Transition from preclinical to clinical application of CTLA4-Ig co-stimulation blockage in beta-cell replacement therapy.

Beta-cell replacement therapies, including islet and pancreas transplantation, offer promising results in term of glycemic control for patients with type 1 diabetes experiencing high glycemic variability and severe hypoglycemia. However, long-term insulin independence remains challenging due to progressive graft function decline. Immunosuppressive regimens, especially calcineurin inhibitors such as tacrolimus, are known to be diabetogenic, contributing to the paradox of impaired beta-cell function in a diabetes treatment setting.

The landscape of autosomal-dominant Alzheimer's disease: global distribution and age of onset.

We present a comprehensive global analysis of genetic variants associated with autosomal-dominant Alzheimer's disease (ADAD). A total of 550 variants in the APP, PSEN1, and PSEN2 genes were identified, of which 279 were classified as pathogenic or likely pathogenic based on ACMG-AMP criteria, utilizing data from the Dominantly Inherited Alzheimer Network (DIAN), literature, and public databases. Symptomatic age at onset (AAO) data was estimated for 227 of these variants, allowing detailed characterization of their frequency, pathogenicity, and AAO.

Allosteric Modulation of Pathological Ataxin-3 Aggregation: A Path to Spinocerebellar Ataxia Type-3 Therapies.

Spinocerebellar ataxia type 3 (SCA3) is a rare inherited neurodegenerative disease caused by the expansion of a polyglutamine repeat in the protease ataxin-3 (Atx3). Despite extensive knowledge of the downstream pathophysiology, no disease-modifying therapies are currently available to halt disease progression. The accumulation of protein inclusions enriched in the polyQ-expanded Atx3 in neurons suggests that inhibiting its self-assembly may yield targeted therapeutic approaches.