EPDR1 promotes PD-L1 expression and tumor immune evasion by inhibiting TRIM21-dependent ubiquitylation of IkappaB kinase-ß.

While immune checkpoint blockade (ICB) has shown promise for clinical cancer therapy, its efficacy has only been observed in a limited subset of patients and the underlying mechanisms regulating innate and acquired resistance to ICB of tumor cells remain poorly understood. Here, we identified ependymin-related protein 1 (EPDR1) as an important tumor-intrinsic regulator of PD-L1 expression and tumor immune evasion. Aberrant expression of EPDR1 in hepatocellular carcinoma is associated with immunosuppression. Mechanistically, EPDR1 binds to E3 ligase TRIM21 and disrupts its interaction with IkappaB kinase-b, suppressing its ubiquitylation and autophagosomal degradation and enhancing NF-κB-mediated transcriptional activation of PD-L1. Further, we validated through a mouse liver cancer model that EPDR1 mediates exhaustion of CD8+ T cells and promotes tumor progression. In addition, we observed a positive correlation between EPDR1 and PD-L1 expression in both human and mouse liver cancer samples. Collectively, our study reveals a previously unappreciated role of EPDR1 in orchestrating tumor immune evasion and cancer progression.

Clinical efficacy of gamma-oryzanol combined with Femoston for perimenopausal syndrome.

BACKGROUND: Perimenopausal syndrome (PMS) is a chronic disease associated with estrogen deficiency. Because of the unsatisfactory outcomes of current conventional treatments for this condition, its treatment must be continuously explored and optimized. AIM: To assess the clinical effectiveness of γ-oryzanol in combination with Femoston for PMS. METHODS: A total of 119 patients with PMS were selected from June 2023 to December 2023, which included 59 and 60 patients in the control and observation group, respectively. The control and observation groups were treated with Femoston and γ-oryzanol + Femoston, respectively. Comparative analyses were performed in terms of clinical effectiveness, safety (dizziness and headache, nausea and vomiting, and breast tenderness), sex hormones [estradiol (E2), luteinizing hormone (LH), and follicle-stimulating hormone (FSH)], lumbar spine (L1-4) and bilateral femoral bone mineral density (BMD), and sleep quality (sleeping time and frequency of awakenings from sleep). RESULTS: Compared with the control group, the observation group had statistically higher total effective rates of treatment; lower overall incidence of adverse events; higher post-treatment E2 levels and L1-4 and bilateral femoral BMD; and lower LH and FSH levels, sleeping time, and frequency of awakenings from sleep after treatment. CONCLUSION: Therefore, for the treatment of PMS, γ-oryzanol combined with Femoston is significantly better than Femoston alone in terms of clinical effectiveness, exhibiting more pronounced clinical advantages in improving safety, sex hormone levels, BMD, and sleep quality.

Melatonin alleviates brain injury in copper-laden rats: Underlying benefits for Wilson's disease.

Copper serves as an indispensable cofactor for all living organisms, and its excessive accumulation has been associated with a variety of diseases. Wilson's disease (WD) serves as an illustrative example of copper toxicity in humans, frequently presenting with liver and/or neuropsychiatric symptoms. The current therapeutic drugs, penicillamine (PA) and zinc gluconate (ZnG), have constraints, and research on their combination efficacy remains insufficient. It has been reported that melatonin (MLT) plays a vital role in binding to transition metals and exhibits strong antioxidant capacity. To investigate the therapeutic efficacy of MLT and combined treatment, rats were randomly divided into the following seven groups: the control (Con) group, copper-laden model rat (Mod) group, PA-treated group, ZnG-treated group, MLT- treated group, PA-ZnG-treated group, and PA-MLT-treated group. Then potential mechanisms and targets were investigated using a combination of metabolomics and network pharmacology and verified by molecular docking and qPCR. The findings revealed that MLT and the combination significantly improved behavior, pathology and copper levels in copper-laden rats. The results of the metabolomics study showed that profoundly altered metabolites were identified, and alanine, aspartate and glutamate metabolism, pyruvate metabolism, citrate cycle (TCA cycle), and glycolysis/gluconeogenesis were explored. In addition, molecular docking showed that MLT had high binding affinity with key targets, and qPCR results revealed that MLT could reverse the mRNA expression of targets GOT2 and PKM2. It was concluded that MLT effectively improves brain injury in copper-laden rats, and this effect was linked with the altered features of the metabolite profiles.

Identification and precise mapping of PmHSM, a novel recessive powdery mildew resistance allele from wheat landrace Heshangmai.

Common wheat (Triticum aestivum L.) is the world's primary food crop, and ensuring its safe production is of utmost importance for global peace and human development. However, the continuous threat of fungal diseases, including Fusarium head scab, rusts, sharp eyespot, and powdery mildew (PM), poses a significant challenge to production. PM caused by Blumeria graminis f. sp. tritici (Bgt) causes substantial yield losses. Heshangmai (HSM), a wheat landrace originating from Sichuan Province, possesses high levels of resistance to PM. A comprehensive study using a large segregating population of a cross between HSM and Ningmaizi119 (NMZ119) revealed a single recessive allele conferring resistance. The gene, provisionally designated PmHSM, was located on the long arm of chromosome 4A (4AL). Molecular marker analysis, PM response array, and an allelism test indicated that PmHSM is a novel recessive resistance gene that shares an allelic relationship with PmHHXM. Thirteen simple sequence repeat (SSR) markers were developed using the sequence information of the 4AL region in the Chinese spring reference sequence v2.1 (CS RefSeq v2.1). PmHSM was flanked by markers Xmp1567 and Xmp1444 at genetic distances of 0.11 cM and 0.18 cM, respectively, and co-segregated with markers Xmp1439/Xmp1440/Xmp1442.

A Review of the Risk Factors and Approaches to Prevention of Post-Reperfusion Syndrome During Liver Transplantation.

Post-reperfusion syndrome (PRS) is a severe and highly lethal syndrome that occurs after declamping the portal vein forceps during liver transplantation. It is marked by severe hemodynamic disturbances manifested by decreased mean arterial pressure, increased heart rate and elevated pulmonary artery pressure. The complex pathogenesis of PRS remains understudied. It is generally believed to be related to the large amount of acidic, cold blood that enters the circulation after release of the portal clamp. This blood is rich in oxygen-free radicals and metabolic toxins, which not only aggravate the ischemia-reperfusion injury of the liver but also further attack the systemic organs indiscriminately. Considering the range of possible adverse prognoses including acute kidney injury, delirium and graft nonfunction, it is imperative that clinicians increase their awareness and prevention of PRS. The aim of this article is to review the current risk factors, pathophysiological mechanisms and prevention strategies for PRS.

Molecular Characterization and Classification of HER2-Positive Breast Cancer Inform Tailored Therapeutic Strategies.

HER2-positive breast cancer is an aggressive subtype that accounts for 15-20% of all breast cancers. Recent studies have suggested that HER2-positive breast cancer is a group of heterogeneous diseases with different sensitivities to standard treatment regimens. Revealing the molecular heterogeneity of HER2-positive breast cancer could potentially enable more precise treatment strategies. Here, we performed multiomics profiling on a HER2-positive breast cancer cohort and identified four transcriptome-based subtypes. The classical HER2 (HER2-CLA) subtype comprised 28.3% of the samples and displayed high ERBB2 activation and significant benefit from anti-HER2 therapy. The immunomodulatory (HER2-IM) subtype (20%) featured an immune-activated microenvironment, potentially suitable for de-escalated treatment and immunotherapy. The luminal-like (HER2-LUM) subtype (30.6%) possessed similar molecular features of hormone receptor-positive HER2-negative breast cancer, suggesting endocrine therapy and CDK4/6 inhibitors as a potential therapeutic strategy. Lastly, the basal/mesenchymal-like (HER2-BM) subtype (21.1%), had a poor response to current anti-HER2 dual-targeted therapies and could potentially benefit from tyrosine kinase inhibitors. The molecular characteristics and clinical features of the subtypes were further explored across multiple cohorts, and the feasibility of the proposed treatment strategies was validated in patient-derived organoid and patient-derived tumor fragment models. This study elucidates the molecular heterogeneity of HER2-positive breast cancer and paves the way for a more tailored treatment.

Precision Control of Amphoteric Doping in Cu x Bi2Se3 Nanoplates.

Copper-doped Bi2Se3 (Cu x Bi2Se3) is of considerable interest for tailoring its electronic properties and inducing exotic charge correlations while retaining the unique Dirac surface states. However, the copper dopants in Cu x Bi2Se3 display complex electronic behaviors and may function as either electron donors or acceptors depending on their concentration and atomic sites within the Bi2Se3 crystal lattice. Thus, a precise understanding and control of the doping concentration and sites is of both fundamental and practical significance. Herein, we report a solution-based one-pot synthesis of Cu x Bi2Se3 nanoplates with systematically tunable Cu doping concentrations and doping sites. Our studies reveal a gradual evolution from intercalative sites to substitutional sites with increasing Cu concentrations. The Cu atoms at intercalative sites function as electron donors while those at the substitutional sites function as electron acceptors, producing distinct effects on the electronic properties of the resulting materials. We further show that Cu0.18Bi2Se3 exhibits superconducting behavior, which is not present in Bi2Se3, highlighting the essential role of Cu doping in tailoring exotic quantum properties. This study establishes an efficient methodology for precise synthesis of Cu x Bi2Se3 with tailored doping concentrations, doping sites, and electronic properties.

Histone deacetylases: potential therapeutic targets for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease of unknown origin and the most common interstitial lung disease. However, therapeutic options for IPF are limited, and novel therapies are urgently needed. Histone deacetylases (HDACs) are enzymes that participate in balancing histone acetylation activity for chromatin remodeling and gene transcription regulation. Increasing evidence suggests that the HDAC family is linked to the development and progression of chronic fibrotic diseases, including IPF. This review aims to summarize available information on HDACs and related inhibitors and their potential applications in treating IPF. In the future, HDACs may serve as novel targets, which can aid in understanding the etiology of PF, and selective inhibition of single HDACs or disruption of HDAC genes may serve as a strategy for treating PF.

Analysis of blasting vibration duration considering frequency and energy and its application.

Blasting vibration's effect on ground vibration is essentially an energy transfer and transformation process (Hongtao et al., 2010) [1]. In engineering, the blasting vibration duration is often used as an objective index to evaluate the blasting vibration hazard. Thus, this study on the factors influencing blasting vibration duration is essential. In this study, the blasting vibration duration prediction formula uses frequency and energy as independent parameters, which are analysed using a statistical t probability distribution. With the blasting vibration duration prediction formula, the delay time taken for the structure to reach the resonance frequency is obtained by calculating the dominant frequency of the structure. The results indicate that the frequency and energy of the blasting vibration signal are highly correlated with the duration of blasting vibration, and their introduction as independent parameters in the prediction formula can better improve the prediction accuracy. The dominant frequency should not be neglected in blasting vibration safety evaluations, and the use of blasting vibration duration prediction to calculate the dominant frequency can better avoid the resonance phenomenon in the structure.

Genetic diversity and population structure of wheat landraces in Southern Winter Wheat Region of China.

BACKGROUND: Wheat landraces are considered a valuable source of genetic diversity for breeding programs. It is useful to evaluate the genetic diversity in breeding studies such as marker-assisted selection (MAS), genome-wide association studies (GWAS), and genomic selection. In addition, constructing a core germplasm set that represents the genetic diversity of the entire variety set is of great significance for the efficient conservation and utilization of wheat landrace germplasms. RESULTS: To understand the genetic diversity in wheat landrace, 2,023 accessions in the Jiangsu Provincial Crop Germplasm Resource Bank were used to explore the molecular diversity and population structure using the Illumina 15 K single nucleotide polymorphism (SNP) chip. These accessions were divided into five subpopulations based on population structure, principal coordinate and kinship analysis. A significant variation was found within and among the subpopulations based on the molecular variance analysis (AMOVA). Subpopulation 3 showed more genetic variability based on the different allelic patterns (Na, Ne and I). The M strategy as implemented in MStratv 4.1 software was used to construct the representative core collection. A core collection with a total of 311 accessions (15.37%) was selected from the entire landrace germplasm based on genotype and 12 different phenotypic traits. Compared to the initial landrace collections, the core collection displayed higher gene diversity (0.31) and polymorphism information content (PIC) (0.25), and represented almost all phenotypic variation. CONCLUSIONS: A core collection comprising 311 accessions containing 100% of the genetic variation in the initial population was developed. This collection provides a germplasm base for effective management, conservation, and utilization of the variation in the original set.

Pim-1 kinase protects the liver from ischemia reperfusion injury by regulating dynamics-related protein 1.

Hepatic ischemia-reperfusion (IR) injury significantly impacts liver transplantation success, yet current treatments remain inadequate. This study explores the role of Proto-oncogene serine/threonine-protein kinase (Pim-1) in liver IR, an area previously unexplored. Utilizing a mouse liver IR in vivo model and a MIHA cell hypoxia-reoxygenation in vitro model, we observed that Pim-1 expression increases following IR, inversely correlating with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Increased Pim-1 expression stabilizes mitochondrial membranes by modifying Drp1 phosphorylation, reducing mitochondrial fission and apoptosis, thereby mitigating liver damage. Additionally, we discovered that elevated Pim-1 expression is dependent on the trimethylation of histone H3 lysine 9 during liver IR. These findings underscore the importance and potential clinical application of targeting Pim-1 in treating hepatic IR, presenting a novel therapeutic avenue.

Insights into the antineoplastic activity and mechanisms of action of coumarin-coordinated 8-hydroxyquinoline ruthenium(II/III) compounds.

Ruthenium(II/III) coordination compounds have gained widespread attention as chemotherapy drugs, photosensitizers, and photodynamic therapy reagents. Herein, a family of 11 novel coumarin-coordinated 8-hydroxyquinoline ruthenium(II/III) compounds, i.e., [RuII2(µ2-Cl)2(QL1a)2(DMSO)4] (YNU-4a = Yulin Normal University-4a), [RuII2(µ2-Cl)2(QL1b)2(DMSO)4] (YNU-4b), [RuII2(µ2-Cl)2(QL1c)2(DMSO)4] (YNU-4c), [RuII2(µ2-Cl)2(QL1d)2(DMSO)4]⋅2CH3OH (YNU-4d), [RuII(QL1e)2(DMSO)2] (YNU-4e), [RuIII(QL1e)2(QL3a)] (YNU-4f), [RuIII(QL1e)2(QL3b)] (YNU-4g), [RuIII(QL1e)2(QL3c)] (YNU-4h), [RuIICl2(H-QL3a)2(DMSO)2] (YNU-4i), [RuIICl2(H-QL3b)2(DMSO)2] (YNU-4j), and [RuIICl2(H-QL3c)2(DMSO)2] (YNU-4k), featuring the coligands 5,7-diiodo-8-hydroxyquinoline (H-QL1a), 5,7-dichloro-8-quinolinol (H-QL1b), 5-chloro-7-iodo-8-hydroxyquinolin (H-QL1c), 5,7-dibromo-8-hydroxyquinoline (H-QL1d), and 5,7-dichloro-8-hydroxy-2-methylquinoline (H-QL1e) and the main ligands 6,7-dichloro-3-pyridin-2-yl-chromen-2-one (H-QL3a), 6-bromo-3-pyridin-2-yl-chromen-2-one (H-QL3b), and 6-chloro-3-pyridin-2-yl-chromen-2-one (H-QL3c), respectively. The structure of compounds YNU-4a-YNU-4k was fully confirmed by conducting various spectroscopic analyses. The anticancer activity of YNU-4a-YNU-4k was evaluated in cisplatin-resistant A549/DDP lung cancer cells (LC549) versus normal embryonic kidney (HEK293) cells. Notably, compound YNU-4f bearing QL1e and QL3a ligands showed a more pronounced antiproliferative effect against LC549 cells (IC50 = 1.75 ± 0.09 µM) with high intrinsic selectivity toward LC549 cancer cells than YNU-4a-YNU-4e, H-QL1a-H-QL1e, cisplatin (PDD), YNU-4g-YNU-4k, and H-QL3a-H-QL3c. Additionally, a colocalization assay analysis of YNU-4e and YNU-4f showed that these two ruthenium(II/III) compounds were subcellularly accumulated in the mitochondria and other regions of the cytoplasm, where they induce mitophagy, adenosine triphosphate (ATP) reduction, mitochondrial respiratory chain complex I/IV(RC1/RC4) inhibition, and mitochondrial dysfunction. Accordingly, compounds YNU-4a-YNU-4k can be regarded as mitophagy inductors for the eradication of cisplatin-resistant LC549 cancer cells.

[Altitude Distribution Characteristics of Farmland Soil Bacteria in Loess Hilly Region of Ningxia].

It is of great significance for the conservation of biodiversity in farmland ecosystems to study the diversity, structure, functions, and biogeographical distribution of soil microbes in farmland and their influencing factors. High-throughput sequencing technology was used to analyze the distribution characteristics of soil bacterial diversity, community structure, and metabolic function along elevation and their responses to soil physicochemical properties in farmland in the loess hilly areas of Ningxia. The results showed that:① The Alpha diversity index of soil bacterial was significantly negatively correlated with elevation (P < 0.05) and showed a trend of decreasing and then slightly increasing along the elevation. ② Seven phyla, including Proteobacteria, Actinobacteria, and Acidobacteria, were the dominant groups, and five of them showed highly significant differences between altitudes (P < 0.01). ③ At the secondary classification level, there were 36 metabolic functions of bacteria, including membrane transport, carbohydrate metabolism, and amino acid metabolism, of which 22 showed significant differences, and 12 showed extremely significant differences among different altitudes. ④ Pearson correlation analysis showed that soil water content, bulk density, pH, and carbon-nitrogen ratio had the most significant effects on bacterial Alpha diversity, whereas soil nutrients such as total organic carbon, total nitrogen, and total phosphorus had significant effects on bacterial Beta diversity. ⑤ Mantel test analysis showed that the soil water content, total organic carbon, and carbon-nitrogen ratio affected bacterial community structure at the phylum level, and soil pH, total organic carbon, total nitrogen, total phosphorus, and carbon-nitrogen ratio were significantly correlated with bacterial metabolic function. Variance partitioning analysis showed that soil water content had the highest explanation for the community structure of soil bacteria, whereas soil pH had the highest explanation for metabolic function. In conclusion, soil water content and pH were the main factors affecting the diversity, community composition, and metabolic function of soil bacteria in farmland in the loess hilly region of Ningxia.

Single-Cell Molecular Profiling of Head and Neck Squamous Cell Carcinoma Reveals Five Dysregulated Signaling Pathways Associated With Circulating Tumor Cells.

OBJECTIVES: To determine the dysregulated signaling pathways of head and neck squamous cell carcinoma associated with circulating tumor cells (CTCs) via single-cell molecular characterization. INTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) has a significant global burden and is a disease with poor survival. Despite trials exploring new treatment modalities to improve disease control rates, the 5 year survival rate remains low at only 60%. Most cancer malignancies are reported to progress to a fatal phase due to the metastatic activity derived from treatment-resistant cancer cells, regarded as one of the most significant obstacles to develope effective cancer treatment options. However, the molecular profiles of cancer cells have not been thoroughly studied. METHODS: Here, we examined in-situ HNSCC tumors and pairwisely followed up with the downstream circulating tumor cells (CTCs)-based on the surrogate biomarkers to detect metastasis that is established in other cancers - not yet being fully adopted in HNSCC treatment algorithms. RESULTS: Specifically, we revealed metastatic HNSCC patients have complex CTCs that could be defined through gene expression and mutational gene profiling derived from completed single-cell RNASeq (scRNASeq) that served to confirm molecular pathways inherent in these CTCs. To enhance the reliability of our findings, we cross-validated those molecular profiles with results from previously published studies. CONCLUSION: Thus, we identified 5 dysregulated signaling pathways in CTCs to derive HNSCC biomarker panels for screening HNSCC in situ tumors.

ObjectivesInvestigating the dysregulated signaling pathways of head and neck squamous cell carcinoma (HNSCC) linked with circulating tumor cells (CTCs) using single-cell molecular characterization.IntroductionHNSCC poses a significant global health burden with poor survival rates despite advancements in treatment. Metastatic activity from treatment-resistant cancer cells remains a major challenge in developing effective treatments. However, the molecular profiles of cancer cells, particularly CTCs, are not well-understood.MethodsWe analyzed in-situ HNSCC tumors and corresponding CTCs using surrogate biomarkers to detect metastasis, a technique not widely used in HNSCC treatment protocols.ResultsOur study revealed complex CTCs in metastatic HNSCC patients characterized by gene expression and mutational gene profiling via single-cell RNASeq (scRNASeq). These profiles confirmed molecular pathways inherent in CTCs, further validated by previous research.ConclusionThrough our research, we identified five dysregulated signaling pathways in CTCs, suggesting potential biomarker panels for HNSCC screening in situ tumors.

Field assessment of active ingredient quantity in pharmaceutical tablets with limited calibration of near infrared spectra: An application to ciprofloxacin tablets.

Portable near-infrared (NIR) spectrophotometers have emerged as valuable tools for identifying substandard and falsified pharmaceuticals (SFPs). Integration of these devices with chemometric and machine learning models enhances their ability to provide quantitative chemical insights. However, different NIR spectrophotometer models vary in resolution, sensitivity, and responses to environmental factors such as temperature and humidity, necessitating instrument-specific libraries that hinder the wider adoption of NIR technology. This study addresses these challenges and seeks to establish a robust approach to promote the use of NIR technology in post-market pharmaceutical analysis. We developed support vector machine and partial least squares regression models based on binary mixtures of lab-made ciprofloxacin and microcrystalline cellulose, then applied the models to ciprofloxacin dosage forms that were assayed with high performance liquid chromatography (HPLC). A receiver operating characteristic (ROC) analysis was performed to set spectrophotometer independent NIR metrics to evaluate ciprofloxacin dosage forms as "meets standard," "needs HPLC assay," or "fails standard." Over 200 ciprofloxacin tablets representing 50 different brands were evaluated using spectra acquired from three types of NIR spectrophotometer with 85% of the prediction agreeing with HPLC testing. This study shows that non-brand-specific predictive models can be applied across multiple spectrophotometers for rapid screening of the conformity of pharmaceutical active ingredients to regulatory standard.

Effect of concomitant tricuspid annuloplasty on postoperative wound complications in heart failure patients undergoing mitral valve repair.

Tricuspid valve repair (TVR) combined with mitral valve surgery (MVS) has been a controversial issue. It is not clear whether the combined surgery has any influence on the occurrence of postoperative complications. The aim of this study was to compare the occurrence of complications including wound infection, wound bleeding, and mortality after MVS combined with or without TVR. By meta-analysis, a total of 1576 papers were collected from 3 databases, and 7 of them were included. We provided the necessary data of 7 included studies such as the authors, publication date, country, surgical approach and case number, patient age, and so on. Statistical analysis was carried out with RevMan 5.3 software. We found that patients with heart failure accepting MVS combined with or without TVR, performed no statistically significant difference in postoperative wound infection (OR: 0.88; 95% CI: 0.29, 2.62; P = 0.81), wound bleeding (OR: 0.74; 95% CI: 0.3, 1.48; P = 0.39), and mortality (OR: 1.05; 95% CI: 0.42, 2.61; P = 0.92). In conclusion, current evidence indicated that the combined surgery had no additional risk of postoperative complications, and might be an effective alternative surgical approach to mitral valve diseases accompany with tricuspid regurgitation. However, for the limited case size, it was required to support the findings with a large number of cases in further studies.

[Ecosystem Service Trade-off Synergy Strength and Spatial Pattern Optimization Based on Bayesian Network： A Case Study of the Fenhe River Basin].

Understanding the strength of trade-off and synergistic relationships among ecosystem services (ESs) is crucial for ecological management and restoration in the Fenhe River Basin. However, there is still a lack of sufficient research on the driving variables and spatial pattern optimization of the strength of ESs relationships in this area. Based on the quantitative assessment of six ESs in the Fenhe River Basin in 2000 and 2020, the ecosystem services trade-off synergy index (TSI) was introduced to quantitatively measure the strength of trade-off and synergistic relationships between each pair of ESs. A Bayesian network was constructed to identify the driving variables of trade-off and synergistic relationships, and sensitivity analysis was conducted to determine the degree of influence of key variables on the strength of these relationships. The optimization area of the strength of ESs trade-off and synergistic relationships was characterized in spatial patterns. The results showed that:① There were significant spatiotemporal differences in the six ESs in the Fenhe River Basin in 2000 and 2020. In terms of time scale, water yield, net primary productivity, crop productivity, soil conservation, and carbon storage all showed a trend of fluctuating increase. In terms of spatial scale, the spatial distribution changes in the six ESs were relatively small over the 20 years. ② The TSI of carbon storage was high in the surrounding area and low in the middle, showing a four-high and four-low pattern. The areas with the highest TSI between grain supply and other services were distributed from north to south. ③ Sensitivity analysis found that the strength of water yield, soil conservation, and habitat quality were significantly affected by precipitation, plant root depth restriction, and rainfall erosion. According to the conditional probability of different states of key variables, Wenshui County, Qingxu County, and Qi County in the central part of the Fenhe River Basin were identified as high-value areas for trade-off and synergistic relationships, which could be used as key areas for ecological restoration. These findings have important theoretical and practical significance for understanding the complex relationship between multiple ESs trade-off and synergistic relationships and their driving variables and for proposing sustainable ecological environment management policies.

Genetic interactions reveal distinct biological and therapeutic implications in breast cancer.

Co-occurrence and mutual exclusivity of genomic alterations may reflect the existence of genetic interactions, potentially shaping distinct biological phenotypes and impacting therapeutic response in breast cancer. However, our understanding of them remains limited. Herein, we investigate a large-scale multi-omics cohort (n = 873) and a real-world clinical sequencing cohort (n = 4,405) including several clinical trials with detailed treatment outcomes and perform functional validation in patient-derived organoids, tumor fragments, and in vivo models. Through this comprehensive approach, we construct a network comprising co-alterations and mutually exclusive events and characterize their therapeutic potential and underlying biological basis. Notably, we identify associations between TP53mut-AURKAamp and endocrine therapy resistance, germline BRCA1mut-MYCamp and improved sensitivity to PARP inhibitors, and TP53mut-MYBamp and immunotherapy resistance. Furthermore, we reveal that precision treatment strategies informed by co-alterations hold promise to improve patient outcomes. Our study highlights the significance of genetic interactions in guiding genome-informed treatment decisions beyond single driver alterations.

Postbiotic properties of exopolysaccharide produced by Levilactobacillus brevis M-10 isolated from natural fermented sour porridge through in vitro simulated digestion and fermentation.

The simulated digestion and fermentation characteristics in vitro of exopolysaccharide (EPS) of Levilactobacillus brevis M-10 were studied to evaluate its postbiotic properties. The simulated digestion results showed that EPS could not be degraded in saliva but could be very slightly degraded in gastric juice and could be degraded in intestinal juice. The results of simulated fermentation demonstrated that EPS could lower the intestine pH and be utilized by gut microbes to produce short-chain fatty acids such as propionic acid and butyric acid. Meanwhile, EPS significantly raised the diversity of human gut microbiota, and the relative abundances of Phascolarctobacterium were significantly increased, whereas Fusobacterium and Morganella significantly decreased. In conclusion, EPS from L. brevis M-10 was a good postbiotic as inulin. This was the first report about EPS as the postbiotic of L. brevis M-10 screened from broomcorn millet sour porridge in northwestern Shanxi Province, China.

Design, synthesis and activity evaluation of quinolinone derivatives as EZH2 inhibitors.

The enhancer of zeste homologue 2 (EZH2) is the core catalytic subunit of polycomb repressive complex 2, which catalyzes lysine 27 methylation of histone H3. Herein, a series of quinolinone derivatives were designed and synthesized based on the structure of Tazemetostat as the lead compound. Compound 9l (EZH2WT IC50 = 0.94 nM) showed stronger antiproliferative activity in HeLa cells than the lead compound. Moreover, compound 9e (EZH2WT IC50 = 1.01 nM) significantly inhibited the proliferation and induced apoptosis in A549 cells.