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1.
Front Cell Infect Microbiol ; 12: 880915, 2022.
Article in English | MEDLINE | ID: covidwho-1847156

ABSTRACT

With the epidemic of betacoronavirus increasing frequently, it poses a great threat to human public health. Therefore, the research on the pathogenic mechanism of betacoronavirus is becoming greatly important. Murine hepatitis virus strain-3 (MHV-3) is a strain of betacoronavirus which cause tissue damage especially fulminant hepatic failure (FHF) in mice, and is commonly used to establish models of acute liver injury. Recently, MHV-3-infected mice have also been introduced to a mouse model of COVID-19 that does not require a Biosafety Level 3 (BSL-3) facility. FHF induced by MHV-3 is a type of severe liver damage imbalanced by regenerative hepatocellular activity, which is related to numerous factors. The complement system plays an important role in host defense and inflammation and is involved in first-line immunity and/or pathogenesis of severe organ disorders. In this study, we investigated the role of aberrant complement activation in MHV-3 infection-induced FHF by strategies that use C3-deficient mice and intervene in the complement system. Our results showed that mice deficient in C3 had more severe liver damage, a higher viral load in the liver and higher serum concentrations of inflammatory cytokines than wild-type controls. Treatment of C57BL/6 mice with C3aR antagonist or anti-C5aR antibody reduced liver damage, viral load, and serum IFN-γ concentration compared with the control group. These findings indicated that complement system acts as a double-edged sword during acute MHV-3 infection. However, its dysregulated activation leads to sustained inflammatory responses and induces extensive liver damage. Collectively, by investigating the role of complement activation in MHV-3 infection, we can further understand the pathogenic mechanism of betacoronavirus, and appropriate regulation of immune responses by fine-tuning complement activation may be an intervention for the treatment of diseases induced by betacoronavirus infection.


Subject(s)
COVID-19 , Liver Failure, Acute , Murine hepatitis virus , Animals , Complement Activation , Liver Failure, Acute/pathology , Mice , Mice, Inbred C57BL
2.
Exp Biol Med (Maywood) ; : 15353702221091180, 2022 May 01.
Article in English | MEDLINE | ID: covidwho-1820101

ABSTRACT

Epidemiological data across the United States show health disparities in COVID-19 infection, hospitalization, and mortality by race/ethnicity. While the association between elevated SARS-CoV-2 viral loads (VLs) (i.e. upper respiratory tract (URT) and peripheral blood (PB)) and increased COVID-19 severity has been reported, data remain largely unavailable for some disproportionately impacted racial/ethnic groups, particularly for American Indian or Alaska Native (AI/AN) populations. As such, we determined the relationship between SARS-CoV-2 VL dynamics and disease severity in a diverse cohort of hospitalized patients. Results presented here are for study participants (n = 94, ages 21-88 years) enrolled in a prospective observational study between May and October 2020 who had SARS-CoV-2 viral clades 20A, C, and G. Based on self-reported race/ethnicity and sample size distribution, the cohort was stratified into two groups: (AI/AN, n = 43) and all other races/ethnicities combined (non-AI/AN, n = 51). SARS-CoV-2 VLs were quantified in the URT and PB on days 0-3, 6, 9, and 14. The strongest predictor of severe COVID-19 in the study population was the mean VL in PB (OR = 3.34; P = 2.00 × 10-4). The AI/AN group had the following: (1) comparable co-morbidities and admission laboratory values, yet more severe COVID-19 (OR = 4.81; P = 0.014); (2) a 2.1 longer duration of hospital stay (P = 0.023); and (3) higher initial and cumulative PB VLs during severe disease (P = 0.025). Moreover, self-reported race/ethnicity as AI/AN was the strongest predictor of elevated PB VLs (ß = 1.08; P = 6.00 × 10-4) and detection of SARS-CoV-2 in PB (hazard ratio = 3.58; P = 0.004). The findings presented here suggest a strong relationship between PB VL (magnitude and frequency) and severe COVID-19, particularly for the AI/AN group.

3.
Front Microbiol ; 13: 860851, 2022.
Article in English | MEDLINE | ID: covidwho-1775716

ABSTRACT

Porcine hemagglutinating encephalomyelitis virus (PHEV) is a Betacoronavirus characterized by neurological symptoms and a worldwide prevalence. Although PHEV is one of the earliest discovered porcine coronaviruses, it remains poorly studied. The full-length genome of the earliest PHEV strain collected in 1970 in the United States (PHEV/67 N/US/1970) was determined in October 2020. Using this virus as a prototype, we comparatively analyzed all available PHEV full-length sequences during 1970-2015. In phylogenetic trees based on PHEV full-length or spike glycoprotein open reading frame genomic sequences, PHEV/67 N/US/1970 was sorted into a clade different from that of viruses isolated in the United States in 2015. Intriguingly, United States and Belgium viruses isolated in 2015 and 2005, respectively, revealed multiple deletion mutation patterns compared to the strain PHEV/67 N/US/1970, leading to a truncated or a non-functional NS2A coding region. In addition, the genomic similarity analysis showed a hypervariability of the spike glycoprotein coding region, which can affect at least eight potential linear B cell epitopes located in the spike glycoprotein. This report indicates that PHEVs in the United States underwent a significant genetic drift, which might influence PHEV surveillance in other countries.

4.
Research in Transportation Economics ; : 101185, 2022.
Article in English | ScienceDirect | ID: covidwho-1768488

ABSTRACT

Using high-frequency logistics data from China, this paper quantitatively examines the negative impact of the COVID-19 pandemic on logistics. Meanwhile, our research focuses on the toll-free highway policy during the COVID-19 pandemic, analyzing the promoting effect of this policy on road freight in China. Three main conclusions are drawn from the study. Firstly, the COVID-19 pandemic led to an average daily drop of 0.67% in road freight volume and an increase of 0.48% in logistic cost compared to the pre-pandemic period. Secondly, the toll-free highway policy had a significant offset effect of pandemic on freight volume and price, stimulating the resumption of work and production. However, the dynamic effect shows that the toll-free highway policy is only temporarily effective rather than the long term. Thirdly, the effectiveness of the toll-free highway policy is moderated by the severity of the epidemic and the transportation distance. This paper contributes to research on economy recovery and transportation policy under the COVID-19 pandemic shock.

5.
Nanomaterials (Basel) ; 12(5)2022 Feb 22.
Article in English | MEDLINE | ID: covidwho-1742560

ABSTRACT

Proteinaceous nanovaccine delivery systems have significantly promoted the development of various high-efficiency vaccines. However, the widely used method of coupling the expression of scaffolds and antigens may result in their structural interference with each other. Monovalent streptavidin (mSA) is a short monomer sequence, which has a strong affinity for biotin. Here, we discuss an orthogonal, modular, and highly versatile self-assembled proteinaceous nanoparticle chassis that facilitates combinations with various antigen cargos by using mSA and biotin to produce nanovaccines. We first improved the yield of these nanoparticles by appending a short sugar chain on their surfaces in a constructed host strain. After confirming the strong ability to induce both Th1- and Th2-mediated immune responses based on the plasma cytokine spectrum from immunized mice, we further verified the binding ability of biotinylated nanoparticles to mSA-antigens. These results demonstrate that our biotinylated nanoparticle chassis could load both protein and polysaccharide antigens containing mSA at a high affinity. Our approach thus offers an attractive technology for combining nanoparticles and antigen cargos to generate various high-performance nanovaccines. In particular, the designed mSA connector (mSA containing glycosylation modification sequences) could couple with polysaccharide antigens, providing a new attractive strategy to prepare nanoscale conjugate vaccines.

6.
BMC Health Serv Res ; 22(1): 299, 2022 Mar 04.
Article in English | MEDLINE | ID: covidwho-1724483

ABSTRACT

BACKGROUND: The COVID-19 pandemic has exerted an unprecedented and universal impact on global health system, resulting in noticeable challenges in traditional chronic disease care, of which diabetes was reported to be most influenced by the reduction in healthcare resources in the pandemic. China has the world's largest diabetes population, and current diabetes management in China is unsatisfactory, particularly in rural areas. Studies in developed countries have demonstrated that physician-pharmacist collaborative clinics are efficient and cost-effective for diabetes management, but little is known if this mode could be adapted in primary hospitals in China. The aim of this proposed study is to develop and evaluate physician-pharmacist collaborative clinics to manage type 2 diabetes mellitus (T2DM) in primary hospitals in Hunan province. METHODS: A multi-site randomized controlled trial will be conducted to evaluate the effectiveness and cost-effectiveness of the physician-pharmacist collaborative clinics compared with usual care for Chinese patients with T2DM. Six primary hospitals will participate in the study, which will recruit 600 eligible patients. Patients in the intervention group will receive services from both physicians and pharmacists in the collaborative clinics, while the control group will receive usual care from physicians. Patients will be followed up at the 3rd, 6th, 9th and 12th month. Comparison between the two groups will be conducted by assessing the clinical parameters, process indicators and costs on diabetes. A satisfaction survey will also be carried out at the end of the study. DISCUSSION: If effective, the physician-pharmacist collaborative clinics can be adapted and used in primary hospitals of China to improve glycemic control, enhance medication adherence, decrease incidence of complications and reduce patients' dependence on physicians. Findings from the present study are meaningful for developing evidence-based diabetes care policy in rural China, especially in the COVID-19 pandemic era. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000031839 , Registered 12 April 2020.


Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Interprofessional Relations , Pharmacists , Physicians , COVID-19/epidemiology , China/epidemiology , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/epidemiology , Hospitals , Humans , Multicenter Studies as Topic , Pandemics , Randomized Controlled Trials as Topic
7.
Innovation (Camb) ; 3(2): 100221, 2022 Mar 29.
Article in English | MEDLINE | ID: covidwho-1713028

ABSTRACT

The highly pathogenic and readily transmissible SARS-CoV-2 has caused a global coronavirus pandemic, urgently requiring effective countermeasures against its rapid expansion. All available vaccine platforms are being used to generate safe and effective COVID-19 vaccines. Here, we generated a live-attenuated candidate vaccine strain by serial passaging of a SARS-CoV-2 clinical isolate in Vero cells. Deep sequencing revealed the dynamic adaptation of SARS-CoV-2 in Vero cells, resulting in a stable clone with a deletion of seven amino acids (N679SPRRAR685) at the S1/S2 junction of the S protein (named VAS5). VAS5 showed significant attenuation of replication in multiple human cell lines, human airway epithelium organoids, and hACE2 mice. Viral fitness competition assays demonstrated that VAS5 showed specific tropism to Vero cells but decreased fitness in human cells compared with the parental virus. More importantly, a single intranasal injection of VAS5 elicited a high level of neutralizing antibodies and prevented SARS-CoV-2 infection in mice as well as close-contact transmission in golden Syrian hamsters. Structural and biochemical analysis revealed a stable and locked prefusion conformation of the S trimer of VAS5, which most resembles SARS-CoV-2-3Q-2P, an advanced vaccine immunogen (NVAX-CoV2373). Further systematic antigenic profiling and immunogenicity validation confirmed that the VAS5 S trimer presents an enhanced antigenic mimic of the wild-type S trimer. Our results not only provide a potent live-attenuated vaccine candidate against COVID-19 but also clarify the molecular and structural basis for the highly attenuated and super immunogenic phenotype of VAS5.

8.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-315346

ABSTRACT

Background: The World Health Organization declared on 11 March 2020 that the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has escalated from epidemic into pandemic. As the initial outbreak area, China has taken multiple active measures to deal with the epidemic. Updated versions of diagnosis and treatment guideline for novel coronavirus (COVID-19) patients have been issued, and traditional Chinese herbal medicine has been recommended as a treatment. The objective of this study will be to summarize the recommendations in current clinical practice guidelines about the use of traditional Chinese herbal medicine for COVID-19 patients. We will also evaluate and report on the methodological and reporting quality of these guidelines. Methods: : In this systematic review, we will search for guidelines, expert consensuses and policy documents published since December 2019 in electronic databases (e.g. PubMed, EMBASE, and Chinese databases) and on websites of governments or organizations (e.g. The National Guideline Clearinghouse [NGC], Guidelines International Network [GIN], National Institute for Health and Clinical Excellence (NICE), Scottish Intercollegiate Guidelines Network [SIGN] and WHO]). Eligible documents will be independently selected, and relevant data will be independently extracted by two reviewers. We will also independently evaluate the methodological quality and reporting quality of the included guidelines, using the Appraisal of Guidelines for REsearch & Evaluation (AGREE) II tool and Reporting Items for Practice Guidelines in healthcare (RIGHT) statement, respectively. Any discrepancies will be discussed and resolved through discussion among the reviewers. We will use the extracted information to summarize their recommendations for traditional Chinese herbal formulae and Chinese patent medicine for COVID-19 patients, and to summarize the strength and quality of these recommendations with reference to the results of AGREE II and RIGHT tools. Discussion: This review will summarize the recommendations in current clinical practice guidelines and provide insight into the implementation strategies for traditional Chinese herbal medicine in COVID-19 patients. Systematic review registration: PROSPERO registration number: CRD42020179205

9.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-325434

ABSTRACT

Objective: To compare the epidemiological and clinical characteristics of confirmed and suspected corona virus disease 2019 (COVID-19) cases via the process of “triage-screening-isolation-transfer” in the hospitals of non-epidemic areas. Methods: : The general data, epidemiological history, clinical symptoms, laboratory examination, and chest computed tomography (CT) imaging characteristics of 38 patients with suspected COVID-19, admitted between January 21 and March 5, 2020, were analyzed. Results: : According to the results of the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) ribonucleic acid (RNA) testing, the patients were divided into study group (RNA positive) and control group (RNA negative). Ultimately, 8 cases were RNA-positive and diagnosed as CDVID-19, and 30 cases were negative. Approximately half of the patients in the study group returned to Chongqing from Wuhan;this number was significantly larger than that of the control group (P<0.05). The number of subjects in close contact with the confirmed cases with SARS-CoV-2 RNA-positive and the incidence of aggregation was significantly larger in the study group than in the control group (both P<0.05). The clinical symptom of the study group was mainly low fever (with or without cough). The patients with decreased white blood cells (WBC) in the study group were significantly more than those in the control group (P<0.05). Both group had reduced lymphocytes (Lym) but the number of patients with increased C-reactive protein (CRP) in the study group was significantly more than that in the control group (P<0.05). There were different degrees of chest CT abnormalities in both study and control group (P > 0.05). Conclusion: The epidemiological investigations in screening for infectious diseases is crucial. The risk of infection was high from the primary epidemic area and/or in close contact with the confirmed case. The most common form of clustering occurrence was family aggregation. CDVID-19 was mainly characterized by fever and respiratory symptoms, although asymptomatic infection may also occur. Decreased WBC, decreased Lym, and increased CRP are common characteristics but can also be combined with other respiratory tract virus infections. COVID 19 screening by chest CT alone had certain limitations in non- epidemic areas.

10.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-324789

ABSTRACT

Background: Frontline epidemic prevention workers play a pivotal role against COVID-19. Their baseline of dietary and behavior habits and willingness to change these habits after experiencing the outbreak of COVID-19 remains unclear.Methods: A self-developed online questionnaire survey was carried out via the WeChat platform, and 22,459 participated, including 9402 frontline epidemic prevention workers.Findings: Before COVID-19, 23.9% of frontline epidemic prevention workers reported a high-salt diet, 46.9% reported a high frequency of fried food intake, 21.6% reported a low frequency of fresh vegetable intake, and 50.9% smoked cigarettes. After experiencing the outbreak of COVID-19, 34.6% had the willingness to reduce salt intake, and 43.7% want to reduce the frequency of pickled vegetable intake. 37.9% had the willingness to decrease or quit smoking, and 44.5% want to increase sleep duration. Significant differences in the baseline of dietary and behavioral habits and willingness to change their habits were observed between the frontline epidemic prevention worker and others(P<0.05). However, for the frontline epidemic prevention workers with poor dietary and behavioral habits, the frontline epidemic prevention experience might be a promoting factor to adopt worse dietary and behavioral habits, including the high-salt intake subgroup (OR 2.824, 95% CI 2.341-3.405) and shortest physical exercise time subgroup (OR 1.379, 95% CI 1.041-1.828).Interpretation: The dietary and behavior habits of the frontline epidemic prevention workers were worse than others before COVID-19. They had more willingness to adopt healthy dietary and behavior habits after experiencing the outbreak of COVID-19. Because the frontline epidemic prevention workers, who had poor dietary and behavior habits before COVID-19, still choose worse habits, dietary and behavior intervention policies should be drafted to protect their health, especially for those poor habits subgroups.Funding: This work was supported by The Science and Technology Project of Bao'an (NO.2020JD101).Declaration of Interests: The authors declare that they have no competing interests.Ethics Approval Statement: This study was approved by the ethics committee of Guangdong Medical University.

11.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-324331

ABSTRACT

Background: To investigate impact of the 2019 novel coronavirus disease (COVID-19) pandemic on willingness to adopt healthy dietary habits in China. Methods: : A survey was carried out, and subjective perception of impact due to COVID-19 and willingness to change dietary habits were obtained. Results: : A total of 22,459 subjects were derived from China, with an average age of 27.9±7.8 years old. Of them, the mean score of willingness to adopt healthy dietary habits was 2.2 (ranges from -9 to 9). Multivariate regression analysis showed that the impact of the COVID-19 pandemic (epidemic concern, impact of psychology, impact of work or study) are associated with a higher score of willingness to adopt healthy dietary habits among female, the older, on-medical worker, and individuals married or with higher education level, normal BMI. Conclusions: : There was a positive improvement to a proper diet, so the changing features of diets should be considered in nutritional interventions for maintaining health, and prevention and control COVID-19 during the pandemic period.

12.
BMJ Open ; 11(12): e053068, 2021 12 17.
Article in English | MEDLINE | ID: covidwho-1583099

ABSTRACT

BACKGROUND: The early spatiotemporal transmission of COVID-19 remains unclear. The community to healthcare agencies and back to community (CHC) model was tested in our study to simulate the early phase of COVID-19 transmission in Wuhan, China. METHODS: We conducted a retrospective study. COVID-19 case series reported to the Municipal Notifiable Disease Report System of Wuhan from December 2019 to March 2020 from 17 communities were collected. Cases from healthcare workers (HW) and from community members (CM) were distinguished by documented occupations. Overall spatial and temporal relationships between HW and CM COVID-19 cases were visualised. The CHC model was then simulated. The turning point separating phase 1 and phase 2 was determined using a quadratic model. For phases 1 and 2, linear regression was used to quantify the relationship between HW and CM COVID-19 cases. RESULTS: The spatial and temporal distributions of COVID-19 cases between HWs and CMs were closely correlated. The turning point was 36.85±18.37 (range 15-70). The linear model fitted well for phase 1 (mean R2=0.98) and phase 2 (mean R2=0.93). In phase 1, the estimated [Formula: see text]s were positive (from 18.03 to 94.99), with smaller [Formula: see text]s (from 2.98 to 15.14); in phase 2, the estimated [Formula: see text]s were negative (from -4.22 to -81.87), with larger [Formula: see text]s (from 5.37 to 78.12). CONCLUSION: Transmission of COVID-19 from the community to healthcare agencies and back to the community was confirmed in Wuhan. Prevention and control measures for COVID-19 in hospitals and among HWs are crucial and warrant further attention.


Subject(s)
COVID-19 , China , Delivery of Health Care , Humans , Retrospective Studies , SARS-CoV-2
13.
Lancet Public Health ; 6(12): e867-e868, 2021 12.
Article in English | MEDLINE | ID: covidwho-1550172
14.
Non-conventional in English | [Unspecified Source], Grey literature | ID: grc-750465

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates infection of cells expressing angiotensin-converting enzyme 2 (ACE2). ACE2 is also the viral receptor of SARS-CoV (SARS-CoV-1), a related coronavirus that emerged in 2002-2003. Horseshoe bats (genus Rhinolophus ) are presumed to be the original reservoir of both viruses, and a SARS-like coronavirus, RaTG13, closely related SARS-CoV-2, has been isolated from one horseshoe-bat species. Here we characterize the ability of S-protein receptor-binding domains (RBDs) of SARS-CoV-1, SARS-CoV-2, and RaTG13 to bind a range of ACE2 orthologs. We observed that the SARS-CoV-2 RBD bound human, pangolin, and horseshoe bat ( R. macrotis) ACE2 more efficiently than the SARS-CoV-1 or RaTG13 RBD. Only the RaTG13 RBD bound rodent ACE2 orthologs efficiently. Five mutations drawn from ACE2 orthologs of nine Rhinolophus species enhanced human ACE2 binding to the SARS-CoV-2 RBD and neutralization of SARS-CoV-2 by an immunoadhesin form of human ACE2 (ACE2-Fc). Two of these mutations impaired neutralization of SARS-CoV-1. An ACE2-Fc variant bearing all five mutations neutralized SARS-CoV-2 five-fold more efficiently than human ACE2-Fc. These data narrow the potential SARS-CoV-2 reservoir, suggest that SARS-CoV-1 and -2 originate from distinct bat species, and identify a more potently neutralizing form of ACE2-Fc.

15.
Front Med (Lausanne) ; 8: 659793, 2021.
Article in English | MEDLINE | ID: covidwho-1497084

ABSTRACT

Background: Extracorporeal membrane oxygenation (ECMO) might benefit critically ill COVID-19 patients. But the considerations besides indications guiding ECMO initiation under extreme pressure during the COVID-19 epidemic was not clear. We aimed to analyze the clinical characteristics and in-hospital mortality of severe critically ill COVID-19 patients supported with ECMO and without ECMO, exploring potential parameters for guiding the initiation during the COVID-19 epidemic. Methods: Observational cohort study of all the critically ill patients indicated for ECMO support from January 1 to May 1, 2020, in all 62 authorized hospitals in Wuhan, China. Results: Among the 168 patients enrolled, 74 patients actually received ECMO support and 94 not were analyzed. The in-hospital mortality of the ECMO supported patients was significantly lower than non-ECMO ones (71.6 vs. 85.1%, P = 0.033), but the role of ECMO was affected by patients' age (Logistic regression OR 0.62, P = 0.24). As for the ECMO patients, the median age was 58 (47-66) years old and 62.2% (46/74) were male. The 28-day, 60-day, and 90-day mortality of these ECMO supported patients were 32.4, 68.9, and 74.3% respectively. Patients survived to discharge were younger (49 vs. 62 years, P = 0.042), demonstrated higher lymphocyte count (886 vs. 638 cells/uL, P = 0.022), and better CO2 removal (PaCO2 immediately after ECMO initiation 39.7 vs. 46.9 mmHg, P = 0.041). Age was an independent risk factor for in-hospital mortality of the ECMO supported patients, and a cutoff age of 51 years enabled prediction of in-hospital mortality with a sensitivity of 84.3% and specificity of 55%. The surviving ECMO supported patients had longer ICU and hospital stays (26 vs. 18 days, P = 0.018; 49 vs. 29 days, P = 0.001 respectively), and ECMO procedure was widely carried out after the supplement of medical resources after February 15 (67.6%, 50/74). Conclusions: ECMO might be a benefit for severe critically ill COVID-19 patients at the early stage of epidemic, although the in-hospital mortality was still high. To initiate ECMO therapy under tremendous pressure, patients' age, lymphocyte count, and adequacy of medical resources should be fully considered.

16.
Int J Biol Sci ; 17(14): 3795-3817, 2021.
Article in English | MEDLINE | ID: covidwho-1459010

ABSTRACT

Background: SARS-CoV-2, the cause of the worldwide COVID-19 pandemic, utilizes the mechanism of binding to ACE2 (a crucial component of the renin-angiotensin system [RAS]), subsequently mediating a secondary imbalance of the RAS family and leading to severe injury to the host. However, very few studies have been conducted to reveal the mechanism behind the effect of SARS-CoV-2 on tumors. Methods: Demographic data extracted from 33 cancer types and over 10,000 samples were employed to determine the comprehensive landscape of the RAS. Expression distribution, pretranscriptional and posttranscriptional regulation and posttranslational modifications (PTMs) as well as genomic alterations, DNA methylation and m6A modification were analyzed in both tissue and cell lines. The clinical phenotype, prognostic value and significance of the RAS during immune infiltration were identified. Results: Low expression of AGTR1 was common in tumors compared to normal tissues, while very low expression of AGTR2 and MAS1 was detected in both tissues and cell lines. Differential expression patterns of ACE in ovarian serous cystadenocarcinoma (OV) and kidney renal clear cell carcinoma (KIRC) were correlated with ubiquitin modification involving E3 ligases. Genomic alterations of the RAS family were infrequent across TCGA pan-cancer program, and ACE had the highest alteration frequency compared with other members. Low expression of AGTR1 may result from hypermethylation in the promoter. Downregulation of RAS family was linked to higher clinical stage and worse survival (as measured by disease-specific survival [DSS], overall survival [OS] or progression-free interval [PFI]), especially for ACE2 and AGTR1 in KIRC. ACE-AGTR1, a classical axis of the RAS family related to immune infiltration, was positively correlated with M2-type macrophages, cancer-associated fibroblasts (CAFs) and immune checkpoint genes in most cancers. Conclusion: ACE, ACE2, AGT and AGTR1 were differentially expressed in 33 types of cancers. PTM of RAS family was found to rely on ubiquitination. ACE2 and AGTR1 might serve as independent prognostic factors for LGG and KIRC. SARS-CoV-2 might modify the tumor microenvironment by regulating the RAS family, thus affecting the biological processes of cancer.


Subject(s)
Neoplasms/metabolism , Renin-Angiotensin System , SARS-CoV-2/metabolism , COVID-19/complications , COVID-19/metabolism , DNA Methylation , Gene Expression Regulation, Neoplastic , Humans , Immunotherapy , Neoplasms/etiology , Neoplasms/mortality , Neoplasms/therapy , Protein Processing, Post-Translational
17.
Nucleic Acids Res ; 50(1): e4, 2022 01 11.
Article in English | MEDLINE | ID: covidwho-1450402

ABSTRACT

Efficient annotation of alterations in binding sequences of molecular regulators can help identify novel candidates for mechanisms study and offer original therapeutic hypotheses. In this work, we developed Somatic Binding Sequence Annotator (SBSA) as a full-capacity online tool to annotate altered binding motifs/sequences, addressing diverse types of genomic variants and molecular regulators. The genomic variants can be somatic mutation, single nucleotide polymorphism, RNA editing, etc. The binding motifs/sequences involve transcription factors (TFs), RNA-binding proteins, miRNA seeds, miRNA-mRNA 3'-UTR binding target, or can be any custom motifs/sequences. Compared to similar tools, SBSA is the first to support miRNA seeds and miRNA-mRNA 3'-UTR binding target, and it unprecedentedly implements a personalized genome approach that accommodates joint adjacent variants. SBSA is empowered to support an indefinite species, including preloaded reference genomes for SARS-Cov-2 and 25 other common organisms. We demonstrated SBSA by annotating multi-omics data from over 30,890 human subjects. Of the millions of somatic binding sequences identified, many are with known severe biological repercussions, such as the somatic mutation in TERT promoter region which causes a gained binding sequence for E26 transformation-specific factor (ETS1). We further validated the function of this TERT mutation using experimental data in cancer cells. Availability:http://innovebioinfo.com/Annotation/SBSA/SBSA.php.


Subject(s)
COVID-19/virology , Computational Biology/instrumentation , Genomics/instrumentation , Mutation , Proteomics/instrumentation , SARS-CoV-2 , 3' Untranslated Regions , Algorithms , Amino Acid Motifs , COVID-19/metabolism , Computational Biology/methods , Computers , Genetic Techniques , Genome, Human , Genomics/methods , Humans , Internet , MicroRNAs/metabolism , Phenotype , Promoter Regions, Genetic , Protein Binding , Proteomics/methods , Proto-Oncogene Protein c-ets-1/genetics , Proto-Oncogene Protein c-ets-1/metabolism , RNA-Binding Proteins/metabolism , Telomerase/metabolism
18.
Nat Commun ; 12(1): 5654, 2021 09 27.
Article in English | MEDLINE | ID: covidwho-1440471

ABSTRACT

There is an urgent need for animal models to study SARS-CoV-2 pathogenicity. Here, we generate and characterize a novel mouse-adapted SARS-CoV-2 strain, MASCp36, that causes severe respiratory symptoms, and mortality. Our model exhibits age- and gender-related mortality akin to severe COVID-19. Deep sequencing identified three amino acid substitutions, N501Y, Q493H, and K417N, at the receptor binding domain (RBD) of MASCp36, during in vivo passaging. All three RBD mutations significantly enhance binding affinity to its endogenous receptor, ACE2. Cryo-electron microscopy analysis of human ACE2 (hACE2), or mouse ACE2 (mACE2), in complex with the RBD of MASCp36, at 3.1 to 3.7 Å resolution, reveals the molecular basis for the receptor-binding switch. N501Y and Q493H enhance the binding affinity to hACE2, whereas triple mutations at N501Y/Q493H/K417N decrease affinity and reduce infectivity of MASCp36. Our study provides a platform for studying SARS-CoV-2 pathogenesis, and unveils the molecular mechanism for its rapid adaptation and evolution.


Subject(s)
COVID-19/diagnosis , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Substitution , Angiotensin-Converting Enzyme 2/metabolism , Animals , Binding Sites/genetics , COVID-19/mortality , COVID-19/virology , Disease Models, Animal , Female , Humans , Male , Mice , Protein Binding/genetics , Protein Domains/genetics , SARS-CoV-2/genetics , Severity of Illness Index , Spike Glycoprotein, Coronavirus/genetics
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