Transcriptome analysis of Citrus Aurantium L. to study synephrine biosynthesis during developmental stages.

Citrus aurantium L., sometimes known as "sour orange," is an important Chinese herb with young, immature fruits, or "zhishi," that are high in synephrine. Synephrine is a commonly utilized natural chemical with promising applications in effectively increasing metabolism, heat expenditure, energy level, oxidative fat, and weight loss. However, little is known about the genes and pathways involved in synephrine production during the critical developmental stages of C. aurantium L., which limits the development of the industry. According to this study, the concentration of synephrine gradually decreased as the fruit developed. Transcriptome sequencing was used to examine the DEGs associated with synephrine connections and served as the foundation for creating synephrine-rich C. aurantium L. Comparisons conducted between different developmental stages to obtain DEGs, and the number of DEGs varied from 690 to 3,019. Tyrosine and tryptophan biosynthesis, glycolysis/gluconeogenesis, pentose phosphate pathway, phenylalanine, and tyrosine metabolism were the main KEGG pathways that were substantially enriched. The results showed that 25 genes among these KEGG pathways may be related to synephrine synthesis. The WGCNA and one-way ANOVA analysis adoption variance across the groups suggested that 11 genes might play a crucial role in synephrine synthesis and should therefore be further analyzed. We also selected six DEGs at random and analyzed their expression levels by RT-qPCR, and high repeatability and reliability were demonstrated by our finished RNA-seq study results. These results may be useful in selecting or modifying genes to increase the quantity of synephrine in sour oranges.

Enhancing chiral molecule detection: A weak measurement approach utilizing two-dimensional information.

This study addresses the critical need for high purity chiral molecules in biological systems by overcoming the challenges associated with the quantitative detection of chiral molecules and their enantiomeric mixtures. We developed an innovative detection approach that leverages the two-dimensional information gleaned from natural optical rotation (NOR) and Faraday optical rotation (FOR) under magnetic fields in chiral molecules, combined with an ultrahigh-resolution weak measurement sensor. This novel weak measurement system achieves unparalleled accuracy in detecting spin angles, with a precision of 1.86 × 10-5°. Notably, our method introduces no chemical reactions or interference with the substances under test. It offers enhanced discrimination capabilities through the dual-dimensional analysis of both natural and Faraday optical rotation, alongside a simple and compact sensor design. Conclusively, our study introduces a novel, high-precision, and multi-dimensional optical detection paradigm for chiral molecules. By incorporating Faraday rotation in the presence of a magnetic field, we expand the informational dimensionality accessible to the original weak measurement sensor, facilitating the quantitative analysis of chiral molecules and their enantiomers. This breakthrough not only furnishes a novel instrument for the exploration and development of chiral pharmaceuticals but also propels the advancement of weak measurement sensing technology forward.

[Inhibition of type 3 deiodinase expression can improve mitochondrial function in skeletal muscle of sepsis by up-regulating peroxisome proliferator-activated receptor-γ coactivator-1α].

OBJECTIVE: To investigate the protective effects and mechanisms of targeted inhibition of type 3 deiodinase (Dio3) on skeletal muscle mitochondria in sepsis. METHODS: (1) In vivo experiments: adeno-associated virus (AAV) was employed to specifically target Dio3 expression in the anterior tibial muscle of rats, and a septic rat model was generated using cecal ligation and puncture (CLP). The male Sprague-Dawley (SD) rats were divided into shNC+Sham group, shD3+Sham group, shNC+CLP group, and shD3+CLP group by random number table method, with 8 rats in each group. After CLP modeling, tibial samples were collected and Western blotting analysis was conducted to assess the protein levels of Dio3, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), and silence-regulatory protein 1 (SIRT1). Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was utilized to examine mRNA expression of genes including thyroid hormone receptors (THRα, THRß), monocarboxylate transporter 10 (MCT10), mitochondrial DNA (mtDNA), and PGC1α. Transmission electron microscopy was employed to investigate mitochondrial morphology. (2) In vitro experiments: involved culturing C2C12 myoblasts, interfering with Dio3 expression using lentivirus, and constructing an endotoxin cell model by treating cells with lipopolysaccharide (LPS). C2C12 cells were divided into shNC group, shD3 group, shNC+LPS group, and shD3+LPS group. Immunofluorescence colocalization analysis was performed to determine the intracellular distribution of PGC1α. Co-immunoprecipitation assay coupled with Western blotting was carried out to evaluate the acetylation level of PGC1α. RESULTS: (1) In vivo experiments: compared with the shNC+Sham group, the expression of Dio3 protein in skeletal muscle of the shNC+CLP group was significantly increased (Dio3/ß-Tubulin: 3.32±0.70 vs. 1.00±0.49, P < 0.05), however, there was no significant difference in the shD3+Sham group. Dio3 expression in the shD3+CLP group was markedly reduced relative to the shNC+CLP group (Dio3/ß-Tubulin: 1.42±0.54 vs. 3.32±0.70, P < 0.05). Compared with the shNC+CLP group, the expression of T3-regulated genes in the shD3+CLP group were restored [THRα mRNA (2-ΔΔCt): 0.67±0.05 vs. 0.33±0.01, THRß mRNA (2-ΔΔCt): 0.94±0.05 vs. 0.67±0.02, MCT10 mRNA (2-ΔΔCt): 0.65±0.03 vs. 0.57±0.02, all P < 0.05]. Morphology analysis by electron microscopy suggested prominent mitochondrial damage in the skeletal muscle of the shNC+CLP group, while the shD3+CLP group exhibited a marked improvement. Compared with the shNC+Sham group, the shNC+CLP group significantly reduced the number of mitochondria (cells/HP: 10.375±1.375 vs. 13.750±2.063, P < 0.05), while the shD3+CLP group significantly increased the number of mitochondria compared to the shNC+CLP group (cells/HP: 11.250±2.063 vs. 10.375±1.375, P < 0.05). The expression of mtDNA in shNC+CLP group was markedly reduced compared with shNC+Sham group (copies: 0.842±0.035 vs. 1.002±0.064, P < 0.05). Although no difference was detected in the mtDNA expression between shD3+CLP group and shNC+CLP group, but significant increase was found when compared with the shD3+Sham group (copies: 0.758±0.035 vs. 0.474±0.050, P < 0.05). In the shD3+CLP group, PGC1α expression was significantly improved at both transcriptional and protein levels relative to the shNC+CLP group [PGC1α mRNA (2-ΔΔCt): 1.49±0.13 vs. 0.68±0.06, PGC1α/ß-Tubulin: 0.76±0.02 vs. 0.62±0.04, both P < 0.05]. (2) In vitro experiments: post-24-hour LPS treatment of C2C12 cells, the cellular localization of PGC1α became diffuse; interference with Dio3 expression promoted PGC1α translocation to the perinuclear region and nucleus. Moreover, the acetylated PGC1α level in the shD3+LPS group was significantly lower than that in the shNC+LPS group (acetylated PGC1α/ß-Tubulin: 0.59±0.01 vs. 1.24±0.01, P < 0.05), while the expression of the deacetylating agent SIRT1 was substantially elevated following Dio3 inhibition (SIRT1/ß-Tubulin: 1.04±0.04 vs. 0.58±0.03, P < 0.05). When SIRT1 activity was inhibited by using EX527, PGC1α protein expression was notably decreased compared to the shD3+LPS group (PGC1α/ß-Tubulin: 0.92±0.03 vs. 1.58±0.03, P < 0.05). CONCLUSIONS: Inhibition of Dio3 in skeletal muscle reduced the acetylation of PGC1α through activating SIRT1, facilitating nuclear translocation of PGC1α, thereby offering protection against sepsis-induced skeletal muscle mitochondrial damage.

Macrophage MKL1 contributes to cardiac fibrosis in a mouse model of myocardial infarction.

AIMS: Cardiac fibrosis is characterized by aberrant collagen deposition in the heart. Macrophage polarization or infiltration is the main reason to accelerate the collagen deposition. We attempted to investigate the involvement of MKL1 in macrophages during the development of cardiac fibrosis. MATERIALS AND METHODS: Cardiac fibrosis is induced by myocardial infarction (MI). The MKL1f/f mice were crossed to the Lyz2-cre mice to generate macrophage conditional MKL1 knockout mice (MKL1ΔMφ). In addition, macrophage conditional MKL1 overexpression mice (MKL1Mϕ-OE) were constructed by crossing Lyz2-cre mice to MKL1ΔN200-Rosa26 mice. KEY FINDINGS: MKL1 expression was significantly increased in macrophages of both ischemic cardiomyopathy (ICM) patients and mice induced to develop myocardial infarction. Deletion of MKL1 in macrophages improved the heart function after MI-induced cardiac fibrosis. Consistently, MKL1Mϕ-OE mice displayed more severe cardiac fibrosis and worsened heart function than the control mice after MI. Moreover, administration of a small-molecule MKL1 inhibitor CCG-1423 also decreased the collagen deposition after MI. SIGNIFICANCE: Our data demonstrate that MKL1 in macrophages contributes to cardiac fibrosis pathogenesis and reinforce the notion that targeting MKL1 may yield effective antifibrotic therapeutics in the heart.

The combined toxicity of polystyrene microplastic and arsenate: From the view of biochemical process in wheat seedlings (Triticum aestivum L.).

Microplastics (MPs) are important carriers of various toxic metals and can alter their toxicity pattern in agricultural soil, leading to combined pollution, therefore posing new challenges to soil pollution management and environmental risk assessment. In this study, we observed the internalization of MPs in plants and conducted incubation experiments to evaluated the effects of arsenate (As(V)) alone and in combination with polystyrene (PS) MPs on wheat seedlings (Triticum aestivum L.). Under As(V) alone and combined with PS-MP exposure, dose-dependent toxicity in terms of root and stem elongation and biomass accumulation was observed. Compared with As(V) alone, the presence of PS-MPs reduced the accumulation of As in wheat roots by 11.43-58.91%, but PS-MPs intensified the transport of As to the aboveground parts of wheat, increasing As accumulation in wheat stems by 27.77-1011.54%. This causes more serious mechanical damage and oxidative stress to plant cells, increasing the accumulation of reactive oxygen species and lipid peroxidation in wheat roots and upregulating the activities of antioxidant enzymes such as superoxide dismutase (SOD) and peroxidase (POD). In addition, the co-exposure of As(V) and PS-MPs disrupts the photosynthetic system of wheat leaves and the secretion activities of roots. Therefore, the combination of As(V) and PS-MPs caused greater damage to wheat growth. Our findings contribute to a more comprehensive assessment of the combined toxicity of MPs and heavy metal to crops.

Development of an m6A subtype classifier to guide precision therapy for patients with bladder cancer.

Purpose: Bladder cancer (BLCA) is a highly heterogeneous tumor. We aim to construct a classifier from the perspective of N6-methyladenosine methylation (m6A) to identify patients with different prognostic risks and treatment responsiveness for precision therapy. Methods: Data on gene expression profile, mutation, and clinical characteristics were mainly obtained from the TCGA-BLCA cohort. Unsupervised clustering was performed to construct m6A subtypes. The tumor microenvironment (TME) landscapes were explored by using ssGSEA, ESTIMATE, and MCPcounter algorithms. K-M survival curves and Cox regression analysis were used to demonstrate the significance of m6A subtypes in predicting prognosis. pRRophetic, oncoPredict, and TIDE algorithms were used to evaluate responsiveness to antitumor therapy. A classifier of m6a subtypes was finally developed based on random forest and artificial neural network (ANN). Results: The two m6A subtypes have significantly different m6A-related gene expression profiles and mutational landscapes. TME analysis showed a higher level of stromal and Inhibitory immune components in subtype B compared with subtype A. The m6A subtype is a clinically independent prognostic predictor of BLCA, subtype B has a poorer prognosis. Drug sensitivity analysis showed that subtype B has lower IC50 values and AUC values for cisplatin and docetaxel. Efficacy assessment showed significantly poorer radiotherapy efficacy and lower immunotherapy responsiveness in subtype B. We finally constructed an ANN classifier to accurately classify BLCA patients into two m6A subtypes. Conclusion: Our study developed a classifier for identifying subtypes with different m6A characteristics, and BLCA patients with different m6A subtypes have significantly different prognosis and responsiveness to antitumor therapy.

SEH1L siliencing induces ferroptosis and suppresses hepatocellular carcinoma progression via ATF3/HMOX1/GPX4 axis.

SEH1 like nucleoporin (SEH1L) is an important component of nuclear pore complex (NPC), which is crucial in the regulation of cell division. However, the interrelation between SEH1L expression and tumor progression is less studied. In this research, we performed a systematic bioinformatic analysis about SEH1L using TCGA, Timer 2.0, Cbioportal, UCLAN and CellMiner™ databases in pan-cancer. Besides, we further validated the bioinformatic results through in vitro and in vivo experiments in HCC, including transcriptome sequencing, real-time quantitative PCR (RT-qPCR), western blotting (WB), immunohistochemistry (IHC), cell proliferation assays, clone formation, EdU, transwell, flow cytometry and subcutaneous tumor model. Our results suggested that SEH1L was significantly up-regulated and related to poor prognosis in most cancers, and may serve as a potential biomarker. SEH1L could promote HCC progression in vitro and in vivo. Besides, the next generation sequencing suggested that 684 genes was significantly up-regulated and 678 genes was down-regulated after the knock down of SEH1L. SEH1L siliencing could activate ATF3/HMOX1/GPX4 axis, decrease mitochondrial membrane potential and GSH, but increase ROS and MDA, and these effects could be reversed by the knock down of ATF3. This study indicated that SEH1L siliencing could induce ferroptosis and suppresses hepatocellular carcinoma (HCC) progression via ATF3/HMOX1/GPX4 axis.

Research on comprehensive evaluation & development of aesthetic education based on PCA and CEM model.

Aesthetic education, conveyed through public art courses, serves as a vital form of humanistic literacy education. It represents an effective approach to fostering innovative and creative thinking among college students. In order to effectively analyze the aesthetic education work of 46 universities, an aesthetic education index evaluation system is constructed, involving indicators including faculty strength, curriculum setting, teaching management, artistic practice, and teaching support. The secondary indicators corresponding to the five indicators are statistically analyzed, and a comprehensive evaluation analysis of the current development status of aesthetic education in 46 universities in Anhui Province is conducted by combining theoretical analysis with empirical analysis. Based on principal component analysis, an integrated evaluation model for the development of aesthetic education in universities in Anhui Province is further constructed. The model designed quantifies the influence weight of each aesthetic education index on the development of aesthetic education in Anhui Province, and forges a theoretical basis for determining the precursors of rapid development of aesthetic education in Anhui Province. Additionally, a novel approach is introduced to gauge the progression of aesthetic education within universities in Anhui Province, considering the dispersion of aesthetic education index data across the province. The comprehensive evaluation model for the development of aesthetic education in Anhui Province exhibits an overall declining trend. Hence, it is suggested to utilize the maximum value of the first derivative of the comprehensive evaluation model as an indicator of the imminent rapid development of aesthetic education in Anhui Province. On this basis, the probability equation of sustainable development of aesthetic education in Anhui Province is defined. Overall, the research results lay a theoretical foundation for the development of aesthetic education in Anhui Province.

Multi-omics reveals the impact of cancer-associated fibroblasts on the prognosis and treatment response of adult diffuse highest-grade gliomas.

Background: Cancer associated fibroblasts (CAF), an important cancer-promoting and immunosuppressive component of the tumor immune microenvironment (TIME), have recently been found to infiltrate adult diffuse highest-grade gliomas (ADHGG) (gliomas of grade IV). Methods: Gene expression and clinical data of ADHGG patients were obtained from the CGGA and TCGA databases. Consensus clustering was used to identify CAF subtypes based on CAF key genes acquired from single-cell omics and spatial transcriptomomics. CIBERSORT, ssGSEA, MCPcounter, and ESTIMATE analyses were used to assess the TIME of GBM. Survival analysis, drug sensitivity analysis, TCIA database, TIDE and cMap algorithms were used to compare the prognosis and treatment response between patients with different CAF subtypes. An artificial neural network (ANN) model based on random forest was constructed to exactly identify CAF subtypes, which was validated in a real-world patient cohort of ADHGG. Results: Consensus clustering classified ADHGG into two CAF subtypes. Compared with subtype B, patients with ADHGG subtype A had a poorer prognosis, worse responsiveness to immunotherapy and radiotherapy, higher CAF infiltration in TIME, but higher sensitivity to temozolomide. Furthermore, patients with subtype A had a much lower proportion of IDH mutations. Finally, the ANN model based on five genes (COL3A1, COL1A2, CD248, FN1, and COL1A1) could exactly discriminate CAF subtypes, and the validation of the real-world cohort indicated consistent results with the bioinformatics analyses. Conclusion: This study revealed a novel CAF subtype to distinguish ADHGG patients with different prognosis and treatment responsiveness, which may be helpful for accurate clinical decision-making of ADHGG.

Synergistic ferrate(VI) and chlorine for reclaimed water disinfection: Microbial control and chlorine decay mitigation.

Chlorination is the most widely used disinfection technology due to its simplicity and continuous disinfection ability. However, the drawbacks of disinfection by-products and chlorine-resistant bacteria have gained increasing attention. Nowadays, ferrate (Fe(VI)) is a multifunctional and environmentally friendly agent which has great potential in wastewater reclamation and reuse. This study investigated synergistic Fe(VI) and chlorine technology for reclaimed water disinfection in terms of microbial control and chlorine decay mitigation. Specifically, synergistic disinfection significantly improved the inactivation efficiency on total coliform, Escherichia coli and heterotrophic bacteria compared to sole chlorination. Synergistic disinfection also exhibited superior performance on controlling the relative abundance of chlorine-resistant bacteria and pathogenic bacteria. In addition, the decay rate of residual chlorine was relatively lower after Fe(VI) pretreatment, which was beneficial for microbial control during the reclaimed water distribution process. Technical and economic analyses revealed that synergistic Fe(VI) and chlorine disinfection was suitable and feasible. Results of this study are believed to provide useful information and alternative options on the optimization of reclaimed water disinfection.

Aurantiacibacter hainanensis sp. nov. and Qipengyuania zhejiangensis sp. nov., two novel Erythrobacteraceae species isolated from tidal flat sediments.

Two Gram-stain-negative, rod-shaped, non-motile, aerobic and carotenoid-producing strains, belonging to the family Erythrobacteraceae, designated as H149T and Z2T, were isolated from tidal flat sediment samples collected in Hainan and Zhejiang, PR China, respectively. Growth of strain H149T occurred at 15-42 °C, 0-10.0 % (w/v) NaCl, and pH 6.0-8.5, with the optima at 35-37 °C, 3.0-3.5 % (w/v) NaCl and pH 7.0. Strain Z2T grew at 15-37 °C, 0-6.0 % (w/v) NaCl, and pH 6.0-9.5, with the optima at 25-30 °C, 0.5-1.0 % (w/v) NaCl and pH 6.0-6.5. Ubiquinone-10 was the sole ubiquinone in two strains. The predominant cellular fatty acids of strain H149T were C16 : 0, summed feature 3 and summed feature 8, while those of strain Z2T were C17 : 1 ω6c, summed feature 3 and summed feature 8. Strains H149T and Z2T shared diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine and sphingoglycolipid as major polar lipids. The 16S rRNA gene sequence identity analysis indicated that strain H149T had the highest sequence identity of 98.4 % with Aurantiacibacter odishensis KCTC 23981T, and strain Z2T had that of 98.2 % with Qipengyuania pacifica NZ-96T. Phylogenetic trees based on 16S rRNA gene and core-genome sequences revealed that strains H149T and Z2T formed two independent clades in the genera Aurantiacibacter and Qipengyuania, respectively. Strain H149T had average nucleotide identity values of 74.0-81.3 % and in silico DNA-DNA hybridization values of 18.5-23.1 % with Aurantiacibacter type strains, while strain Z2T had values of 73.3-78.7 % and 14.5-33.3 % with Qipengyuania type strains. The genomic DNA G+C contents of strains H149T and Z2T were 64.3 and 61.8 %, respectively. Based on the genetic, genomic, phylogenetic, physiological and chemotaxonomic results, strains H149T (=KCTC 8397T=MCCC 1K08920T) and Z2T (=KCTC 8396T=MCCC 1K08946T) are concluded to represent two novel Erythrobacteraceae species for which the names Aurantiacibacter hainanensis sp. nov. and Qipengyuania zhejiangensis sp. nov. are proposed, respectively.

Comparative population genomics reveals convergent and divergent selection in the apricot-peach-plum-mei complex.

The economically significant genus Prunus includes fruit and nut crops that have been domesticated for shared and specific agronomic traits; however, the genomic signals of convergent and divergent selection have not been elucidated. In this study, we aimed to detect genomic signatures of convergent and divergent selection by conducting comparative population genomic analyses of the apricot-peach-plum-mei (APPM) complex, utilizing a haplotype-resolved telomere-to-telomere (T2T) genome assembly and population resequencing data. The haplotype-resolved T2T reference genome for the plum cultivar was assembled through HiFi and Hi-C reads, resulting in two haplotypes 251.25 and 251.29 Mb in size, respectively. Comparative genomics reveals a chromosomal translocation of ~1.17 Mb in the apricot genomes compared with peach, plum, and mei. Notably, the translocation involves the D locus, significantly impacting titratable acidity (TA), pH, and sugar content. Population genetic analysis detected substantial gene flow between plum and apricot, with introgression regions enriched in post-embryonic development and pollen germination processes. Comparative population genetic analyses revealed convergent selection for stress tolerance, flower development, and fruit ripening, along with divergent selection shaping specific crop, such as somatic embryogenesis in plum, pollen germination in mei, and hormone regulation in peach. Notably, selective sweeps on chromosome 7 coincide with a chromosomal collinearity from the comparative genomics, impacting key fruit-softening genes such as PG, regulated by ERF and RMA1H1. Overall, this study provides insights into the genetic diversity, evolutionary history, and domestication of the APPM complex, offering valuable implications for genetic studies and breeding programs of Prunus crops.

Influence of anionic species on the low temperature pyrolysis performance of heated tobacco sheets catalyzed by sodium salts.

Development of low temperature catalytic pyrolysis technology for heated tobacco sheets is expected to increase the aroma of heated tobacco products and improve their overall smoking quality. In this study, the low temperature pyrolysis performances of heated tobacco sheets catalyzed by various anionic sodium salts were investigated using TG-DTG, Py-GC-MS technology and smoke routine chemical composition analysis. The results showed that the total weight loss between 100°C and 300°C increased by 7.8%-13.15% after adding various anionic sodium salts, among which, sodium acetate and sodium tartrate showed a relatively higher weight loss. The relative content of free hydroxyacetone, furfuryl alcohol, butyrolactone and megastigmatrienone in the pyrolysis gas increased, while the relative content of free nicotine decreased. With the change of anionic species, the catalytic decomposition ability of cellulose, lignin, and other substances may change, resulting in the distribution alteration of compounds in the pyrolysis gas. After adding sodium acetate and sodium citrate, the release of total particulate matter (TPM), glycerol, and nicotine in flue gas increased. Overall, the addition of sodium acetate and sodium citrate showed a higher low temperature pyrolysis performance of heated tobacco sheets. The research results in this paper provide data support for changing the low temperature catalytic pyrolysis performance of heated tobacco sheets by adjusting the type of anions in sodium salts.

Identifying disulfidptosis subtypes in hepatocellular carcinoma through machine learning and preliminary exploration of its connection with immunotherapy.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly prevalent and deadly cancer, with limited treatment options for advanced-stage patients. Disulfidptosis is a recently identified mechanism of programmed cell death that occurs in SLC7A11 high-expressing cells due to glucose starvation-induced disintegration of the cellular disulfide skeleton. We aimed to explore the potential of disulfidptosis, as a prognostic and therapeutic marker in HCC. METHODS: We classified HCC patients into two disulfidptosis subtypes (C1 and C2) based on the transcriptional profiles of 31 disulfrgs using a non-negative matrix factorization (NMF) algorithm. Further, five genes (NEIL3, MMP1, STC2, ADH4 and CFHR3) were screened by Cox regression analysis and machine learning algorithm to construct a disulfidptosis scoring system (disulfS). Cell proliferation assay, F-actin staining and PBMC co-culture model were used to validate that disulfidptosis occurs in HCC and correlates with immunotherapy response. RESULTS: Our results suggests that the low disulfidptosis subtype (C2) demonstrated better overall survival (OS) and progression-free survival (PFS) prognosis, along with lower levels of immunosuppressive cell infiltration and activation of the glycine/serine/threonine metabolic pathway. Additionally, the low disulfidptosis group showed better responses to immunotherapy and potential antagonism with sorafenib treatment. As a total survival risk factor, disulfS demonstrated high predictive efficacy in multiple validation cohorts. We demonstrated the presence of disulfidptosis in HCC cells and its possible relevance to immunotherapeutic sensitization. CONCLUSION: The present study indicates that novel biomarkers related to disulfidptosis may serve as useful clinical diagnostic indicators for liver cancer, enabling the prediction of prognosis and identification of potential treatment targets.

Defective mesenchymal Bmpr1a-mediated BMP signaling causes congenital pulmonary cysts.

Abnormal lung development can cause congenital pulmonary cysts, the mechanisms of which remain largely unknown. Although the cystic lesions are believed to result directly from disrupted airway epithelial cell growth, the extent to which developmental defects in lung mesenchymal cells contribute to abnormal airway epithelial cell growth and subsequent cystic lesions has not been thoroughly examined. In the present study using genetic mouse models, we dissected the roles of bone morphogenetic protein (BMP) receptor 1a (Bmpr1a)-mediated BMP signaling in lung mesenchyme during prenatal lung development and discovered that abrogation of mesenchymal Bmpr1a disrupted normal lung branching morphogenesis, leading to the formation of prenatal pulmonary cystic lesions. Severe deficiency of airway smooth muscle cells and subepithelial elastin fibers were found in the cystic airways of the mesenchymal Bmpr1a knockout lungs. In addition, ectopic mesenchymal expression of BMP ligands and airway epithelial perturbation of the Sox2-Sox9 proximal-distal axis were detected in the mesenchymal Bmpr1a knockout lungs. However, deletion of Smad1/5, two major BMP signaling downstream effectors, from the lung mesenchyme did not phenocopy the cystic abnormalities observed in the mesenchymal Bmpr1a knockout lungs, suggesting that a Smad-independent mechanism contributes to prenatal pulmonary cystic lesions. These findings reveal for the first time the role of mesenchymal BMP signaling in lung development and a potential pathogenic mechanism underlying congenital pulmonary cysts.

Congenital disorders are medical conditions that are present from birth. Although many congenital disorders are rare, they can have a severe impact on the quality of life of those affected. For example, congenital pulmonary airway malformation (CPAM) is a rare congenital disorder that occurs in around 1 out of every 25,000 pregnancies. In CPAM, abnormal, fluid-filled sac-like pockets of tissue, known as cysts, form within the lungs of unborn babies. After birth, these cysts become air-filled and do not behave like normal lung tissue and stop a baby's lungs from working properly. In severe cases, babies with CPAM need surgery immediately after birth. We still do not understand exactly what the underlying causes of CPAM might be. CPAM is not considered to be hereditary ­ that is, it does not appear to be passed down in families ­ nor is it obviously linked to any environmental factors. CPAM is also very difficult to study, because researchers cannot access tissue samples during the critical early stages of the disease. To overcome these difficulties, Luo et al. wanted to find a way to study CPAM in the laboratory. First, they developed a non-human animal 'model' that naturally forms CPAM-like lung cysts, using genetically modified mice where the gene for the signaling molecule Bmpr1a had been deleted in lung cells. Normally, Bmpr1a is part of a set of the molecular instructions, collectively termed BMP signaling, which guide healthy lung development early in life. However, mouse embryos lacking Bmpr1a developed abnormal lung cysts that were similar to those found in CPAM patients, suggesting that problems with BMP signalling might also trigger CPAM in humans. Luo et al. also identified several other genes in the Bmpr1a-deficient mouse lungs that had abnormal patterns of activity. All these genes were known to be controlled by BMP signaling, and to play a role in the development and organisation of lung tissue. This suggests that when these genes are not controlled properly, they could drive formation of CPAM cysts when BMP signaling is compromised. This work is a significant advance in the tools available to study CPAM. Luo et al.'s results also shed new light on the molecular mechanisms underpinning this rare disorder. In the future, Luo et al. hope this knowledge will help us develop better treatments for CPAM, or even help to prevent it altogether.

Interacted Ternary Component Ensuring High-Security Eutectic Electrolyte for High Performance Sodium-Metal Batteries.

Due to the intrinsic flame-retardant, eutectic electrolytes are considered a promising candidate for sodium-metal batteries (SMBs). However, the high viscosity and ruinous side reaction with Na metal anode greatly hinder their further development. Herein, based on the Lewis acid-base theory, a new eutectic electrolyte (EE) composed of sodium bis(trifluoromethanesulfonyl)imide (NaTFSI), succinonitrile (SN), and fluoroethylene carbonate (FEC) is reported. As a strong Lewis base, the ─C≡N group of SN can effectively weaken the interaction between Na+ and TFSI-, achieving the dynamic equilibrium and reducing the viscosity of EE. Moreover, the FEC additive shows a low energy level to construct thicker and denser solid electrolyte interphase (SEI) on the Na metal surface, which can effectively eliminate the side reaction between EE and Na metal anode. Therefore, EE-1:6 + 5% FEC shows high ionic conductivity (2.62 mS cm-1) and ultra-high transference number of Na+ (0.96). The Na||Na symmetric cell achieves stable Na plating/stripping for 1100 h and Na||Na3V2(PO4)3/C cell shows superior long-term cycling stability over 2000 cycles (99.1% retention) at 5 C. More importantly, the Na||NVP/C pouch cell demonstrates good cycling performance of 102.1 mAh g-1 after 135 cycles at 0.5 C with an average coulombic efficiency of 99.63%.

Understanding the Role of Low-Dose Polystyrene Microplastic in Copper Toxicity to Rice Seed (Oryza sativa L.).

There is still much to learn with respect to the potential for microplastics (MPs) to interact with environmental toxins and biota. In the present study, we investigated the effect of MPs on the toxicity of copper (Cu) to rice seeds (Oryza sativa L.). The 7-day median effective concentration (EC50) value of MPs on rice seed germination was 864 mg/L (95% confidence interval [CI] 839 to 897 mg/L). We found that MPs slightly reduced Cu toxicity to rice seeds. The 7-day EC50 of Cu on rice seed germination increased from 7.29 mg/L (95% CI 7.10-7.52 mg/L) to 7.93 mg/L (95% CI 7.58-8.08 mg/L) in the presence of 20 mg/L MPs. We examined this toxicity reduction phenomenon by investigating the role of MPs in the process of Cu transport, Cu accumulation, and metabolic responses. Further investigation found that the MPs used in the present study hardly adsorbed Cu, but these MPs accumulated on the coats of rice seeds and significantly reduced Cu accumulation in rice seedlings. When Cu concentration was 10 mg/L, the presence of MPs reduced the accumulation of Cu in rice seedlings by 34%. We also found that, compared with only Cu present, the addition of MPs resulted in lower reactive oxygen species accumulation and higher catalase activity and glutathione levels in rice seedlings, which also contributed to Cu toxicity reduction. Collectively, the present study shows that polystyrene MPs have the potential to form associations with plant structures which can ultimately impact heavy metal bioaccessibility and therefore toxicity. Environ Toxicol Chem 2024;43:1870-1879. © 2024 SETAC.

Ginsenoside Rh4 prevents endothelial dysfunction as a novel AMPK activator.

BACKGROUND AND PURPOSE: The AMP-activated protein kinase (AMPK) signalling pathway is a desirable target for various cardiovascular diseases (CVD), while the involvement of AMPK-mediated specific downstream pathways and effective interventions in hyperlipidaemia-induced endothelial dysfunction remain largely unknown. Herein, we aim to identify an effective AMPK activator and to explore its efficacy and mechanism against endothelial dysfunction. EXPERIMENTAL APPROACH: Molecular docking technique was adopted to screen for the potent AMPK activator among 11 most common rare ginsenosides. In vivo, poloxamer 407 (P407) was used to induce acute hyperlipidaemia in C57BL/6J mice. In vitro, palmitic acid (PA) was used to induce lipid toxicity in HAEC cells. KEY RESULTS: We discovered the strongest binding of ginsenoside Rh4 to AMPKα1 and confirmed the action of Rh4 on AMPK activation. Rh4 effectively attenuated hyperlipidaemia-related endothelial injury and oxidative stress both in vivo and in vitro and restored cell viability, mitochondrial membrane potential and mitochondrial oxygen consumption rate in HAEC cells. Mechanistically, Rh4 bound to AMPKα1 and simultaneously up-regulated AKT/eNOS-mediated NO release, promoted PGC-1α-mediated mitochondrial biogenesis and inhibited P38 MAPK/NFκB-mediated inflammatory responses in both P407-treated mice and PA-treated HAEC cells. The AMPK inhibitor Compound C treatment completely abrogated the regulation of Rh4 on the above pathways and weakened the lowering effect of Rh4 on endothelial impairment markers, suggesting that the beneficial effects of Rh4 are AMPK dependent. CONCLUSION AND IMPLICATIONS: Rh4 may serve as a novel AMPK activator to protect against hyperlipidaemia-induced endothelial dysfunction, providing new insights into the prevention and treatment of endothelial injury-associated CVD.

A combination of a TLR7/8 agonist and an epigenetic inhibitor suppresses triple-negative breast cancer through triggering anti-tumor immune.

BACKGROUND: Combination therapy involving immune checkpoint blockade (ICB) and other drugs is a potential strategy for converting immune-cold tumors into immune-hot tumors to benefit from immunotherapy. To achieve drug synergy, we developed a homologous cancer cell membrane vesicle (CM)-coated metal-organic framework (MOF) nanodelivery platform for the codelivery of a TLR7/8 agonist with an epigenetic inhibitor. METHODS: A novel biomimetic codelivery system (MCM@UN) was constructed by MOF nanoparticles UiO-66 loading with a bromodomain-containing protein 4 (BRD4) inhibitor and then coated with the membrane vesicles of homologous cancer cells that embedding the 18 C lipid tail of 3M-052 (M). The antitumor immune ability and tumor suppressive effect of MCM@UN were evaluated in a mouse model of triple-negative breast cancer (TNBC) and in vitro. The tumor immune microenvironment was analyzed by multicolor immunofluorescence staining. RESULTS: In vitro and in vivo data showed that MCM@UN specifically targeted to TNBC cells and was superior to the free drug in terms of tumor growth inhibition and antitumor immune activity. In terms of mechanism, MCM@UN blocked BRD4 and PD-L1 to prompt dying tumor cells to disintegrate and expose tumor antigens. The disintegrated tumor cells released damage-associated molecular patterns (DAMPs), recruited dendritic cells (DCs) to efficiently activate CD8+ T cells to mediate effective and long-lasting antitumor immunity. In addition, TLR7/8 agonist on MCM@UN enhanced lymphocytes infiltration and immunogenic cell death and decreased regulatory T-cells (Tregs). On clinical specimens, we found that mature DCs infiltrating tumor tissues of TNBC patients were negatively correlated with the expression of BRD4, which was consistent with the result in animal model. CONCLUSION: MCM@UN specifically targeted to TNBC cells and remodeled tumor immune microenvironment to inhibit malignant behaviors of TNBC.