Efficacy of the tetravalent protein COVID-19 vaccine, SCTV01E: a phase 3 double-blind, randomized, placebo-controlled trial.

Evolution of SARS-CoV-2 variants emphasizes the need for multivalent vaccines capable of simultaneously targeting multiple strains. SCTV01E is a tetravalent COVID-19 vaccine derived from the spike protein of SARS-CoV-2 variants Alpha, Beta, Delta, and Omicron BA.1. In this double-blinded placebo-controlled pivotal efficacy trial (NCT05308576), the primary endpoint was vaccine efficacy (VE) against COVID-19 seven days post-vaccination in individuals without recent infection. Other endpoints included evaluating safety, immunogenicity, and the VE against all SARS-CoV-2 infections in individuals meeting the study criteria. Between December 26, 2022, and January 15, 2023, 9,223 individuals were randomized at a 1:1 ratio to receive SCTV01E or a placebo. SCTV01E showed a VE of 69.4% (95% CI: 50.6, 81.0) 7 days post-vaccination, with 75 cases in the placebo group and 23 in the SCTV01E group for the primary endpoint. VEs were 79.7% (95% CI: 51.0, 91.6) and 82.4% (95% CI: 57.9, 92.6), respectively, for preventing symptomatic infection and all SARS-CoV-2 infections 14 days post-vaccination. SCTV01E elicited a 25.0-fold higher neutralizing antibody response against Omicron BA.5 28 days post-vaccination compared to placebo. Reactogenicity was generally mild and transient, with no reported vaccine-related SAE, adverse events of special interest (AESI), or deaths. The trial aligned with the shift from dominant variants BA.5 and BF.7 to XBB, suggesting SCTV01E as a potential vaccine alternative effective against present and future variants.

A Review of Protein-Based COVID-19 Vaccines: From Monovalent to Multivalent Formulations.

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in the COVID-19 pandemic, has profoundly impacted global healthcare systems and the trajectory of economic advancement. As nations grapple with the far-reaching consequences of this unprecedented health crisis, the administration of COVID-19 vaccines has proven to be a pivotal strategy in managing this crisis. Protein-based vaccines have garnered significant attention owing to their commendable safety profile and precise immune targeting advantages. Nonetheless, the unpredictable mutations and widespread transmission of SARS-CoV-2 have posed challenges for vaccine developers and governments worldwide. Monovalent and multivalent vaccines represent two strategies in COVID-19 vaccine development, with ongoing controversy surrounding their efficacy. This review concentrates on the development of protein-based COVID-19 vaccines, specifically addressing the transition from monovalent to multivalent formulations, and synthesizes data on vaccine manufacturers, antigen composition, pivotal clinical study findings, and other features that shape their distinct profiles and overall effectiveness. Our hypothesis is that multivalent vaccine strategies for COVID-19 could offer enhanced capability with broad-spectrum protection.

Computed tomography-based radiomics to predict early recurrence of hepatocellular carcinoma post-hepatectomy in patients background on cirrhosis.

BACKGROUND: The prognosis for hepatocellular carcinoma (HCC) in the presence of cirrhosis is unfavourable, primarily attributable to the high incidence of recurrence. AIM: To develop a machine learning model for predicting early recurrence (ER) of post-hepatectomy HCC in patients with cirrhosis and to stratify patients' overall survival (OS) based on the predicted risk of recurrence. METHODS: In this retrospective study, 214 HCC patients with cirrhosis who underwent curative hepatectomy were examined. Radiomics feature selection was conducted using the least absolute shrinkage and selection operator and recursive feature elimination methods. Clinical-radiologic features were selected through univariate and multivariate logistic regression analyses. Five machine learning methods were used for model comparison, aiming to identify the optimal model. The model's performance was evaluated using the receiver operating characteristic curve [area under the curve (AUC)], calibration, and decision curve analysis. Additionally, the Kaplan-Meier (K-M) curve was used to evaluate the stratification effect of the model on patient OS. RESULTS: Within this study, the most effective predictive performance for ER of post-hepatectomy HCC in the background of cirrhosis was demonstrated by a model that integrated radiomics features and clinical-radiologic features. In the training cohort, this model attained an AUC of 0.844, while in the validation cohort, it achieved a value of 0.790. The K-M curves illustrated that the combined model not only facilitated risk stratification but also exhibited significant discriminatory ability concerning patients' OS. CONCLUSION: The combined model, integrating both radiomics and clinical-radiologic characteristics, exhibited excellent performance in HCC with cirrhosis. The K-M curves assessing OS revealed statistically significant differences.

[Evolution and implementation pathways from desertification prevention and control to sandy land management and use in China]. / 中国从防沙治沙到管沙用沙的演变过程与实现路径.

The construction of ecological civilization emphasizes holistic protection of "mountain-water-forest-farmland-lake-grassland-sand", which has become an important concept of desertification prevention projects in arid and semi-arid areas of China. In the past, sandy land management and use have been neglected in desertification prevention and control, in that the links have not been effectively connected and the long-term and efficient desertification prevention has not been realized. Therefore, combining Qian Xuesen's understanding of "deserticulture", we comprehensively discussed the "long-term achievements" of China's desertification control miracle from the perspective of the historical evolution of the interaction of technology and practice, and the strategic development of policy guidance. Further, we defined the concepts of desertification prevention, desertification control, and sandy land management and use. We analyzed the coupling and coordination relationship between the four links and the scientific principle based on the development of ecological industry chain. Finally, we put forward the policy and market realization pathways, with efficient sandy land management as the core, desertification prevention as the basis, desertification control as the channel, and long-term sandy land use as the foundation. We expected to provide theoretical and practical guidance for creating a new miracle of China's desertification prevention and control.

Immunogenicity of Tetravalent Protein Vaccine SCTV01E-2 against SARS-CoV-2 EG.5 Subvaraint: A Phase 2 Trial.

The Omicron EG.5 lineage of SARS-CoV-2 is currently on a trajectory to become the dominant strain. This phase 2 study aims to evaluate the immunogenicity of SCTV01E-2, a tetravalent protein vaccine, with a specific emphasis on its immunogenicity against Omicron EG.5, comparing it with its progenitor vaccine, SCTV01E (NCT05933512). As of 12 September 2023, 429 participants aged ≥18 years were randomized into the groups SCTV01E (N = 215) and SCTV01E-2 (N = 214). Both vaccines showed increases in neutralizing antibody (nAb) against Omicron EG.5, with a 5.7-fold increase and a 9.0-fold increase in the SCTV01E and SCTV01E-2 groups 14 days post-vaccination, respectively. The predetermined statistical endpoints were achieved, showing that the geometric mean titer (GMT) of nAb and the seroresponse rate (SRR) against Omicron EG.5 were significantly higher in the SCTV01E-2 group than in the SCTV01E group. Additionally, SCTV01E and SCTV01E-2 induced a 5.5-fold and a 5.9-fold increase in nAb against XBB.1, respectively. Reactogenicity was generally mild and transient. No vaccine-related serious adverse events (SAEs), adverse events of special interest (AESIs), or deaths were reported. In summary, SCTV01E-2 elicited robust neutralizing responses against Omicron EG.5 and XBB.1 without raising safety concerns, highlighting its potential as a versatile COVID-19 vaccine against SARS-CoV-2 variants.

Glutamylation of an HIV-1 protein inhibits the immune response by hijacking STING.

Cyclic GMP-AMP synthase (cGAS) recognizes Y-form cDNA of human immunodeficiency virus type 1 (HIV-1) and initiates antiviral immune response through cGAS-stimulator of interferon genes (STING)-TBK1-IRF3-type I interferon (IFN-I) signalingcascade. Here, we report that the HIV-1 p6 protein suppresses HIV-1-stimulated expression of IFN-I and promotes immune evasion. Mechanistically, the glutamylated p6 at residue Glu6 inhibits the interaction between STING and tripartite motif protein 32 (TRIM32) or autocrine motility factor receptor (AMFR). This subsequently suppresses the K27- and K63-linked polyubiquitination of STING at K337, therefore inhibiting STING activation, whereas mutation of the Glu6 residue partially reverses the inhibitory effect. However, CoCl2, an agonist of cytosolic carboxypeptidases (CCPs), counteracts the glutamylation of p6 at the Glu6 residue and inhibits HIV-1 immune evasion. These findings reveal a mechanism through which an HIV-1 protein mediates immune evasion and provides a therapeutic drug candidate to treat HIV-1 infection.

Acute effects of polystyrene nanoplastics on the immune response in Sepia esculenta larvae.

With extensive use of plastic products, microplastics (MPs, < 5 mm) and nanoplastics (NPs, < 1 µm) have become major pollutants in ecosystem, especially in marine environment. In recent years, researches on the impact of NPs on organisms have gradually increased. However, studies on the influence of NPs on cephalopods are still limited. Golden cuttlefish (Sepia esculenta), an important economic cephalopod, is a shallow marine benthic organism. In this study, the effect of acute exposure (4 h) to 50-nm polystyrene nanoplastics (PS-NPs, 100 µg/L) on the immune response of S. esculenta larvae was analyzed via transcriptome data. A total of 1260 DEGs were obtained in the gene expression analysis. The analyses of GO, KEGG signaling pathway enrichment, and protein-protein interaction (PPI) network were then performed to explore the potential molecular mechanisms of the immune response. Finally, 16 key immune-related DEGs were obtained according to the number of KEGG signaling pathways involved and the PPI number. This study not only confirmed that NPs had an impact on cephalopod immune response, but also provided novel insights for further unmasking the toxicological mechanisms of NPs.

HIV-1 Vif suppresses antiviral immunity by targeting STING.

HIV-1 infection-induced cGAS-STING-TBK1-IRF3 signaling activates innate immunity to produce type I interferon (IFN). The HIV-1 nonstructural protein viral infectivity factor (Vif) is essential in HIV-1 replication, as it degrades the host restriction factor APOBEC3G. However, whether and how it regulates the host immune response remains to be determined. In this study, we found that Vif inhibited the production of type I IFN to promote immune evasion. HIV-1 infection induced the activation of the host tyrosine kinase FRK, which subsequently phosphorylated the immunoreceptor tyrosine-based inhibitory motif (ITIM) of Vif and enhanced the interaction between Vif and the cellular tyrosine phosphatase SHP-1 to inhibit type I IFN. Mechanistically, the association of Vif with SHP-1 facilitated SHP-1 recruitment to STING and inhibited the K63-linked ubiquitination of STING at Lys337 by dephosphorylating STING at Tyr162. However, the FRK inhibitor D-65495 counteracted the phosphorylation of Vif to block the immune evasion of HIV-1 and antagonize infection. These findings reveal a previously unknown mechanism through which HIV-1 evades antiviral immunity via the ITIM-containing protein to inhibit the posttranslational modification of STING. These results provide a molecular basis for the development of new therapeutic strategies to treat HIV-1 infection.

Genome-Wide Identification and Expression Analysis of Tomato ADK Gene Family during Development and Stress.

Adenylate kinase (ADK) is widely distributed in organisms and plays an important role in cellular energy homeostasis. In plants, ADK has important functions in plant growth and development regulation as well as in adaptation to the environment. However, little information is available about the ADK genes in tomato (Solanum lycopersicum), an important economic crop. To investigate the characteristics and functions of ADK genes in tomato, a total of 11 ADK genes were identified and named according to their chromosomal locations. The ADK family in Arabidopsis, tomato, potato, and rice was divided into six groups, and motif analysis revealed that each SlADK protein contained five to eight conserved motifs. A total of 4 to 19 exons were identified in tomato ADK gene family members, and interestingly, most members possessed 4 exons. Several stress response elements were identified in the promoter regions of SlADKs. The 11 SlADKs were randomly distributed on 9 of the 12 tomato chromosomes. Three duplication events were observed between tomato chromosomes, and a high degree of conservation of synteny was demonstrated between tomato and potato. The online TomExpress platform prediction revealed that SlADKs were expressed in various tissues and organs, basically consistent with the data obtained from real-time quantitative PCR (qPCR). The qPCR verification was also performed to determine the expression level of SlADKs and demonstrated that the genes responded to multiple abiotic stresses, such as drought, salt, and cold. Besides, the qPCR results showed that SlADK transcription was responsive to most of the applied hormone treatment. For correlation network analysis under 44 global conditions, the results showed that the number of 17, 3, 4, and 6 coexpressed genes matched with SlADK5, 8, 9, and 11, respectively. For specific gene function analysis, expression of SlADK10 was inhibited using virus-induced gene silencing (VIGS). Compared to wild-type plants, plants with silenced SlADK10 gene had poor drought resistance, indicating SlADK10 regulated drought tolerance of tomato positively. In summary, the information provided in the present study will be helpful to understand the evolutionary relationship and their roles of tomato ADK gene family in further research.

Helicobacter pylori CagA Interacts with SHP-1 to Suppress the Immune Response by Targeting TRAF6 for K63-Linked Ubiquitination.

Helicobacter pylori is the major etiological agent for most gastric cancer. CagA has been reported to be an important virulence factor of H. pylori, but its effect on the immune response is not yet clear. In this study, wild-type C57BL/6 mice and Ptpn6me-v/me-v mice were randomly assigned for infection with H. pylori We demonstrated that CagA suppressed H. pylori-stimulated expression of proinflammatory cytokines in vivo. Besides, we infected mouse peritoneal macrophages RAW264.7 and AGS with H. pylori Our results showed that CagA suppressed expression of proinflammatory cytokines through inhibiting the MAPKs and NF-κB pathways activation in vitro. Mechanistically, we found that CagA interacted with the host cellular tyrosine phosphatase SHP-1, which facilitated the recruitment of SHP-1 to TRAF6 and inhibited the K63-linked ubiquitination of TRAF6, which obstructed the transmission of signal downstream. Taken together, these findings reveal a previously unknown mechanism by which CagA negatively regulates the posttranslational modification of TRAF6 in innate antibacterial immune response and provide molecular basis for new therapeutics to treat microbial infection.

ß-arrestin 2 as an activator of cGAS-STING signaling and target of viral immune evasion.

Virus infection may induce excessive interferon (IFN) responses that can lead to host tissue injury or even death. ß-arrestin 2 regulates multiple cellular events through the G protein-coupled receptor (GPCR) signaling pathways. Here we demonstrate that ß-arrestin 2 also promotes virus-induced production of IFN-ß and clearance of viruses in macrophages. ß-arrestin 2 interacts with cyclic GMP-AMP synthase (cGAS) and increases the binding of dsDNA to cGAS to enhance cyclic GMP-AMP (cGAMP) production and the downstream stimulator of interferon genes (STING) and innate immune responses. Mechanistically, deacetylation of ß-arrestin 2 at Lys171 facilitates the activation of the cGAS-STING signaling and the production of IFN-ß. In vitro, viral infection induces the degradation of ß-arrestin 2 to facilitate immune evasion, while a ß-blocker, carvedilol, rescues ß-arrestin 2 expression to maintain the antiviral immune response. Our results thus identify a viral immune-evasion pathway via the degradation of ß-arrestin 2, and also hint that carvedilol, approved for treating heart failure, can potentially be repurposed as an antiviral drug candidate.

SHP-1 suppresses the antiviral innate immune response by targeting TRAF3.

Type I interferons play a pivotal role in innate immune response to virus infection. The protein tyrosine phosphatase SHP-1 was reported to function as a negative regulator of inflammatory cytokine production by inhibiting activation of NF-κB and MAPKs during bacterial infection, however, the role of SHP-1 in regulating type I interferons remains unknown. Here, we demonstrated that knockout or knockdown of SHP-1 in macrophages promoted both HSV-1- and VSV-induced antiviral immune response. Conversely, overexpression of SHP-1 in L929 cells suppressed the HSV-1- and VSV-induced immune response; suppression was directly dependent on phosphatase activity. We identified a direct interaction between SHP-1 and TRAF3; the association between these two proteins resulted in diminished recruitment of CK1ε to TRAF3 and inhibited its K63-linked ubiquitination; SHP-1 inhibited K63-linked ubiquitination of TRAF3 by promoting dephosphorylation at Tyr116 and Tyr446. Taken together, our results identify SHP-1 as a negative regulator of antiviral immunity and suggest that SHP-1 may be a target for intervention in acute virus infection.

Inhibition of microRNA-495 suppresses chondrocyte apoptosis through activation of the NF-κB signaling pathway by regulating CCL4 in osteoarthritis.

As a common form of arthritis, osteoarthritis (OA) represents a degenerative disease, characterized by articular cartilage damage and synovium inflammation. Recently, the role of various microRNAs (miRs) and their specific expression in OA has been highlighted. Therefore, the aim of the current study was to elucidate the role by which miR-495 and chemokine ligand 4 (CCL4) influence the development and progression of OA. OA mice models were established, after which the CCL4 and collagen levels as well as cell apoptosis were determined in cartilage tissue of OA mice. The chondrocytes of the OA mice models were subsequently treated with a series of miR-495 mimic, inhibitor, and siRNA against CCL4. Afterwards, miR-495 expressions as well as the levels of CCL4, p50, p65, and IkBa and the extent of IkBa phosphorylation in addition to the luciferase activity of NF-kB were measured accordingly. Finally, cell apoptosis and cell cycle distribution were detected. miR-495 was highly expressed while NF-κB, CCL4, and collagen II were poorly expressed. Cell apoptosis was elevated in the cartilage tissue of the OA mice. CCL4 was a potential target gene of miR-495. Downregulation of miR-495 led to accelerated chondrocyte proliferation accompanied by diminished cell apoptosis among the OA mice. Taken together, the results of the current study demonstrated that inhibition of miR-495 suppressed chondrocyte apoptosis and promoted its proliferation through activation of the NF-κB signaling pathway by up-regulation of CCL4 in OA.

Downregulation of long noncoding RNA LOC101928134 inhibits the synovial hyperplasia and cartilage destruction of osteoarthritis rats through the activation of the Janus kinase/signal transducers and activators of transcription signaling pathway by upregulating IFNA1.

Osteoarthritis (OA) is the most common disease of arthritis, a chronic joint disease that is always correlated with massive destruction such as cartilage destruction, inflammation of the synovial membrane, and so on. This study aims to explore the role of long noncoding RNA (lncRNA) LOC101928134 in the synovial hyperplasia and cartilage destruction, more specifically, in the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway in an OA rat model. Microarray-based gene expression analysis was conducted to screen out the lncRNA differentially expressed in OA and predict the target gene of the lncRNA with the involvement of the signaling pathway through Kyoto encyclopedia of genes and genomes (KEGG) analysis. A model of OA was established and treated with the small interfering RNA LOC101928134/inhibitor of JAK/STAT signaling pathway to investigate the relationship among LOC101928134, IFNA1, and the JAK/STAT signaling pathway in OA. The effect of LOC101928134 on the serum levels of IFNA1, interleukin-1ß, and tumor necrosis factor-α, and the apoptosis of synovial and cartilage cells was evaluated. LOC101928134, which was found to be highly expressed in knee joint synovial tissues of OA rats, regulated the expression of IFNA1 gene and inhibited JAK/STAT signaling pathway. Downregulation of LOC101928134 resulted in reduced knee joint synovitis, relived inflammatory damage, and knee joint cartilage damage of OA rats. Besides, synovial cell apoptosis was enhanced upon LOC101928134 downregulation, while cartilage cell apoptosis of OA rats was suppressed. These results demonstrate that downregulation of LOC101928134 suppresses the synovial hyperplasia and cartilage destruction of OA rats via activation of JAK/STAT signaling pathway by upregulating IFNA1, providing a new candidate for the treatment of OA.

FHC, an NS4B-interacting Protein, Enhances Classical Swine Fever Virus Propagation and Acts Positively in Viral Anti-apoptosis.

Classical swine fever virus (CSFV), the etiological agent of classical swine fever, causes enormous economic loss to the pig industry. Ferritin heavy chain (FHC) is a notable anti-apoptotic protein, and existing evidence suggests that CSFV cannot induce apoptosis of host cells, however, the role of FHC in CSFV replication remains unclear. In the present study, we found that recombinant lentivirus-mediated knockdown or overexpression of FHC inhibited or enhanced CSFV replication, respectively, indicating a positive role for FHC in CSFV proliferation. Furthermore, interaction between the CSFV NS4B protein and FHC was confirmed by glutathione S-transferase (GST) pull-down, co-immunoprecipitation (co-IP) and confocal imaging assays. In addition, both CSFV replication and NS4B expression upregulated expression of FHC, which counteracts apoptosis by modulating cellular reactive oxygen species (ROS). These results suggest that FHC, an NS4B-interacting protein, enhances CSFV replication and has a positive role in viral anti-apoptosis by regulating ROS accumulation. This work may provide a new perspective for understanding the mechanism of CSFV pathogenesis.

MAVS induces a host cell defense to inhibit CSFV infection.

Classical swine fever virus (CSFV) infection results in highly significant economic losses. Previous studies have suggested that CSFV can be recognized by RIG-I-like receptors (RLRs) to trigger innate defenses. However, the role of mitochondrial antiviral signaling protein (MAVS), the adaptor of RLRs, is still unknown during CSFV infection. Here, we showed that CSFV infection increased MAVS expression in porcine alveolar macrophages (PAMs). Additionally, intracellular reactive oxygen species (ROS) were involved in MAVS expression in CSFV-infected PAMs. Moreover, MAVS enhanced the induction of antiviral and pro-inflammatory cytokines and apoptosis, and inhibited CSFV replication. However, CSFV still establishes a persistent infection in the host. Thus, how CSFV antagonises MAVS-mediated host cell defense was investigated. Importantly, CSFV Npro inhibited MAVS-induced interferons and pro-inflammatory cytokines and apoptosis. Furthermore, IRF3-knockdown also suppressed MAVS-induced host cell defense. Taken together, these results demonstrate that intracellular ROS is involved in CSFV-induced MAVS expression and MAVS induces antiviral cytokines and apoptosis to inhibit CSFV replication while CSFV Npro inhibits MAVS-mediated host cell defenses possibly through degradation of IRF3. These data offer novel insights into the immunomodulatory effects of CSFV infection on the host innate response.

Rab5 Enhances Classical Swine Fever Virus Proliferation and Interacts with Viral NS4B Protein to Facilitate Formation of NS4B Related Complex.

Classical swine fever virus (CSFV) is a fatal pig pestivirus and causes serious financial losses to the pig industry. CSFV NS4B protein is one of the most important viral replicase proteins. Rab5, a member of the small Rab GTPase family, is involved in infection and replication of numerous viruses including hepatitis C virus and dengue virus. Until now, the effects of Rab5 on the proliferation of CSFV are poorly defined. In the present study, we showed that Rab5 could enhance CSFV proliferation by utilizing lentivirus-mediated constitutive overexpression and eukaryotic plasmid transient overexpression approaches. On the other hand, lentivirus-mediated short hairpin RNA knockdown of Rab5 dramatically inhibited virus production. Co-immunoprecipitation, glutathione S-transferase pulldown and laser confocal microscopy assays further confirmed the interaction between Rab5 and CSFV NS4B protein. In addition, intracellular distribution of NS4B-Red presented many granular fluorescent signals (GFS) in CSFV infected PK-15 cells. Inhibition of basal Rab5 function with Rab5 dominant negative mutant Rab5S34N resulted in disruption of the GFS. These results indicate that Rab5 plays a critical role in facilitating the formation of the NS4B related complexes. Furthermore, it was observed that NS4B co-localized with viral NS3 and NS5A proteins in the cytoplasm, suggesting that NS3 and NS5A might be components of the NS4B related complex. Taken together, these results demonstrate that Rab5 positively modulates CSFV propagation and interacts with NS4B protein to facilitate the NS4B related complexes formation.

TRAF6 is a novel NS3-interacting protein that inhibits classical swine fever virus replication.

Classical swine fever virus (CSFV) non-structural protein 3 (NS3) is a multifunctional non-structural protein that plays a major role in viral replication. However, how exactly NS3 exerts these functions remains unknown. Here, we identified tumour necrosis factor receptor-associated factor 6 (TRAF6) as a novel NS3-interacting protein via yeast two-hybrid analysis, co-immunoprecipitation, and glutathione S-transferase pull-down assays. Furthermore, we observed that TRAF6 overexpression significantly inhibited CSFV replication, and TRAF6 knockdown promoted CSFV replication in porcine alveolar macrophages. Additionally, TRAF6 was degraded during CSFV infection or NS3 expression exclusively, indicating that CSFV and TRAF6 were mutually antagonistic and that TRAF6 degradation might contribute to persistent CSFV replication. Moreover, nuclear factor-kappa B (NF-κB) activity and interferon (IFN)-ß and interleukin (IL)-6 expression were increased in TRAF6-overexpressing cells, whereas TRAF6-knockdown cells exhibited decreased NF-κB activity and IFN-ß and IL-6 levels. Notably, TRAF6 overexpression did not reduce CSFV replication following inhibition of NF-κB activation by p65 knockdown. Our findings revealed that TRAF6 inhibits CSFV replication via activation of NF-κB-signalling pathways along with increases in the expression of its targets IFN-ß and IL-6. This work addresses a novel aspect concerning the regulation of innate antiviral immune response during CSFV infection.

uS10, a novel Npro-interacting protein, inhibits classical swine fever virus replication.

Classical swine fever (CSF) is a severe, febrile and highly contagious disease caused by classical swine fever virus (CSFV) that has resulted in huge economic losses in the pig industry worldwide. CSFV Npro has been actively studied but remains incompletely understood. Few studies have investigated the cellular proteins that interact with Npro and their participation in viral replication. Here, the yeast two-hybrid (Y2H) system was employed to screen Npro-interacting proteins from a porcine alveolar macrophage (PAM) cDNA library, and a blast search of the NCBI database revealed that 15 cellular proteins interact with Npro. The interaction of Npro with ribosomal protein S20, also known as universal S10 (uS10), was further confirmed by co-immunoprecipitation and glutathione S-transferase pull-down assays. Furthermore, uS10 overexpression inhibited CSFV replication, whereas the knockdown of uS10 promoted CSFV replication in PAMs. In addition, Npro or CSFV reduced uS10 expression in PAMs in a proteasome-dependent manner, indicating that Npro-uS10 interaction might contribute to persistent CSFV replication. Our previous research showed that CSFV decreases Toll-like receptor 3 (TLR3) expression. The results showed that uS10 knockdown reduced TLR3 expression, and that uS10 overexpression increased TLR3 expression. Notably, uS10 knockdown did not promote CSFV replication following TLR3 overexpression. Conversely, uS10 overexpression did not inhibit CSFV replication following TLR3 knockdown. These results revealed that uS10 inhibits CSFV replication by modulating TLR3 expression. This work addresses a novel aspect of the regulation of the innate antiviral immune response during CSFV infection.

Trigonelline Inhibits Inflammation and Protects ß Cells to Prevent Fetal Growth Restriction during Pregnancy in a Mouse Model of Diabetes.

BACKGROUND: As an active component from traditional Chinese medicine, trigonelline has a protective effect on diabetes. This study evaluated the protective effects of trigonelline on diabetic mice during pregnancy. METHODS: Diabetes was induced in female mice by intraperitoneal injection for continuous 5-day of 40 mg/kg/day streptozotocin. Female mice were divided into 4 groups after they were allowed to mate with normal male mice: nondiabetic, nondiabetic treated with trigonelline (70 mg/kg) for 18 days, diabetic, and diabetic treated with trigonelline (70 mg/kg). RESULTS: Diabetic pregnant mice had significantly higher levels of blood glucose, serum total cholesterol, triglyceride, insulin, and leptin but lower serum omentin-1 level and insulin sensitivity index than the nondiabetic ones. Trigonelline improved the hyperglycemia, dyslipidemia, insulin resistance, and adipocytokine of diabetic pregnant mice. Diabetic pregnant mice had significantly reduced fetus numbers, fetal weight, and fetal/placental ratio, which were reversed by trigonelline. Trigonelline prevented the increase in proinflammatory cytokines and reduced interleukin-10 level in placenta of diabetic pregnant mice. Trigonelline increased ß-cell replication and the decreased ß-cell mass, and decreased the ß-cell apoptosis of diabetic pregnant mice. CONCLUSION: These findings suggest that trigonelline protects diabetic pregnancy partly by suppressing inflammation, regulating the secretion of adipocytokines, increasing ß-cell mass, replication, and decreasing ß-cell apoptosis.