Muscleblind-like 2 knockout shifts adducin 1 isoform expression and alters dendritic spine dynamics of cortical neurons during brain development.

AIMS: Muscleblind-like 2 (MBNL2) plays a crucial role in regulating alternative splicing during development and mouse loss of MBNL2 recapitulates brain phenotypes in myotonic dystrophy (DM). However, the mechanisms underlying DM neuropathogenesis during brain development remain unclear. In this study, we aim to investigate the impact of MBNL2 elimination on neuronal development by Mbnl2 conditional knockout (CKO) mouse models. METHODS: To create Mbnl2 knockout neurons, cDNA encoding Cre-recombinase was delivered into neural progenitors of Mbnl2flox/flox mouse brains by in utero electroporation. The morphologies and dynamics of dendritic spines were monitored by confocal and two-photon microscopy in brain slices and live animals from the neonatal period into adulthood. To investigate the underlying molecular mechanism, we further detected the changes in the splicing and molecular interactions of proteins associated with spinogenesis. RESULTS: We found that Mbnl2 knockout in cortical neurons decreased dendritic spine density and dynamics in adolescent mice. Mbnl2 ablation caused the adducin 1 (ADD1) isoform to switch from adult to fetal with a frameshift, and the truncated ADD1 failed to interact with alpha-II spectrin (SPTAN1), a critical protein for spinogenesis. In addition, expression of ADD1 adult isoform compensated for the reduced dendritic spine density in cortical neurons deprived of MBNL2. CONCLUSION: MBNL2 plays a critical role in maintaining the dynamics and homeostasis of dendritic spines in the developing brain. Mis-splicing of downstream ADD1 may account for the alterations and contribute to the DM brain pathogenesis.

Differential prognoses among male and female patients with hepatocellular carcinoma.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) is significantly higher in men than women. Nonetheless, the impact of sex disparities on HCC outcomes remains unclear. We aimed to compare the clinical manifestations and prognoses between male and female patients with HCC. METHODS: This retrospective study enrolled 5337 consecutive patients (3976 men, 1361 women) who were diagnosed with HCC from 2007 to 2020. The prognostic factors were identified by the Cox proportional hazards model. RESULTS: Male patients were younger upon HCC diagnosis (median age 64 vs 69 years; p < 0.001) with more favorable hepatic functional reserves (39.0% vs 35.1% albumin-bilirubin grade 1; p = 0.025) but had greater tumor burdens than the female patients. Furthermore, fewer male patients underwent curative therapies for HCC compared with the female patients (49.0% vs 57.0%; p < 0.001). After a median follow-up of 20.1 months (interquartile range, 5.8-47.3 months), 3133 patients died. The cumulative 5-year overall survival rates were 37.1% and 41.9% for male and female patients, respectively (p < 0.001). From the multivariate analysis, male sex was not an independent factor predictive of poor overall survival in all patients and in the subgroup analysis stratified by treatment modalities. When stratified by age, the female sex was an independent factor associated with lower mortality in younger (≤50 years) patients but not in older patients with HCC. CONCLUSION: Sex was not an independent predictor of the outcome of patients with HCC, especially for those aged more than 50 years.