Disrupted individual-level morphological brain network in spinal muscular atrophy types 2 and 3.

BACKGROUND AND OBJECTIVE: Spinal muscular atrophy (SMA) is one of the most common monogenic neuromuscular diseases, and the pathogenesis mechanisms, especially the brain network topological properties, remain unknown. This study aimed to use individual-level morphological brain network analysis to explore the brain neural network mechanisms in SMA. METHODS: Individual-level gray matter (GM) networks were constructed by estimating the interregional similarity of GM volume distribution using both Kullback-Leibler divergence-based similarity (KLDs) and Jesen-Shannon divergence-based similarity (JSDs) measurements based on Automated Anatomical Labeling 116 and Hammersmith 83 atlases for 38 individuals with SMA types 2 and 3 and 38 age- and sex-matched healthy controls (HCs). The topological properties were analyzed by the graph theory approach and compared between groups by a nonparametric permutation test. Additionally, correlation analysis was used to assess the associations between altered topological metrics and clinical characteristics. RESULTS: Compared with HCs, although global network topology remained preserved in individuals with SMA, brain regions with altered nodal properties mainly involved the right olfactory gyrus, right insula, bilateral parahippocampal gyrus, right amygdala, right thalamus, left superior temporal gyrus, left cerebellar lobule IV-V, bilateral cerebellar lobule VI, right cerebellar lobule VII, and vermis VII and IX. Further correlation analysis showed that the nodal degree of the right cerebellar lobule VII was positively correlated with the disease duration, and the right amygdala was negatively correlated with the Hammersmith Functional Motor Scale Expanded (HFMSE) scores. CONCLUSIONS: Our findings demonstrated that topological reorganization may prioritize global properties over nodal properties, and disrupted topological properties in the cortical-limbic-cerebellum circuit in SMA may help to further understand the network pathogenesis underlying SMA.

Altered expression of eNOS, prostacyclin synthase, prostaglandin G/H synthase, and thromboxane synthase in porcine aortic endothelial cells after exposure to human serum-relevance to xenotransplantation.

Under normal conditions, the activity of platelets is stringently and precisely balanced between activation and quiescent state. This guarantees rapid hemostasis and avoids uncontrolled thrombosis. However, excessive platelet activation and resulting thrombotic microangiopathy are frequently observed in pig-to-primate xenotransplantation models. Endothelium-derived inhibitory mechanisms play an important role in regulation of platelet activation. These mainly include nitric oxide (NO), prostacyclin PGI2 , and adenosine, which are synthesized by endothelial NO synthases (eNOS), prostacyclin synthase, and CD39/CD73, respectively. We investigated whether endothelium-derived regulatory mechanisms are affected in porcine aortic endothelial cells (PAECs) after exposure to human serum. In the present study, exposure of PAECs or porcine iliac arteries to human serum suppressed gene expression of eNOS and prostacyclin synthase, while induced gene expression of prostaglandin G/H synthase and thromboxane synthase. Simultaneously, exposure to human serum reduced NO and PGI2 production in PAEC culture supernatants. Thus, human serum altered the balance of endothelium-derived inhibitory mechanisms in PAECs, which may indicate a regulatory mechanism of excessive platelet activation in pig-to-primate xenotransplantation.