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Abstract The pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has had a profound impact on the global health and economy. While mass vaccination for herd immunity is effective, emerging SARS-CoV-2 variants can evade spike protein-based COVID-19 vaccines. In this study, we develop a new immunization strategy by utilizing a nanocarrier, dendritic mesoporous silica nanoparticle (DMSN), to deliver the receptor-binding domain (RBD) and conserved T-cell epitope peptides (DMSN-P-R), aiming to activate both humoral and cellular immune responses in the host. The synthesized DMSN had good uniformity and dispersion and showed a strong ability to load the RBD and peptide antigens, enhancing their uptake by antigen-presenting cells (APCs) and promoting antigen delivery to lymph nodes. The DMSN-P-R vaccine elicited potent humoral immunity, characterized by highly specific RBD antibodies. Neutralization tests demonstrated significant antibody-mediated neutralizing activity against live SARS-CoV-2. Crucially, the DMSN-P-R vaccine also induced robust T-cell responses that were specifically stimulated by the RBD and conserved T-cell epitope peptides of SARS-CoV-2. The DMSN demonstrated excellent biocompatibility and biosafety in vitro and in vivo, along with degradability. Our study introduces a promising vaccine strategy that utilizes nanocarriers to deliver a range of antigens, effectively enhancing both humoral and cellular immune responses to prevent virus transmission.

Abstract Background Hepatic inflammation is the major risk factor of hepatocellular carcinoma (HCC). However, the underlying mechanism by which hepatic inflammation progresses to HCC is poorly understood. This study was designed to investigate the role of ETS translocation variant 4 (ETV4) in linking hepatic inflammation to HCC. Methods Quantitative real‐time PCR and immunoblotting were used to detect the expression of ETV4 in HCC tissues and cell lines. RNA sequencing and luciferase reporter assays were performed to identify the target genes of ETV4. Hepatocyte‐specific ETV4‐knockout (ETV4fl/fl, alb‐cre) and transgenic (ETV4Hep‐TG) mice and diethylnitrosamine‐carbon tetrachloride (DEN‐CCL4) treatment experiments were applied to investigate the function of ETV4 in vivo. The Cancer Genome Atlas (TCGA) database mining and pathological analysis were carried out to determine the correlation of ETV4 with tumor necrosis factor‐alpha (TNF‐α) and mitogen‐activated protein kinase 11 (MAPK11). Results We revealed that ETV4 was highly expressed in HCC. High levels of ETV4 predicted a poor survival rate of HCC patients. Then we identified ETV4 as a transcription activator of TNF‐α and MAPK11. ETV4 was positively correlated with TNF‐α and MAPK11 in HCC patients. As expected, an increase in hepatic TNF‐α secretion and macrophage accumulation were observed in the livers of ETV4Hep‐TG mice. The protein levels of TNF‐α, MAPK11, and CD68 were significantly higher in the livers of ETV4Hep‐TG mice compared with wild type mice but lower in ETV4fl/fl, alb‐cre mice compared with ETV4fl/fl mice as treated with DEN‐CCL4, indicating that ETV4 functioned as a driver of TNF‐α/MAPK11 expression and macrophage accumulation during hepatic inflammation. Hepatocyte‐specific knockout of ETV4 significantly prevented development of DEN‐CCL4‐induced HCC, while transgenic expression of ETV4 promoted growth of HCC. Conclusions ETV4 promoted hepatic inflammation and HCC by activating transcription of TNF‐α and MAPK11. Both the ETV4/TNF‐α and ETV4/MAPK11 axes represented two potential therapeutic targets for highly associated hepatic inflammation and HCC. ETV4+TNF‐α were potential prognostic markers for HCC patients.

The multi-modality action recognition aims to learn the complementary information from multiple modalities to improve the action recognition performance. However, there exists a significant modality channel difference, the equal transferring channel semantic features from multi-modalities to RGB will result in competition and redundancy during knowledge distillation. To address this issue, we propose a focal channel knowledge distillation strategy to transfer the key semantic correlations and distributions of multi-modality teachers into the RGB student network. The focal channel correlations provide intrinsic relationships and diversity properties of key semantics, and focal channel distributions provide salient channel activation of features. By ignoring the less-discriminative and irrelevant channels, the student can more efficiently utilize the channel capability to learn the complementary semantic features from the other modalities. Our focal channel knowledge distillation achieves 91.2%, 95.6%, 98.3% and 81.0% accuracy with 4.5%, 4.2%, 3.7% and 7.1% improvement on NTU 60 (CS), UTD-MHAD, N-UCLA and HMDB51 datasets comparing to unimodal RGB models. This focal channel knowledge distillation framework can also be integrated with the unimodal models to achieve the state-of-the-art performance. The extensive experiments show that the proposed method achieves 92.5%, 96.0%, 98.9%, and 82.3% accuracy on NTU 60 (CS), UTD-MHAD, N-UCLA, and HMDB51 datasets respectively.

Abstract Background Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most significant threats to the global swine industry. It is of great importance to understand viral-host interactions to develop novel antiviral strategies. Long non-coding RNAs (lncRNAs) have emerged as critical factors regulating host antiviral immune responses. However, lncRNAs participating in virus-host interactions during PRRSV infection remain largely unexplored. Method RNA transcripts of porcine alveolar macrophages (PAMs) infected with two different PRRSV strains, GSWW/2015 and VR2332, at 24 h post-infection were sequenced by high-throughput sequencing. Four programs namely, CNCI, CPC, PFAM, and phyloCSF, were utilized to predict the coding potential of transcripts. mRNAs co-localized or co-expressed with differentially expressed lncRNAs were considered as their targets. Fuction of lncRNAs was predicted by GO and KEGG analysis of their target mRNAs. The effect of LNC_000397 on PRRSV replication was validated by knockdown its expression using siRNA. Target genes of LNC_000397 were identified by RNA-Sequencing and validated by RT-qPCR. Result In this study, we analyzed lncRNA and mRNA expression profiles of PRRSV GSWW/2015 and VR2332 infected porcine alveolar macrophages. A total of 1,147 novel lncRNAs were characterized, and 293 lncRNAs were differentially expressed. mRNAs co-localized and co-expressed with lncRNAs were enriched in pathogen-infection-related biological processes such as Influenza A and Herpes simplex infection. Functional analysis revealed the lncRNA, LNC_000397, which was up-regulated by PRRSV infection, negatively regulated PRRSV replication. Knockdown of LNC_000397 significantly impaired expression of antiviral ISGs such as MX dynamin-like GTPase 1 (MX1), ISG15 Ubiquitin-like modifier (ISG15), and radical S-adenosyl methionine domain containing 2 (RSAD2). Conclusions LNC_000397 negatively regulated PRRSV replication by inducing interferon-stimulated genes (ISGs) expression. Our study is the first report unveiling the role of host lncRNA in regulating PRRSV replication, which might be beneficial for the development of novel antiviral therapeutics.

Abstract Porcine reproductive and respiratory syndrome (PRRS) is a major threat to the global swine industry and causes tremendous economic losses. Its causative agent, porcine reproductive and respiratory syndrome virus (PRRSV), primarily infects immune cells, such as porcine alveolar macrophages and dendritic cells. PRRSV infection results in immune suppression, antibody-dependent enhancement, and persistent infection. Highly pathogenic strains in China cause high fever and severe inflammatory responses in the lungs. However, the pathogenesis of PRRSV is still not fully understood. In this study, we analysed the long noncoding RNA (lncRNA) and mRNA expression profiles of the HP-PRRSV GSWW15 and the North American strain FL-12 in infected porcine alveolar macrophages (PAMs) at 12 and 24 hours post-infection. We predicted 12,867 novel lncRNAs, 299 of which were differentially expressed after viral infection. The Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) analyses of the genes adjacent to lncRNAs showed that they were enriched in pathways related to viral infection and immune response, indicating that lncRNAs might play regulatory roles in virus-host interactions. Our study provided information about lncRNAs in the porcine immune system and offers new insights into the pathogenic mechanism of PRRSV infection and novel antiviral therapy development.