COVID-19, caused by SARS-CoV-2, is a virulent pneumonia, with >4,000,000 confirmed cases worldwide and >290,000 deaths as of May 15, 2020. It is critical that vaccines and therapeutics be developed ...very rapidly. Mice, the ideal animal for assessing such interventions, are resistant to SARS-CoV-2. Here, we overcome this difficulty by exogenous delivery of human ACE2 with a replication-deficient adenovirus (Ad5-hACE2). Ad5-hACE2-sensitized mice developed pneumonia characterized by weight loss, severe pulmonary pathology, and high-titer virus replication in lungs. Type I interferon, T cells, and, most importantly, signal transducer and activator of transcription 1 (STAT1) are critical for virus clearance and disease resolution in these mice. Ad5-hACE2-transduced mice enabled rapid assessments of a vaccine candidate, of human convalescent plasma, and of two antiviral therapies (poly I:C and remdesivir). In summary, we describe a murine model of broad and immediate utility to investigate COVID-19 pathogenesis and to evaluate new therapies and vaccines.
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•Mice are sensitized for SARS-CoV-2 infection by Ad5-hACE2 transduction•Genetically deficient strains can be directly assessed without additional breeding•Mice useful for determining host factors necessary for optimal virus clearance•Useful for assessing efficacy of vaccines and therapies such as convalescent plasma
An adenoviral transduction-based mouse model that can be infected with SARS-CoV-2 provides a tool to understand host factors involved in viral infection and clearance as well as potential therapeutic modalities.
Gastric cancer is a clinically common tumor, showing an upward trend of both incidence and mortality. GRB7 has been identified as a vital regulator in tumor progression. This study aims to uncover ...the biological function of GRB7 in gastric cancer process.
immunohistochemical (IHC) staining using a tissue microarray (TMA), quantitative reverse transcription PCR (qRT-PCR) and Western blotting were performed to detect the expression of genes. Furthermore, gastric cancer cell lines AGS and MGC-803 were transfected with short hairpin RNAs against GRB7. The biological function of GRB7 in gastric cancer cells were examined by CCK-8, flow cytometry, wound healing and Transwell assays. Then, in vivo tumor formation assay was conducted to explore the effects of GRB7 on tumor growth. Finally, expression levels of proteins related to cell functions were determined by Western blotting. Coimmunoprecipitation (CoIP) assay was performed to assess the protein-protein interaction.
GRB7 was up-regulated in gastric cancer tissues and cell lines, and its expression was inversely proportional to survival of gastric cancer patients. Moreover, GRB7 knockdown inhibited proliferative, migratory abilities, as well as promoted cell apoptosis in gastric cancer cells. Further study suggested that GRB7 silencing could suppress gastric cancer tumor growth in vivo. Furthermore, our study uncovered an important interaction between GRB7 and MyD88. Silencing MyD88 was observed to alleviate the malignant phenotypes promoted by GRB7 in gastric cancer cells.
Together, this study provided evidence that GRB7 may be an effective molecular targets for the treatment of gastric cancer.
The large-scale exploitation and wanton use of fossil energy have led to the increasing global warming and environmental pollution. The development and utilization of clean energy urgently need to be ...put on the agenda. At the same time, the development of Internet technology and big data technology is constantly promoting the development and popularization of clean energy. However, Internet information security is the number one factor threatening the development and supply of clean energy in today’s society. Therefore, based on the relevant theories of statistical learning, an evaluation model of information security reliability of clean energy internet based on statistical learning is constructed. At the same time, the reliability of the evaluation model is tested and analyzed. Finally, the role of the evaluation model in the carbon sequestration of natural gas hydrate, the reduction of greenhouse effect and the development of clean energy is analyzed. It is expected to lay a foundation for the efficient development and environmental protection of clean energy (natural gas) through this research. It is found that the predicted results of data transmission by coaxial cable are completely consistent with the actual results, and neither will generate hydrate within 2.5 m from the entrance. Moreover, the reliability of data transmission using coaxial cable is higher than that of wireless transmission. The study also found that the increase of carbon dioxide injection rate will accelerate the decomposition and gas production of hydrate, and it is more obvious in the small range of carbon dioxide injection rate. Considering the development efficiency and burial efficiency, the carbon dioxide injection rate is designed as 20·104 m
3
/day is the best. At the same time, the greenhouse effect of carbon dioxide will become more and more significant with the increase of its concentration, and based on the prediction of the built model, it is found that the replacement rate of natural gas in hydrate by carbon dioxide can reach 92.35%.
Disease progression prediction and therapeutic drug target discovery for Coronavirus disease 2019 (COVID-19) are particularly important, as there is still no effective strategy for severe COVID-19 ...patient treatment. Herein, we performed multi-platform omics analysis of serial plasma and urine samples collected from patients during the course of COVID-19. Integrative analyses of these omics data revealed several potential therapeutic targets, such as ANXA1 and CLEC3B. Molecular changes in plasma indicated dysregulation of macrophage and suppression of T cell functions in severe patients compared to those in non-severe patients. Further, we chose 25 important molecular signatures as potential biomarkers for the prediction of disease severity. The prediction power was validated using corresponding urine samples and plasma samples from new COVID-19 patient cohort, with AUC reached to 0.904 and 0.988, respectively. In conclusion, our omics data proposed not only potential therapeutic targets, but also biomarkers for understanding the pathogenesis of severe COVID-19.
Within the framework of China’s socioeconomic transition from a phase of rapid growth to one of high-quality development, it becomes crucial to focus on advancing the green economy to sustain ...economic progress. Green finance plays a pivotal role in underpinning green industries and fostering the progression of a green economy. Under the auspices of green finance, social capital is increasingly directed towards industries that prioritize energy efficiency, low carbon emissions, and environmental friendliness, thereby spurring technological innovation and industrial metamorphosis in businesses. In this paper, data envelopment approach (DEA) is used to measure the green economic development efficiency of 30 Chinese provinces from 2008 to 2018 in general and by sub-region. The two-way fixed-effects model (Two-way FE) and difference-in-difference (DID) model are established to empirically analyze the effect of green finance on green economy development efficiency and the influence of green polices on these two, with sub-region models examining the heterogeneity of this impact in eastern, western and central regions. The findings suggest that green finance significantly enhances a positive influence on green economic development efficiency, albeit with regional variations. Furthermore, the implementation of green policies facilitates green finance and green economic development.
Middle East respiratory syndrome coronavirus (MERS-CoV) is a beta coronavirus that emerged in 2012, causing severe pneumonia and renal failure. MERS-CoV encodes five accessory proteins. Some of them ...have been shown to interfere with host antiviral immune response. However, the roles of protein 8b in innate immunity and viral virulence was rarely studied. Here, we introduced individual MERS-CoV accessory protein genes into the genome of an attenuated murine coronavirus (Mouse hepatitis virus, MHV), respectively, and found accessory protein 8b could enhance viral replication
and
and increase the lethality of infected mice. RNA-seq analysis revealed that protein 8b could significantly inhibit type I interferon production (IFN-I) and innate immune response in mice infected with MHV expressing protein 8b. We also found that MERS-CoV protein 8b could initiate from multiple internal methionine sites and at least three protein variants were identified. Residues 1-23 of protein 8b was demonstrated to be responsible for increased virulence
. In addition, the inhibitory effect on IFN-I of protein 8b might not contribute to its virulence enhancement as aa1-23 deletion did not affect IFN-I production
and
. Next, we also found that protein 8b was localized to the endoplasmic reticulum (ER)/Golgi membrane in infected cells, which was disrupted by C-terminal region aa 88-112 deletion. This study will provide new insight into the pathogenesis of MERS-CoV infection.
Multiple coronaviruses (CoV) cause severe respiratory infections and become global public health threats such as SARS-CoV, MERS-CoV, and SARS-CoV-2. Each coronavirus contains different numbers of accessory proteins which show high variability among different CoVs. Accessory proteins are demonstrated to play essential roles in pathogenesis of CoVs. MERS-CoV contains 5 accessory proteins (protein 3, 4a, 4b, 5, 8b), and deletion of all four accessory proteins (protein 3, 4a, 4b, 5), significantly affects MERS-CoV replication and pathogenesis. However, whether ORF8b also regulates MERS-CoV infection is unknown. Here, we constructed mouse hepatitis virus (MHV) recombinant virus expressing MERS-CoV protein 8b and demonstrated protein 8b could significantly enhance the virulence of MHV, which is mediated by N-terminal domain of protein 8b. This study will shed light on the understanding of pathogenesis of MERS-CoV infection.
High-throughput sequencing was used to screen expressing differences of miRNA, lncRNA, and mRNA in CD19+ B peripheral blood samples of newly diagnosed immune thrombocytopenia (ITP) patients and ...healthy controls. The study aimed to explore the regulatory role of ceRNA network in the pathogenesis of dysfunctional CD19 + B lymphocytes of ITP patients.
CD19+ B lymphocytes were isolated from peripheral blood samples of ITP patients and their healthy counterparts. High-throughput sequencing was used to screen for the expression of miRNA, lncRNA, and mRNA of ITP patients and healthy controls, which were analysed by the ceRNA network. Moreover, qPCR was used to verify the differential expression of miRNA, lncRNA, and mRNA in ITP patients and healthy controls. The correlation between differentially expressed miRNA, lncRNA, mRNA, and B lymphocyte subsets was also analysed.
The CD19+ B lymphocytes of 4 newly diagnosed ITP patients and 4 healthy controls were sequenced and analysed. There were 65 differentially expressed lncRNA and 149 mRNA forming a ceRNA network showed that 12 lncRNA and 136 differentially expressed mRNA were closely associated. Similarly, miR-144-3p, miR-374c-3p, and miR-451a were highly expressed in ITP patients, as confirmed by qPCR, which was consistent with the high-throughput sequence results. LOC102724852 and CCL20 were highly expressed in ITP patients, while LOC105378901, LOC112268311, ALAS2, and TBC1D3F were not as compared to healthy controls, which was consistent with the high-throughput sequence results. In addition, the expression of miR-374c-3p, LOC112268311, LOC105378901, and CXCL3 were correlated with the percentage of B lymphocyte subsets.
The ceRNA network of miRNA, lncRNA, and mRNA in peripheral CD19 + B lymphocytes plays an essential role in the pathogenesis of ITP.
In this paper, a network slice resource allocation algorithm based on delay sensing is proposed for the problems of service delay and QoS reduction, and resource utilization reduction caused by ...unreasonable network slice resource allocation. MIMO technology is being studied to establish a communication system that supports multiple inputs and outputs for channels. A resource preallocation method for 5G edge computing is proposed by reasonably allocating resources in the 5G edge computing environment. Then, the performance of the 5G network is optimized, and the optimized network performance is analyzed based on case studies. The results show that the buffer depth of the optimized 5G network is reduced by 1.25, the network delay is reduced by 0.02s, and the network throughput is significantly improved. This study provides the theoretical basis and technical support for the further development of a smart grid in a 5G environment.
The nucleocapsid protein (NP) plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long half-life. Despite its vital role in severe acute respiratory ...syndrome coronavirus 2 (SARS-CoV-2) assembly and host inflammatory response, it remains an unexplored target for drug development. In this study, we identified a small-molecule compound (ciclopirox) that promotes NP degradation using an FDA-approved library and a drug-screening cell model. Ciclopirox significantly inhibited SARS-CoV-2 replication both in vitro and in vivo by inducing NP degradation. Ciclopirox induced abnormal NP aggregation through indirect interaction, leading to the formation of condensates with higher viscosity and lower mobility. These condensates were subsequently degraded via the autophagy-lysosomal pathway, ultimately resulting in a shortened NP half-life and reduced NP expression. Our results suggest that NP is a potential drug target, and that ciclopirox holds substantial promise for further development to combat SARS-CoV-2 replication.
Ciclopirox exhibited potent anti-SARS-CoV-2 activity in vivo and in vitro by inducing NP abnormal aggregation and degrading NP condensates via autophagy–lysosome pathway. Display omitted
To combat SARS‐CoV‐2 variants and MERS‐CoV, as well as the potential re‐emergence of SARS‐CoV and spillovers of sarbecoviruses, which pose a significant threat to global public health, vaccines that ...can confer broad‐spectrum protection against betacoronaviruses (β‐CoVs) are urgently needed. A mosaic ferritin nanoparticle vaccine is developed that co‐displays the spike receptor‐binding domains of SARS‐CoV, MERS‐CoV, and SARS‐CoV‐2 Wild‐type (WT) strain and evaluated its immunogenicity and protective efficacy in mice and nonhuman primates. A low dose of 10 µg administered at a 21‐day interval induced a Th1‐biased immune response in mice and elicited robust cross‐reactive neutralizing antibody responses against a variety of β‐CoVs, including a series of SARS‐CoV‐2 variants. It is also able to effectively protect against challenges of SARS‐CoV, MERS‐CoV, and SARS‐CoV‐2 variants in not only young mice but also the more vulnerable mice through induction of long‐lived immunity. Together, these results suggest that this mosaic 3‐RBD nanoparticle has the potential to be developed as a pan‐β‐CoV vaccine.
The mosaic ferritin nanoparticle vaccine that co‐displays the spike receptor‐binding domains of SARS‐CoV, MERS‐CoV, and SARS‐CoV‐2 Wild‐type (WT) strain induce Th1‐biased immune response in mice and elicits robust cross‐reactive neutralizing antibody responses against a variety of β‐CoVs, including a series of SARS‐CoV‐2 variants. This vaccine effectively protects against challenges of SARS‐CoV, MERS‐CoV, and SARS‐CoV‐2 variants in mice.
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