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Heavy metals are a growing threat to human health due to the resulting damage to the ecology; the removal of heavy metals by lactic acid bacteria (LAB) has been a focus of many studies. In this study, 10 LAB strains were evaluated for their ability to absorb and tolerate lead. Lactobacillus plantarum YW11 was found to possess the strongest ability of lead absorbing and tolerance, with the rate of absorption as high as 99.9% and the minimum inhibitory concentration of lead on YW11 higher than 1000 mg/L. Based on the isobaric tags for relative and absolute quantitation (iTRAQ) proteomics analysis of YW11, a total of 2009 proteins were identified both in the lead-treated strain and the control without the lead treatment. Among these proteins, 44 different proteins were identified. The abundance of 25 proteins increased significantly, and 19 proteins decreased significantly in the treatment group. These significantly differential abundant proteins are involved in the biological processes of amino acid and lipid metabolism, energy metabolism, cell wall biosynthesis, and substance transport. This study contributed further understanding of the molecular mechanism of L. plantarum in the binding and removal of lead to explore its potential application in counteracting heavy metal pollution of environment, food, and other fields.

Background Osteosarcoma demonstrates limited responsiveness to PD-1 blockade, largely due to its immunosuppressive tumor microenvironment (TME). The specific mechanisms by which cancer-associated fibroblasts (CAFs) contribute to immunosuppression in osteosarcoma are not fully understood. Methods We performed single-cell RNA sequencing (scRNA-seq) on osteosarcoma tissues from patients treated with neoadjuvant chemotherapy and anti-PD-1 therapy to investigate the tumor microenvironment. Cellular composition, gene expression programs, and signaling pathways were analyzed. Functional assays, pull-down and PLA-flow binding validation, and in vivo mouse models were used to dissect the mechanisms by which CAF-derived factors influence CD8⁺ T cell function and contribute to immunotherapy response. Results We identified a subpopulation of CD36⁺ CAFs, characterized by adaptive uptake of oxidized low-density lipoprotein (OxLDL) and activation of the PPARG–FABP4 axis. This metabolic program promoted ANGPTL4 secretion, which bound integrin on CD8⁺ T cells and activated the JAK2–STAT3 pathway, leading to T cell exhaustion and impaired effector function. In vivo, administration of VitE effectively scavenged OxLDL, reprogrammed the TME, enhanced CD8⁺ T cell infiltration, and synergized with PD-1 blockade to improve tumor control. Conclusions CD36⁺ CAFs drive immunosuppressive metabolic reprogramming via the OxLDL–PPARG–ANGPTL4 axis, promoting CD8⁺ T cell exhaustion and resistance to immunotherapy in osteosarcoma. Targeting this pathway with VitE alleviated CAF-mediated immune suppression and enhanced PD-1 blockade responses in preclinical models, providing a rationale for metabolism-based combinatorial strategies in osteosarcoma. Graphical abstract

Background Although numerous studies have investigated the clinicopathologic and prognostic relevance of mucinous adenocarcinoma (MAC) and signet-ring cell carcinoma (SRCC) compared with classic adenocarcinoma (CA), little is known about the prognosis of adenocarcinoma with mixed subtypes (AM) and the differences among these four subtypes. Methods The statistics of colorectal cancer registered in the Surveillance, Epidemiology and End Results (SEER) database were retrieved and analyzed. We also compared the clinicopathologic and prognostic relevance between CA, SRCC, MAC, and AM. Results The frequencies of these four subtypes were 69.9% (CA, n  = 15,812), 25.1% (MAC, n  = 5689), 3.6% (SRCC, n  = 814) and 1.4% (AM, n  = 321), respectively. All of MAC, SRCC, and AM were significantly related with aggressive features. Only SRCC and AM were identified as independent poor prognostic markers for overall survival by multivariate analysis. The aggressiveness of AM was between MAC and SRCC according to the clinicopathologic associations. The prognosis of AM was significantly worse than MAC but comparable with SRCC. Conclusions We confirmed the clinicopathologic relevance with aggressive features of MAC and SRCC, as well as poor prognostic relevance of SRCC by analyzing a large study population data set. Furthermore, we identified AM as a rare but aggressive histologic subtype in colorectal cancer, to which particular attention should be given in clinical practice.

The high heterogeneity and severe side effects of chemotherapy are major factors contributing to the failure of osteosarcoma treatment. Herein, a comprehensive genomic analysis is conducted, and identified two prominent characteristics of osteosarcoma: significant cyclin‐dependent kinases 4 (CDK4) amplification and homologous recombination repair deficiency. Based on these findings, a co‐delivery system loaded with CDK4/6 inhibitors and poly ADP‐ribose polymerase (PARP) inhibitors is designed. By employing metal–organic frameworks (MOFs) as carriers, issue of drug insolubility is effectively addressed, while also enabling controlled release in response to the tumor microenvironment. To enhance targeting capability and biocompatibility, the MOFs are further coated with a bio‐membrane targeting B7H3. This targeted biomimetic co‐delivery system possesses several key features: 1) it can precisely target osteosarcoma with high B7H3 expression; 2) the combination of CDK4/6 inhibitors and PARP inhibitors exhibits synergistic effects, significantly impairing tumor's DNA repair capacity; and 3) the system has the potential for combination with photodynamic therapy, amplifying DNA repair defects to maximize tumor cell eradication. Furthermore, it is observed that this co‐delivery system can activate immune microenvironment, increasing CD8+ T cell infiltration and converting osteosarcoma from an immune‐cold to an immune‐hot tumor. In summary, the co‐delivery system is an effective therapeutic strategy and holds promise as a novel approach for osteosarcoma treatment. Based on comprehensive genomic analysis, a targeting B7H3 co‐delivery system loaded with cyclin‐dependent kinases 4/6 (CDK4/6) inhibitors and poly ADP‐ribose polymerase (PARP) inhibitors is developed. Through combined photodynamic therapy, the co‐delivery system can eliminate tumor cells through dual synergistic mechanisms while activating immune microenvironment via the cGAS‐STING pathway.

Gastric cancer is a malignant tumor with high morbidity and mortality worldwide. However, increasing evidences have revealed the correlation between the glycolysis process and tumorigenesis. This study is aim to develop a list of glycolysis-related genes for risk stratification in gastric cancer patients. We included 500 patients’ sample data from GSE62254 and GSE26942 datasets, and classified patients into training (n = 350) and testing sets (n = 150) at a ratio of 7: 3. Univariate and multivariate Cox regression analysis were performed to screen genes having prognostic value. Based on HALLMARK gene sets, we identified 9 glycolysis-related genes (BPNT1, DCN, FUT8, GMPPA, GPC3, LDHC, ME2, PLOD2, and UGP2). On the basis of risk score developed by the 9 genes, patients were classified into high- and low-risk groups. The survival analysis showed that the high-risk patients had a worse prognosis (p < 0.001). Similar finding was observed in the testing cohort and 2 independent cohorts (GSE13861 and TCGA-STAD, all p < 0.001). The multivariate Cox regression analysis showed that the risk score was an independent prognostic factor for overall survival (p < 0.001). Furthermore, we constructed a nomogram that integrated the risk score and tumor stage, age, and adjuvant chemotherapy. Through comparing the results of the receiver operating characteristic curves and decision curve analysis, we found that the nomogram had a superior predictive accuracy than conventional TNM staging system, suggesting that the risk score combined with other clinical factors (age, tumor stage, and adjuvant chemotherapy) can develop a robust prediction for survival and improve the individualized clinical decision making of the patient. In conclusion, we identified 9 glycolysis-related genes from hallmark glycolysis pathway. Based on the 9 genes, gastric cancer patients were separated into different risk groups related to survival.

Background As a member of the tumor necrosis factor (TNF) family, TNF superfamily 4 ( TNFSF4 ) plays a crucial role in various immune-related processes. However, its biological function in pan-cancer remains largely unexplored. Methods RNA-sequencing (RNA-seq) data and corresponding clinical variables were obtained from the Cancer Genome Atlas (TCGA). Immunotherapy cohorts were retrieved from Gene Expression Omnibus (GEO). Tumor Immune Estimation Resource was used to evaluate tumor-infiltrating immune cell levels. The Tumor Immune Single-cell Hub (TISCH) 2 database was used to examine TNFSF4 expression across various tumor cell subsets. Gene set enrichment analysis (GSEA) was performed to investigate TNFSF4- associated signaling pathways. Results Bioinformatic analyses of TNFSF4 across TCGA cancers revealed that TNFSF4 expression was highly increased in cancers compared to normal tissues. Further immunohistochemistry staining of multiple tumor samples validated this finding. Univariate Cox regression and survival analyses identified TNFSF4 as a risk factor in most cancers. Furthermore, TNFSF4 expression increased with tumor stage progression in several cancers. In the two immunotherapy cohorts from the GEO database, the proportion of partial response/complete response patients was higher in the TNFSF4 low-expression group. Single-cell RNA-seq data from the TISCH database indicated that TNFSF4 expression was predominantly observed in proliferative and exhausted T cells. Correlation analysis demonstrated a positive association between TNFSF4 and immunomodulatory genes. Ultimately, GSEA revealed that TNFSF4 was related to immune response and epithelial-mesenchymal transition pathways. Conclusions This multi-omics analysis highlights the role of TNFSF4 in tumor progression and immune modulation. High TNFSF4 expression correlates with poor survival and may affect immunotherapy efficacy, suggesting its potential prognostic biomarker and therapeutic target.

Blood culture-negative endocarditis is often severe and difficult to diagnose. It is necessary to emphasize the importance for the early diagnosis and accurate treatment of blood culture-negative endocarditis. Here, we described the relevant clinical information of a blood culture-negative but clinically diagnosed infective endocarditis complicated by intracranial mycotic aneurysm, brain abscess, and posterior tibial artery pseudoaneurysm. This patient was a 65-year-old man with a 9-month history of intermittent fever and died in the end for the progressive neurological deterioration. Although the blood culture is negative, this patient was clinically diagnosed as infective endocarditis according to Duke criteria. This patient course was complicated not only by cerebral embolism, intracranial mycotic aneurysm, and brain abscess but also by posterior tibial artery aneurysm of the lower extremity. The clinical findings of this patient suggest that the confirmatory microbiology is essential for the treatment of blood culture-negative infective endocarditis. Clinicians should be aware of the detriment of blood culture-negative infective endocarditis for its multiple complications may occur in one patient. The delayed etiological diagnosis and insufficient treatment may aggregate the clinical outcome of blood culture-negative infective endocarditis.

A two-degree-of-freedom periodically forced system with multiple motion limiting constraints is considered. The incidence relation between dynamics and key parameters (clearance, constraint stiffness and forcing frequency) is numerically studied by selecting different values of constraint stiffness and finely scanning the (forcing frequency, clearance)–parameter plane. Two cases, associated with the non-prepressing and prepressing constraints, are considered in the research. The fundamental group of impact motions with an excitation period and the different impact number is studied with emphasis on the generation mechanism. The complicated and regular transition characteristics between adjacent fundamental impact motions are analyzed by their existence domains and bifurcation boundaries in the (forcing frequency, clearance)–parameter plane. The influence of the constraint parameters on multiformity and transitional characters of periodic–impact motions of the system is studied in relatively large parameter spaces. An electronic circuit in the framework of state-controlled cellular neural network (SC-CNN) is designed for experimental verification of dynamic mechanical behaviors of the non-smooth system driven by periodical exciting forces. Real electronic circuit, based on four SC-CNN cells, is made by using printed circuit board, and the oscilloscope output of phase portraits of electrical waveforms generated by the circuit itself is experimentally observed. A good agreement among the numerical results of the mechanical model, the electronic design simulation of the circuit and the real oscilloscope outputs of hardware implementation is confirmed. The results fully show that the modeling method using the strategy based on SC-CNN is suitable for the modeling of the periodically forced systems with multiple motion limiting constraints. The high availability and reliability of the electronic circuit, based on the SC-CNN framework, are verified by the contrast analyses.

Two electronic circuits are designed according to the dynamical model of a harmonically forced system with clearances by both conventional approach and SC-CNN strategy. Dynamics of the piecewise smooth mechanical system, in low forcing frequency domain, is investigated by double-parameter simulation analysis and experiment conducted on these two electronic circuits. The outputs of the designed circuits are well consistent with the numerical results of the mechanical model, which validates the experimental approach.

In this paper, the effects of different parameters on the dynamic behavior of the nonlinear dynamical system are investigated based on modified Hindmarsh–Rose neural nonlinear dynamical system model. We have calculated and analyzed dynamic characteristics of the model under different parameters by using single parameter bifurcation diagram, time response diagram and two parameter bifurcation diagram. The results show that the period-adding bifurcation (with or without chaos), period-doubling bifurcation and intermittent chaos phenomenon (periodic and intermittent chaotic) can be observed more clearly and directly from the two parameter bifurcation diagram, and the optimal parameters matching interval can also be found easily.