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Abstract Premature infants are often exposed to hyperoxia. However, there is limited data regarding the mechanistic underpinnings linking neonatal hyperoxia exposure and its contribution to cardio-renal dysfunction in adults born preterm. Our objective was to determine whether neonatal hyperoxia induces systemic vascular stiffness and cardio-renal dysfunction in adulthood. Newborn rats were randomly assigned to room air (RA) or hyperoxia (85% O2) from postnatal day 1 to 14, then recovered in RA until 1 year of life. Arterial stiffness, cardio-renal histomorphometry, and fibrosis in the aorta, heart, and kidney were assessed. RNA-sequencing (RNA-seq) of the aorta and kidney was also done. Adult rats exposed to neonatal hyperoxia had increased aortic and mesenteric artery stiffness as demonstrated by wire and pressure myography. They also had cardiomyocyte hypertrophy, glomerulomegaly, and tubular injury. Hyperoxia exposure altered the transcriptome profile associated with fibrosis and matrix remodeling in the aorta and kidney. There was also increased TGF-β1 levels and fibrosis in the aorta, left ventricle, and kidney. In conclusion, neonatal hyperoxia exposure was associated with systemic vascular and cardio-renal alterations in 1-year-old rats. Further studies to determine how targeted therapies could reprogram cardio-renal injury after neonatal hyperoxia exposure are indicated.

Abstract It is important to ensure the nutritional quality and safe production of rice. Here, plot experiments were used to analyze the effects of three soil amendments—10 t ha−1 of biochar (BC), 1.5 t ha−1 of lime (LM), and 2.25 t ha−1 of silicon–calcium fertilizer (SC)—on the soil characteristics, rice yield and quality of double-cropping rice grown in mildly cadmium-polluted paddy fields. Compared with the control treatment (CK), the BC and SC treatments significantly improved rice processing, appearance and nutritional quality, but reduced cooking quality. All three soil amendments significantly reduced cadmium (Cd) content in brown rice. Soil amendments could significantly increase soil pH and reduce soil available Cd content. The application of the BC and SC treatments increased the content of each nutrient index in the soil (SOM, NN, AP, AK). Correlation analysis showed that the improvement in rice processing, appearance, and nutritional quality was mainly affected by the comprehensive effects of soil SOM, NN, AP and AK; the hygiene quality was mainly affected by soil pH and available Cd. In terms of benefit analysis combined with cost, the SC treatment had the highest benefit effect. Taken together, in mildly cadmium-polluted paddy fields, the application of silicon–calcium fertilizer improved the soil quality, thereby increased the yield and quality of rice, and had the best effect on increasing income.

Abstract Cuproptosis and disulfidptosis, recently discovered mechanisms of cell death, have demonstrated that differential expression of key genes and long non-coding RNAs (lncRNAs) profoundly influences tumor development and affects their drug sensitivity. Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, presently lacks research utilizing cuproptosis and disulfidptosis-related lncRNAs (CDRLRs) as prognostic markers. In this study, we analyzed RNA-seq data, clinical information, and mutation data from The Cancer Genome Atlas (TCGA) on ccRCC and cross-referenced it with known cuproptosis and disulfidptosis-related genes (CDRGs). Using the LASSO machine learning algorithm, we identified four CDRLRs—ACVR2B-AS1, AC095055.1, AL161782.1, and MANEA-DT—that are strongly associated with prognosis and used them to construct a prognostic risk model. To verify the model's reliability and validate these four CDRLRs as significant prognostic factors, we performed dataset grouping validation, followed by RT-qPCR and external database validation for differential expression and prognosis of CDRLRs in ccRCC. Gene function and pathway analysis were conducted using Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) for high- and low-risk groups. Additionally, we have analyzed the tumor mutation burden (TMB) and the immune microenvironment (TME), employing the oncoPredict and Immunophenoscore (IPS) algorithms to assess the sensitivity of diverse risk categories to targeted therapeutics and immunosuppressants. Our predominant objective is to refine prognostic predictions for patients with ccRCC and inform treatment decisions by conducting an exhaustive study on cuproptosis and disulfidptosis.

Abstract The upper lip bite test (ULBT) is considered an effective method for predicting difficult airways, but data on the ULBT for predicting difficult tracheal intubation are lacking. This study aimed to examine the clinical utility of the ULBT in predicting difficult endotracheal intubation. We conducted an observational case-cohort study of adult patients undergoing elective surgery and requiring endotracheal intubation for general anesthesia. Difficult airway assessment was performed on the recruited patients before the operation, including the ULBT, mouth opening, thyromental distance, modified Mallampati test, and body mass index. The primary outcome was the incidence of difficult tracheal intubation. The receiver operating characteristic curve analysis was used to compare the performance of variables in predicting difficult tracheal intubation. We successfully recruited 2522 patients for analysis and observed 64 patients with difficult tracheal intubation. When predicting difficult tracheal intubation, grade 2 ULBT had a sensitivity of 0.75 and a specificity of 0.54, and grade 3 had a sensitivity of 0.28 and a specificity of 0.75. Compared with mouth opening, the area under the receiver operating characteristic curve of the ULBT was lower in predicting difficult tracheal intubation (0.69 [95% confidence interval: 0.67–0.71] vs. 0.84 [95% confidence interval: 0.82–0.87], P

Abstract Epidermal growth factor receptor‐targeted (EGFR‐targeted) therapies show promise for non‐small cell lung cancer (NSCLC), but they are ineffective in a third of patients who lack EGFR mutations. This underlines the need for personalized treatments for patients with EGFR wild‐type NSCLC. A genome‐wide CRISPR/Cas9 screen has identified the enzyme phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), which is vital in de novo purine biosynthesis and tumor development, as a potential drug target for EGFR wild‐type NSCLC. We have further confirmed that PAICS expression is significantly increased in NSCLC tissues and correlates with poor patient prognosis. Knockdown of PAICS resulted in a marked reduction in both in vitro and in vivo proliferation of EGFR wild‐type NSCLC cells. Additionally, PAICS silencing led to cell‐cycle arrest in these cells, with genes involved in the cell cycle pathway being differentially expressed. Consistently, an increase in cell proliferation ability and colony number was observed in cells with upregulated PAICS in EGFR wild‐type NSCLC. PAICS silencing also caused DNA damage and cell‐cycle arrest by interacting with DNA repair genes. Moreover, decreased IMPDH2 activity and activated PI3K–AKT signaling were observed in NSCLC cells with EGFR mutations, which may compromise the effectiveness of PAICS knockdown. Therefore, PAICS plays an oncogenic role in EGFR wild‐type NSCLC and represents a potential therapeutic target for this disease.

Abstract Neonatal hyperoxia induces long-term systemic vascular stiffness and cardiovascular remodeling, but the mechanisms are unclear. Chemokine receptor 7 (CXCR7) represents a key regulator of vascular homeostasis and repair by modulating TGF-β1 signaling. This study investigated whether pharmacological CXCR7 agonism prevents neonatal hyperoxia-induced systemic vascular stiffness and cardiac dysfunction in juvenile rats. Newborn Sprague Dawley rat pups assigned to room air or hyperoxia (85% oxygen), received CXCR7 agonist, TC14012 or placebo for 3 weeks. These rat pups were maintained in room air until 6 weeks when aortic pulse wave velocity doppler, cardiac echocardiography, aortic and left ventricular (LV) fibrosis were assessed. Neonatal hyperoxia induced systemic vascular stiffness and cardiac dysfunction in 6-week-old rats. This was associated with decreased aortic and LV CXCR7 expression. Early treatment with TC14012, partially protected against neonatal hyperoxia-induced systemic vascular stiffness and improved LV dysfunction and fibrosis in juvenile rats by decreasing TGF-β1 expression. In vitro, hyperoxia-exposed human umbilical arterial endothelial cells and coronary artery endothelial cells had increased TGF-β1 levels. However, treatment with TC14012 significantly reduced the TGF-β1 levels. These results suggest that dysregulation of endothelial CXCR7 signaling may contribute to neonatal hyperoxia-induced systemic vascular stiffness and cardiac dysfunction.

Abstract Hypertension is the most prevalent chronic disease World-wide, and the leading preventable risk factor for cardiovascular disease (CVD). Few patients accomplish the objective of decreasing blood pressure and avoiding hypertensive target organ damage after treatments with antihypertensive agents which opens the door for other treatments, such as herbal-and antihypertensive combination therapy. Captopril (CAP), as a-pril which inhibits angiotensin converting enzyme has long been used in the management of hypertension and CVD. Gedan Jiangya Decoction (GJD) is known for antihypertensive effects in prior studies. The research is aimed to determine whether GJD in combination with captopril has antihypertensive, kidney protective, antioxidant, and vasoactive effects in spontaneously hypertensive rats (SHR). Regular measurements of systolic and diastolic blood pressure (SBP and DBP), and body weight were monitored weekly. H&E staining was utilized to examine histopathology. The combined effects were studied using ELISA, immunohistochemistry, and qRT-PCR. Significant reductions in SBP, DBP, aortic wall thickness, and improvement in renal tissue were observed following GJD + CAP treatment, with increased serum levels of NO, SOD, GSH-Px, and CAT and decreases in Ang II, ET-1, and MDA. Similarly, GJD + CAP treatment of SHR's significantly decreased ET-1 and AGTR1 mRNA and protein expression while increasing eNOS mRNA and protein expression in thoracic aorta and kidney tissue. In conclusion, the present investigation found that GJD + CAP treatment decreases SHR blood pressure, improves aorta remodeling and renal protection, and that this effect could be attributable, in part, due to antioxidant and vascular tone improvement.

Abstract Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is currently the standard first-line therapy for EGFR-mutated advanced non-small cell lung cancer (NSCLC). The life quality and survival of this subgroup of patients were constantly improving owing to the continuous iteration and optimization of EGFR-TKI. Osimertinib, an oral, third-generation, irreversible EGFR-TKI, was initially approved for the treatment of NSCLC patients carrying EGFR T790M mutations, and has currently become the dominant first-line targeted therapy for most EGFR mutant lung cancer. Unfortunately, resistance to osimertinib inevitably develops during the treatment and therefore limits its long-term effectiveness. For both fundamental and clinical researchers, it stands for a major challenge to reveal the mechanism, and a dire need to develop novel therapeutics to overcome the resistance. In this article, we focus on the acquired resistance to osimertinib caused by EGFR mutations which account for approximately 1/3 of all reported resistance mechanisms. We also review the proposed therapeutic strategies for each type of mutation conferring resistance to osimertinib and give an outlook to the development of the next generation EGFR inhibitors. Video Abstract

Abstract Bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) are among the most common morbidities affecting extremely premature infants who receive oxygen therapy. Many clinical studies indicate that BPD is associated with advanced ROP. However, the mechanistic link between hyperoxia, BPD, and ROP remains to be explored. Gasdermin D (GSDMD) is a key executor of inflammasome-induced pyroptosis and inflammation. Inhibition of GSDMD has been shown to attenuate hyperoxia-induced BPD and brain injury in neonatal mice. The objective of this study was to further define the mechanistic roles of GSDMD in the pathogenesis of hyperoxia-induced BPD and ROP in mouse models. Here we show that global GSDMD knockout (GSDMD-KO) protects against hyperoxia-induced BPD by reducing macrophage infiltration, improving alveolarization and vascular development, and decreasing cell death. In addition, GSDMD deficiency prevented hyperoxia-induced ROP by reducing vasoobliteration and neovascularization, improving thinning of multiple retinal tissue layers, and decreasing microglial activation. RNA sequencing analyses of lungs and retinas showed that similar genes, including those from inflammatory, cell death, tissue remodeling, and tissue and vascular developmental signaling pathways, were induced by hyperoxia and impacted by GSDMD-KO in both models. These data highlight the importance of GSDMD in the pathogenesis of BPD and ROP and suggest that targeting GSDMD may be beneficial in preventing and treating BPD and ROP in premature infants.

Abstract Traditional calibration technology has been widely used in measurement and monitoring; however, there are limitations of poor calibration accuracy, which can not meet the accuracy requirements in some scenarios. About this problem, we proposed a grey wolf optimization algorithm based on levy flight and mutation mechanism to solve camera internal parameters in this paper. The algorithm is based on the actual nonlinear model, which takes the minimum average value of reprojection error as the objective function. The grey wolf position is randomly generated within a given range. Then, the grey wolf optimization algorithm based on levy flight and mutation mechanism is used to iteratively calculate the optimal position, which is the internal parameters of cameras. The two groups of experimental data were performed to verify the algorithm. The result shows better effectiveness and calibration accuracy of the proposed algorithm compared with other optimization methods.

Abstract Hyperoxia-induced lung injury plays a key role in the development of bronchopulmonary dysplasia (BPD), characterized by inflammatory injury and impaired lung development in preterm infants. Although BPD is a predictor of poor neurodevelopmental outcomes, currently it is uncertain how lung injury contributes to brain injury in preterm infants. Extracellular vesicles (EVs) are a heterogeneous group of cell-derived membranous structures that regulate intercellular and inter-organ communications. Gasdermin D (GSDMD) has emerged as a key executor of inflammasome-mediated cell death and inflammation. In this study, we utilized a neonatal rat model of BPD to assess if hyperoxia stimulates lung release of circulating EVs and if these EVs induce lung and brain injury. We found that hyperoxia-exposed rats had elevated numbers of plasma-derived EVs compared to rats maintained in room air. These EVs also had increased cargos of surfactant protein C, a marker of type II alveolar epithelial cells (AEC), and the active (p30) form of GSDMD. When these EVs were adoptively transferred into normal newborn rats via intravenous injection, they were taken up both by lung and brain tissues. Moreover, EVs from hyperoxic animals induced not only the pathological hallmarks of BPD, but also brain inflammatory injury in recipient rats, as well as inducing cell death in cultured pulmonary vascular endothelial cells and neural stem cells (NSC). Similarly, hyperoxia-exposed cultured AEC-like cells released EVs that also contained increased GSDMD-p30 and these EVs induced pyroptotic cell death in NSC. Overall, these data indicate that hyperoxia-activated circulating EVs mediate a lung to brain crosstalk resulting in brain injury and suggest a mechanism that links lung injury and neurodevelopmental impairment in BPD infants.

Salmon calcitonin has chondroprotective effect both in vitro and in vivo, and is therefore being tested as a candidate drug for cartilage degenerative diseases. Recent studies have indicated that different chondrocyte phenotypes may express the calcitonin receptor (CTR) differentially. We tested for the presence of the CTR in chondrocytes from tri-iodothyronin (T3)-induced bovine articular cartilage explants. Moreover, investigated the effects of human and salmon calcitonin on the explants.Early chondrocyte hypertrophy was induced in bovine articular cartilage explants by stimulation over four days with 20 ng/mL T3. The degree of hypertrophy was investigated by molecular markers of hypertrophy (ALP, IHH, COLX and MMP13), by biochemical markers of cartilage turnover (C2M, P2NP and AGNxII) and histology. The expression of the CTR was detected by qPCR and immunohistochemistry. T3-induced explants were treated with salmon or human calcitonin. Calcitonin down-stream signaling was measured by levels of cAMP, and by the molecular markers.Compared with untreated control explants, T3 induction increased expression of the hypertrophic markers (p