Ailian Du

Pathogenic variants in ASXL3 underlie autism spectrum disorder (ASD), but how they perturb neural circuits and whether defects are reversible remain unclear. Here we show that Asxl3 haploinsufficiency in mice reduces cortical thickness and upper-layer projection neurons while increasing parvalbumin (PV) interneuron number and producing ASD-like behavioral abnormalities. Mechanistically, Asxl3 loss derepresses the thyroid hormone (TH)–inactivating enzyme DIO3 via altered histone H2A monoubiquitination, depleting brain TH. Conditional deletion of the TH receptor Thra in inhibitory neuron progenitors phenocopies the PV interneuron expansion, linking impaired TH signaling to PV circuit remodeling. Neonatal, but not adolescent, TH supplementation restores PV interneuron numbers and rescues behavior in Asxl3 ^+/− mice, defining a critical early window for intervention. An intein-based AAV system that reconstitutes full-length ASXL3 normalizes cortical architecture and behavior in Asxl3 ^+/− mice and drives efficient ASXL3 expression in non-human primate brain, establishing an ASXL3–TH–PV interneuron axis as a targetable pathway in ASD.

Myasthenia gravis (MG) is a classical auto-antibody-mediated autoimmune disorder characterized by muscle weakness ranging from isolated ocular manifestations to life-threatening respiratory comprom...

Background: In cerebral small vessel disease (CSVD), the burden of white matter hyperintensities (WMH) does not fully account for cognitive impairment, suggesting the involvement of intermediary mechanisms. Objective: We investigated whether a gray matter atrophy network acts as the key mediator linking topologically specific (deep) WMH to multidomain cognitive dysfunction. Methods: In this retrospective study, 260 patients with CSVD (62 cognitively normal, 125 with mild impairment, 73 with dementia) were included. Cognitive status was assessed neuropsychologically. 3.0 T MRI identified an atrophy network. We then conducted pre-specified mediation analyses and a primary confirmatory analysis using structural equation modeling (SEM) to test whether this atrophy network mediated the effect of deep WMH on cognitive performance. Results: A 41-region atrophy network was identified , primarily involving the medial temporal lobe and thalamus, that was significantly associated with cognitive status. The final SEM demonstrated excellent fit, showing that higher deep WMH burden was associated with greater network atrophy ( β = 0.145, p < 0.05), which in turn was strongly associated with poorer executive function ( β = −0.64, p < 0.001) and memory ( β = −0.572, p < 0.001). The direct effect of WMH on cognition was not statistically significant in the model. Conclusions: Our findings suggest that in CSVD, a unified network of gray matter atrophy acts as a powerful statistical mediator in the effect of deep white matter injury on cognitive decline. This atrophy pattern may represent a more direct biomarker of the neurodegenerative process underlying cognitive impairment than WMH burden alone.

White matter, constituting nearly half of the human brain, is increasingly recognized as a dynamic regulator of neural communication, metabolism, and cognition rather than a passive conduit for signal transmission. Recent advances in neuroimaging, molecular biology, and single-cell transcriptomics have revealed that myelin and oligodendrocytes play essential roles in neural plasticity and disease. Here, we synthesize current understanding of white matter organization and myelin function, emphasizing its contributions to conduction efficiency, metabolic support, and network optimization. We further discuss mechanisms of myelin plasticity and highlight its role in learning, adaptation, and repair. Integrating evidence across developmental, immune-mediated, neurodegenerative, and psychiatric disorders, we propose that white matter pathology constitutes a primary driver of brain dysfunction. Finally, we summarize emerging regenerative strategies—including cell and gene therapies, OPC-targeted interventions, and neuromodulation—highlighting translational opportunities for restoring myelin integrity and circuit function. This review reframes white matter as a promising therapeutic frontier.

Skeletal muscle function gradually declines with aging, presenting substantial health and societal challenges. Comparative analysis of how aging affects fast‐ and slow‐twitch muscles remains lacking. We utilized 20‐month‐old mice to reveal the aging effects on muscle structure and fiber composition, followed by bulk RNA sequencing for fast‐ and slow‐twitch muscles and integration with human single‐cell RNA sequencing dataset providing a comparative analysis across species. In mouse slow‐twitch muscles, aging induced a switch from fast to slow fibers and distinctively altered lipid metabolism in ceramide and triglyceride, with the upregulation of regulatory genes Gk and Ppargc1a also observed in human slow fibers. Additionally, both types of muscles exhibited common collagen deposition and fibrosis, possibly due to the imbalance between collagen synthesis and degradation. The extracellular matrix gene changes substantially overlapped between mice and humans in aging, yet also highlighted clear differences. This integrative analysis provides further understanding of aged fast‐ and slow‐twitch muscles and offers new insights into the molecular changes in aging.