Role of histone methyltransferase SETDB1 in regulation of tumourigenesis and immune response

Epigenetic alterations are implicated in tumour immune evasion and immune checkpoint blockade (ICB) resistance. SET domain bifurcated histone methyltransferase 1 (SETDB1) is a histone lysine methyltransferase that catalyses histone H3K9 di- and tri-methylation on euchromatin, and growing evidence indicates that SETDB1 amplification and abnormal activation are significantly correlated with the unfavourable prognosis of multiple malignant tumours and contribute to tumourigenesis and progression, immune evasion and ICB resistance. The main underlying mechanism is H3K9me3 deposition by SETDB1 on tumour-suppressive genes, retrotransposons, and immune genes. SETDB1 targeting is a promising approach to cancer therapy, particularly immunotherapy, because of its regulatory effects on endogenous retroviruses. However, SETDB1-targeted therapy remains challenging due to potential side effects and the lack of antagonists with high selectivity and potency. Here, we review the role of SETDB1 in tumourigenesis and immune regulation and present the current challenges and future perspectives of SETDB1 targeted therapy

EEHV1A glycoprotein B subunit vaccine elicits humoral and cell-mediated immune responses in mice

Asian elephants are an endangered species facing many threats, including severe hemorrhagic disease (HD) caused by the elephant endotheliotropic herpesvirus (EEHV). EEHV-HD is the leading cause of death in captive juvenile Asian elephants in North America and Europe, and also affects elephants in their natural range countries. Significant challenges exist for successful treatment of EEHV-HD, which include timely recognition of disease onset and limited availability of highly effective treatment options. To address this problem, our goal is to prevent lethal disease in young elephants by developing a vaccine that elicits robust and durable humoral and cell-mediated immunity against EEHV. EEHV glycoprotein B (gB) is a major target for cellular and humoral immunity in elephants previously exposed to EEHV. Therefore, we generated a vaccine containing recombinant EEHV1A gB together with a liposome formulated TLR-4 and saponin combination adjuvant (SLA-LSQ). CD-1 mice that received one or two vaccinations with the vaccine elicited significant anti-gB antibody and polyfunctional CD4+ and CD8+ T cell responses, while no adverse effects of vaccination were observed. Overall, our findings demonstrate that an adjuvanted gB protein subunit vaccine stimulates robust humoral and cell-mediated immune responses and supports its potential use in elephants

EEHV1A glycoprotein B subunit vaccine elicits humoral and cell-mediated immune responses in mice

DATA AVAILABILITY : Data will be made available on request.Asian elephants are an endangered species facing many threats, including severe hemorrhagic disease (HD) caused by the elephant endotheliotropic herpesvirus (EEHV). EEHV-HD is the leading cause of death in captive juvenile Asian elephants in North America and Europe, and also affects elephants in their natural range countries. Significant challenges exist for successful treatment of EEHV-HD, which include timely recognition of disease onset and limited availability of highly effective treatment options. To address this problem, our goal is to prevent lethal disease in young elephants by developing a vaccine that elicits robust and durable humoral and cell-mediated immunity against EEHV. EEHV glycoprotein B (gB) is a major target for cellular and humoral immunity in elephants previously exposed to EEHV. Therefore, we generated a vaccine containing recombinant EEHV1A gB together with a liposome formulated TLR-4 and saponin combination adjuvant (SLA-LSQ). CD-1 mice that received one or two vaccinations with the vaccine elicited significant anti-gB antibody and polyfunctional CD4+ and CD8+ T cell responses, while no adverse effects of vaccination were observed. Overall, our findings demonstrate that an adjuvanted gB protein subunit vaccine stimulates robust humoral and cell-mediated immune responses and supports its potential use in elephants.The Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award, the NIH, the International Elephant Foundation (IEF) and Houston Zoo and funds acquired via Named Fund Friends of VetMed to the Utrecht University EEHV research group.http://www.elsevier.com/locate/vaccineam2023Veterinary Tropical Disease

Receptor binding mechanisms of Clostridioides difficile toxin B and implications for therapeutics development.

Clostridioides difficile is classified as an urgent antibiotic resistance threat by the Centers for Disease Control and Prevention (CDC). C. difficile infection (CDI) is mainly caused by the C. difficile exotoxin TcdB, which invades host cells via receptor-mediated endocytosis. However, many natural variants of TcdB have been identified including some from the hypervirulent strains, which pose significant challenges for developing effective CDI therapies. Here, we review the recent research progress on the molecular mechanisms by which TcdB recognizes Frizzed proteins (FZDs) and chondroitin sulfate proteoglycan 4 (CSPG4) as two major host receptors. We suggest that the receptor-binding sites and several previously identified neutralizing epitopes on TcdB are ideal targets for the development of broad-spectrum inhibitors to protect against diverse TcdB variants

Ultra-Short-Term Wind Power Prediction Based on Multivariate Phase Space Reconstruction and Multivariate Linear Regression

In order to improve the accuracy of wind power prediction (WPP), we propose a WPP based on multivariate phase space reconstruction (MPSR) and multivariate linear regression (MLR). Firstly, the multivariate time series (TS) are constructed through reasonable selection of wind power and weather factors, which are closely associated with wind power. Secondly, the phase space of the multivariate time series is reconstructed based on the chaos theory and C-C method. Thirdly, an auto regression model for multivariate phase space is created by regarding phase variables as state variables, and the very-short-term wind power is predicted by using a multi-linear regression algorithm. Finally, a parallel algorithm based on map/reduce is presented to improve computing speed. A cloud computing platform, Hadoop consisting of five nodes, is established as a matter of convenience, followed by the prediction of wind power of a wind farm in the Hunan province of China. The experimental results show that the model based on MPSR and MLR is more accurate than both the continuous method and the simple approximation method, and the parallel algorithm based on map/reduce effectively accelerates the computing speed

Nuclear-Cytoplasmic Shuttling Is Not Required for the Epstein-Barr Virus EBNA-LP Transcriptional Coactivation Function ▿

Epstein-Barr virus (EBV) EBNA-LP is a transcriptional coactivator of EBNA2 that works though interaction with the promyelocytic leukemia nuclear-body-associated protein Sp100A. EBNA-LP localizes predominantly in the nucleus through the action of nuclear localization signals in the repeated regions of the protein. EBNA-LP has also been detected in the cytoplasm, and a previous study suggested that some of the EBNA-LP coactivation function is mediated by relocalizing histone deacetylase 4 (HDAC4) from the nucleus to the cytoplasm. Although EBNA-LP can be found in the cytoplasm, it has no obvious nuclear export signal, and there is no direct evidence for active shuttling between these cellular compartments. Whether active shuttling between the nucleus and cytoplasm is required for coactivation remains to be clarified. To address these issues, we tested a variety of EBNA-LP isoforms and mutants for nuclear-cytoplasmic shuttling activity in an interspecies heterokaryon assay and for the ability to associate with HDAC4. EBNA-LP isoforms smaller than 42 kDa shuttle efficiently in the heterokaryon assay via a crm-1-independent mechanism. In addition, no specific EBNA-LP domain that mediates nuclear export could be identified. In contrast, an EBNA-LP 62-kDa isoform does not demonstrate detectable shuttling in the heterokaryon assay yet still coactivates EBNA2 similarly to the smaller EBNA-LP isoforms. All of the EBNA-LP mutants tested, including the coactivation-deficient ΔCR3 mutant and the nonshuttling 62-kDa isoform, were capable of associating with HDAC4. Taken together, our results suggest that simple diffusion may account for the nuclear export observed with smaller isoforms of EBNA-LP, that nuclear-cytoplasmic shuttling is not required for efficient EBNA-LP coactivation function, and that competence for HDAC4 association is not sufficient to mediate nuclear-cytoplasmic shuttling or EBNA-LP coactivation in the absence of a functional interaction with Sp100A

Structural insight into Wnt signaling inhibition by Clostridium difficile toxin B

The incidence of Clostridium difficile infection (CDI) has increased significantly worldwide, causing substantial morbidity and mortality. One of the major virulence factor, TcdB, manages to enter the colonic epithelia via the human frizzled proteins (FZDs), which are physiological receptors for Wnt morphogens. Binding of TcdB to FZDs inhibits Wnt signaling, which may contribute to pathogenesis of CDI. Here, we review the structural mechanism by which TcdB exploits to recognize FZDs for cell entry and inhibiting Wnt signaling, which reveals new strategies to modulate Wnt signaling for therapeutic interventions

Evaluation of the Biocontrol Efficiency of Bacillus subtilis Wettable Powder on Pepper Root Rot Caused by Fusarium solani

The plant-growth-promoting rhizobacteria (PGPR) B. subtilis PTS-394 has been utilized as a biocontrol agent (in a wettable powder form) due to its excellent ability to suppress tomato soil-borne diseases caused by Fusarium oxysporum and Ralstonia solanacearum. In this study, we evaluated the biocontrol efficiency of Bacillus subtilis PTS-394 wettable powder on pepper root rot in pot experiments and field trials. B. subtilis PTS-394 and its lipopeptide crude extract possessed excellent inhibition activity against Fusarium solani, causing pepper root rot; in an antifungal activity test B. subtilis PTS-394 wettable powder exhibited a good ability to promote pepper seed germination and plant height. The experiments in pots and the field indicated that B. subtilis PTS-394 wettable powder had an excellent control effect at 100-fold dilution, and its biocontrol efficacy reached 69.63% and 74.43%, respectively. In this study, the biocontrol properties of B. subtilis PTS-394 wettable powder on pepper root rot were evaluated and its application method was established. It was concluded that B. subtilis PTS-394 wettable powder is a potential biocontrol agent with an excellent efficiency against pepper root rot