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Abstract Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI) approved for patients with EGFR T790M resistance mutations as first- or second-line treatment of EGFR-positive patients. Resistance to Osimertinib will inevitably develop, and the underlying mechanisms are largely unknown. In this study, we discovered that acquired resistance to Osimertinib is associated with abnormal DNA damage response (DDR) in lung adenocarcinoma cells. We discovered that the polycomb protein Lethal(3) Malignant Brain Tumor-Like Protein 1 (L3MBTL1) regulates chromatin structure, thereby contributing to DDR and Osimertinib resistance. EGFR oncogene inhibition reduced L3MBTL1 ubiquitination while stabilizing its expression in Osimertinib-resistant cells. L3MBTL1 reduction and treatment with Osimertinib significantly inhibited DDR and proliferation of Osimertinib-resistant lung cancer cells in vitro and in vivo. L3MBTL1 binds throughout the genome and plays an important role in EGFR-TKI resistance. It also competes with 53BP1 for H4K20Me2 and inhibits the development of drug resistance in Osimertinib-resistant lung cancer cells in vitro and in vivo. Our findings suggest that L3MBTL1 inhibition is a novel approach to overcoming EGFR-TKI-acquired resistance.

Abstract Xanthoma typically occurs in the subcutaneous tissues, with rare cases of xanthoma in the joints. However, the case of knee joint osteonecrosis combined with xanthoma is even more uncommon. In this article, we described a 50-year-old female patient who suffered xanthoma in the knee joint on the basis of osteonecrosis of the knee joint. The primary clinical symptoms were knee joint pain and limited mobility. The patient initially received conventional treatment for osteonecrosis. However, there was no significant improvement. Later, we found a synovial xanthoma in the patient’s knee. Finally, she underwent arthroscopic excision of the knee joint synovial xanthoma. Following the procedure, her VAS score decreased from 7 to 2, and knee joint mobility increased from 10–103° to 10–140°. Through our follow-up, the patient did not exhibit symptom recurrence. This case is valuable as it provides a feasible therapeutic approach for future clinical applications.

Abstract In mammals, global passive demethylation contributes to epigenetic reprogramming during early embryonic development. At this stage, the majority of DNA-methyltransferase 1 (DNMT1) protein is excluded from nucleus, which is considered the primary cause. However, whether the remaining nuclear activity of DNMT1 is regulated by additional mechanisms is unclear. Here, we report that nuclear DNMT1 abundance is finetuned through proteasomal degradation in mouse zygotes. We identify a maternal factor, Pramel15, which targets DNMT1 for degradation via Cullin-RING E3 ligases. Loss of Pramel15 elevates DNMT1 levels in the zygote pronuclei, impairs zygotic DNA demethylation, and causes a stochastic gain of DNA methylation in early embryos. Thus, Pramel15 can modulate the residual level of DNMT1 in the nucleus during zygotic DNA replication, thereby ensuring efficient DNA methylation reprogramming in early embryos.

Abstract Lung cancer is a leading cause of cancer-related mortality globally, with a dismal 5-year survival rate, particularly for Lung Adenocarcinoma (LUAD). Mechanical changes within the tumor microenvironment, such as extracellular matrix (ECM) remodeling and fibroblast activity, play pivotal roles in cancer progression and metastasis. However, the specific impact of the basement membrane (BM) on the mechanical characteristics of LUAD remains unclear. This study aims to identify BM genes influencing internal mechanical stress in tumors, elucidating their effects on LUAD metastasis and therapy resistance, and exploring strategies to counteract these effects. Using Matrigel overlay and Transwell assays, we found that mechanical stress, mimicked by matrix application, augmented LUAD cell migration and invasion, correlating with ECM alterations and activation of the epithelial-mesenchymal transition (EMT) pathway. Employing machine learning, we developed the SVM_Score model based on relevant BM genes, which accurately predicted LUAD patient prognosis and EMT propensity across multiple datasets. Lower SVM_Scores were associated with worse survival outcomes, elevated cancer-related pathways, increased Tumor Mutation Burden, and higher internal mechanical stress in LUAD tissues. Notably, the SVM_Score was closely linked to COL5A1 expression in myofibroblasts, a key marker of mechanical stress. High COL5A1 expression from myofibroblasts promoted tumor invasiveness and EMT pathway activation in LUAD cells. Additionally, treatment with Sorafenib, which targets COL5A1 secretion, attenuated the tumor-promoting effects of myofibroblast-derived COL5A1, inhibiting LUAD cell proliferation, migration, and enhancing chemosensitivity. In conclusion, this study elucidates the complex interplay between mechanical stress, ECM alterations, and LUAD progression. The SVM_Score emerges as a robust prognostic tool reflecting tumor mechanical characteristics, while Sorafenib intervention targeting COL5A1 secretion presents a promising therapeutic strategy to mitigate LUAD aggressiveness. These findings deepen our understanding of the biomechanical aspects of LUAD and offer insights for future research and clinical applications.

Objective Total hip arthroplasty (THA) effectively treats end‐stage hemophilic hip arthropathy. Given hemophilia's unique characteristics, perioperative bleeding remains a significant risk for patients undergoing THA. Tranexamic acid (TXA), an efficient antifibrinolytic agent, may benefit the outcomes of THA for patients with hemophilia (PWH). This study aims to explore the clinical efficacy of intra‐articular injection of TXA in treating perioperative bleeding in PWH and assess its additional clinical benefits. Methods The retrospective study comprised data of PWH who received THA from January 2015 to December 2021 in the research center. A total of 59 individuals were included in the study, divided into a TXA group (n = 31) and a non‐TXA group (n = 28). We compared various parameters, including total blood loss (TBL), visible blood loss (VBL), occult blood loss (OBL), intraoperative coagulation factor VIII (FVIII) consumption, perioperative total FVIII consumption, hemoglobin (HB), erythrocyte sedimentation rate (ESR), C‐reactive protein (CRP), length of hospital stay, hospitalization costs, length of surgery, total protein, activated partial thromboplastin time (APTT), D‐dimer, rate of joint swelling, hip joint range of motion (ROM), visual analogue scale (VAS), and Harris hip joint function scale (HHS) between the two groups. Follow‐up assessments were conducted for up to 24 months. A Student's t test was utilized for the statistical analysis. Results This study demonstrated that intra‐articular TXA effectively reduced TBL (1248.19 ± 439.88 mL, p

Abstract Background Purple flowering stalk (Brassica rapa var. purpuraria) is a widely cultivated plant with high nutritional and medicinal value and exhibiting strong adaptability during growing. Mitochondrial (mt) play important role in plant cells for energy production, developing with an independent genetic system. Therefore, it is meaningful to assemble and annotate the functions for the mt genome of plants independently. Though there have been several reports referring the mt genome of in Brassica species, the genome of mt in B. rapa var. purpuraria and its functional gene variations when compared to its closely related species has not yet been addressed. Results The mt genome of B. rapa var. purpuraria was assembled through the Illumina and Nanopore sequencing platforms, which revealed a length of 219,775 bp with a typical circular structure. The base composition of the whole B. rapa var. purpuraria mt genome revealed A (27.45%), T (27.31%), C (22.91%), and G (22.32%). 59 functional genes, composing of 33 protein-coding genes (PCGs), 23 tRNA genes, and 3 rRNA genes, were annotated. The sequence repeats, codon usage, RNA editing, nucleotide diversity and gene transfer between the cp genome and mt genome were examined in the B. rapa var. purpuraria mt genome. Phylogenetic analysis show that B. rapa var. Purpuraria was closely related to B. rapa subsp. Oleifera and B. juncea. Ka/Ks analysis reflected that most of the PCGs in the B. rapa var. Purpuraria were negatively selected, illustrating that those mt genes were conserved during evolution. Conclusions The results of our findings provide valuable information on the B.rapa var. Purpuraria genome, which might facilitate molecular breeding, genetic variation and evolutionary researches for Brassica species in the future.

Abstract The identification of effective therapeutic targets plays a pivotal role in advancing cancer treatment outcomes. We employed a comprehensive pan-cancer analysis, complemented by experimental validation, to explore the potential of Nicotinamide N-methyltransferase (NNMT) as a promising therapeutic strategy for human cancers. By analyzing large-scale transcriptomic datasets across various cancer types, we consistently observed upregulated expression of NNMT. Furthermore, elevated NNMT expression correlated with inferior overall survival in multiple cancer cohorts, underscoring its significance as a prognostic biomarker. Additionally, we investigated the relationship between NNMT expression and the tumor immune microenvironment, which plays a crucial role in regulating anti-tumor immune responses. To confirm the malignant functions of NNMT in tumor cells, we conducted a series of cell-based experiments, revealing that NNMT promotes cancer cell proliferation and invasion, indicative of its oncogenic properties. The integration of computational analysis and experimental validation in our study firmly establishes NNMT as a potential therapeutic target for human cancers. Specifically, targeting NNMT holds promise for the development of innovative and effective cancer treatments. Further investigations into NNMT's role in cancer pathogenesis could potentially pave the way for groundbreaking advancements in cancer treatment.

Abstract A key mechanism employed by plants to adapt to salinity stress involves maintaining ion homeostasis via the actions of ion transporters. While the function of cation transporters in maintaining ion homeostasis in plants has been extensively studied, little is known about the roles of their anion counterparts in this process. Here, we describe a mechanism of salt adaptation in plants. We characterized the chloride channel (CLC) gene AtCLCf, whose expression is regulated by WRKY transcription factor under salt stress in Arabidopsis thaliana. Loss-of-function atclcf seedlings show increased sensitivity to salt, whereas AtCLCf overexpression confers enhanced resistance to salt stress. Salt stress induces the translocation of GFP-AtCLCf fusion protein to the plasma membrane (PM). Blocking AtCLCf translocation using the exocytosis inhibitor brefeldin-A or mutating the small GTPase gene AtRABA1b/BEX5 (RAS GENES FROM RAT BRAINA1b homolog) increases salt sensitivity in plants. Electrophysiology and liposome-based assays confirm the Cl−/H+ antiport function of AtCLCf. Therefore, we have uncovered a mechanism of plant adaptation to salt stress involving the NaCl-induced translocation of AtCLCf to the PM, thus facilitating Cl− removal at the roots, and increasing the plant’s salinity tolerance.

Abstract Evidence from Europe shows that perioperative chemotherapy may be beneficial for the treatment of locally advanced gastric cancer, but reliable and robust data is lacking. To rectify this, the phase 3 RESONANCE trial investigated the efficacy and safety of S-1 plus oxaliplatin (SOX) as a perioperative chemotherapy regimen for gastric cancer. This randomized, open-label trial enrolled patients from 19 medical centers with stage II/III resectable gastric cancer who were centrally randomly assigned to either perioperative chemotherapy (PC) arm or adjuvant chemotherapy (AC) arm. Patients in the PC arm received two to four cycles of SOX followed by surgery and four to six cycles of SOX. Patients in the AC arm received upfront surgery and eight cycles of SOX. 386 patients in each group were enrolled and 756 (382 in PC and 374 in AC) were included in the mITT population. The three-year DFS rate was 61.7% in the PC arm and 53.8% in the AC arm (log-rank p = 0.019). The R0 resection rate in the PC arm was significantly higher than that in the AC arm (94.9% vs. 83.7%, p

Abstract Alpha‐1‐antitrypsin (AAT) plays a homeostatic role in attenuating excessive inflammation and augmenting host defense against microbes. We demonstrated previously that AAT binds to the glucocorticoid receptor (GR) resulting in significant anti‐inflammatory and antimycobacterial consequences in macrophages. Our current investigation aims to uncover AAT‐regulated genes that rely on GR in macrophages. We incubated control THP‐1 cells (THP‐1control) and THP‐1 cells knocked down for GR (THP‐1GR‐KD) with AAT, performed bulk RNA sequencing, and analyzed the findings. In THP‐1control cells, AAT significantly upregulated 408 genes and downregulated 376 genes. Comparing THP‐1control and THP‐1GR‐KD cells, 125 (30.6%) of the AAT‐upregulated genes and 154 (41.0%) of the AAT‐downregulated genes were significantly dependent on GR. Among the AAT‐upregulated, GR‐dependent genes, CSF‐2 that encodes for granulocyte‐monocyte colony‐stimulating factor (GM‐CSF), known to be host‐protective against nontuberculous mycobacteria, was strongly upregulated by AAT and dependent on GR. We further quantified the mRNA and protein of several AAT‐upregulated, GR‐dependent genes in macrophages and the mRNA of several AAT‐downregulated, GR‐dependent genes. We also discussed the function(s) of selected AAT‐regulated, GR‐dependent gene products largely in the context of mycobacterial infections. In conclusion, AAT regulated several genes that are dependent on GR and play roles in host immunity against mycobacteria.

The bile acids (BA) in the intestine promote inflammation by interacting with immune cells, playing a crucial role in the progression of UC, but the specific mechanism between the two remains elusive. This study aims to explore the relationship between BAMand UC inflammation and determine its potential mechanisms.Firstly, we employed a hybrid approach using Lasso regression and support vector machine (SVM) feature selection in bioinformatics to identify genes linked to UC and BAM. The relationship between these genes and immune infiltration was explored, along with their correlation with immune factors in the Tumor-Immune System Interaction Database (TISIDB) database. Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis was then used to predict signaling pathways associated with key genes in UC. Single-cell data from the GSE13464 dataset was also analyzed. Finally, Five differentially expressed genes (DEGs) related to BAM (APOA1, AMACR, PEX19, CH25H, and AQP9) were significantly upregulated/downregulated in UC immune cells. The expression of important genes in UC tissue was confirmed in the experimental validation section and AQP9, which showed significant differential expression, was chosen for further validation. The results showed that the AQP9 gene may regulate the IFN - γ/JAK signaling axis, thereby promoting CD8+T cell activation. This research has greatly advanced our comprehension of the pathogenesis and underlying mechanism of BAM in immune cells linked to UC.

Abstract The study discussed the effects of different mineral incorporations and the curing time on the strength of modified magnesium phosphate cement (MPC) mortars through mechanical tests, mathematical model analysis and microstructure characterization. Fly ash (FA), silica fume (SF), and metakaolin (MK), which exhibit excellent durability and bonding properties, were used to modify the MPC. A quantitative relationship was established between the strength of modified MPC mortars and the mineral incorporation and curing time. First, the strength of each mineral-modified MPC mortar cured in air with different mineral incorporations and curing durations was evaluated. The strengths of MPC mortars containing 10% fly ash, 15% silica fume, and 10% metakaolin—which perform best in their incorporations—were compared to analyze the function of the three minerals. To establish the relationship between strength and mineral incorporation and curing time, three mathematical models, linear model, general nonlinear model, and data distribution shape nonlinear model (DDSNM), are commonly used for material property analysis based on statistics. DDSNM best describes the trend of strength change among the three models and the error is small for three minerals. Based on DDSNM, the influence of various minerals on the strength of MPC mortar was quantitatively evaluated by calculating the variable partial derivatives, and verified by scanning electron microscopy and X-ray diffraction. MK performs the best in improving the flexural strength performance of MPC, while SF performs the best in the compressive strength. FA-MPC has low sensitivity to dosage fluctuations and is easy to prepare.

Abstract Background Acute kidney injury (AKI) is a common clinical disorder with complex etiology and poor prognosis, and currently lacks specific and effective treatment options. Mitochondrial dynamics dysfunction is a prominent feature in AKI, and modulation of mitochondrial morphology may serve as a potential therapeutic approach for AKI. Methods We induced ischemia–reperfusion injury (IRI) in mice (bilateral) and Bama pigs (unilateral) by occluding the renal arteries. ATP depletion and recovery (ATP-DR) was performed on proximal renal tubular cells to simulate in vitro IRI. Renal function was evaluated using creatinine and urea nitrogen levels, while renal structural damage was assessed through histopathological staining. The role of Drp1 was investigated using immunoblotting, immunohistochemistry, immunofluorescence, and immunoprecipitation techniques. Mitochondrial morphology was evaluated using confocal microscopy. Results Renal IRI induced significant mitochondrial fragmentation, accompanied by Dynamin-related protein 1 (Drp1) translocation to the mitochondria and Drp1 phosphorylation at Ser616 in the early stages (30 min after reperfusion), when there was no apparent structural damage to the kidney. The use of the Drp1 inhibitor P110 significantly improved kidney function and structural damage. P110 reduced Drp1 mitochondrial translocation, disrupted the interaction between Drp1 and Fis1, without affecting the binding of Drp1 to other mitochondrial receptors such as MFF and Mid51. High-dose administration had no apparent toxic side effects. Furthermore, ATP-DR induced mitochondrial fission in renal tubular cells, accompanied by a decrease in mitochondrial membrane potential and an increase in the translocation of the pro-apoptotic protein Bax. This process facilitated the release of dsDNA, triggering the activation of the cGAS-STING pathway and promoting inflammation. P110 attenuated mitochondrial fission, suppressed Bax mitochondrial translocation, prevented dsDNA release, and reduced the activation of the cGAS-STING pathway. Furthermore, these protective effects of P110 were also observed renal IRI model in the Bama pig and folic acid-induced nephropathy in mice. Conclusions Dysfunction of mitochondrial dynamics mediated by Drp1 contributes to renal IRI. The specific inhibitor of Drp1, P110, demonstrated protective effects in both in vivo and in vitro models of AKI.

Background and objective Lung cancer is a leading cause of cancer-related deaths. Non-small cell lung cancer (NSCLC) is the most common pathological subtype, with adenocarcinoma being the predominant type. FAT atypical cadherin 1 (FAT1) is a receptor-like protein with a high frequency of mutations in lung adenocarcinoma. The protein encoded by FAT1 plays a crucial role in processes such as cell adhesion, proliferation, and differentiation. This study aims to investigate the expression of FAT1 in lung adenocarcinoma and its relationship with immune infiltration. Methods Gene expression levels and relevant clinical information of 513 lung adenocarcinoma samples and 397 adjacent lung samples were obtained through The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data. The mRNA expression levels of the FAT1 gene in lung adenocarcinoma tissues were analyzed, along with its association with the prognosis of lung adenocarcinoma patients. Pathway enrichment analysis was conducted to explore the signaling pathways regulated by the FAT1 gene. Immunoblotting was used to detect the differential expression of FAT1 in lung epithelial cells and various lung cancer cell lines, while immunohistochemistry was employed to assess FAT1 expression in lung cancer and adjacent tissues. Results FAT1 gene mutations were identified in 14% of lung adenocarcinoma patients. TCGA database data revealed significantly higher FAT1 mRNA expression in lung adenocarcinoma tissues compared to adjacent lung tissues. Kaplan-Meier analysis indicated lower survival rates in lung adenocarcinoma patients with higher FAT gene expression. Pathway enrichment analysis suggested the involvement of FAT1 in tumor development pathways, and its expression was closely associated with immune cell infiltration. Immunohistochemical validation demonstrated significantly higher expression of FAT1 in cancer tissues compared to adjacent lung tissues. Conclusion FAT1 mRNA is highly expressed in lung adenocarcinoma tissues, and elevated FAT1 mRNA expression is associated with poor prognosis in lung adenocarcinoma patients. FAT1 may serve as a potential biomarker for lung cancer.

Unmanned surface vehicles (USVs) often encounter unknown obstacles, adverse weather, and emergency situations during missions, especially external disturbances such as wind, waves, and ocean currents at sea, which pose challenges for operators to respond promptly. To solve this issue, a Fixed-time prescribed performance adaptive state feedback shared control method for unmanned surface vehicles is proposed in this paper. The method comprises two parts: autonomous control based on Fixed-time prescribed performance adaptive state feedback for unmanned surface vehicles and shared control with adaptive state feedback, combining direct control commands with autonomous control. To ensure the convergence of tracking errors, a predefined performance control function is designed to guarantee transient error of the tracking error. Subsequently, an error transformation function is introduced for convenient controller design, and a nonlinear filter is used to compensate for boundary errors. Finally, utilizing the backstepping method, a controller is designed, and a Lyapunov function is formulated to verify the stability of unmanned surface vehicles using the designed transformation error. A state feedback shared control function is also designed to implement the shared control algorithm. Experimental results demonstrate the feasibility and effectiveness of this approach.

Abstract Alzheimer’s Disease (AD) is a disorder characterized by cognitive decline, neurodegeneration, and accumulation of amyloid plaques and tau neurofibrillary tangles in the brain. Dysregulation of epigenetic histone modifications may lead to expression of transcriptional programs that play a role either in protecting against disease genesis or in worsening of disease pathology. One such histone modification, acetylation of histone H3 lysine residue 27 (H3K27ac), is primarily localized to genomic enhancer regions and promotes active gene transcription. We previously discovered H3K27ac to be more abundant in AD patient brain tissue compared to the brains of age-matched non-demented controls. In this study, we use iPSC-neurons derived from familial AD patients with an amyloid precursor protein (APP) duplication (APPDup neurons) as a model to study the functional effect of lowering CBP/P300 enzymes that catalyze H3K27ac. We found that homeostatic amyloid-reducing genes were upregulated in the APPDup neurons compared to non-demented controls. We lowered CBP/P300 to reduce H3K27ac, which led to decreased expression of numerous of these homeostatic amyloid-reducing genes, along with increased extracellular secretion of a toxic amyloid-β species, Aβ(1–42). Our findings suggest that epigenomic histone acetylation, including H3K27ac, drives expression of compensatory genetic programs in response to AD-associated insults, specifically those resulting from APP duplication, and thus may play a role in mitigating AD pathology in neurons.

Background and objective Transcription factor (TF) can bind specific sequences that either promotes or represses the transcription of target genes, and exerts important effects on tumorigenesis, migration, invasion. Staphylococcal nuclease-containing structural domain 1 (SND1), which is a transcriptional co-activator, is considered as a promising target for tumor therapy. However, its role in lung adenocarcinoma (LUAD) remains unclear. This study aims to explore the role of SND1 in LUAD. Methods Data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Human Protein Atlas (HPA) database was obtained to explore the association between SND1 and the prognosis, as well as the immune cell infiltration, and subcellular localization in LUAD tissues. Furthermore, the functional role of SND1 in LUAD was verified in vitro. EdU assay, CCK-8 assay, flow cytometry, scratch assay, Transwell assay and Western blot were performed. Results SND1 was found to be upregulated and high expression of SND1 is correlated with poor prognosis of LUAD patients. In addition, SND1 was predominantly present in the cytoplasm of LUAD cells. Enrichment analysis showed that SND1 was closely associated with the cell cycle, as well as DNA replication, and chromosome segregation. Immune infiltration analysis showed that SND1 was closely associated with various immune cell populations, including T cells, B cells, cytotoxic cells and dendritic cells. In vitro studies demonstrated that silencing of SND1 inhibited cell proliferation, invasion and migration of LUAD cells. Besides, cell cycle was blocked at G1 phase by down-regulating SND1. Conclusion SND1 might be an important prognostic biomarker of LUAD and may promote LUAD cells proliferation and migration.

Rice body synovitis (RBS) is a rare disease, especially in children. Rheumatoid disorders and tuberculosis are the first two reasons for the formation of the RB. The diagnosis is mainly based on imaging and histopathological features. Herein, we report three cases of RBS in children diagnosed with congenital synovial chondromatosis, tuberculosis (unconfirmed), and ANA -positive juvenile idiopathic arthritis. Clinical features, radiographic findings, pathophysiology, treatment process, and prognosis were reviewed and documented meticulously to enhance cognition in this population and provide some references for clinicians in diagnosing and treating the disease.

Abstract Accumulating evidence indicates that metabolic reprogramming of cancer cells supports the energy and metabolic demands during tumor metastasis. However, the metabolic alterations underlying lymph node metastasis (LNM) of cervical cancer (CCa) have not been well recognized. In the present study, it is found that lymphatic metastatic CCa cells have reduced dependency on glucose and glycolysis but increased fatty acid oxidation (FAO). Inhibition of carnitine palmitoyl transferase 1A (CPT1A) significantly compromises palmitate‐induced cell stemness. Mechanistically, FAO‐derived acetyl‐CoA enhances H3K27 acetylation (H3K27Ac) modification level in the promoter of stemness genes, increasing stemness and nodal metastasis in the lipid‐rich nodal environment. Genetic and pharmacological loss of CPT1A function markedly suppresses the metastatic colonization of CCa cells in tumor‐draining lymph nodes. Together, these findings propose an effective method of cancer therapy by targeting FAO in patients with CCa and lymph node metastasis.

Medical implant-associated infections (IAI) is a growing threat to patients undergoing implantation surgery. IAI prevention typically relies on medical implants endowed with bactericidal properties achieved through surface modifications with antibiotics. However, the clinical efficacy of this traditional paradigm remains suboptimal, often necessitating revision surgery and posing potentially lethal consequences for patients. To bolster the existing anti-IAI arsenal, we propose herein a chitosan-based bioactive coating, i.e., ChitoAntibac, which exerts bacteria-inhibitory effects either through immune modulation or phage-directed microbial clearance, without relying on conventional antibiotics. The immuno-stimulating effects and phage-induced bactericidal properties can be tailored by engineering the loading dynamic of macrophage migration inhibitory factor (MIF), which polarizes macrophages towards the proinflammatory subtype (M1) with enhanced bacterial phagocytosis, and Staphylococcal Phage K, resulting in rapid and targeted pathogenic clearance (>99.99%) in less than 8 h. Our innovative antibacterial coating opens a new avenue in the pursuit of effective IAI prevention through immuno-stimulation and phage therapeutics.

BackgroundThe involvement of ATP and cAMP in sperm function has been extensively documented, but the understanding of the role of adenosine and adenosine receptors remains incomplete. This study aimed to examine the presence of adenosine A2A receptor (A2AR) and study the functional role of A2AR in human sperm.MethodsThe presence and localization of A2AR in human sperm were examined by western blotting and immunofluorescence assays. The functional role of A2AR in sperm was assessed by incubating human sperm with an A2AR agonist (regadenoson) and an A2AR antagonist (SCH58261). The sperm level of A2AR was examined by western blotting in normozoospermic and asthenozoospermic men to evaluate the association of A2AR with sperm motility and in vitro fertilization (IVF) outcomes.ResultsA2AR with a molecular weight of 43 kDa was detected in the tail of human sperm. SCH58261 decreased the motility, penetration ability, intracellular Ca2+ concentration, and CatSper current of human sperm. Although regadenoson did not affect these sperm parameters, it alleviated the adverse effects of SCH58261 on these parameters. In addition, the mean level of A2AR in sperm from asthenozoospermic men was lower than that in sperm from normozoospermic men. The sperm level of A2AR was positively correlated with progressive motility. Furthermore, the fertilization rate during IVF was lower in men with decreased sperm level of A2AR than in men with normal sperm level of A2AR.ConclusionsThese results indicate that A2AR is important for human sperm motility and is associated with IVF outcome.

Rearrangements involving the neurotrophic-tropomyosin receptor kinase (NTRK) gene family (NTRK1, NTRK2, and NTRK3) have been identified as drivers in a wide variety of human cancers. However, the association between NTRK rearranged thyroid carcinoma and clinicopathological characteristics has not yet been established. In our study, we retrospectively reviewed medical records of thyroid cancer patients and identified 2 cases with NTRK rearrangement, no additional molecular alterations were observed in either of these cases. The fusion of the rearrangement in both cases was ETV6(E4)::NTRK3(E14). By analyzing the clinicopathological features of these two cases, we found that both were characterized by multiple tumor nodules, invasive growth, and central lymph node metastases, indicating the follicular subtype of papillary thyroid carcinoma. Immunohistochemical staining profiles showed CD56-, CK19+, Galectin-3+, HBME1+. These clinicopathological features suggest the possibility of ETV6-NTRK3 rearranged thyroid carcinoma and highlight the importance of performing gene fusion testing by FISH or NGS for these patients.

FAT1, a substantial transmembrane protein, plays a pivotal role in cellular adhesion and cell signaling. Numerous studies have documented frequent alterations in FAT1 across various cancer types, with its aberrant expression being linked to unfavorable survival rates and tumor progression. In the present investigation, we employed bioinformatic analyses, as well as in vitro and in vivo experiments to elucidate the functional significance of FAT1 in pan-cancer, with a primary focus on lung cancer. Our findings unveiled FAT1 overexpression in diverse cancer types, including lung cancer, concomitant with its association with an unfavorable prognosis. Furthermore, FAT1 is intricately involved in immune-related pathways and demonstrates a strong correlation with the expression of immune checkpoint genes. The suppression of FAT1 in lung cancer cells results in reduced cell proliferation, migration, and invasion. These collective findings suggest that FAT1 has potential utility both as a biomarker and as a therapeutic target for lung cancer.

BackgroundMany studies demonstrated the safety and efficacy of SBRT in the treatment of elderly patients with early-stage non-small cell lung cancer (NSCLC). However, those studies focused on patients with peripheral lung cancer. This study aimed to evaluate the clinical efficacy and toxicity of SBRT in elderly patients with stage I-II central NSCLC in single institution.MethodsFrom April 2009 to January 2020, a retrospective study was conducted on patients ≥ 65 years old with stage I-II NSCLC that was centrally localized and treated with SBRT at a single institution. Absolute C-reactive protein (CRP)/albumin ratio (CAR) and body mass index (BMI) recorded at pretreatment were analyzed. Endpoints included overall survival (OS), progression-free survival (PFS), cancer-specific death, noncancer-specific death, local progression (LP) and distant progression (DP).ResultsStereotactic body radiation treatment (SBRT) was administered to a total of 44 patients. The most common dose fractionation schedule was 60 Gy given in 5 fractions. The median PFS of the cohort was 31 months (95% CI, 19.47–42.53 months). The median OS of all patients was 69 months (95% CI, 33.8–104.2 months). The median time to noncancer-specific death was 54.5 months. The median time to cancer-specific death was 36 months. The cumulative incidences of cancer-specific death at 1 year, 5 years, and 10 years were 11.63% (95%CI, 4.2–23.23%), 42.99% (95%CI, 27.56–57.53%), and 65.94% (95%CI, 45.76–80.1%), respectively. pre-SBRT BMI of ≤ 22.77 (HR 4.60, 95% CI 1.84–11.51, P=0.001) and pre-SBRT CAR of ≤0.91 (HR 5.19, 95% CI 2.15–12.52, P

BackgroundThe current survival prediction methodologies for primary bone lymphoma (PBL) of the spine are deficient. This study represents the inaugural utilization of conditional survival (CS) to assess the outcome of this disease. Moreover, our objective was to devise a CS-based nomogram for predicting overall survival (OS) in real-time for spinal PBL.MethodsPatients with PBL of the spine diagnosed between January 2000 and December 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The OS was determined through the Kaplan–Meier method. The CS characteristic of patients with spinal PBL was delineated, with the CS being estimated utilizing the formula: CS(α|β) = OS(α+β)/OS(β). CS(α|β) denotes the probability of additional α-year survivorship, assuming the patient has already survived β years after the time of observation. Three methods including univariate Cox regression, best subset regression (BSR) and the least absolute shrinkage and selection operator (LASSO) regression were used to identify predictors for CS-based nomogram construction.ResultsKaplan-Meier analysis was executed to determine the OS rate for these patients, revealing a survival rate of 68% and subsequently 63% at the 3-year and 5-year mark respectively. We then investigated the CS patterning exhibited by these patients and discovered the survival of PBL in the spine progressively improved with time. Meanwhile, through three different prognostic factor selection methods, we identified the best predicter subset including age, tumor histology, tumor stage, chemotherapy and marital status, for survival prediction model construction. Finally, we successfully established and validated a novel CS-based nomogram model for real-time and dynamic survival estimation. Moreover, we further designed a risk stratification system to facilitate the identification of high-risk patients.ConclusionsThis is the first study to analyze the CS pattern of PBL of the spine. And we have also developed a CS-based nomogram that provide dynamic prognostic data in real-time, thereby aiding in the formulation of personalized treatment strategies in clinical practice.

BackgroundIntegrin subunit alpha L (ITGAL) encodes an integrin component of LFA-1 and is a membrane receptor molecule widely expressed on leukocytes. It plays a key role in the interaction between white blood cells and other cells. There was a significant correlation between the expression of ITGAL and the tumor microenvironment in a number of cancers. However, experimental studies targeting ITGAL and immune cell infiltration in non-small-cell lung cancer (NSCLC) and the response to immune checkpoint inhibitor therapy are lacking.MethodsData were obtained from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases to explore the relationship between ITGAL expression and prognosis, as well as the immune cell infiltration in patients with NSCLC. In addition, immunohistochemical staining for ITGAL and multiplex immunofluorescence (mIF) staining for ITGAL, CD20, CD68, CD4, and CD8 from tissue microarrays containing 118 tumor tissues and paired paracancerous tissues from patients with NSCLC were performed. The correlation between ITGAL expression and clinical factors, as well as the immunophenotypes of tumor-infiltrating immune cells, were also analyzed.ResultsIn NSCLC tumor tissues, ITGAL was downregulated compared with matched paracancerous tissues, and low ITGAL expression was associated with a poor prognosis of NSCLC patients. Subsequently, immunohistochemistry results for tissue microarray showed that ITGAL expression was mainly elevated in tumor stroma and areas with highly infiltrated immune cells. ITGAL expression was higher in paracancerous tissues than tumor tissues. Furthermore, mIF results indicated that the patients with ITGAL-high expression tend had significantly higher CD8+ T cells, CD68+ macrophages, CD4+ T cells, and CD20+ B cells infiltration in their tumor tissues. Immunophenotypes were classified into three categories, that is deserted, excluded, and inflamed types, according to each kind of immune cell distribution in or around the cancer cell nest. MIF results showed that ITGAL expression level was correlated with the immunophenotypes. Furthermore, ITGAL expression was associated with the prognosis of NSCLC in patients with immune checkpoint inhibitor therapy and the patients with high ITGAL expression tends have better outcomes.ConclusionsITGAL may be used as a biomarker for assessing the immune microenvironment in patients with NSCLC.

Summary: Nuclear factor kappa B (NF-κB) plays a pivotal role in the development of pancreatic cancer, and its phosphorylation has previously been linked to the regulation of NUAK2. However, the regulatory connection between NF-κB and NUAK2, as well as NUAK2’s role in pancreatic cancer, remains unclear. In this study, we observed that inhibiting NUAK2 impeded the proliferation, migration, and invasion of pancreatic cancer cells while triggering apoptosis. NUAK2 overexpression partially resisted apoptosis and reversed the inhibitory effects of the NF-κB inhibitor. NF-κB transcriptionally regulated NUAK2 transcription by binding to the promoter region of NUAK2. Mechanistically, NUAK2 knockdown remarkably reduced the expression levels of p-SMAD2/3 and SMAD2/3, resulting in decreased nuclear translocation of SMAD4. In SMAD4-negative cells, NUAK2 knockdown impacted FAK signaling by downregulating SMAD2/3. Moreover, NUAK2 knockdown heightened the sensitivity of pancreatic cancer cells to gemcitabine, suggesting that NUAK2 inhibitors could be a promising strategy for pancreatic cancer treatment.

Abstract Background The university years are a developmentally crucial phase and a peak period for the onset of mental disorders. The beliefs about the changeability of negative emotion may play an important role in help-seeking. The brief digital growth mindset intervention is potentially scalable and acceptable to enhance adaptive coping and help-seeking for mental health needs in university students. We adapted the Single-session Intervention on Growth Mindset for adolescents (SIGMA) to be applied in university students (U-SIGMA). This protocol introduces a two-armed waitlist randomized controlled trial study to examine the effectiveness and acceptability of U-SIGMA in promoting help-seeking among university students in the Greater Bay Area. Methods University students (N = 250, ages 18–25) from universities in the Greater Bay Area will be randomized to either the brief digital growth mindset intervention group or the waitlist control group. Participants will report on the mindsets of negative emotions, perceived control over anxiety, attitude toward help-seeking, physical activity, hopelessness, psychological well-being, depression, anxiety, and perceived stress at baseline and the 2-week and 8-week follow-ups through web-based surveys. A 30-min digital intervention will be implemented in the intervention group, with a pre- and post-intervention survey collecting intervention feedback, while the control group will receive the link for intervention after 8 weeks. Discussion This protocol introduces the implementation plan of U-SIMGA in multi-cities of the Greater Bay Area. The findings are expected to help provide pioneer evidence for the effectiveness and acceptability of the brief digital intervention for university students in the Chinese context and beyond and contribute to the development of accessible and effective prevention and early intervention for university students’ mental health. Trial registration HKU Clinical Trials Registry: HKUCTR-3012; Registered 14 April 2023. http://www.hkuctr.com/Study/Show/7a3ffbc0e03f4d1eac0525450fc5187e .

Abstract The mechanism underlying acute kidney injury (AKI) and AKI-to-Chronic kidney disease (CKD) transition remains unclear, but mitochondrial dysfunction may be a key driving factor. Literature reports suggest that dual-specificity phosphatase 1 (DUSP1) plays a critical role in maintaining mitochondrial function and structural integrity. In this study, ischemic Acute Kidney Injury (AKI) and post-ischemic fibrosis models were established by clamping the renal pedicle with different reperfusion times. To investigate the role of DUSP1, constitutional Dusp1 knockout mice and tubular-specific Sting knockout mice were used. Mitochondrial damage was assessed through electron microscopy observation, measurements of mitochondrial membrane potential, mtDNA release, and BAX translocation. We found that Dusp1 expression was significantly upregulated in human transplant kidney tissue and mouse AKI tissue. Dusp1 gene deletion exacerbated acute ischemic injury, post-ischemic renal fibrosis, and tubular mitochondrial dysfunction in mice. Mechanistically, DUSP1 could directly bind to JNK, and DUSP1 deficiency could lead to aberrant phosphorylation of JNK and BAX mitochondria translocation. BAX translocation promoted mitochondrial DNA (mtDNA) leakage and activated the cGAS-STING pathway. Inhibition of JNK or BAX could inhibit mtDNA leakage. Furthermore, STING knockout or JNK inhibition could significantly mitigate the adverse effects of DUSP1 deficiency in ischemic AKI model. Collectively, our findings suggest that DUSP1 is a regulator for the protective response during AKI. DUSP1 protects against AKI by preventing BAX-induced mtDNA leakage and blocking excessive activation of the cGAS-STING signaling axis through JNK dephosphorylation.

Five new orchid species from southwestern China’s Yunnan Province and the Tibetan Autonomous Region, Neottia lihengiae, Neottia chawalongensis, Papilionanthe motuoensis, Gastrochilus lihengiae, and Gastrochilus bernhardtianus, are described and illustrated. To confirm their identities, and to resolve phylogenetic relationships, we sequenced the complete plastomes of these taxa with their congeneric species, adding new plastomes of three Neottia species, two Papilionanthe species and nine Gastrochilus species. Combined with published plastid sequences, our well-resolved phylogeny supported the alliance of N. lihengiae with the the N. grandiflora + N. pinetorum clade. Neottia chawalongensis is now sister to N. alternifolia, while P. motuoensis is closely related to P. subulata + P. teres. Conversely, phylogenetic analyses based on complete plastomes and plastid sequences showed inconsistent relationships among taxa in the genus Gastrochilus, but the two new species, G. lihengiae and G. bernhardtianus were supported by all datasets.

With the development of society, water resources are gradually scarce and water pollution is becoming increasingly serious, which would seriously restrict the development of the urban economy. In response to the current problems of water scarcity and severe water pollution, this article will study the key points of urban environmental design development based on ecological concepts. This article will also use ecological concepts to divide water function zones based on different pollution-carrying capacities in different regions, which can be mainly divided into two levels. In the experimental analysis section, the Xiongan New Area will be analyzed. This article randomly selected three regions in the Xiongan New Area and studied the utilization rate of various types of water in these regions. The pollution capacity and main water resources of each region in the functional area were planned and designed. Through experiments, it can be found that based on ecological concepts, it is beneficial to improve the pollutant-carrying capacity of each functional area and reduce the total amount of ammonia nitrogen. HIGHLIGHT The average utilization rates of these three types of water in 10 administrative regions were 93.01, 93.3, and 93.11%, respectively. Based on ecological concepts, it can help better water resources planning and improve the city's pollution capacity.;

Abstract Regulation of global transcription output is important for normal development and disease, but little is known about the mechanisms involved. DNA topoisomerase I (TOP1) is an enzyme well-known for its role in relieving DNA supercoils for enabling transcription. Here, we report a non-enzymatic function of TOP1 that downregulates RNA synthesis. This function is dependent on specific DNA-interacting residues located on a conserved protein surface. A loss-of-function knock-in mutation on this surface, R548Q, is sufficient to cause hypertranscription and alter differentiation outcomes in mouse embryonic stem cells (mESCs). Hypertranscription in mESCs is accompanied by reduced TOP1 chromatin binding and change in genomic supercoiling. Notably, the mutation does not impact TOP1 enzymatic activity; rather, it diminishes TOP1-DNA binding and formation of compact protein-DNA structures. Thus, TOP1 exhibits opposing influences on transcription through distinct activities which are likely to be coordinated. This highlights TOP1 as a safeguard of appropriate total transcription levels in cells.

Abstract Background Antigenic stimulation through cross-linking the IgE receptor and epithelial cell-derived cytokine IL-33 are potent stimuli of mast cell (MC) activation. Moreover, IL-33 primes a variety of cell types, including MCs to respond more vigorously to external stimuli. However, target genes induced by the combined IL-33 priming and antigenic stimulation have not been investigated in human skin mast cells (HSMCs) in a genome-wide manner. Furthermore, epigenetic changes induced by the combined IL-33 priming and antigenic stimulation have not been evaluated. Results We found that IL-33 priming of HSMCs enhanced their capacity to promote transcriptional synergy of the IL1B and CXCL8 genes by 16- and 3-fold, respectively, in response to combined IL-33 and antigen stimulation compared to without IL-33 priming. We identified the target genes in IL-33-primed HSMCs in response to the combined IL-33 and antigenic stimulation using RNA sequencing (RNA-seq). We found that the majority of genes synergistically upregulated in the IL-33-primed HSMCs in response to the combined IL-33 and antigenic stimulation were predominantly proinflammatory cytokine and chemokine genes. Moreover, the combined IL-33 priming and antigenic stimulation increase chromatin accessibility in the synergy target genes but not synergistically. Transcription factor binding motif analysis revealed more binding sites for NF-κB, AP-1, GABPA, and RAP1 in the induced or increased chromatin accessible regions of the synergy target genes. Conclusions Our study demonstrates that IL-33 priming greatly potentiates MCs’ ability to transcribe proinflammatory cytokine and chemokine genes in response to antigenic stimulation, shining light on how epithelial cell-derived cytokine IL-33 can cause exacerbation of skin MC-mediated allergic inflammation.

Fruits and vegetables are two key daily sources of food for human beings [...]

IntroductionPatients with systemic lupus erythematosus (SLE) are at a higher risk of developing cancer, particularly hematological malignancies such as lymphoma and leukemia. However, existing studies on this topic that assess cancer incidence following SLE diagnosis are limited. In addition, SLE can be diagnosed after cancer, although such cases in children have been rarely reported.Case reportWe present the case of a 2.6-year-old boy who presented to our institute with fever and abdominal pain. His physical examination revealed a periumbilical mass, which was pathologically diagnosed as Burkitt's lymphoma. Autologous stem cell transplantation was performed to consolidate the effect of chemotherapy and reduce the risk of cancer relapse. He was diagnosed with SLE 5 years later, following the presentation of a fever with rash, positive autoantibodies, decreased complement, and kidney involvement. At the final follow-up, the patient was still alive and showed no recurrence of Burkitt's lymphoma or disease activity of SLE.ConclusionDespite the low frequency of SLE in children with lymphoma, cancer and SLE may be induced by a common mechanism involving B-cell cloning and proliferation. Therefore, hematologists and rheumatologists should be aware of the occurrence of these two conditions during patient follow-up.

The success of root canal treatment for deciduous teeth depends upon the shape of the root canal, among other factors. Despite this, there are limited reports on the use of high-resolution micro-CT to describe the root canal morphology of primary maxillary incisors. In this study, we aimed to create a three-dimensional (3D) digital model of the root canal morphology of primary maxillary incisors using microcomputed tomography (micro-CT). To provide a reference for the development of restorative posts for the primary maxillary incisors. Primary maxillary central and lateral incisors (n = 10 each) were analysed. Micro-computed tomography was used to conduct 3D analyses of the root canal system of the primary maxillary incisors. The canal volume and surface area of the primary maxillary central incisors were larger than those of the primary maxillary lateral incisors. The structural model index value was significantly lower in central incisors. At the cervical level and the interface between the cervical and middle one-third cross-sectional levels, the root canals of the primary maxillary lateral incisors were significantly rounder. The labio-palatal dimension and the diameters of the central incisors at the four different levels were significantly smaller than the diameter of the mesio-distal dimension. The taper of the central and lateral incisors gradually increased from the apical one-third to the cervical one-third in the labio-palatal dimension. The data obtained from the 3D analysis of maxillary incisors in this study will contribute to the design of root canal posts.

The Cypripedium forrestii is an orchid species with extremely small populations (PSESP) in Yunnan, China. C. forrestii is range-restricted and less-studied than many orchid species, and it is exposed to various threats to its survival. We investigated its potential habitats and collected 52 samples from eight locations, as well as two outgroup species for reference. We developed genetic markers (SNPs) for C. forrestii based on transcriptome sequencing (RNA-seq) data, and analyzed the genetic diversity, population structure, gene flow and demographic history of C. forrestii in detail. C. forrestii is a taxonomically independent species to protect. We found that the genetic diversity of C. forrestii was very low (1.7e-4) compared with other endangered species. We identified three genetic clusters, and several populations with distinct genetic backgrounds. Most genetic diversity was found within sampling sites (87.87%) and genetic clusters (91.39%). Gene flow has been greatly limited over the most recent generations, probably due to geographical distance, historical climate change and habitat fragmentation. We also detected a severe bottleneck event brought about by the recent population constraints. These factors, together with its reproductive characteristics, contribute to the population fragmentation and low genetic diversity of C. forrestii. Based on our findings, we suggest an integrative conservation strategy to protect and recover the genetic diversity of C. forrestii and a further comprehensive study of its ecological traits in the future.

Summary: Background: The pivotal phase 3 efficacy clinical trial has demonstrated that a two-dose regimen of dNS1-RBD (Beijing Wantai Biological Pharmacy Enterprise, Beijing, China) is well-tolerated and provides wide protection against SARS-CoV-2 infection. However, the effectiveness of a single-dose regimen is still unknown. We aimed to estimate the effectiveness of one-dose of dNS1-RBD against symptomatic Omicron infections in real-world conditions. Methods: This prospective cohort study was conducted during an Omicron outbreak among healthcare workers in Xiamen, China, from December 22, 2022 to January 16, 2023. Participants chose to receive single-dose of dNS1-RBD or remain unvaccinated based on personal preference. Healthcare workers daily validated their SARS-CoV-2 infection status, using either RT-PCR or rapid antigen test. A survey questionnaire was conducted to gather information on acute symptoms from individuals infected with SARS-CoV-2. The primary outcome was the symptomatic SARS-CoV-2 infections after enrollment in the dNS1-RBD recipients or the control group among all participants and by prior COVID-19 vaccination status. Findings: On December 22, 2022, a total of 1391 eligible participants without a history of prior SARS-CoV-2 infection were enrolled. Among them, 550 received single-dose of dNS1-RBD, while 841 remained unvaccinated. In the total cohort, the range of follow-up time was 1∼26 days. During the study period, a total of 880 symptomatic SARS-CoV-2 infections were identified in the total cohort. The adjusted vaccine effectiveness against symptomatic SARS-CoV-2 infections and the infections requiring medical attention were 19.0% (95% CI: 6.7, 29.7, P = 0.004) and 59.4% (95% CI: 25.1, 78.0, P = 0.004) in the total cohort, 11.6% (95% CI: −2.4, 23.7, P = 0.100) and 55.3% (95% CI: 15.3, 76.4, P = 0.014) in the participants with inactivated COVID-19 vaccination history, as well as 87.0% (95% CI: 72.6, 93.9, P < 0.001) and 84.2% (95% CI: −41.8, 98.2, P = 0.099) in the naïve participants, respectively. Interpretation: When administered as a booster to individuals with a history of inactivated COVID-19 vaccination, a single-dose of dNS1-RBD provides protection against infections requiring medical attention at least in the short-term after vaccination. The data also showed that a single-dose of dNS1-RBD is protective against symptomatic SARS-CoV-2 infections as a primary immunization for individuals without prior exposure, but due to the limited sample size of naïve participants, further research with a larger sample size is needed to make a solid conclusion. Funding: Xiamen Science and Technology Bureau 2022 General Science and Technology Plan Project and the Bill & Melinda Gates Foundation.

Abstract Background Wilms’ tumour gene 1 (WT1) is clearly recognized as a tumour promoter in diversiform of human malignancies. Nevertheless, knowledge of its expression, functions and potential molecular mechanisms in non-small cell lung cancer (NSCLC) remains elusive. Methods Differential expression of WT1 mRNA and protein between NSCLC and normal tissues were assessed by analyzing RNA-seq data from Oncomine and protein data from Human Protein Atlas, respectively. Subsequently, prognosis significance and immune cell infiltration were analyzed by Kaplan-Meier plotter and CIBERSORT. 60 pairs of local NSCLC tissues were involved to validate WT1 expression by quantitative PCR (qPCR) and Western blot. Moreover, Cell Counting Kit-8 (CCK-8), colony formation, transwell, dual luciferase reporter assays and in vivo xenograft tumour growth experiments were conducted to explore the function and mechanism of WT1 in NSCLC. Results Our solid data indicated that WT1 was increased in NSCLC tissues and cell lines in comparison with their matched controls. In particular, its upregulation correlated with worse prognosis and immune infiltration of the patients. Functional assays demonstrated that knockdown of WT1 inhibited NSCLC malignancy, including inhibiting cell proliferation, survival and invasion. Further exploration discovered that microRNA-498-5p (miR-498-5p) was the upstream suppressor of WT1 by directly targeting the 3’ untranslated region (UTR) of WT1 mRNA. Moreover, expression of miR-498-5p was notably decreased and inversely correlated with WT1 in NSCLC tissues. Finally, we proved that miR-498-5p was a potent tumour suppressor in NSCLC by suppressing cell proliferation, survival and invasion, while WT1 restoration could in turn disrupt this suppression both in vitro and in vivo. Conclusion The abnormal increase in WT1 contributes to the malignant properties of NSCLC cells, and miR-498-5p is a natural inhibitor of WT1. Our findings might facilitate the development of novel therapeutic strategies against NSCLC in the future.

The anaerobic-anoxic-oxic (AAO) process is one of the most widely used processes for treating industrial organic wastewater, and it has shown significant effectiveness in the removal of organic compounds, as well as denitrification and phosphorus removal. However, for the treatment of industrial organic wastewater, this anaerobic preposition and aerobic postposition process has exposed various limitations. Therefore, for this type of wastewater, the oxic-hydrolytic and denitrification-oxic (OHO) treatment process has been proposed and developed based on the principles of three-sludge separation and fluidization. This study integrated operational data from 203 coking wastewater treatment plants worldwide, and the two-step nitrification-denitrification activated sludge model No.3 (TCW-ASM3) was used for comparative analysis of the pollutant removal efficiency and total operating cost of the AAO process and the OHO process in the face of characteristic pollutants in coking wastewater. The results indicate that the full-scale OHO process achieved removal efficiencies of up to 3784 mg/L for chemical oxygen demand (COD) and 297 mg/L for total nitrogen (TN). The theoretical total cost for OHO and AAO were 9.75 and 14.38 CNY/m3, respectively. The pre-treatment aerobic process effectively reduces the biological toxicity of high-toxicity and refractory industrial wastewater, and the three-sludge system provides a stable living space for functional microorganisms, the combination of multi-mode denitrification processes offers new possibilities for treating similar types of industrial wastewater.

Deep fertilization is a beneficial approach for reducing nitrogen losses. However, the effects of various fertilization depths on maize (Zea mays L.) productivity and environmental footprints have not been thoroughly understood. Therefore, a field experiment was conducted to investigate the effects of different fertilization depths of 5 cm (D5), 15 cm (D15), 25 cm (D25), and 35 cm (D35) on maize productivity and environmental footprints. Reactive nitrogen (Nr) losses and greenhouse gas (GHG) emissions were assessed using life cycle analysis. We hypothesized that deep fertilization can obtain lower carbon and nitrogen footprint. The results indicated that deep fertilization decreased the N2O and NH3 emissions while increasing the CH4 uptake. Compared with D5, D15 resulted in an increase in total GHG emissions and carbon footprint (CF), whereas D25 decreased by 13.0% and 23.6%, respectively. Compared with D5, the Nr losses under D15, D25, and D35 conditions was reduced by 11.3%, 17.3%, and 21.0%, respectively, and the nitrogen footprint (NF) was reduced by 16.0%, 27.4%, and 19.0%, respectively. The maize yield under D15 and D25 increased by 5.7% and 13.8%, respectively, compared with the D5 treatment, and the net economic benefits of the ecosystem increased by 7.1% and 17.1%, respectively. In summary, applying fertilizer at a depth of 25 cm can significantly reduce the environmental footprints and increase maize productivity, making it an effective fertilization strategy in the Loess Plateau region of China.

Abstract Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome (MetS) and has been correlated with coronary atherosclerosis (CAS). Since NAFLD was renamed metabolic-associated fatty liver disease(MAFLD) in 2020, no studies have evaluated the correlation between MAFLD and CAS. The aim of this study was to evaluate the relationship between MAFLD and CAS. A total of 1330 patients underwent continuous coronary computed tomography angiography (CCTA) and abdominal ultrasound as part of a routine physical examination. Ultrasonography was used to assess fatty liver, and CCTA was used to assess coronary artery plaques, degree of stenosis, and diseased blood vessels. Univariate and multivariate logistic regression analyses were performed with plaque type and degree of stenosis as dependent variables and MAFLD and traditional cardiovascular risk factors as independent variables to analyze the correlation between MAFLD and CAS. Among the 1164 patients, 680 (58.4%) were diagnosed with MAFLD through a combination of ultrasound and auxiliary examinations. Compared with the non-MAFLD group, the MAFLD group had more cardiovascular risk factors,and the MAFLD group had more likely to have coronary atherosclerosis, coronary stenosis and multiple coronary artery stenosis.In the univariate logistic regression, MAFLD was significantly correlated with overall plaque, calcified plaques, noncalcified plaques, mixed plaques,and significant stenosis in the coronary arteries.(p

Abstract Whistler mode chorus waves frequently appear as discrete, repetitive, and quasi‐monochromatic emissions with frequency chirping. With different wave amplitude and frequency chirping rate, chorus waves have been observed not only in the magnetosphere of the Earth but also in the magnetospheres of other planets, such as Saturn and Jupiter. Motivated by understanding different properties of chorus waves at these planets using the recently proposed “Trap‐Release‐Amplify” (TaRA) model, we perform a parametric study using Particle‐In‐Cell simulations by varying background magnetic field inhomogeneity and the corresponding threshold hot electron number density. We show the consistency between simulation results and theoretical predictions for threshold hot electron number density, chorus chirping rate, and wave amplitude. Our results suggest the significant role of the background magnetic field inhomogeneity in affecting chorus wave properties, including its amplitude at different planets as predicted by the TaRA model.

BackgroundChemotherapy is an important treatment for children with cancer, and chemotherapy-induced pain is an important role in affecting patients' quality of life. In our study, bibliometric analysis was used to identify current research hotspots and future research trends of chemotherapy and pain in children over the last decade. Our findings can provide a reference for the research in the field of chemotherapy and pain in children.MethodPublications of chemotherapy and pain in children were collected from the Web of Science Core Collection database. CiteSpace was used to analyze publication characteristics from 2013 to 2022.ResultsWe identified 1,130 eligible publications in the field of chemotherapy and pain in children, with an increasing trend of publications over the last decade. In the field of chemotherapy and pain in children, the United States had the most publication with 346, followed by China with 135. The author with the most published papers was Pamela S Hinds (n = 8) from the United States. The journals that published the most papers were the Journal of pediatric hematology oncology (n = 44) and Medicine (n = 44). The Journal of Clinical Oncology was cited the most frequency (n = 422). St. Jude Children's Research Hospital had the most publication (n = 23). The specific keywords related to the field of chemotherapy and pain in children were “children”, “chemotherapy”, “management”, “childhood cancer”, “randomized controlled trial” and “efficacy”. Emerging research focuses predominantly on symptomatic and supportive interventions for chemotherapy and pain in children.ConclusionAttention to chemotherapy and pain in children with cancer was insufficient. This bibliometric analysis showed the upward trend of chemotherapy and pain in children over the last decade. More studies are needed to improve the quality of life in children with chemotherapy-induced pain. This study may provide useful information to guide future research on chemotherapy and pain in children.

ABSTRACTThere are limitations and difficulties in the management of traditional in-person standardized patient (SP) practice. The latest developments in online communication tools and the COVID-19 pandemic have promoted the needs for online clinical skills training objectively. However, existing commercial online platforms may not meet the requests for SP-based medical simulation. This paper described the methodology applied to develop a smartphone-based online platform for the management of clinical skills training and assessment with remote SPs, and aimed to determine whether this new platform is acceptable or useful through a pilot run in September 2020. The post-run survey including questionnaire inspired by technological acceptance model and determinants of the perceived ease of use was used to assess the acceptability and usefulness of the platform. Twenty four-year students of clinical medicine participated in the pilot study with twenty SPs and ten faculties. Data from the post-run survey showed that there was a general recognition that the platform is easy to use among all the users. Two questions regarding the usefulness of the platform showed significant differences between the SPs/faculties and the students. More SPs found the platform useful as a training method than the students did. The faculties showed more attempts than the students to use this platform for clinical skills training in the future. This smartphone-based online platform was widely accepted among the tested students, SPs and faculties, which meets the requests and challenges of the new era. It provides an effective approach for clinical skills training and assessment with remote SPs.

ABSTRACTIntroduction Objective structured clinical examination (OSCE) results could be affected by low homogeneity of examiners, non-retrospectiveness of test results, and examiner-cohort effect. In China, many students participate in medical qualification examinations, and this issue is particularly significant. This study aimed to develop a video recording, video-based rating method and compare the reliability of video and on-site ratings to enhance the quality assurance of OSCEs.Methods The subjects of this study were clinical students one year after graduation participating in the clinical skills portion of the National Medical Licensing Examination. The participants were from four cities in Jiangsu province. Participants were randomly allocated to on-site and video rating groups to evaluate the rating methods consistency. We verified the reliability of recording equipment and evaluability of video recording. Moreover, we compared the consistency and equivalence of the two rating methods and analyzed the impact of video recording on scores.Results The reliability of recording equipment and evaluability of video recording were high. Evaluation consistency between experts and examiners was acceptable, and there was no difference in evaluation results (P = 0.61). There was good consistency between video and on-site rating; however, a difference between the two rating methods was detected. The scores of video-based rating group students were lower than those of all students (P

To solve the problems of low accuracy of crop evapotranspiration (ETc) estimates in arid areas and to optimise ETc for precision irrigation in agriculture.Taking walnut in Wensu County, Aksu Region, Xinjiang as the research object, based on the multivariate time series data of walnut fertility, deep learning sequence models such as LSTM, GRU and BiLSTM were utilized to estimate the crop evapotranspiration (ETc) of walnut in arid zones under different micro-irrigation techniques. The results showed that the coefficient of determination (R2) of the LSTM, GRU and BiLSTM models were up to greater than 0.95 for both microirrigation techniques, and the BiLSTM model was relatively optimal. For the 3 g microirrigation technique, the R2, RMSEV and RPDV of the BiLSTM model were 0.978, 0.294 and 6.965 mm/d respectively. For the Hg microirrigation technique, the R2, RMSEV and RPDV of the BiLSTM model were 0.970, 0.339 and 6.026 mm/d respectively.With different scenarios of missing meteorological environmental variables, the BiLSTM model was used to estimate R2 > 0.98 for walnut crop evapotranspiration under different microirrigation techniques, with a range from 0.958 to 0. 986 under 3 g microirrigation technique, RMSEV ranged from 0.235 to 0.412 and RPDV ranged from 5.028 to 8.494. Under Hg microirrigation technique, R2 ranged from 0.942 to 0.979, RMSEV ranged from 0.288 to 0.477 and RPDV ranged from 4.253 to 6.905. Using the deep learning BiLSTM model, we can efficiently estimate the evapotranspiration of the walnut crop in arid zones with different micro-irrigation technologies. The evapotranspiration can provide a scientific theoretical reference for intelligent irrigation of walnut and agricultural water management.

Summary: Cervical cancer remains a significant health issue in developing countries. However, finding a preclinical model that accurately reproduces tumor characteristics is challenging. Therefore, we established a patient-derived organoids (PDOs) biobank containing 67 cases of heterogeneous cervical cancer that mimic the histopathological and genomic characteristics of parental tumors. The in vitro response of the organoids indicated their ability to capture the radiological heterogeneity of the patients. To model individual responses to adoptive T cell therapy (ACT), we expanded tumor-infiltrating lymphocytes (TILs) ex vivo and co-cultured them with paired organoids. The PDOs-TILs co-culture system demonstrates clear responses that correspond to established immunotherapy efficiency markers like the proportion of CTLs. This study supports the potential of the PDOs platform to guide treatment in prospective interventional trials in cervical cancer.