The distinct binding properties between avian/human influenza A virus NS1 and Postsynaptic density protein-95 (PSD-95), and inhibition of nitric oxide production

<p>Abstract</p> <p>Background</p> <p>The NS1 protein of influenza A virus is able to bind with many proteins that affect cellular signal transduction and protein synthesis in infected cells. The NS1 protein consists of approximately 230 amino acids and the last 4 amino acids of the NS1 C-terminal form a PDZ binding motif. Postsynaptic Density Protein-95 (PSD-95), which is mainly expressed in neurons, has 3 PDZ domains. We hypothesise that NS1 binds to PSD-95, and this binding is able to affect neuronal function.</p> <p>Result</p> <p>We conducted a yeast two-hybrid analysis, GST-pull down assays and co-immunoprecipitations to detect the interaction between NS1 and PSD-95. The results showed that NS1 of avian influenza virus H5N1 (A/chicken/Guangdong/1/2005) is able to bind to PSD-95, whereas NS1 of human influenza virus H1N1 (A/Shantou/169/2006) is unable to do so. The results also revealed that NS1 of H5N1 significantly reduces the production of nitric oxide (NO) in rat hippocampal neurons.</p> <p>Conclusion</p> <p>In summary, our study indicates that NS1 of influenza A virus can bind with neuronal PSD-95, and the avian H5N1 and human H1N1 influenza A viruses possess distinct binding properties.</p

Induction of cytopathic effect and cytokines in coxsackievirus B3-infected murine astrocytes

BACKGROUND: Coxsackievirus commonly infects children and occasionally causes severe meningitis and/or encephalitis in the newborn. The underlying mechanism(s) behind the central nervous system pathology is poorly defined. METHODS: It is hypothesized that astrocytes may be involved in inflammatory response induced by CVB3 infection. Here we discuss this hypothesis in the context of CVB3 infection and associated inflammatory response in primary mouse astrocytes. RESULTS: The results showed that coxsackievirus receptor (CAR) was distributed homogeneously on the astrocytes, and that CVB3 could infect and replicate in astrocytes, with release of infectious virus particles. CVB3 induced cytopathic effect and production of proinflammatory cytokines IL-1β, TNF-α, IL-6, and chemokine CXCL10 from astrocytes. CONCLUSION: These data suggest that direct astrocyte damage and cytokines induction could be a mechanism of virus-induced meningitis and/or encephalitis

A seismological phenomenon preceding the 2017 Ms7.0 Jiuzhaigou earthquake

On 8 August 2017, a Ms7.0 earthquake occurred in Jiuzhaigou in the Sichuan Province of China. In this study, we obtained the vertical continuous data recorded at 12 nearby broadband seismometers from April to December 2017, in order to characterize the temporal and spatial variations in the vertical ground motion prior to the onset of the earthquake. Using the self-mutual information method, we determined that from July to August 2017, the self-mutual information value of the vertical ground motion increased at several stations. The spatiotemporal evolution also shows that the region of highest value migrates from south to north toward the earthquake epicenter. Among them, the change of SPA (the station closest to the epicenter) is the most prominent. We believe that this phenomenon is related to the formation of the Jiuzhaigou earthquake. Our work, in combination with other published works, indicates that the Jiuzhaigou earthquake was caused by the continued eastward movement and obstruction of the Qinghai Tibet Plateau by the Sichuan Basin, and the movement of Longmenshan fault is also one of the causes of the earthquake

Few-Shot Character Understanding in Movies as an Assessment to Meta-Learning of Theory-of-Mind

When reading a story, humans can rapidly understand new fictional characters with a few observations, mainly by drawing analogy to fictional and real people they met before in their lives. This reflects the few-shot and meta-learning essence of humans' inference of characters' mental states, i.e., humans' theory-of-mind (ToM), which is largely ignored in existing research. We fill this gap with a novel NLP benchmark, TOM-IN-AMC, the first assessment of models' ability of meta-learning of ToM in a realistic narrative understanding scenario. Our benchmark consists of $\sim$1,000 parsed movie scripts for this purpose, each corresponding to a few-shot character understanding task; and requires models to mimic humans' ability of fast digesting characters with a few starting scenes in a new movie. Our human study verified that humans can solve our problem by inferring characters' mental states based on their previously seen movies; while the state-of-the-art metric-learning and meta-learning approaches adapted to our task lags 30% behind

A seismological phenomenon preceding the 2017 Ms7.0 Jiuzhaigou earthquake

On 8 August 2017, a Ms7.0 earthquake occurred in Jiuzhaigou in the Sichuan Province of China. In this study, we obtained the vertical continuous data recorded at 12 nearby broadband seismometers from April to December 2017, in order to characterize the temporal and spatial variations in the vertical ground motion prior to the onset of the earthquake. Using the self-mutual information method, we determined that from July to August 2017, the self-mutual information value of the vertical ground motion increased at several stations. The spatiotemporal evolution also shows that the region of highest value migrates from south to north toward the earthquake epicenter. Among them, the change of SPA (the station closest to the epicenter) is the most prominent. We believe that this phenomenon is related to the formation of the Jiuzhaigou earthquake. Our work, in combination with other published works, indicates that the Jiuzhaigou earthquake was caused by the continued eastward movement and obstruction of the Qinghai Tibet Plateau by the Sichuan Basin, and the movement of Longmenshan fault is also one of the causes of the earthquake

Comprehensive analysis of the amino acid metabolism-related gene signature for prognosis, tumor immune microenvironment, and candidate drugs in hepatocellular carcinoma

IntroductionMetabolic rewiring satisfies increased nutritional demands and modulates many oncogenic processes in tumors. Amino acid metabolism is abnormal in many malignancies. Metabolic reprogramming of amino acids not only plays a crucial role in sustaining tumor cell proliferation but also influences the tumor immune microenvironment. Herein, the aim of our study was to elucidate the metabolic signature of amino acids in hepatocellular carcinoma (HCC).MethodsTranscriptome profiles of HCC were obtained from the TCGA and ICGC databases. Based on the expression of amino acid metabolism-related genes (AAMRGs), we clustered the HCC samples into two molecular subtypes using the non-negative matrix factorization algorithm. Then, we constructed the amino acid metabolism-related gene signature (AAMRGS) by Cox regression and LASSO regression. Afterward, the clinical significance of the AAMRGS was evaluated. Additionally, we comprehensively analyzed the differences in mutational profiles, immune cell infiltration, immune checkpoint expression, and drug sensitivity between different risk subgroups. Furthermore, we examined three key gene expressions in liver cancer cells by quantitative real-time PCR and conducted the CCK8 assay to evaluate the influence of two chemotherapy drugs on different liver cancer cells.ResultsA total of 81 differentially expressed AAMRGs were screened between the two molecular subtypes, and these AAMRGs were involved in regulating amino acid metabolism. The AAMRGS containing GLS, IYD, and NQO1 had a high value for prognosis prediction in HCC patients. Besides this, the two AAMRGS subgroups had different genetic mutation probabilities. More importantly, the immunosuppressive cells were more enriched in the AAMRGS-high group. The expression level of inhibitory immune checkpoints was also higher in patients with high AAMRGS scores. Additionally, the two AAMRGS subgroups showed different susceptibility to chemotherapeutic and targeted drugs. In vitro experiments showed that gemcitabine significantly reduced the proliferative capacity of SNU449 cells, and rapamycin remarkedly inhibited Huh7 proliferation. The five HCC cells displayed different mRNA expression levels of GLS, IYD, and NQO1.ConclusionsOur study explored the features of amino acid metabolism in HCC and identified the novel AAMRGS to predict the prognosis, immune microenvironment, and drug sensitivity of HCC patients. These findings might help to guide personalized treatment and improve the clinical outcomes of HCC

Immunomodulatory roles of selenium nanoparticles: Novel arts for potential immunotherapy strategy development

Current chemotherapy strategies used in clinic appear with lots of disadvantages due to the low targeting effects of drugs and strong side effects, which significantly restricts the drug potency, causes multiple dysfunctions in the body, and even drives the emergence of diseases. Immunotherapy has been proved to boost the body’s innate and adaptive defenses for more effective disease control and treatment. As a trace element, selenium plays vital roles in human health by regulating the antioxidant defense, enzyme activity, and immune response through various specific pathways. Profiting from novel nanotechnology, selenium nanoparticles have been widely developed to reveal great potential in anticancer, antibacterial, and anti-inflammation treatments. More interestingly, increasing evidence has also shown that functional selenium nanoparticles can be applied for potential immunotherapy, which would achieve more effective treatment efficiency as adjunctive therapy strategies for the current chemotherapy. By directly interacting with innate immune cells, such as macrophages, dendritic cells, and natural killer cells, selenium nanoparticles can regulate innate immunity to intervene disease developments, which were reported to boost the anticancer, anti-infection, and anti-inflammation treatments. Moreover, selenium nanoparticles can also activate and recover different T cells for adaptive immunity regulations to enhance their cytotoxic to combat cancer cells, indicating the potential of selenium nanoparticles for potential immunotherapy strategy development. Here, aiming to enhance our understanding of the potential immunotherapy strategy development based on Se NPs, this review will summarize the immunological regulation effects of selenium nanoparticles and the application of selenium nanoparticle-based immunotherapy strategies. Furthermore, we will discuss the advancing perspective of selenium nanoparticle-based potential immunotherapy as a kind of novel adjunctive therapy to enhance the efficiency of current chemotherapies and also introduce the current obstacles for the development of selenium nanoparticles for potential immunotherapy strategy development. This work is expected to promote the future research on selenium nanoparticle-assisted immunotherapy and finally benefit the more effective disease treatments against the threatening cancer and infectious and chronic diseases

The regulation of three new members of the cytochrome P450 CYP6 family and their promoters in the cotton aphid Aphis gossypii by plant allelochemicals

BACKGROUND: The expression of P450 genes in insects can be induced by plant allelochemicals. To understand the induction mechanisms, we measured the expression profiles of three P450 genes and their promoter activities under the induction of plant allelochemicals. RESULTS: The inducible expression of CYP6CY19 was the highest among three genes, followed by those of CYP6CY22 and CYP6DA1. The regions from −687 to +586bp of CYP6DA1, from−666 to +140bp of CYP6CY19 and from −530 to +218bp of CYP6CY22 were essential for basal transcriptional activity. The cis-elements for plant allelochemicals induction were identified between −193 and +56bp of CYP6DA1, between −157 and +140bp of CYP6CY19 and between −108 and +218bp of CYP6CY22. These promoter regions were found to contain a potential arylhydrocarbon receptor element binding site with a conservative sequence motif 5′-C/TAC/ANCA/CA-3′. All these four plant allelochemicals were able to induce the expression of these P450 genes. Tannic acid had a better inductive effect than other three plant allelochemicals. CONCLUSIONS: Our study identified the plant allelochemical responsive cis-elements. This provides further research targets aimed at understanding the regulatory mechanisms of P450 genes expression and their interactions with plant allelochemicals in insect pests

Transcriptional analysis of human peripheral blood mononuclear cells stimulated by Mycobacterium tuberculosis antigen

BackgroundMycobacterium tuberculosis antigen (Mtb-Ag) is a polypeptide component with a molecular weight of 10-14 kDa that is obtained from the supernatant of the H37Ra strain after heat treatment. It stimulates the activation and proliferation of γδT cells in the blood to produce an immune response against tuberculosis. Mtb-Ag is therefore crucial for classifying and detecting the central genes and key pathways involved in TB initiation and progression.MethodsIn this study, we performed high-throughput RNA sequencing of peripheral blood mononuclear cells (PBMC) from Mtb-Ag-stimulated and control samples to identify differentially expressed genes and used them for gene ontology (GO) and a Kyoto Encyclopedia of Genomes (KEGG) enrichment analysis. Meanwhile, we used PPI protein interaction network and Cytoscape analysis to identify key genes and qRT-PCR to verify differential gene expression. Single-gene enrichment analysis (GSEA) was used further to elucidate the potential biological functions of key genes. Analysis of immune cell infiltration and correlation of key genes with immune cells after Mtb-Ag-stimulated using R language.ResultsWe identified 597 differentially expressed genes in Mtb-Ag stimulated PBMCs. KEGG and GSEA enrichment analyzed the cellular pathways related to immune function, and DEGs were found to be primarily involved in the TNF signaling pathway, the IL-17 signaling pathway, the JAK-STAT signaling pathway, cytokine-cytokine receptor interactions, and the NF-κB signaling pathway. Wayne analysis using GSEA, KEGG, and the protein-protein interaction (PPI) network showed that 34 genes, including PTGS2, IL-1β, IL-6, TNF and IFN-γ et al., were co-expressed in the five pathways and all were up-regulated by Mtb-Ag stimulation. Twenty-four DEGs were identified using qRT-PCR, including fourteen up-regulated genes (SERPINB7, IL20, IFNG, CSF2, PTGS2, TNF-α, IL36G, IL6, IL10, IL1A, CXCL1, CXCL8, IL4, and CXCL3) and ten down-regulated genes (RTN1, CSF1R CD14, C5AR1, CXCL16, PLXNB2, OLIG1, EEPD1, ENG, and CCR1). These findings were consistent with the RNA-Seq results.ConclusionThe transcriptomic features associated with Mtb-Ag provide the scientific basis for exploring the intracellular immune mechanisms against Mtb. However, more studies on these DEGs in pathways associated with Mtb-Ag stimulation are needed to elucidate the underlying pathologic mechanisms of Mtb-Ag during Mtb infection