spectr ; 9(3): e0101721, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1522923

ABSTRACT

A big challenge for the control of COVID-19 pandemic is the emergence of variants of concern (VOCs) or variants of interest (VOIs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may be more transmissible and/or more virulent and could escape immunity obtained through infection or vaccination. A simple and rapid test for SARS-CoV-2 variants is an unmet need and is of great public health importance. In this study, we designed and analytically validated a CRISPR-Cas12a system for direct detection of SARS-CoV-2 VOCs. We further evaluated the combination of ordinary reverse transcription-PCR (RT-PCR) and CRISPR-Cas12a to improve the detection sensitivity and developed a universal system by introducing a protospacer adjacent motif (PAM) near the target mutation sites through PCR primer design to detect mutations without PAM. Our results indicated that the CRISPR-Cas12a assay could readily detect the signature spike protein mutations (K417N/T, L452R/Q, T478K, E484K/Q, N501Y, and D614G) to distinguish alpha, beta, gamma, delta, kappa, lambda, and epsilon variants of SARS-CoV-2. In addition, the open reading frame 8 (ORF8) mutations (T/C substitution at nt28144 and the corresponding change of amino acid L/S) could differentiate L and S lineages of SARS-CoV-2. The low limit of detection could reach 10 copies/reaction. Our assay successfully distinguished 4 SARS-CoV-2 strains of wild type and alpha (B.1.1.7), beta (B.1.351), and delta (B.1.617.2) variants. By testing 32 SARS-CoV-2-positive clinical samples infected with the wild type (n = 5) and alpha (n = 11), beta (n = 8), and delta variants (n = 8), the concordance between our assay and sequencing was 100%. The CRISPR-based approach is rapid and robust and can be adapted for screening the emerging mutations and immediately implemented in laboratories already performing nucleic acid amplification tests or in resource-limited settings. IMPORTANCE We described CRISPR-Cas12-based multiplex allele-specific assay for rapid SARS-CoV-2 variant genotyping. The new system has the potential to be quickly developed, continuously updated, and easily implemented for screening of SARS-CoV-2 variants in resource-limited settings. This approach can be adapted for emerging mutations and implemented in laboratories already conducting SARS-CoV-2 nucleic acid amplification tests using existing resources and extracted nucleic acid.


Subject(s)
COVID-19 Testing/methods , COVID-19/virology , CRISPR-Cas Systems , SARS-CoV-2/classification , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Alleles , COVID-19/diagnosis , Databases, Nucleic Acid , Humans , Mass Screening , Mutation , Polymerase Chain Reaction , Public Health , Spike Glycoprotein, Coronavirus/genetics
17.
J Virol ; 95(24): e0153721, 2021 11 23.
Article in English | MEDLINE | ID: covidwho-1434898

ABSTRACT

Autophagy is thought to be involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, how SARS-CoV-2 interferes with the autophagic pathway and whether autophagy contributes to virus infection in vivo is unclear. In this study, we identified SARS-CoV-2-triggered autophagy in animal models, including the long-tailed or crab-eating macaque (Macaca fascicularis), human angiotensin-converting enzyme 2 (hACE2) transgenic mice, and xenografted human lung tissues. In Vero E6 and Huh-7 cells, SARS-CoV-2 induces autophagosome formation, accompanied by consistent autophagic events, including inhibition of the Akt-mTOR pathway and activation of the ULK-1-Atg13 and VPS34-VPS15-Beclin1 complexes, but it blocks autophagosome-lysosome fusion. Modulation of autophagic elements, including the VPS34 complex and Atg14, but not Atg5, inhibits SARS-CoV-2 replication. Moreover, this study represents the first to demonstrate that the mouse bearing xenografted human lung tissue is a suitable model for SARS-CoV-2 infection and that autophagy inhibition suppresses SARS-CoV-2 replication and ameliorates virus-associated pneumonia in human lung tissues. We also observed a critical role of autophagy in SARS-CoV-2 infection in an hACE2 transgenic mouse model. This study, therefore, gives insights into the mechanisms by which SARS-CoV-2 manipulates autophagosome formation, and we suggest that autophagy-inhibiting agents might be useful as therapeutic agents against SARS-CoV-2 infection. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic with limited therapeutics. Insights into the virus-host interactions contribute substantially to the development of anti-SARS-CoV-2 therapeutics. The novelty of this study is the use of a new animal model: mice xenografted with human lung tissues. Using a combination of in vitro and in vivo studies, we have obtained experimental evidence that induction of autophagy contributes to SARS-CoV-2 infection and improves our understanding of potential therapeutic targets for SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Autophagy , COVID-19/drug therapy , COVID-19/virology , Lung/virology , SARS-CoV-2 , Virus Replication , Angiotensin-Converting Enzyme 2/metabolism , Animals , Autophagosomes , Cell Line, Tumor , Chlorocebus aethiops , Humans , Lung/pathology , Macaca , Male , Mice , Mice, Transgenic , Pneumonia, Viral/drug therapy , RNA, Small Interfering/metabolism , Vero Cells
18.
Front Psychiatry ; 12: 707342, 2021.
Article in English | MEDLINE | ID: covidwho-1394827

ABSTRACT

Background: The emergence of coronavirus disease 2019 (COVID-19) has created a severe mental health problem for international students living in China. Despite the little information on the psychological impact on international students, we aimed to assess the psychological outcomes and associated factors among international students currently living in China during the COVID-19 pandemic. Methods: An online cross-sectional survey was conducted from May 28, 2020 to June 12, 2020 on 402 full-time international students across 26 provinces in China. The frequency of symptoms of depression, anxiety, stress, insomnia, psychological distress, loneliness, and fear was assessed with the English versions of the Depression Anxiety Stress Scale (DASS-21), Insomnia Severity Index (ISI), Kessler Psychological Distress Scale (K6), University of California, Los Angeles, Loneliness Scale (UCLA-LS), and Fear of COVID-19 scale (FCV-19S) scales, respectively. Results: The prevalence of symptoms of depression (73.4%), anxiety (76.6%), stress (58.5%), insomnia (77.6%), psychological distress (71.4%), loneliness (62.4%), and fear (73.1%) among international students during the COVID-19 pandemic was shown. The prevalence of moderate to extremely severe symptoms of all psychological outcomes was significantly associated with 26-30-year-old students, students who lived with roommates, and students who stayed in China shorter than 2 years. Participants in the central region reported significantly moderate to extremely severe symptom levels of all the psychological outcomes except fear symptoms. Univariate analysis indicated that a significant association of all psychological outcomes was found among 26-30-year-old students and students who stayed in China shorter than 2 years. Multivariate analysis showed that Engineering, Business, Social Sciences and Law, and Language students were significantly associated with the symptoms of depression, anxiety, insomnia, and fear. Participants staying in China for shorter than 2 years were associated with a higher risk of all psychological outcomes except psychological distress and loneliness symptoms. Conclusions: We found a higher prevalence of psychological outcomes and risk factors among international students during the COVID-19 pandemic. We immediately appealed to university authorities, mental health professionals, and government officials to provide mental health interventions and strategies for their international students, particularly young, central region students, living with roommates, different study backgrounds, and short time staying during the pandemic.

20.
Contemp Clin Trials ; 110: 106547, 2021 11.
Article in English | MEDLINE | ID: covidwho-1372905

ABSTRACT

BACKGROUND: Despite improvement in the standard of care (SOC) for hospitalized COVID-19 patients, rates of morbidity and mortality remain high. There continues to be a need for easily available and cost-effective treatments. Colchicine and rosuvastatin are both safe and well-studied medications with anti-inflammatory and other pleiotropic effects that may provide additional benefits to hospitalized COVID-19 patients. METHODS AND RESULTS: The Colchicine/Statin for the Prevention of COVID-19 Complications (COLSTAT) trial is a pragmatic, open-label, multicenter, randomized trial comparing the combination of colchicine and rosuvastatin in addition to SOC to SOC alone in hospitalized COVID-19 patients. Four centers in the Yale New Haven Health network will enroll a total of 466 patients with 1:1 randomization. The trial will utilize the electronic health record (Epic® Systems, Verona, Wisconsin, USA) at all stages including screening, randomization, intervention, event ascertainment, and follow-up. The primary endpoint is the 30-day composite of progression to severe COVID-19 disease as defined by the World Health Organization ordinal scale of clinical improvement and arterial/venous thromboembolic events. The secondary powered endpoint is the 30-day composite of death, respiratory failure requiring intubation, and myocardial injury. CONCLUSIONS: The COLSTAT trial will provide evidence on the efficacy of repurposing colchicine and rosuvastatin for the treatment of hospitalized COVID-19 patients. Moreover, it is designed to be a pragmatic trial that will demonstrate the power of using electronic health records to improve efficiency and enrollment in clinical trials in an adapting landscape. CLINICAL TRIAL REGISTRATION: NCT04472611 (https://clinicaltrials.gov/ct2/show/NCT04472611).


Subject(s)
COVID-19 , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Colchicine/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , SARS-CoV-2 , Treatment Outcome
SELECTION OF CITATIONS
SEARCH DETAIL