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1.
Gigascience ; 112022 05 18.
Article in English | MEDLINE | ID: covidwho-1853072

ABSTRACT

BACKGROUND: The masked palm civet (Paguma larvata) acts as an intermediate host of severe acute respiratory syndrome coronavirus (SARS-CoV), which caused SARS, and transfered this virus from bats to humans. Additionally, P. larvata has the potential to carry a variety of zoonotic viruses that may threaten human health. However, genome resources for P. larvata have not been reported to date. FINDINGS: A chromosome-level genome assembly of P. larvata was generated using PacBio sequencing, Illumina sequencing, and Hi-C technology. The genome assembly was 2.44 Gb in size, of which 95.32% could be grouped into 22 pseudochromosomes, with contig N50 and scaffold N50 values of 12.97 Mb and 111.81 Mb, respectively. A total of 21,582 protein-coding genes were predicted, and 95.20% of the predicted genes were functionally annotated. Phylogenetic analysis of 19 animal species confirmed the close genetic relationship between P. larvata and species belonging to the Felidae family. Gene family clustering revealed 119 unique, 243 significantly expanded, and 58 significantly contracted genes in the P. larvata genome. We identified 971 positively selected genes in P. larvata, and one known human viral receptor gene PDGFRA is positively selected in P. larvata, which is required for human cytomegalovirus infection. CONCLUSIONS: This high-quality genome assembly provides a valuable genomic resource for exploring virus-host interactions. It will also provide a reliable reference for studying the genetic bases of the morphologic characteristics, adaptive evolution, and evolutionary history of this species.


Subject(s)
Genome , Viverridae , Animals , Chromosomes , Genomics , Phylogeny , Viverridae/genetics
2.
Micromachines (Basel) ; 12(11)2021 Nov 19.
Article in English | MEDLINE | ID: covidwho-1534188

ABSTRACT

Digital microfluidic (DMF) has been a unique tool for manipulating micro-droplets with high flexibility and accuracy. To extend the application of DMF for automatic and in-site detection, it is promising to introduce colorimetric sensing based on gold nanoparticles (AuNPs), which have advantages including high sensitivity, label-free, biocompatibility, and easy surface modification. However, there is still a lack of studies for investigating the movement and stability of AuNPs for in-site detection on the electrowetting-based digital microfluidics. Herein, to demonstrate the ability of DMF for colorimetric sensing with AuNPs, we investigated the electrowetting property of the AuNPs droplets on the hydrophobic interface of the DMF chip and examined the stability of the AuNPs on DMF as well as the influence of evaporation to the colorimetric sensing. As a result, we found that the electrowetting of AuNPs fits to a modified Young-Lippmann equation, which suggests that a higher voltage is required to actuate AuNPs droplets compared with actuating water droplets. Moreover, the stability of AuNPs was maintained during the processing of electrowetting. We also proved that the evaporation of droplets has a limited influence on the detections that last several minutes. Finally, a model experiment for the detection of Hg2+ was carried out with similar results to the detections in bulk solution. The proposed method can be further extended to a wide range of AuNPs-based detection for label-free, automatic, and low-cost detection of small molecules, biomarkers, and metal ions.

3.
J Biol Chem ; 297(5): 101315, 2021 11.
Article in English | MEDLINE | ID: covidwho-1472025

ABSTRACT

Coagulopathy is associated with both inflammation and infection, including infections with novel severe acute respiratory syndrome coronavirus-2, the causative agent Coagulopathy is associated with both inflammation and infection, including infection with novel severe acute respiratory syndrome coronavirus-2, the causative agent of COVID-19. Clot formation is promoted via cAMP-mediated secretion of von Willebrand factor (vWF), which fine-tunes the process of hemostasis. The exchange protein directly activated by cAMP (EPAC) is a ubiquitously expressed intracellular cAMP receptor that plays a regulatory role in suppressing inflammation. To assess whether EPAC could regulate vWF release during inflammation, we utilized our EPAC1-null mouse model and revealed increased secretion of vWF in endotoxemic mice in the absence of the EPAC1 gene. Pharmacological inhibition of EPAC1 in vitro mimicked the EPAC1-/- phenotype. In addition, EPAC1 regulated tumor necrosis factor-α-triggered vWF secretion from human umbilical vein endothelial cells in a manner dependent upon inflammatory effector molecules PI3K and endothelial nitric oxide synthase. Furthermore, EPAC1 activation reduced inflammation-triggered vWF release, both in vivo and in vitro. Our data delineate a novel regulatory role for EPAC1 in vWF secretion and shed light on the potential development of new strategies to control thrombosis during inflammation.


Subject(s)
Endothelial Cells/metabolism , Guanine Nucleotide Exchange Factors/metabolism , Nitric Oxide Synthase Type III/metabolism , Phosphatidylinositol 3-Kinases/metabolism , von Willebrand Factor/metabolism , Animals , COVID-19/metabolism , Disease Models, Animal , Guanine Nucleotide Exchange Factors/deficiency , Guanine Nucleotide Exchange Factors/genetics , Inflammation/metabolism , Mice , Mice, Knockout
4.
Cell Discov ; 7(1): 49, 2021 Jul 06.
Article in English | MEDLINE | ID: covidwho-1298837

ABSTRACT

SARS-CoV-2 infection causes a wide spectrum of clinical manifestations in humans, and olfactory dysfunction is one of the most predictive and common symptoms in COVID-19 patients. However, the underlying mechanism by which SARS-CoV-2 infection leads to olfactory disorders remains elusive. Herein, we demonstrate that intranasal inoculation with SARS-CoV-2 induces robust viral replication in the olfactory epithelium (OE), not the olfactory bulb (OB), resulting in transient olfactory dysfunction in humanized ACE2 (hACE2) mice. The sustentacular cells and Bowman's gland cells in the OE were identified as the major target cells of SARS-CoV-2 before invasion into olfactory sensory neurons (OSNs). Remarkably, SARS-CoV-2 infection triggers massive cell death and immune cell infiltration and directly impairs the uniformity of the OE structure. Combined transcriptomic and quantitative proteomic analyses revealed the induction of antiviral and inflammatory responses, as well as the downregulation of olfactory receptor (OR) genes in the OE from the infected animals. Overall, our mouse model recapitulates olfactory dysfunction in COVID-19 patients and provides critical clues for understanding the physiological basis for extrapulmonary manifestations of COVID-19.

5.
Viruses ; 13(6)2021 06 21.
Article in English | MEDLINE | ID: covidwho-1287275

ABSTRACT

The recently discovered exchange protein directly activated by cAMP (EPAC), compared with protein kinase A (PKA), is a fairly new family of cAMP effectors. Soon after the discovery, EPAC has shown its significance in many diseases including its emerging role in infectious diseases. In a recent study, we demonstrated that EPAC, but not PKA, is a promising therapeutic target to regulate respiratory syncytial virus (RSV) replication and its associated inflammation. In mammals, there are two isoforms of EPAC-EPAC1 and EPAC2. Unlike other viruses, including Middle East respiratory syndrome coronavirus (MERS-CoV) and Ebola virus, which use EPAC1 to regulate viral replication, RSV uses EPAC2 to control its replication and associated cytokine/chemokine responses. To determine whether EPAC2 protein has a broad impact on other respiratory viral infections, we used an EPAC2-specific inhibitor, MAY0132, to examine the functions of EPAC2 in human metapneumovirus (HMPV) and adenovirus (AdV) infections. HMPV is a negative-sense single-stranded RNA virus belonging to the family Pneumoviridae, which also includes RSV, while AdV is a double-stranded DNA virus. Treatment with an EPAC1-specific inhibitor was also included to investigate the impact of EPAC1 on these two viruses. We found that the replication of HMPV, AdV, and RSV and the viral-induced immune mediators are significantly impaired by MAY0132, while an EPAC1-specific inhibitor, CE3F4, does not impact or slightly impacts, demonstrating that EPAC2 could serve as a novel common therapeutic target to control these viruses, all of which do not have effective treatment and prevention strategies.


Subject(s)
Adenoviridae/physiology , Guanine Nucleotide Exchange Factors/genetics , Guanine Nucleotide Exchange Factors/metabolism , Metapneumovirus/physiology , Respiratory Syncytial Virus, Human/physiology , Virus Replication , A549 Cells , Cell Line , Chemokines/immunology , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Cyclic AMP-Dependent Protein Kinases/metabolism , Epithelial Cells/drug effects , Epithelial Cells/virology , Guanine Nucleotide Exchange Factors/antagonists & inhibitors , HEK293 Cells , Humans , Quinolines/pharmacology
6.
Nano Today ; 38: 101139, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1142163

ABSTRACT

Effective vaccines are vital to fight against the COVID-19 global pandemic. As a critical component of a subunit vaccine, the adjuvant is responsible for strengthening the antigen-induced immune responses. Here, we present a new nanovaccine that comprising the Receptor-Binding Domain (RBD) of spike protein and the manganese nanoadjuvant (MnARK), which induces humoral and cellular responses. Notably, even at a 5-fold lower antigen dose and with fewer injections, the MnARK vaccine immunized mice showed stronger neutralizing abilities against the infection of the pseudovirus (~270-fold) and live coronavirus (>8-fold) in vitro than that of Alum-adsorbed RBD vaccine (Alu-RBD). Furthermore, we found that the effective co-delivery of RBD antigen and MnARK to lymph nodes (LNs) elicited an increased cellular internalization and the activation of immune cells, including DCs, CD4+ and CD8+ T lymphocytes. Our findings highlight the importance of MnARK adjuvant in the design of novel coronavirus vaccines and provide a rationale strategy to design protective vaccines through promoting cellular internalization and the activation of immune-related pathways.

7.
Cell Res ; 31(4): 404-414, 2021 04.
Article in English | MEDLINE | ID: covidwho-1054016

ABSTRACT

The newly identified Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has resulted in a global health emergency because of its rapid spread and high mortality. The molecular mechanism of interaction between host and viral genomic RNA is yet unclear. We demonstrate herein that SARS-CoV-2 genomic RNA, as well as the negative-sense RNA, is dynamically N6-methyladenosine (m6A)-modified in human and monkey cells. Combined RIP-seq and miCLIP analyses identified a total of 8 m6A sites at single-base resolution in the genome. Especially, epidemic strains with mutations at these identified m6A sites have emerged worldwide, and formed a unique cluster in the US as indicated by phylogenetic analysis. Further functional experiments showed that m6A methylation negatively regulates SARS-CoV-2 infection. SARS-CoV-2 infection also triggered a global increase in host m6A methylome, exhibiting altered localization and motifs of m6A methylation in mRNAs. Altogether, our results identify m6A as a dynamic epitranscriptomic mark mediating the virus-host interaction.


Subject(s)
Adenosine/analogs & derivatives , Genome, Viral , SARS-CoV-2/genetics , Adenosine/metabolism , Animals , COVID-19/pathology , COVID-19/virology , Cell Line , Chlorocebus aethiops , DNA Methylation , Gene Expression Regulation , Host-Pathogen Interactions , Humans , Mutagenesis, Site-Directed , Phylogeny , RNA, Messenger/genetics , SARS-CoV-2/classification , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Vero Cells , Virus Replication
8.
SciFinder; 2020.
Preprint | SciFinder | ID: ppcovidwho-5272

ABSTRACT

A review. OBJECTIVE To explore the rational use of drugs and pharmaceutical care strategies under COVID-19 epidemic. METHODS This paper introduced our pharmaceutical care practices in the aspects of rational drug application anal., evidence-based pharmaceutical evaluations, medication decisions in special populations, pharmaceutical care, online consultation, and education, based on the first-line anti-epidemic experience. RESULTS On the basis of the practice, strategies of Clin. pharmacy under COVID-19 epidemic have been developed. CONCLUSION In the face of the sudden epidemic, clin. pharmacists adjusted their work focus rapidly, and became a new line of defense to guarantee the safety, effectiveness of drug therapy and promote rational drug use ultimately.

9.
Med Res Rev ; 41(3): 1375-1426, 2021 05.
Article in English | MEDLINE | ID: covidwho-956732

ABSTRACT

In the past two decades, three highly pathogenic human coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus, and, recently, SARS-CoV-2, have caused pandemics of severe acute respiratory diseases with alarming morbidity and mortality. Due to the lack of specific anti-CoV therapies, the ongoing pandemic of coronavirus disease 2019 (COVID-19) poses a great challenge to clinical management and highlights an urgent need for effective interventions. Drug repurposing is a rapid and feasible strategy to identify effective drugs for combating this deadly infection. In this review, we summarize the therapeutic CoV targets, focus on the existing small molecule drugs that have the potential to be repurposed for existing and emerging CoV infections of the future, and discuss the clinical progress of developing small molecule drugs for COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Repositioning , Antiviral Agents/pharmacology , COVID-19/virology , Drug Delivery Systems , Humans , SARS-CoV-2/drug effects , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use
10.
Chinese Journal of Nosocomiology ; 30(19):2881-2885, 2020.
Article in Chinese | GIM | ID: covidwho-923213

ABSTRACT

Objective: Angiotensin-converting enzyme 2(ACE2) in metallopeptidase has been identified as a functional receptor for COVID-19. The purpose of this study was to explore the difference in the expression of ACE2 in COVID-19-induced pneumonia(hereinafter referred to as "COVID-19").

11.
Aging (Albany NY) ; 12(19): 18878-18888, 2020 Oct 08.
Article in English | MEDLINE | ID: covidwho-841406

ABSTRACT

In this retrospective study we assessed the efficacy and safety of tocilizumab in patients with critical or severe coronavirus disease 2019 (COVID-19). We enrolled 181 patients admitted to Huoshenshan Hospital (Wuhan, China) with confirmed COVID-19 between January 2020 and February 2020. Ninety-two patients were treated with tocilizumab, and 89 patients were treated conventionally. We analyzed the clinical manifestations, changes in CT scan images, and laboratory tests before and after tocilizumab treatment, and compared these results with the conventionally treated group. A significant reduction in the level of C-reactive protein was observed 1 week after tocilizumab administration. In some cases this meant the end of the IL-6-related cytokine storm. In addition, tocilizumab relieved fever, cough, and shortness of breath with no reported adverse drug reactions. These findings suggest tocilizumab improves clinical outcomes and is effective for treatment of patients with critical or severe COVID-19. However, future clinical trials are needed to better understand the impact of tocilizumab interference with IL-6 and provide a therapeutic strategy for treatment of COVID-19.

12.
World J Acupunct Moxibustion ; 30(3): 171-174, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-654760

ABSTRACT

The paper reports the experiences in treatment of two cases of corona virus disease 2019 (COVID-19) with the combination of acupuncture and medication in bedridden patients confirmed in C7 Inpatient Ward, Wuhan Leishenshan Hospital, China. The combined treatment of acupuncture with the oral administration of "Shanghai leishen No.1 formula" was given every day. The prescription was modified weekly according the symptoms of the patients. Besides, the antivirus, anti-infectious and symptomatic treatment of western medicine was combined. Both of the two cases were improved and discharged. It is anticipated that the treatment experiences in these two cases may provide the instruction and enlightenment for the prevention and treatment of COVID-19.

13.
ACS Infect Dis ; 6(5): 909-915, 2020 05 08.
Article in English | MEDLINE | ID: covidwho-3265

ABSTRACT

The recent outbreak of coronavirus disease 2019 (COVID-19) highlights an urgent need for therapeutics. Through a series of drug repurposing screening campaigns, niclosamide, an FDA-approved anthelminthic drug, was found to be effective against various viral infections with nanomolar to micromolar potency such as SARS-CoV, MERS-CoV, ZIKV, HCV, and human adenovirus, indicating its potential as an antiviral agent. In this brief review, we summarize the broad antiviral activity of niclosamide and highlight its potential clinical use in the treatment of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus Infections/drug therapy , Drug Repositioning , Niclosamide/pharmacology , Pneumonia, Viral/drug therapy , Betacoronavirus/drug effects , COVID-19 , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , Pandemics , SARS Virus/drug effects , SARS-CoV-2
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