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Sulforaphane (SFN), a natural compound found in cruciferous vegetables, possesses well-documented antitumor properties. However, the precise functions and mechanisms of SFN in cancer suppression remain poorly understood. Here we provide evidence to demonstrate that SFN exerts more pronounced antitumor effects in immunocompetent mice compared to immunodeficient mice, suggesting the involvement of the host immune system in SFN-mediated tumor suppression. Furthermore, we reveal that SFN primarily acts through CD8+ cytotoxic T lymphocytes (CTLs) to enhance antitumor immunity by blocking the IFN-γ-mediated induction of PD-L1, a critical immune checkpoint receptor expressed in cancer cells. Importantly, our findings indicate that the suppression of PD-L1 expression by SFN is independent of the NRF2 protein stabilization pathway. Instead, SFN inhibits IFN-γ-mediated activation of STAT1, a key transcription factor involved in PD-L1 induction. Mechanistically, SFN covalently modifies specific cysteine residues (C155 and C174) on STAT1, resulting in the inhibition of its transcriptional activity. Notably, SFN-mediated downregulation of PD-L1 contributes to its antitumor immune effects, as demonstrated by enhanced anti-CTLA-4-mediated cytotoxicity. These findings indicate that SFN's antitumor effect extends beyond its direct cytotoxic properties, as it also actively engages the host immune system. This underscores SFN's immense potential as an immune-modulating agent in cancer therapy.

Abstract Two novel compounds including a cyclohelminthol type polyketide (namely oxaleimide K, 1) and a maleimide derivative (namely peniroquefortine A, 2), and a new natural product (namely 2-(acetylamino)-N-[(1E)-2-phenylethenyl]-acetamide, 3), together with four known compounds (4–7), were isolated and identified from fungus Penicillium roqueforti, which was separated from the root soil of Hypericum beanii N. Robson collected from the Shennongjia Forestry District, Hubei Province. Their structures including absolute configurations were mainly established by the NMR spectroscopy analyses and single-crystal X-ray diffraction experiment. Compound 1 represents the second example of a cyclohelminthol type polyketide, which features a rare 6/6/5/5 tetracyclic system and a branched aliphatic chain containing a terminal olefin (oct-1-en-3-yl) moiety, and compound 2 possesses an unprecedented carbon skeleton that is uniquely defined by a maleimide moiety linked to the respective 4-methylene-2-(3-methylbut-2-en-1-yl)-phenol and para-substituted aromatic moieties via the carbon-carbon bonds. Remarkably, the absolute configuration of a cyclohelminthol type polyketide as exemplified by compound 1 is determined by the single-crystal diffraction analysis for the first time, highlighting an E-configuration for the linkage of a succinimide moiety and a tetrahydrofuran moiety for 1 rather than a Z-configuration as previously reported in the biosynthesis study, which gives a new insight into the structural elucidation of this category of polyketides. Additionally, compound 1 exhibited significant cytotoxic activity against multiple tumor cells, especially against the Farage and SU-DHL-2 cells (IC50

Objectives: In this study, we aimed to evaluate the non-inferiority of a quadrivalent influenza vaccine (QIV) developed by Sinovac Biotech Co., Ltd. (Sinovac, Beijing, China) by comparing its immunogenicity and safety with a comparator QIV (Vaxigrip Tetra®) in a population aged 3 years and older in Chile and the Philippines. Methods: A phase 3, non-inferiority, double-blind, randomized controlled, multicenter clinical trial was conducted in the southern hemisphere (SH) 2023 influenza season. Participants aged ≥ 3 years old with stable health were randomized 1:1 to receive either Sinovac QIV or comparator QIV. The co-primary outcomes were immunological non-inferiority for Sinovac QIV versus the comparator against each strain contained in the vaccines in terms of seroconversion rates (SCRs) and geometric mean titers (GMTs) of hemagglutination inhibition (HI) antibodies 28 days after final vaccination. Results: A total of 2039 participants were vaccinated (1019 Sinovac QIV; 1020 comparator QIV). Sinovac QIV induced non-inferior immune responses to all four strains as compared to comparator QIV, with slightly higher GMTs than those of comparator QIV: GMT ratios (lower limit 95% confidence interval (CI)) were 1.8 (1.6) for A(H1N1), 1.4 (1.3) for A (H3N2), 1.3 (1.1) for B Victoria and 1.2 (1.1) for B Yamagata; observed seroconversion rate differences (lower limit 95% CI) were 9.6% (6.7) for A(H1N1), 7.0% (3.5) for A(H3N2), 2.4% (−0.03) for B Victoria and 6.8% (3.0) for B Yamagata. Adverse reactions were similar across the two groups and no vaccine-related serious adverse events were reported. Conclusions: The immunogenicity of Sinovac QIV was non-inferior to that of the comparator QIV in these populations aged 3 years and older, and safety was comparable.

Food fraud is widespread in the aquatic food market, hence fast and non-destructive methods of identification of fish flesh are needed. In this study, multispectral imaging (MSI) was used to screen flesh slices from 20 edible fish species commonly found in the sea around Yantai, China, by combining identification based on the mitochondrial COI gene. We found that nCDA images transformed from MSI data showed significant differences in flesh splices of the 20 fish species. We then employed eight models to compare their prediction performances based on the hold-out method with 70% training and 30% test sets. Convolutional neural network (CNN), quadratic discriminant analysis (QDA), support vector machine (SVM), and linear discriminant analysis (LDA) models perform well on cross-validation and test data. CNN and QDA achieved more than 99% accuracy on the test set. By extracting the CNN features for optimization, a very high degree of separation was obtained for all species. Furthermore, based on the Gini index in RF, 11 bands were selected as key classification features for CNN, and an accuracy of 98% was achieved. Our study developed a successful pipeline for employing machine learning models (especially CNN) on MSI identification of fish flesh, and provided a convenient and non-destructive method to determine the marketing of fish flesh in the future.

Abstract Background The gene encoding the E3 ubiquitin ligase substrate-binding adapter Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC); however, the molecular mechanisms underlying the contribution of SPOP mutations to tumorigenesis remain poorly understood. Methods BRAF harbors a potential SPOP-binding consensus motif (SBC) motif. Co-immunoprecipitation assays demonstrated that BRAF interacts with SPOP. A series of functional analyses in cell lines were performed to investigate the biological significance of MAPK/ERK activation caused by SPOP mutations. Results Cytoplasmic SPOP binds to and induces non-degradative ubiquitination of BRAF, thereby reducing the interaction between BRAF and other core components of the MAPK/ERK pathway. SPOP ablation increased MAPK/ERK activation. EC- or PCa-associated SPOP mutants showed a reduced capacity to bind and ubiquitinate BRAF. Moreover, cancer-associated BRAF mutations disrupted the BRAF-SPOP interaction and allowed BRAF to evade SPOP-mediated ubiquitination, thereby upregulating MAPK/ERK signaling and enhancing the neoplastic phenotypes of cancer cells. Conclusions Our findings provide new insights into the molecular link between SPOP mutation-driven tumorigenesis and aberrant BRAF-dependent activation of the MAPK/ERK pathway.

Co-administration of vaccines could be an efficient strategy to increase vaccination uptake and reduce the number of clinic visits. This randomized controlled study aimed to evaluate the immunogenicity and safety of enterovirus 71 (EV71) vaccine co-administered with measles-mumps-rubella (MMR) vaccine and live-attenuated Japanese encephalitis vaccine (LA-JEV). A total of 372 healthy infants were randomly assigned in a 1:1:1 ratio to receive simultaneous administration of EV71 vaccine (dose 1) and MMR on d 0 and EV71 vaccine (dose 2) and LA-JEV on d 30 (Group 1); administration of MMR and LA-JEV on d 0 and 30, respectively (Group 2); or administration of doses 1 and 2 of EV71 vaccine on d 0 and 30, respectively (Group 3). The non-inferiority analysis of the seroconversion for EV71 neutralizing antibody after vaccination was the primary outcome. According to per protocol set, antibody response against EV71, measles, mumps, rubella, and Japanese encephalitis (JE) virus was similar regardless of administration schedule. After vaccination, the seroconversion rate of EV71 neutralizing antibody in Group 1 (107 [97.27%] of 110) was non-inferior to that in Group 3 (109 [97.32%] of 112; difference – 0.05% [95% CI – 5.38 to 5.21]). The incidences of adverse reactions were 62.60% (77/123) in Group 1, 54.84% (68/124) in Group 2, and 37.70% (46/122) in Group 3, and most of them were mild to moderate in severity. No vaccine-related serious adverse events were reported. In total, the co-administration of combined EV71 vaccine with MMR and LA-JEV showed no interference with antibody response and demonstrated good safety profiles.

Two doses of the inactivated influenza vaccine (IIV) are generally recommended for children under 9 years old. This study assessed the necessity for a second dose of quadrivalent IIV (IIV4) in children aged 3–8 years. In this randomized, open-label, paralleled-controlled study, 400 children aged 3–8 years who were vaccine-unprimed were randomly assigned at a 1:1 ratio to receive a two-dose (Group 1) or one-dose (Group 2) regimen of IIV4, and 200 who were vaccine-primed received one dose of IIV4 (Group 3). A serum sample was collected before and 28 days after the last dose to determine the hemagglutination inhibition (HI) antibody level. Adverse events were collected within 28 days after each dose. One-dose or two-doses of IIV4 were well tolerated and safe in children aged 3–8 years, and no serious adverse events related to the vaccine were reported. The seroconversion rates (SCRs) of HI antibody ranged from 61.86% to 95.86%, and the post-vaccination seroprotection rates (SPRs) were all >70% in three groups against the four virus strains. The two-dose regimen in vaccine-unprimed participants (Group 1) achieved similar SPRs in comparison with the one-dose in the vaccine-primed group (Group 3), and the SPRs in Group 1 and Group 3 were higher in vaccine-unprimed participants of the one-dose regimen (Group 2). The present study supports the recommendations of a two-dose regimen for IIV4 use in children aged 3–8 years.

Abstract Heme oxygenase-1 (HO-1) has attracted accumulating attention for its antioxidant enzymatic activity. However, the exact regulatory role of its non-enzymatic activity in the cardiovascular system remains unaddressed. Here, we show that HO-1 was accumulated in the nuclei of stress-induced senescent endothelial cells, and conferred protection against endothelial senescence independent of its enzymatic activity. Overexpression of ΔHO-1, a truncated HO-1 without transmembrane segment (TMS), inhibited H2O2-induced endothelial senescence. Overexpression of ΔHO-1H25A, the catalytically inactive form of ΔHO-1, also exhibited anti-senescent effect. In addition, infection of recombinant adenovirus encoding ΔHO-1 with three nuclear localization sequences (NLS), alleviated endothelial senescence induced by knockdown of endogenous HO-1 by CRISPR/Cas9. Moreover, repression of HO-1 nuclear translocation by silencing of signal peptide peptidase (SPP), which is responsible for enzymatic cleavage of the TMS of HO-1, exacerbated endothelial senescence. Mechanistically, nuclear HO-1 interacted with NPM1 N-terminal portion, prevented NPM1 translocation from nucleolus to nucleoplasm, thus disrupted NPM1/p53/MDM2 interactions and inhibited p53 activation by NPM1, finally resisted endothelial senescence. This study provides a novel understanding of HO-1 as a promising therapeutic strategy for vascular senescence-related cardiovascular diseases.

This study aimed to examine first-born children's sibling jealousy and explore the relationships among first-born children's sibling jealousy, temperament, and emotion regulation in China during COVID-19 pandemic. The research hypotheses of this study are empirically examined through online and offline surveys. A sample of 304 two-child families from China participated in the study; the first-born children were aged between 1.17 and 7 years. The results indicated the following: (1) the older the first-born children and the greater the age difference between siblings, the lower the sibling jealousy. (2) Difficult temperament of first-born children could predict sibling jealousy significantly and positively, and emotion regulation could predict sibling jealousy negatively. (3) There was a partially mediating effect of emotion regulation between temperament and sibling jealousy. Compared with intermediate temperament, first-born children with difficult temperament had weaker emotion regulation and higher sibling jealousy. Overall, findings have important implications for psychological interventions for families of first-born children with difficult temperament.

The Collaborative Filtering (CF) recommendation algorithm, one of the most popular algorithms in Recommendation Systems (RS), mainly includes memory-based and model-based methods. When performing rating prediction using a memory-based method, the approach used to measure the similarity between users or items can significantly influence the recommendation performance. Traditional CFs suffer from data sparsity when making recommendations based on a rating matrix, and cannot effectively capture changes in user interest. In this paper, we propose an improved hybrid collaborative filtering algorithm based on tags and a time factor (TT-HybridCF), which fully utilizes tag information that characterizes users and items. This algorithm utilizes both tag and rating information to calculate the similarity between users or items. In addition, we introduce a time weighting factor to measure user interest, which changes over time. Our experimental results show that our method alleviates the sparsity problem and demonstrates promising prediction accuracy.

Acute diarrhea leads to a substantial disease burden among the elderly worldwide. However, in the context of increasingly aging trend in China, the prevalence of etiological agents among elderly diarrheal patients was undetermined. This study aimed to explore the major enteropathogens of acute diarrhea among outpatients older than 65 years in China, and also the epidemiological features of the pathogens. Demographic and clinical data for acute diarrhea among outpatients older than 65 years were collected from 213 participating hospitals from 2009 to 2014. Stool specimens were collected and tested for 13 enteric viruses and bacteria. The proportion of outpatients positive for targeted pathogens was analyzed by residential areas and seasonal patterns. Among the 7,725 patients enrolled, 1,617 (20.9%)were positive for any one of the 13 study pathogens. The predominant pathogen was norovirus (9.0%), followed by diarrheagenic Escherichia coli (DEC) (5.5%), rotavirus (3.9%), non-typhoidal Salmonella (NTS) (2.9%), and Shigella spp. (2.5%). The prevalence of Shigella spp. among rural patients (6.9%) was higher than that among urban patients (1.6%) (p < 0.001), with opposite trend for DEC (3.6% versus 5.9%, p = 0.007). An obvious seasonal pattern was observed for major pathogens, with peak for norovirus in autumn, rotavirus in winter and DEC, NTS, and Shigella spp. in summer. A wide variety of enteropathogens were detected among the elderly with acute diarrhea in China, with norovirus and DEC being the most commonly isolated pathogens. A strong seasonal pattern was observed for major pathogens of acute diarrhea among the elderly.