Identification and Validation of Immune Implication of R-Spondin 1 and an R-Spondin 1-Related Prognostic Signature in Esophagus Cancer.

R-spondin 1 (RSPO1), which encodes a secretory-activating protein, is a promising therapeutic target for various tumors. The aim of this study was to establish a robust RSPO1-related signature specific to esophageal cancer (ESCA). Our comprehensive study involved meticulous analysis of RSPO1 expression in ESCA tissues and validation across ESCA cell lines and clinical samples using The Cancer Genome Atlas (TCGA) and GTEx databases. Using TCGA-ESCA dataset, we employed single-sample gene set enrichment analysis (ssGSEA) to elucidate the complex interaction between RSPO1 expression and the abundance of 22 specific immune cell types infiltrating ESCA. The biological significance of RSPO1 was further elucidated using KEGG, GO, and GSEA, demonstrating its relevance to pivotal tumor and immune pathways. This study culminated in the construction of prognostic nomograms enriched by calibration curves, facilitating the projection of individual survival probabilities at intervals of one, three, and five years. A substantial decrease in RSPO1 expression was observed within ESCA tissues and cell lines compared to their normal esophageal counterparts, and a significant decrease in the proportion of activated dendritic cells was evident within ESCA, accompanied by an augmented presence of macrophages and naive B cells relative to normal tissue. GSEA and KEGG analyses showed that RSPO1 was associated with tumor and immune pathways. Additionally, an independent prognostic risk score based on the RSPO1-related gene signature was developed and validated for patients with ESCA. Finally, RT-qPCR and western blotting were performed to confirm RSPO1 expression in normal and ESCA cell lines and tissue samples. In summary, our investigation underscores the pivotal role of RSPO1 in orchestrating tumor immunity and proposes RSPO1 as a prospective target for immunotherapeutic interventions in ESCA. Furthermore, the intricate profile of the two RSPO1-related genes has emerged as a promising predictive biomarker with notable potential for application in ESCA.

Mineralocorticoid promotes intestinal inflammation through receptor dependent IL17 production in ILC3s.

Aldosterone is a key mineralocorticoid involved in regulating the concentration of blood electrolytes and physiological volume balance. Activation of mineralocorticoid receptor (MR) has been recently reported to participate in adaptive and innate immune responses under inflammation. Here, we evaluated the role of aldosterone and MR in inflammation bowel diseases (IBD). Aldosterone elevated in the colon of DSS-induced colitis mice. Aldosterone addition induced IL17 production and ROS/RNS level in group 3 innate lymphoid cells (ILC3s) and exacerbated intestinal injury. A selective mineralocorticoid receptor antagonism, eplerenone, inhibited IL17-producing ILC3s and its ROS/RNS production, protected mice from DSS-induced colitis. Mice lacking Nr3c2 (MR coding gene) in ILC3s exhibited decreased IL17 and ROS/RNS production, which alleviated colitis and colitis-associated colorectal cancer (CAC). Further experiments revealed that MR could directly bind to IL17A promoter and facilitate its transcription, which could be enhanced by aldosterone. Thus, our findings demonstrated the critical role of aldosterone-MR-IL17 signaling in ILC3s and gut homeostasis, indicating the therapeutic strategy of eplerenone in IBD clinical trial.

Study on the poroelastic behaviors of the defected osteochondral unit.

Osteoarthritis has become a major disease threatening human health. The mechanism of injury under fluid involvement can be studied by finite element method. However, most models only model the articular cartilage to study the subchondral bone structure, which is too simplistic. In this study, a complete osteochondral unit was modeled and provided with a poroelastic material, and as osteoarthritis develops and the size, thickness, and shape of the osteochondral unit defect varies, the fluid flow behavior is altered, which may have functional consequences that feed back into the progression of the injury. The results of the study showed that interstitial fluid pressure and velocity decreased in defective osteochondral units. This trend was exacerbated as the size and thickness of the defect in the osteochondral unit increased. When the defect reached the trabeculae, pressure around the cartilage defect in the osteochondral unit was greatest, flow velocity in the subchondral cortical bone was greatest, and pressure and flow velocity around the trabecular defect were lowest. As osteoarthritis develops, the osteochondral unit becomes more permeable, and the pressure of the interstitial fluid decreases while the flow rate increases, resulting in severe nutrient loss. This may be the fluid flow mechanism behind osteochondral defects and osteoarthritis.

Single-cell RNA-seq of heart reveals intercellular communication drivers of myocardial fibrosis in diabetic cardiomyopathy.

Myocardial fibrosis is the characteristic pathology of diabetes-induced cardiomyopathy. Therefore, an in-depth study of cardiac heterogeneity and cell-to-cell interactions can help elucidate the pathogenesis of diabetic myocardial fibrosis and identify treatment targets for the treatment of this disease. In this study, we investigated intercellular communication drivers of myocardial fibrosis in mouse heart with high-fat-diet/streptozotocin-induced diabetes at single-cell resolution. Intercellular and protein-protein interaction networks of fibroblasts and macrophages, endothelial cells, as well as fibroblasts and epicardial cells revealed critical changes in ligand-receptor interactions such as Pdgf(s)-Pdgfra and Efemp1-Egfr, which promote the development of a profibrotic microenvironment during the progression of and confirmed that the specific inhibition of the Pdgfra axis could significantly improve diabetic myocardial fibrosis. We also identified phenotypically distinct Hrchi and Postnhi fibroblast subpopulations associated with pathological extracellular matrix remodeling, of which the Hrchi fibroblasts were found to be the most profibrogenic under diabetic conditions. Finally, we validated the role of the Itgb1 hub gene-mediated intercellular communication drivers of diabetic myocardial fibrosis in Hrchi fibroblasts, and confirmed the results through AAV9-mediated Itgb1 knockdown in the heart of diabetic mice. In summary, cardiac cell mapping provides novel insights into intercellular communication drivers involved in pathological extracellular matrix remodeling during diabetic myocardial fibrosis.

Biomechanical evaluation and optimal design of a pedicle screw with double bent rods internal fixation system based on PE-PLIF fusion.

Problems, such as broken screws, broken rods, and cage subsidence after clinical spinal fusion surgery affect the success rate of fusion surgery and the fixation effect of fusion segments, and these problems still affect the treatment and postoperative recovery of patients. In this study, we used the biomechanical finite element analysis method to analyze and study the fixation effect of three kinds of spinal internal fixation systems on L4-L5 lumbar spine segments in percutaneous endoscopic posterior lumbar interbody fusion (PE-PLIF). The three different fixation systems compared in this study include bilateral pedicle screw fixation (M1); bilateral pedicle screw with cross-link fixation (M2); bilateral pedicle screws with double bent rods fixation (M3). The internal fixation systems with different structures were analyzed with the help of Hypermesh, and Abaqus. It was found that the internal fixation system with double bent rods reduced screw stresses by 23.8 and 22.2% in right and left axial rotation than the traditional bilateral pedicle screw system, while titanium rod stresses were reduced by 9.6, 3.7, 9.6, and 2.9% in flexion, left and right lateral bending, and right axial rotation, respectively, and L5 upper endplate stresses were reduced by 35.5, 18.9, 38.4, 10.2, and 48.3% in flexion, left and right lateral bending, and left and right axial rotation, respectively. The spinal range of motion (ROM) of the M3 internal fixation system was less than that of the M1 and M2 internal fixation systems in left lateral bending, left lateral rotation, and right axial rotation, and the intact vertebral ROM was reduced by 93.7, 94.9, and 90.9%, respectively. The double bent rod structure of the spinal internal fixation system has better biomechanical properties, which can effectively reduce the risk of screw breakage, loosening, cage subsidence, and endplate collapse after fusion surgery.