Lysozyme 1 Inflamed CCR2+ Macrophages Promote Obesity-Induced Cardiac Dysfunction.

BACKGROUND: Macrophages are key players in obesity-associated cardiovascular diseases, which are marked by inflammatory and immune alterations. However, the pathophysiological mechanisms underlying macrophage's role in obesity-induced cardiac inflammation are incompletely understood. Our study aimed to identify the key macrophage population involved in obesity-induced cardiac dysfunction and investigate the molecular mechanism that contributes to the inflammatory response. METHODS AND RESULTS: Though analyzing in-depth cardiac macrophage clusters identified by single macrophage RNA-sequencing, we find that the Ccr2 cluster undergoes a functional transition from homeostatic maintenance to proinflammation. Our data highlight specific changes in macrophage behavior during cardiac dysfunction under metabolic challenge. Consistently, inducible ablation of CCR2+CX3CR1+ macrophages by a dual recombinase-based lineage-tracing approach or selective deletion of macrophage C-C chemokine receptor 2 (CCR2) prevents obesity-induced cardiac dysfunction. At the mechanistic level, we demonstrate that the obesity-induced functional shift of CCR2-expressing macrophages is mediated by the CCR2/ATF3/lysozyme 1/NF-κB (nuclear factor kappa B) signaling. Finally, we uncover a noncanonical role for lysozyme 1 as a transcription activator, binding to the RelA promoter, driving NF-κB signaling, and strongly promoting inflammation and cardiac dysfunction in obesity. CONCLUSIONS: Our findings suggest that lysozyme 1 may represent a potential target for the diagnosis of obesity-induced inflammation and the treatment of obesity-induced heart disease.

Long-term prognosis in patients with thymoma combined with myasthenia gravis: a propensity score-matching analysis.

Introduction: We aimed to assess the impact of myasthenia gravis (MG) on the long-term prognosis in patients with thymoma after surgery and identify related prognostic factors or predictors. Methods: This retrospective observational study included 509 patients with thymoma (thymoma combined with MG [MG group] and thymoma alone [non-MG group]). Propensity score matching was performed to obtain comparable subsets of 96 patients in each group. A comparative analysis was conducted on various parameters. Results: Before matching, the 10-year survival and recurrence-free survival rates in both groups were 93.8 and 98.4%, and 85.9 and 93.4%, respectively, with no statistically significant difference observed in the survival curves between the groups (p > 0.05). After propensity score matching, 96 matched pairs of patients from both groups were created. The 10-year survival and recurrence-free survival rates in these matched pairs were 96.9 and 97.7%, and 86.9 and 91.1%, respectively, with no statistical significance in the survival curves between the groups (p > 0.05). Univariate analysis of patients with thymoma postoperatively revealed that the World Health Organization histopathological classification, Masaoka-Koga stage, Tumor Node Metastasis stage, resection status, and postoperative adjuvant therapy were potentially associated with tumor recurrence after thymoma surgery. Multivariate analysis demonstrated that the Masaoka-Koga stage and postoperative adjuvant therapy independently predicted the risk of recurrence in patients with thymoma after surgery. Conclusion: There was no difference in prognosis in patients with thymoma with or without MG. The Masaoka-Koga stage has emerged as an independent prognostic factor affecting recurrence-free survival in patients with thymoma, while postoperative adjuvant therapy represents a poor prognostic factor.

Macrophage scavenger receptor-A1 promotes skeletal muscle regeneration after hindlimb ischemia.

Macrophages mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia. Thus, it's necessary to exploit macrophages based therapeutic targets for ischemic disease. Here, we found mRNA level of SR-A1 was elevated in patients with critical limb ischemia by analysis of gene expression omnibus (GEO) database. Then we investigated the role and the underlined mechanisms of macrophage SR-A1 in a mouse HLI model. Compared with the SR-A1 fl/fl mice, the Lyz Cre/+/SR-A1 flox/flox (SR-A1 ΔMΦ) mice showed significantly lower laser doppler blood flow in the ischemic limb at day 7 after HLI. Consistently, histological analysis exhibited that ischemic limb of SR-A1 ΔMΦ mice displayed more sever and sustained necrotic morphology, inflammation and fibrosis, decreased vessel density and regeneration rate, compared with which of control SR-A1 fl/fl mice. Furthermore, restoration of wild-type myeloid cells to SR-A1 knock-out mice effectively relieved the doppler perfusion in the ischemic limb and restrained skeletal muscle damage 7 days post HLI. In line with in vivo findings, when co-cultivating macrophages with the mouse myoblast line C2C12, SR-A1 -/- bone marrow macrophage significantly inhibited myoblast differentiation in vitro. Mechanically, SR-A1 enhanced skeletal muscle regeneration response to HLI by inhibiting the oncostatin M (OSM) production via suppressed NF-κB signaling activation. These results indicates that SR-A1 is a promising candidate molecule to improve tissue repair and regeneration in peripheral ischemic arterial disease.

Balanced Standing on One Foot of Biped Robot Based on Three-Particle Model Predictive Control.

Balancing is a fundamental task in the motion control of bipedal robots. Compared to two-foot balancing, one-foot balancing introduces new challenges, such as a smaller supporting polygon and control difficulty coming from the kinematic coupling between the center of mass (CoM) and the swinging leg. Although nonlinear model predictive control (NMPC) may solve this problem, it is not feasible to implement it on the actual robot because of its large amount of calculation. This paper proposes the three-particle model predictive control (TP-MPC) approach. It combines with the hierarchical whole-body control (WBC) to solve the one-leg balancing problem in real time. The bipedal robot's torso and two legs are modeled as three separate particles without inertia. The TP-MPC generates feasible swing leg trajectories, followed by the WBC to adjust the robot's center of mass. Since the three-particle model is linear, the TP-MPC requires less computational cost, which implies real-time execution on an actual robot. The proposed method is verified in simulation. Simulation results show that our method can resist much larger external disturbance than the WBC-only control scheme.

Tumor microenvironment features decipher the outperformance of neoadjuvant immunochemotherapy over chemotherapy in resectable non-small cell lung cancer.

This study evaluated the efficacy of neoadjuvant immunochemotherapy (Io+Chemo) versus chemotherapy alone (Chemo) in resectable non-small cell lung cancer (NSCLC) in a real-world setting. The association of tumor immune microenvironment (TIME) with pathologic response to different neoadjuvant therapies was also explored.Stage I-III NSCLC patients who received Io+Chemo or Chemo alone followed by surgery were included in the study. Tumor tissues collected during surgery were subjected to TIME evaluation using multiplex immunohistochemistry to measure immune cell subsets, including T cells, B cells, NK cells, and macrophages. Fifty-five patients were included, including 24 treated with neoadjuvant Io+Chemo and 31 with Chemo alone. Io+Chemo induced significantly higher major pathologic response (MPR) (75.0% vs. 38.7%, P = 0.0133) and numerically better pathologic complete response (pCR) (33.3% vs. 12.9%, P = 0.1013) than Chemo. Compared with tumors with Chemo, tumors with Io+Chemo demonstrated a significantly higher ratio of M1 macrophage density in the tumor to that in the stroma (P = 0.0446), more abundant CD8+ cells in the stroma (P = 0.0335), and fewer PD-L1+CD68+ cells in both tumor and stroma. pCR/MPR patients displayed significantly higher density of CD3+, CD3+CD4+, CD20+, CD56 bright cell subsets and more tertiary lymphoid structures and significantly lower density of PD-L1+CD68+ and CD3+CD4+Foxp3+cells in the tumor or stroma. This study favored neoadjuvant Io+Chemo over Chemo and revealed the TIME features underlying the outperformance of Io+Chemo over Chemo.

Epigenetic Alterations of DNA Methylation and miRNA Contribution to Lung Adenocarcinoma.

This study focused on the epigenetic alterations of DNA methylation and miRNAs for lung adenocarcinoma (LUAD) diagnosis and treatment using bioinformatics analyses. DNA methylation data and mRNA and miRNA expression microarray data were obtained from The Cancer Genome Atlas (TCGA) database. The differentially methylated genes (DMGs), differentially expressed genes (DEGs), and differentially expressed miRNAs were analyzed by using the limma package. The DAVID database performed GO and KEGG pathway enrichment analyses. Using STRING and Cytoscape, we constructed the protein-protein interaction (PPI) network and achieved visualization. The online analysis tool CMap was used to identify potential small-molecule drugs for LUAD. In LUAD, 607 high miRNA-targeting downregulated genes and 925 low miRNA-targeting upregulated genes, as well as 284 hypermethylated low-expression genes and 315 hypomethylated high-expression genes, were obtained. They were mainly enriched in terms of pathways in cancer, neuroactive ligand-receptor interaction, cAMP signaling pathway, and cytosolic DNA-sensing pathway. In addition, 40 upregulated and 84 downregulated genes were regulated by both aberrant alternations of DNA methylation and miRNAs. Five small-molecule drugs were identified as a potential treatment for LUAD, and five hub genes (SLC2A1, PAX6, LEP, KLF4, and FGF10) were found in PPI, and two of them (SLC2A1 and KLF4) may be related to the prognosis of LUAD. In summary, our study identified a series of differentially expressed genes associated with epigenetic alterations of DNA methylation and miRNA in LUAD. Five small-molecule drugs and five hub genes may be promising drugs and targets for LUAD treatment.