Aim Bronchopulmonary dysplasia (BPD) remains a major cause of chronic lung disease following preterm birth. We aimed to establish a normobaric hyperoxia-induced preterm pig model that reflects respiratory and cardiovascular consequences of BPD. Methods Preterm piglets (n=18) were delivered by caesarean section at gestational day 106 and exposed either to sustained hyperoxia (85% O₂) or ambient air for 94 hours. Data on echocardiography, pulmonary arterial pressure, and detailed lung and heart histopathology were collected. Results There was clear structural lung injury in hyperoxia-exposed piglets, with increased septal thickness, reduced alveolar density, higher mean linear intercepts and more alveolar necrosis (all p<0.05). Echocardiography revealed a higher prevalence of persistent ductus arteriosus (55.6% in BPD vs. 12.5% in controls; p=0.091). Histology showed right ventricular cardiomyocyte hyperplasia and hypertrophy in hyperoxia-exposed pigs, yet pulmonary arterial pressure was unaffected. Conclusion The preterm pig model recapitulates key physiological and structural hallmarks of “new BPD” and the broader chronic lung disease of prematurity. This model represents a promising platform for investigating mechanisms and interventions in preterm infants at risk of BPD.
Peripheral nerve injury caused by cut, crush, or excessive stretch can lead to disordered regeneration and painful neuroma formation. Regrowing axons may terminate in a swollen, hypersensitive nerve stump, producing pain that can outweigh sensory or motor deficits. Despite the frequency of neuromas, treatment outcomes remain inconsistent, and the mechanisms that initiate and sustain neuroma-associated pain are poorly understood. A proximal nerve crush performed upstream of a neuroma or transection may reshape axonal growth and interrupt retrograde injury signaling, potentially promoting a regenerative, pain-resolving state. However, its long-term effects on dorsal root ganglion (DRG) programs remain unclear. Here, we use single-cell RNA sequencing to build an atlas of DRG remodeling after neuroma-forming injury and compare it with two interventions: proximal nerve crush and nerve resection. By resolving transcriptional responses across sensory neurons, satellite glial cells, Schwann cells, and macrophages, we identify intervention-specific glial, neuronal, and immune programs that distinguish regenerative from persistent injury-associated states and nominate pathways that may guide mechanism-based therapies for painful neuromas.
Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome in which translational progress is limited by experimental models that insufficiently reflect the cardiometabolic phenotype while affecting endogenous endothelial function. We aimed to characterize a cardiometabolic “two-hit” HFpEF model combining metabolic stress (db/db) with chronic mineralocorticoid excess (d-aldosterone), focusing on integrated cardiac, vascular, and pulmonary phenotyping. Methods: Female db/db mice received 4-week d-aldosterone (0.3 µg/h) or vehicle via osmotic minipumps. Metabolic profiling, high-resolution echocardiography including strain and left atrial mechanics, invasive right-heart catheterization, and thoracic aortic wire myography were performed. Results: Aldosterone-treated db/db mice developed cardiac hypertrophy and pulmonary congestion with preserved LVEF but marked diastolic dysfunction, left atrial remodeling with increased stiffness, and impaired global longitudinal LV strain. Pulmonary hypertension with right ventricular dysfunction was evidenced by elevated RVSP/estimated mPAP, reduced PAT/PET, and reduced TAPSE. Thoracic aortae from untreated db/db mice already showed impaired endothelium-dependent relaxation, which was further aggravated by aldosterone, whereas maximal endothelium-independent relaxation remained largely preserved. Conclusions: The db/db+d-aldosterone model recapitulates key features of cardiometabolic HFpEF across the cardiac-vascular-pulmonary axis and provides a translational platform for mechanistic and therapeutic studies targeting endothelial and ventricular-vascular dysfunction in HFpEF. New & Noteworthy: Current HFpEF animal models often limit the investigation of vascular dysfunction, a central component of cardiometabolic HFpEF. We provide a comprehensive functional characterization of a db/db+d-aldosterone two-hit model demonstrating obesity, diabetes, diastolic dysfunction, atrial remodeling, endothelial dysfunction, pulmonary hypertension, and right ventricular impairment. By preserving endogenous endothelial nitric oxide signaling, this model offers a translational platform for studying vascular and cardiopulmonary mechanisms in cardiometabolic HFpEF.
The temporomandibular joint (TMJ) and knee joint are both prone to degenerative diseases such as osteoarthritis (OA); however, TMJ-OA generally manifests earlier than knee OA, with underlying mechanisms largely unknown. In this study, we explored potential explanations through comprehensive biological and biomechanical analyses in mice. Structurally, the mandibular condylar cartilage (MCC) exhibits prominent differences from tibial articular cartilage (AC) at occlusion establishment, evidenced by distinct extracellular matrix organization and enriched transcription factor expression toward the posterior TMJ. Both jaw and knee cartilage house progenitor-like, slow-cycling cells at the cartilage surface, but these cells are depleted more rapidly in the MCC, associated with faster tissue turnover and cellular replenishment. Biomechanically, the MCC exhibits a lower elastic modulus (EIT) than the tibial AC. This biomechanical feature is correlated with its unique extracellular matrix composition to support the force-bearing jaw movement at the anterior TMJ, while providing cushioning and compliance to protect a putative stem/progenitor cell niche at the posterior TMJ. Together, these findings highlight fundamental biological and biomechanical distinctions between jaw and knee cartilage that may underlie their different susceptibility to degeneration.
Amyotrophic lateral sclerosis (ALS) is a multi-system disease in which skeletal muscle actively contributes to pathology, yet the regulatory circuits that drive muscle dysfunction remain unclear. We examined microRNA (miRNA)-messenger RNA (mRNA) interactions in the gastrocnemius of hSOD1G93A mice across presymptomatic, early- and late-symptomatic stages, using RNA-seq, bioinformatics, and RT-qPCR. Compared with hSOD1WT and non-transgenic controls, hSOD1G93A muscle showed mutation-specific transcriptome reprogramming: 48 dysregulated miRNAs and 558 mRNAs at presymptomatic, and 64 miRNAs and 685 mRNAs at late-symptomatic stages. Functional enrichment pinpointed carbohydrate-handling pathways (glycolysis/gluconeogenesis, pentose-phosphate, fructose-mannose metabolism) as the dominant downregulated gene sets. Network analysis revealed clusters in which upregulated miRNAs converged on, and showed inverse expression patterns relative to metabolic transcripts. RT-qPCR confirmed inverse expression of 10 candidate miRNAs and 11 metabolic mRNAs, substantiating miRNA-guided repression of glycolytic enzymes and energy-sensing nodes. Collectively, we show that SOD1G93A drives an early, sustained miRNA signature that dampens glycolysis gene expression, which could promote the fast-to-slow fibre-type transition and exacerbate energy deficit in ALS muscle. Targeting these circuits offers a strategy to restore metabolic balance and slow disease progression.
