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Abstract Tea gray blight disease is a significant threat to the tea industry. In this study, a biological activity approach was utilized to investigate the efficacy of green fungicides from Magnolia officinalis stem bark against Neopestalotiopsis ellipsospora. The active compounds were isolated and purified, and their structures were elucidated. In vitro and in vivo activity screenings revealed that the n-hexane extract, which contained magnolol and honokiol, exhibited strong activity against N. ellipsospora, showing complete inhibition at 100 mg/L. The EC50 values of magnolol and honokiol were 5.11 and 6.09 mg/L, respectively. Mechanistically, magnolol was found to disrupt N. ellipsospora invasion by damaging the cell membrane, increasing permeability, and causing leakage of intracellular substances. Transcriptome analysis revealed that magnolol treatment downregulates membrane-related genes and leads to the enrichment of lipid metabolism pathway genes. This study revealed that magnolol inhibits N. ellipsospora growth by affecting lipid metabolism and compromising cell membrane integrity.

Meniscus injury is one of the most common sports injuries within the knee joint, which is also a crucial pathogenic factor for osteoarthritis (OA). The current meniscus substitution products are far from able to restore meniscal biofunctions due to the inability to reconstruct the gradient heterogeneity of natural meniscus from biological and biomechanical perspectives. Here, inspired by the topology self-induced effect and native meniscus microstructure, we present an innovative tissue-engineered meniscus (TEM) with a unique gradient-sized diamond-pored microstructure (GSDP-TEM) through dual-stage temperature control 3D-printing system based on the mechanical/biocompatibility compatible high Mw poly(ε-caprolactone) (PCL). Biologically, the unique gradient microtopology allows the seeded mesenchymal stem cells with spatially heterogeneous differentiation, triggering gradient transition of the extracellular matrix (ECM) from the inside out. Biomechanically, GSDP-TEM presents excellent circumferential tensile modulus and load transmission ability similar to the natural meniscus. After implantation in rabbit knee, GSDP-TEM induces the regeneration of biomimetic heterogeneous neomeniscus and efficiently alleviates joint degeneration. This study provides an innovative strategy for functional meniscus reconstruction. Topological self-induced cell differentiation and biomechanical property also provides a simple and effective solution for other complex heterogeneous structure reconstructions in the human body and possesses high clinical translational potential.

IntroductionBreast cancer is a heterogeneous disease comprising various molecular subtypes, including Luminal A, Luminal B, human epidermal growth factor receptor-2 (HER2) positive, and triple negative types, each with distinct biological characteristics and behaviors. Triple negative breast cancer (TNBC) remains a particularly challenging subtype worldwide. Our study aims to evaluate whether Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT) parameters, clinical pathological features, and biochemical indicators serve as prognostic risk factors for TNBC. Additionally, we explore correlations between biochemical indicators and 18F-FDG PET/CT parameters.MethodsWe conducted a retrospective analysis of 95 TNBC patients who underwent preoperative 18F-FDG PET/CT examinations at Tianjin Medical University Cancer Institute and Hospital from 2013 to 2018. Collected data included 18F-FDG PET/CT parameters, clinical and pathological features, and biochemical indicators. We used Kaplan-Meier survival analysis and multivariate Cox regression analysis to evaluate associations between 18F-FDG PET/CT parameters/biochemical indicators and disease free survival (DFS)/overall survival (OS). The log-rank test determined significant differences in survival curves, and the Spearman correlation coefficient analyzed correlations between quantitative variables. Visualization and analysis were performed using R packages.ResultsAmong 95 TNBC patients, mean standardized uptake value (SUVmean) was significantly correlated with DFS. Fasting blood glucose (FBG), α- L-fucosylase (AFU) and Creatine kinase (CK) were independent predictors of DFS, while Precursor albumin (PALB) and CK were independent predictors of OS. FBG showed correlations with SUVpeak and SUVmean, and CK was correlated with peak standardized uptake value (SUVpeak). Our results indicated that 18F-FDG PET/CT parameters and biochemical indicators may constitute a new prognostic model for TNBC patients post-surgery.DiscussionWe found that SUVmean, FBG, AFU and CK are predictive factors for DFS in TNBC patients post-surgery, while PALB and CK are predictive factors for OS, which prompts us to pay more attention to these indicators in clinical practice. Also 18F-FDG PET/CT parameters and biochemical indicators have potential utility in constituting a new prognostic model for TNBC patients post-surgery.

Immune rejection presents a significant challenge in xenogenic meniscal transplantation. Pigs are widely regarded as an advantageous tissue source for such transplants, with porcine GGTA1, CMAH, and B4GALNT2 being among the most common xenoreactive antigen (Ag) genes. While some studies have suggested that allogeneic meniscus (AM) transplants may exhibit immunoprivileged properties, our study observed slight immunological rejection has been observed following contact between human meniscal cells (HMCs) and human peripheral blood mononuclear cells (PBMCs). Given the limited systematic research on immune responses following xenograft meniscus transplantation, we established porcine meniscus transplantation (PMT) models to comprehensively assess the immunogenicity of porcine meniscus (PM) from both innate and adaptive immune perspectives. Our investigations confirmed that PMT beneath the epidermis led to innate cell infiltration into the xenografts and T-cell activation in local lymph nodes. T-cell activation upregulated the interleukin (IL)-17 signaling pathway, disrupting collagen organization and metabolic processes, thereby hindering PM regeneration. Using freeze-thaw treatment on PM alleviated T-cell activation post-transplantation by eliminating xenogenic DNA. In vitro findings demonstrated that gene editing in porcine meniscal cells (PMCs) suppressed human T-cell activation by downregulating the expression of xenoreactive Ag genes. These results suggest that GGTA1/CMAH/B4GALNT2 knockout (KO) pigs hold significant promise for advancing the field of meniscal transplantation.

Background: Postoperative hypothermia (POH) is a common issue in colorectal surgery patients, leading to complications. This study aimed to develop and validate a predictive model for identifying POH in colorectal surgery patients. Methods: A retrospective analysis of 1,316 patients who underwent colorectal surgery between June 2020 and September 2022 was conducted using institutional medical records. Intraoperative core temperatures and potential influencing factors were collected, and regression analysis was used to identify risk factors for POH and create a model. The model's performance was evaluated using the receiver operating characteristic curve analysis. Results: Intraoperative hypothermia occurred in 51.5 % of patients. Significant predictors of POH included gender, alcohol consumption, surgery duration, platelet count, and age. The constructed model included factors like fluid intake, platelets, cigarette use, alcohol consumption, surgery type, muscle relaxants, age, ABSI, and gender. The model showed good predictive performance with an area under the ROC curve of 0.981 and a Hosmer-Lemeshow test p-value of 0.676. The Youden index, sensitivity, specificity, and practical application rate were 0.602, 0.790, 0.812, and 98.81 %, respectively. Conclusion: This study developed a predictive model for POH in colorectal surgery patients, considering individual factors and exploring underlying causes. Understanding risk factors and consequences of POH is crucial for nurses and perioperative professionals in clinical practice.

ABSTRACTPeripheral glia, specifically the Schwann cells (SCs), have been implicated in the formation of the tumor microenvironment (TME) and in cancer progression. However, in vivo and ex vivo analyses of how cancers reprogram SC functions in different organs of tumor-bearing mice are lacking. We generated Plp1-CreERT/tdTomato mice which harbor fluorescently labeled myelinated and non-myelin forming SCs. We show that this model enables the isolation of the SCs with high purity from the skin and multiple other organs. We used this model to study phenotypic and functional reprogramming of the SCs in the skin adjacent to melanoma tumors. Transcriptomic analyses of the peritumoral skin SCs versus skin SCs from tumor-free mice revealed that the former existed in a repair-like state typically activated during nerve and tissue injury. Peritumoral skin SCs also downregulated pro-inflammatory genes and pathways related to protective anti-tumor responses. In vivo and ex vivo functional assays confirmed immunosuppressive activities of the peritumoral skin SCs. Specifically, melanoma-reprogrammed SCs upregulated 12/15-lipoxygenase (12/15-LOX) and cyclooxygenase (COX)-2, and increased production of anti-inflammatory polyunsaturated fatty acid (PUFA) metabolites prostaglandin E2 (PGE2) and lipoxins A4/B4. Inhibition of 12/15-LOX or COX2 in SCs, or EP4 receptor on lymphocytes reversed SC-dependent suppression of anti-tumor T-cell activation. Therefore, SCs within the skin adjacent to melanoma tumors demonstrate functional switching to repair-like immunosuppressive cells with dysregulated lipid oxidation. Our study suggests the involvement of the melanoma-associated repair-like peritumoral SCs in the modulation of locoregional and systemic anti-tumor immune responses.

PfENT1 is a promising antimalarial drug target. Here, authors report cryo-EM structures of PfENT1 that, together with biochemical work, suggests PfENT1 is an inosine transporter and describe the inhibitory mechanism of the endofacial inhibitor, GSK4.

This study demonstrates a role of cholesterol metabolism-related gene, Lrp3, in cartilage degeneration and osteoarthritis pathogenesis. LRP3 positively regulates cartilage extracellular matrix metabolism by targeting syndecan-4 via Ras signalling, implicating the cholesterol-LRP3-SDC4 axis in osteoarthritic cartilage degeneration.

IntroductionA previous study suggested that loss of CFAP47 function is involved in multiple morphological abnormalities of the sperm flagella (MMAF) in humans and mice. However, the comprehensive role of CFAP47 in spermatogenesis is largely unknown.MethodsWhole-exome sequencing (WES) was conducted to identify pathogenic variant in two patients with MMAF. The functional effect of the identified mutations was investigated by immunofluorescence staining and western blotting. Intracytoplasmic sperm injection (ICSI) was used to assist fertilization for the patient with MMAF.ResultsIn this study, we identified a novel missense mutation (c.1414G>A; p.V472M) in CFAP47 in two unrelated patients with oligoasthenoteratozoospermia. Intriguingly, in addition to the MMAF phenotype very analogous to the previous report, the two patients notably presented abnormal morphology of sperm heads, the sperm mitochondrial sheath was obviously disorganized, and the sperm annulus were almost defective. Further functional experiments confirmed that the expression of CFAP47 was markedly reduced in the spermatozoa of the patients. Mechanism analysis suggested that CFAP47 might regulate the expression of CFAP65, CFAP69 and SEPTIN4 through their physical interactions and thus modulating sperm morphogenesis.Conclusionwe revealed a novel mutation in CFAP47 and further expanded the phenotype and mutation spectrum of CFAP47, as well as the potential mechanism of CFAP47 manipulating spermatogenesis, finally providing important guidance for genetic counseling and targeted treatment for CFAP47 mutation-related male infertility.

HIV Tat is an essential protein required for the transcription elongation of HIV genome. It has been shown that Tat can be degraded by either proteasome or autophagy pathways. In this study, it was shown that proteasome inhibitor MG132 could significantly prevent HIV Tat protein degradation in Tat over-expressing HeLa cells but it had a moderate effect in preventing Tat protein degradation in Jurkat T cells. A screening of the available UBE2 siRNA family identified that UBE2R1 had a high repressive effect on Tat protein but not on Tat mRNA level. This study further showed that RNF20 might not be the E3 ligase of Tat but was required to maintain a high level of H2B-monoubiquitylation (H2Bub1) on HIV-1 genome for efficient elongation. Overall, our study indicated that UBE2R1 might be the potential ubiquitin E2 ligase for HIV Tat protein turnover and RNF20 regulated HIV expression in the transcription elongation level.

Summary: Sustainable global immunization campaigns against COVID-19 and other emerging infectious diseases require effective, broadly deployable vaccines. Here, we report a dissolvable microarray patch (MAP) SARS-CoV-2 vaccine that targets the immunoresponsive skin microenvironment, enabling efficacious needle-free immunization. Multicomponent MAPs delivering both SARS-CoV-2 S1 subunit antigen and the TLR3 agonist Poly(I:C) induce robust antibody and cellular immune responses systemically and in the respiratory mucosa. MAP vaccine-induced antibodies bind S1 and the SARS-CoV-2 receptor-binding domain, efficiently neutralize the virus, and persist at high levels for more than a year. The MAP platform reduces systemic toxicity of the delivered adjuvant and maintains vaccine stability without refrigeration. When applied to human skin, MAP vaccines activate skin-derived migratory antigen-presenting cells, supporting the feasibility of human translation. Ultimately, this shelf-stable MAP vaccine improves immunogenicity and safety compared to traditional intramuscular vaccines and offers an attractive alternative for global immunization efforts against a range of infectious pathogens.

Introduction: Breast cancer is a heterogeneous disease comprising various molecular subtypes, including Luminal A, Luminal B, human epidermal growth factor receptor-2 (HER2) positive, and triple negative types, each with distinct biological characteristics and behaviors. Triple negative breast cancer (TNBC) remains a particularly challenging subtype worldwide. Our study aims to evaluate whether Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT) parameters, clinical pathological features, and biochemical indicators serve as prognostic risk factors for TNBC. Additionally, we explore correlations between biochemical indicators and 18F-FDG PET/CT parameters. Methods: We conducted a retrospective analysis of 95 TNBC patients who underwent preoperative 18F-FDG PET/CT examinations at Tianjin Medical University Cancer Institute and Hospital from 2013 to 2018. Collected data included 18F-FDG PET/CT parameters, clinical and pathological features, and biochemical indicators. We used Kaplan-Meier survival analysis and multivariate Cox regression analysis to evaluate associations between 18F-FDG PET/CT parameters/biochemical indicators and disease free survival (DFS)/overall survival (OS). The log-rank test determined significant differences in survival curves, and the Spearman correlation coefficient analyzed correlations between quantitative variables. Visualization and analysis were performed using R packages. Results: Among 95 TNBC patients, mean standardized uptake value (SUVmean) was significantly correlated with DFS. Fasting blood glucose (FBG), a-L-fucosylase (AFU) and Creatine kinase (CK) were independent predictors of DFS, while Precursor albumin (PALB) and CK were independent predictors of OS. FBG showed correlations with SUVpeak and SUVmean, and CK was correlated with peak standardized uptake value (SUVpeak). Our results indicated that 18F-FDG PET/CT parameters and biochemical indicators may constitute a new prognostic model for TNBC patients post-surgery. Discussion: We found that SUVmean, FBG, AFU and CK are predictive factors for DFS in TNBC patients post-surgery, while PALB and CK are predictive factors for OS, which prompts us to pay more attention to these indicators in clinical practice. Also 18F-FDG PET/CT parameters and biochemical indicators have potential utility in constituting a new prognostic model for TNBC patients postsurgery. [ABSTRACT FROM AUTHOR]