NR4A3 prevents diabetes induced atrial cardiomyopathy by maintaining mitochondrial energy metabolism and reducing oxidative stress.

BACKGROUND: Atrial cardiomyopathy (ACM) is responsible for atrial fibrillation (AF) and thromboembolic events. Diabetes mellitus (DM) is an important risk factor for ACM. However, the potential mechanism between ACM and DM remains elusive. METHODS: Atrial tissue samples were obtained from patients diagnosed with AF or sinus rhythm (SR) to assess alterations in NR4A3 expression, and then two distinct animal models were generated by subjecting Nr4a3-/- mice and WT mice to a high-fat diet (HFD) and Streptozotocin (STZ), while db/db mice were administered AAV9-Nr4a3 or AAV9-ctrl. Subsequently, in vivo and in vitro experiments were conducted to assess the impact of NR4A3 on diabetes-induced atrial remodeling through electrophysiological, biological, and histological analyses. RNA sequencing (RNA-seq) and metabolomics analysis were employed to unravel the downstream mechanisms. FINDINGS: The expression of NR4A3 was significantly decreased in atrial tissues of both AF patients and diabetic mice compared to their respective control groups. NR4A3 deficiency exacerbated atrial hypertrophy and atrial fibrosis, and increased susceptibility to pacing-induced AF. Conversely, overexpression of NR4A3 alleviated atrial structural remodeling and reduced AF induction rate. Mechanistically, we confirmed that NR4A3 improves mitochondrial energy metabolism and reduces oxidative stress injury by preserving the transcriptional expression of Sdha, thereby exerting a protective influence on atrial remodeling induced by diabetes. INTERPRETATION: Our data confirm that NR4A3 plays a protective role in atrial remodeling caused by diabetes, so it may be a new target for treating ACM. FUNDING: This study was supported by the major research program of National Natural Science Foundation of China (NSFC) No: 82370316 (to Q-S. W.), No. 81974041 (to Y-P. W.), and No. 82270447 (to Y-P. W.) and Fundation of Shanghai Hospital Development Center (No. SHDC2022CRD044 to Q-S. W.).

An Automatic Needle Puncture Path-Planning Method for Thermal Ablation of Lung Tumors.

Computed tomography (CT)-guided thermal ablation is an emerging treatment method for lung tumors. Ablation needle path planning in preoperative diagnosis is of critical importance. In this work, we proposed an automatic needle path-planning method for thermal lung tumor ablation. First, based on the improved cube mapping algorithm, binary classification was performed on the surface of the bounding box of the patient's CT image to obtain a feasible puncture area that satisfied all hard constraints. Then, for different clinical soft constraint conditions, corresponding grayscale constraint maps were generated, respectively, and the multi-objective optimization problem was solved by combining Pareto optimization and weighted product algorithms. Finally, several optimal puncture paths were planned within the feasible puncture area obtained for the clinicians to choose. The proposed method was evaluated with 18 tumors of varying sizes (482.79 mm3 to 9313.81 mm3) and the automatically planned paths were compared and evaluated with manually planned puncture paths by two clinicians. The results showed that over 82% of the paths (74 of 90) were considered reasonable, with clinician A finding the automated planning path superior in 7 of 18 cases, and clinician B in 9 cases. Additionally, the time efficiency of the algorithm (35 s) was much higher than that of manual planning. The proposed method is expected to aid clinicians in preoperative path planning for thermal ablation of lung tumors. By providing a valuable reference for the puncture path during preoperative diagnosis, it may reduce the clinicians' workload and enhance the objectivity and rationality of the planning process, which in turn improves the effectiveness of treatment.

Characteristics and Influence Factors of Natural Desorption in Coal Bodies from Fukang Mining Area, Xinjiang, China.

Coal body desorption characteristics are one of the key factors that influence the development of coalbed methane (CBM). In this study, 91 coal core samples from 11 CBM wells in the Fukang mining area were collected from Xinjiang, China, and the coal quality, high-pressure mercury compression, gas content, and natural desorption characteristics measurements were launched. With the detailed analyses of the differences in cumulative desorption volume, desorption ratio, and on-site average desorption rate for the coal samples with different body structures and macrolithotypes, the influence of the maximum reflectance of vitrinite, microscopic coal rock composition, and coal quality and pore characteristics on CBM desorption characteristics were discussed. The results showed that the cumulative desorption volume, desorption ratio, and desorption rate of cataclastic structure-bright coal are higher than those of primary structure-semibright coal. With the increase of RO,max and vitrinite content, the adsorption capacity of coal increases, and the increased methane concentration difference during desorption leads to an increase in cumulative desorption volume and on-site average desorption rate. The higher contents of moisture and ash yield would occupy the adsorption sites and hinder gas diffusion, which would decrease the desorption of coalbed methane. The greater porosity/pore volume ratio of medium and large pores can enhance the connectivity of pores, which increases the desorption ratio and the average desorption rate, while the higher micropore porosity/pore volume ratio can increase the gas adsorption space and the cumulative desorption volume. The pore characteristics have the most significant effect on the cumulative desorption volume and desorption ratio. The results of the study can help guide coal mine gas management and CBM development from middle-and low-rank coal reservoirs in Xinjiang.

A Novel Small Molecular Inhibitor of DNMT1 Enhances the Antitumor Effect of Radiofrequency Ablation in Lung Squamous Cell Carcinoma Cells.

Radiofrequency ablation (RFA) is a relatively new and effective therapeutic strategy for treating lung squamous cell carcinomas (LSCCs). However, RFA is rarely used in the clinic for LSCC which still suffers from a lack of effective comprehensive treatment strategies. In the present work, we investigate iDNMT, a novel small molecular inhibitor of DNMT1 with a unique structure. In clinical LSCC specimens, endogenous DNMT1 was positively associated with methylation rates of miR-27-3p's promoter. Moreover, endogenous DNMT1 was negatively correlated with miR-27-3p expression which targets PSEN-1, the catalytic subunit of γ-secretase, which mediates the cleavage and activation of the Notch pathway. We found that DNMT1 increased activation of the Notch pathway in clinical LSCC samples while downregulating miR-27-3p expression and hypermethylation of miR-27-3p's promoter. In addition of inhibiting activation of the Notch pathway by repressing methylation of the miR-27-3p promoter, treatment of LSCC cells with iDNMT1 also enhanced the sensitivity of LSCC tumor tissues to RFA treatment. These data suggest that iDNMT-induced inhibition of DNMT-1 enhances miR-27-3p expression in LSCC to inhibit activation of the Notch pathway. Furthermore, the combination of iDNMT and RFA may be a promising therapeutic strategy for LSCC.