People's Hospital of Yangzhong

High-throughput sequencing has generated vast genomic repositories that remain under-annotated, hampering enzyme discovery. We present an integrated pipeline that (i) builds a high-resolution, cross-kingdom phylogenetic database, (ii) mines candidates via multilocus phylogeny, (iii) predicts activities using an evolutionary-scale protein language model, and (iv) removes false positives through multilevel residue-atom contact rescoring. When applied to the r-BOX pathway, this approach uncovered numerous previously undocumented FadB, BktB, Ter, and YdiI homologues. Our activity model achieved R2 = 0.68 and reduced the RMSE on high-value targets by 11% compared to the prior SOTA (UniKP). Contact scoring improved early enrichment (EF1%) by 16-fold. Experimental validation targeting FadB increased titers from 0.65 g/L (shake flasks) to 1.7 g/L, reaching 10.2 g/L in a fermentation process. Together, these results establish a robust, generalizable framework for discovering scarce, high-value enzymes and prioritizing functional variants at scale.

Secondary pulmonary infections are crucial and pivotal contributing factors to clinical deterioration in patients with pulmonary tuberculosis. Research remains limited regarding the specific population and regional epidemiology of these secondary infections, despite its clinical importance. This study provides an in-depth analysis of the primary bacterial pathogens and their antimicrobial resistance rates among hospitalized pulmonary tuberculosis patients with concurrent pulmonary infections in Yangzhou, China, from 2021 to 2024. Suitable sputum samples and leftover bronchoalveolar lavage fluid samples were collected for bacterial culture identification and drug sensitivity testing. The annual and regional distributions of strains and the evolution of resistance rates were analyzed using the chi-square test and the Cochran-Armitage trend test. A total of 514 strains of pathogenic bacteria were cultured from 410 samples, with 499 strains (97.08 %) being Gram-negative bacteria. Klebsiella pneumoniae was the most common Gram-negative bacterium (40.27 %), followed by Pseudomonas aeruginosa (15.18 %), while Staphylococcus aureus was the primary Gram-positive bacterium (1.75 %). The drug sensitivity tests results over different years showed that K. pneumoniae exhibited significant resistance rates against doxycycline, ceftazidime, cefepime, cefuroxime, cefazolin, cefotaxime, levofloxacin, ticarcillin/clavulanate, amikacin, and norfloxacin (P < 0.05). The resistance rates of P. aeruginosa to cefazolin and ciprofloxacin were also statistically significant (P < 0.05). The drug sensitivity test results across different regions showed that the resistance rate of K. pneumoniae to minocycline in urban patients was statistically significant (P = 0.012), while the resistance rates of P. aeruginosa to tobramycin and ciprofloxacin in rural patients were statistically significant (P < 0.05). Annual statistics of extended-spectrum beta-lactamase ESBL-producing K. pneumoniae resistant strains showed significant annual increases (P < 0.05). Moreover, data on resistant strains in urban and rural areas indicated that the detection rate of ESBL-producing Escherichia coli in rural areas was higher than that in urban areas (P = 0.052), and the detection rate of ESBL-producing K. pneumoniae resistant strains in rural areas was significantly higher than in urban areas (P = 0.005). The rise of new carbapenem-resistant K. pneumoniae strains in 2023 should be monitored. This study provides strong data support to formulate antibiotic treatment plans for patients with tuberculosis and respiratory infections, reduce the risk of resistant strain transmission, and optimize clinical treatment strategies.

Abstract Background MicroRNAs (miRNAs) play a crucial role in tumorigenesis and malignant transformation. Studies indicate that miR-4652-3p is aberrantly expressed in various cancer types. However, its impact and underlying mechanisms in non-small cell lung cancer (NSCLC) have not been investigated. Methods A549 cells were stimulated with IL-1β, TNF-α, and IL-6 (each at 10 ng/ml) to mimic an inflammatory microenvironment. Metabolic status was evaluated by measuring glutamine uptake, α-ketoglutarate (α-KG), and ATP levels. Functional studies employed the glutaminase inhibitor (CB-839), the MYC inhibitor (10058-F4), SLC1A5 small interfering RNA (siSLC1A5-2), a miR-4652-3p mimic, and overexpression plasmids. Molecular interactions were validated using chromatin immunoprecipitation (ChIP), dual-luciferase reporter assays, and RNA pull-down experiment. CCK-8 and Transwell assays were used for the assessment of cell malignant phenotypes. The functional significance of miR-4652-3p was further verified in a xenograft mouse model. Results miR-4652-3p was downregulated in NSCLC, while MYC and SLC1A5 were upregulated. Inflammatory stimulation enhanced A549 cell proliferation, glutamine uptake, and α-KG/ATP production; these effects were attenuated by CB-839. ChIP and dual-luciferase assays demonstrated that MYC binds the SLC1A5 promoter and activates its transcription. Inhibiting MYC or knocking down SLC1A5 significantly reduced glutamine uptake. Mechanistic analysis revealed that miR-4652-3p directly targets both MYC and SLC1A5 mRNA. miR-4652-3p suppressed glutamine metabolism in NSCLC cells by negatively regulating the MYC/SLC1A5 axis, consequently inhibiting cell growth and tumor progression in a xenograft mouse model, an effect reversed by MYC or SLC1A5 overexpression. Conclusions miR-4652-3p blocked the inflammatory microenvironment-induced glutamine metabolic reprogramming by directly suppressing the MYC/SLC1A5 axis, thereby inhibiting NSCLC progression. The miR-4652-3p/MYC/SLC1A5 pathway represents a key regulatory mechanism for metabolic adaptation in NSCLC.

Gut microbiota plays a pivotal role in modulating therapeutic responses in malignancies. Elucidating microbial dynamics during cancer treatment provides critical insights for optimizing therapeutic strategies and prognostic prediction. To investigate longitudinal alterations in oral and gut microbiota during chemotherapy in advanced gastric cancer (GC) patients and their prognostic implications. This study enrolled 29 advanced GC patients, with tongue coating and fecal samples collected before the 1st (GC0), 2nd (GC1), and 3rd (GC2) chemotherapy cycles, alongside 35 healthy controls. Bacterial communities were profiled via 16 S rRNA V3-V4 sequencing, and fungal communities via 18 S rRNA ITS1-ITS2 sequencing. LEfSe, ROC analysis, Zero-Inflated Beta Regression (ZIBR) modeling, and co-occurrence network analysis were employed to evaluate microbial dynamics and prognostic utility. During chemotherapy, oral fungal and gut bacterial richness (ACE and Chao indices) significantly decreased, while gut fungal richness increased. β-diversity analysis revealed minimal structural alterations in oral-gut microbiota. The abundance of intestinal bacterial Subdoligranulum genus and the fungal Candida (in both intestine and oral cavity) exhibited a decreasing trend, whereas the abundance of intestinal bacterial genera including Escherichia-Shigella and Streptococcus significantly increased (P < 0.05) during chemotherapy in patients with advanced GC. In the GC0 group, 23 genera (e.g., oral/gut Bacillus, oral Veillonella) predicted 12-month progression-free survival (PFS) (AUC > 0.7). Longitudinal analysis identified 25 genera (e.g., oral Clostridium_sensu_stricto_1, gut Bacillus and Howardella) significantly associated with PFS across GC0-GC2 (Joint P < 0.05). Co-occurrence networks demonstrated oral bacterial dominance in GC patients, with chemotherapy reducing network complexity. Continuous chemotherapy exerted significant effects on the oral-gut microbiota co-occurrence networks in advanced GC patients, with pre-chemotherapy microbiota demonstrating prognostic diagnostic value. This study provided microbiological evidence to inform future GC monitoring and personalized therapeutic strategies.

Radiation resistance is the major cause of non-small cell lung cancer (NSCLC) treatment failure. Homologous recombination (HR), which mediates the repair of DNA double-strand breaks (DSB), is crucial for maintaining genomic integrity and enhancing survival in response to radiotherapy in NSCLC. However, the mechanisms of HR repair in radiation resistance remains unclear. In this study, we investigated the functional role of the transcription factor Spermatogenesis and oogenesis basic helix-loop-helix transcription factor 2 (SOHLH2) in NSCLC HR repair and radioresistance. Our research unveiled that the expression levels of SOHLH2 increased in NSCLC compared with adjacent non-tumor tissues. Elevated SOHLH2 expression promotes NSCLC cell proliferation and radiation resistance, while knocking down SOHLH2 has the opposite effect. Mechanistically, SOHLH2 transcriptionally activated the expression of RAD54L, thereby promoting HR repair and the survival of cancer cells in response to radiation. Notably, RAD54L overexpression was able to rescue the suppression of NSCLC HR repair and radioresistance induced by SOHLH2 knockdown. Therefore, SOHLH2-RAD54L axis may serve as a potential therapeutic target for overcoming radioresistance in NSCLC.

The safety and reliability of the instrumentation and control (I&C) system in nuclear power plants is key to safe operation. The precise identification of critical component management(CCM) and its related single-point vulnerabilities (SPV) is a core link to prevent system cascading failures and enhance the overall safety margin. Currently, SPV identification highly relies on manual engineer analysis, which has flaws such as low efficiency, inconsistent standards, excessive subjective judgment, and difficulty in adapting to frequent system changes. This paper proposes an automated SPV identification method using full-link configuration modeling and a fault propagation rule engine. It first parses diverse engineering drawings into a unified directed graph with rich attributes to form a full-link digital model. Then, it constructs a modular, scalable fault propagation rule library, and via graph traversal algorithms, automatically simulates single-point faults at each node, calculating real-time propagation paths and impacts to identify SPV equipment. Yangjiang Nuclear Power Plant tests showed high consistency with expert analysis. Analysis time dropped from weeks to hours, improving efficiency and accuracy. This method effectively overcomes the technical bottlenecks, providing key technical support for the automation and intelligence of reliability management in nuclear power plant I&C systems, and has significant engineering application value.

Macrophage is educated by the tubule epithelial cell with maladaptive repair during the renal maladaptive repair, which is one of the most important characteristic features in acute kidney injury (AKI) to chronic kidney disease (CKD) transition. However, the underlying mechanism of orchestrating characterization of macrophage in renal maladaptive repair remains largely unclear. Accordingly, we found that pro-inflammatory macrophage educated by tubule epithelial cell with maladaptive repair was the primary contributor to the renal maladaptive repair in AKI to CKD transition, because macrophages depletion significantly attenuated tubulointerstitial fibrosis. Meanwhile, we found that glycolysis was essential for maintaining pro-inflammatory macrophage phenotype. Further, we demonstrated that HIF-1α played a crucial role in macrophage glycolysis as myeloid HIF-1α knockout alleviated tubulointerstitial fibrosis and AKI to CKD transition in vivo. Mechanistically, NF-κB directly binds to the HIF-1α promoter, boosting its transcription and significantly contributing to tubulointerstitial fibrosis in the AKI to CKD transition. Blockage of NF-κB ameliorated the CKD progression following AKI in vivo. Taken together, our studies provide a novel paradigm in which pro-inflammatory macrophage orchestrates renal maladaptive repair, contributing to the AKI to CKD transition. Blockade of NF-κB-HIF-1 signaling-mediated macrophage metabolic reprogramming may provide attractive strategy for pharmacologic therapy of the AKI to CKD transition.