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BackgroundIn 2015, herpes simplex virus 1 (HSV-1)-derived talimogene laherparepvec (T-VEC) was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment. However, its antitumor application is limited to local treatment of melanoma, and there is a lack of understanding of the mechanisms underlying the regulation of HSV-1 replication in cancer cells and the associated antitumor immunity. We hypothesized that increasing the replication capacity of HSV-1 in tumor cells would enhance the antitumor effect of this virus.MethodsWe systematically identified IFN-stimulated genes induced by HSV-1 by performing functional screens and clarified the mechanism by which BACH1 acts against HSV-1. Then, we tested the effect of BACH1 deficiency on immunogenic cell death induced by HSV-1. Furthermore, we investigated the antitumor effect of BACH1 deficiency on HSV-1 in MCA205 and B16 murine tumor models.ResultsWe identified eight IFN-stimulated genes (ISGs) controlling HSV-1 replication, among which BTB and CNC homology 1 (BACH1) suppressed HSV-1 replication by inhibiting the transcription of ICP4, ICP27, and UL39. Loss of Bach1 function not only increased HSV-1 proliferation but also promoted HSV-1-induced cell apoptosis, HMGB1 secretion, and calreticulin exposure in tumor cells. More importantly, hemin, an FDA-approved drug known to downregulate BACH1, significantly enhanced HSV-1-mediated antitumor activity with increased T lymphocyte infiltration at the tumor site.ConclusionsOur studies uncovered a novel antiviral activity of BACH1 and provided a new strategy for improving the clinical efficiency of the oncolytic virus HSV-1.

BackgroundZika virus (ZIKV) infection and ZIKV epidemic have been continuously spreading silently throughout the world and its associated microcephaly and other serious congenital neurological complications poses a significant global threat to public health. Type I interferon response to ZIKV infection in host cells suppresses viral replication by inducing the expression of interferon-stimulated genes (ISGs).MethodsThe study aims to demonstrate the anti-ZIKV mechanism of PARP11. PARP11 knock out and overexpressing A549 cell lines were constructed to evaluate the anti-ZIKV function of PARP11. PARP11-/-, PARP12-/- and PARP11-/-PARP12-/- HEK293T cell lines were constructed to explain the synergistic effect of PARP11 and PARP12 on NS1 and NS3 protein degradation. Western blotting, immunofluorescence and immunoprecipitation assay were performed to illustrate the interaction between PARP11 and PARP12.ResultsBoth mRNA and protein levels of PARP11 were induced in WT but not IFNAR1-/- cells in response to IFNα or IFNβ stimulation and ZIKV infection. ZIKV replication was suppressed in cells expressed PARP11 but was enhanced in PARP11-/- cells. PARP11 suppressed ZIKV independently on itself PARP enzyme activity. PARP11 interacted with PARP12 and promoted PARP12-mediated ZIKV NS1 and NS3 protein degradation.ConclusionWe identified ADP-ribosyltransferase PARP11 as an anti-ZIKV ISG and found that it cooperated with PARP12 to enhance ZIKV NS1 and NS3 protein degradation. Our findings have broadened the understanding of the anti-viral function of ADP-ribosyltransferase family members, and provided potential therapeutic targets against viral ZIKV infection.

The tumor microenvironment (TME), including infiltrated immune cells, is known to play an important role in tumor growth; however, the mechanisms underlying tumor immunogenicity have not been fully elucidated. Here, we discovered an unexpected role for the transcription factor SIX1 in regulating the tumor immune microenvironment. Based on analyses of patient datasets, we found that SIX1 was upregulated in human tumor tissues and that its expression levels were negatively correlated with immune cell infiltration in the TME and the overall survival rates of cancer patients. Deletion of Six1 in cancer cells significantly reduced tumor growth in an immune-dependent manner with enhanced antitumor immunity in the TME. Mechanistically, SIX1 was required for the expression of multiple collagen genes via the TGFBR2-dependent Smad2/3 activation pathway, and collagen deposition in the TME hampered immune cell infiltration and activation. Thus, our study uncovers a crucial role for SIX1 in modulating tumor immunogenicity and provides proof-of-concept evidence for targeting SIX1 in cancer immunotherapy.

Terahertz (THz) light, probing electronic responses near the Fermi level, is closely linked to DC transport. In this study, we investigate the in situ THz and DC conductivity of epitaxial VO 2 films near the heating-induced insulator–metal transition. We find that the THz conductivity transition occurs at lower temperatures than the DC conductivity transition, with the separation increasing with film thickness and crystallization quality. Analysis of the complex conductivity spectra attributes this separation to released carrier confinement at THz frequencies. Our findings contribute to a deeper understanding of electron dynamics in VO 2 films. [ABSTRACT FROM AUTHOR]

The widespread prevalence of coronavirus disease-2019 (COVID-19) which is caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has resulted in a severe global public health emergency. However, there are no sensitive biomarkers to predict the disease prognosis of COVID-19 patients. Here, we have identified interleukin-8 (IL-8) as a biomarker candidate to predict different disease severity and prognosis of COVID-19 patients. While serum IL-6 become obviously elevated in severe COVID-19 patients, serum IL-8 was easily detectible in COVID-19 patients with mild syndromes. Furthermore, lL-8 levels correlated better than IL-6 levels with the overall clinical disease scores at different stages of the same COVID-19 patients. Thus, our studies suggest that IL-6 and IL-8 can be respectively used as biomarkers for severe COVID-19 patients and for COVID-19 disease prognosis.

Aiming at the problem that lightweight algorithm models are difficult to accurately detect and locate tapping surfaces and tapping key points in complex rubber forest environments, this paper proposes an improved YOLOv8n-IRP model based on the YOLOv8n-Pose. First, the receptive field attention mechanism is introduced into the backbone network to enhance the feature extraction ability of the tapping surface. Secondly, the AFPN structure is used to reduce the loss and degradation of the low-level and high-level feature information. Finally, this paper designs a dual-branch key point detection head to improve the screening ability of key point features in the tapping surface. In the detection performance comparison experiment, the YOLOv8n-IRP improves the D_mAP50 and P_mAP50 by 1.4% and 2.3%, respectively, over the original model while achieving an average detection success rate of 87% in the variable illumination test, which demonstrates enhanced robustness. In the positioning performance comparison experiment, the YOLOv8n-IRP achieves an overall better localization performance than YOLOv8n-Pose and YOLOv5n-Pose, realizing an average Euclidean distance error of less than 40 pixels. In summary, YOLOv8n-IRP shows excellent detection and positioning performance, which not only provides a new method for the key point localization of the rubber-tapping robot but also provides technical support for the unmanned rubber-tapping operation of the intelligent rubber-tapping robot. [ABSTRACT FROM AUTHOR]

Xp11.2 translocation renal cell carcinomas (tRCC) are a rare and highly malignant type of renal cancer, lacking efficient diagnostic indicators and therapeutic targets. Through the analysis of public databases and our cohort, we identified NMRK2 as a potential diagnostic marker for distinguishing Xp11.2 tRCC from kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP) due to its specific upregulation in Xp11.2 tRCC tissues. Mechanistically, we discovered that TFE3 fusion protein binds to the promoter of the NMRK2 gene, leading to its upregulation. Importantly, we established RNA‐ and protein‐based diagnostic methods for identifying Xp11.2 tRCC based on NMRK2 expression levels, and the diagnostic performance of our methods was comparable to a dual‐color break‐apart fluorescence in situ hybridization assay. Moreover, we successfully identified fresh Xp11.2 tRCC tissues after surgical excision using our diagnostic methods and established an immortalized Xp11.2 tRCC cell line for further research purposes. Functional studies revealed that NMRK2 promotes the progression of Xp11.2 tRCC by upregulating the NAD+/NADH ratio, and supplementation with β‐nicotinamide mononucleotide (NMN) or nicotinamide riboside chloride (NR), effectively rescued the phenotypes induced by the knockdown of NMRK2 in Xp11.2 tRCC. Taken together, these data introduce a new diagnostic indicator capable of accurately distinguishing Xp11.2 tRCC and highlight the possibility of developing novel targeted therapeutics. © 2024 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]