Modeling and Correction of Protein Conformational Disease in iPSC-derived Neurons through Personalized Base Editing.

Altered protein conformation can cause incurable neurodegenerative disorders. Mutations in SERPINI1 , the gene encoding neuroserpin, alter protein conformation resulting in cytotoxic aggregation in neuronal endoplasmic reticulum. Aggregates cause oxidative stress impairing function, leading to neuronal death. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare autosomal dominant progressive myoclonic epilepsy. Patients present with seizures and cognitive impairments that progress to dementia and premature death. We developed HEK293T and induced pluripotent stem cell (iPSC) models of FENIB, harboring the patient's pathogenic SERPINI1 variant or stably overexpressing mutant neuroserpin fused to GFP (MUT NS-GFP). FENIB cells form neuroserpin inclusions which increase in size and number. Here, we utilized a personalized adenine base editor (ABE)-mediated approach to efficiently correct the pathogenic variant and to restore neuronal dendritic morphology. ABE-treated MUT NS-GFP cells demonstrated reduced inclusion size and number. Using an inducible MUT NS-GFP neuron system, we identified early prevention of toxic protein expression allowed aggregate clearance, while late prevention halted neuronal impairments. To address several challenges for clinical applications of gene correction, we developed a neuron-specific engineered virus-like particle to optimize neuronal ABE delivery. Preventing mutant protein with altered conformation production improved toxic protein clearance. Our findings provide a targeted strategy and may treat FENIB and potentially other neurodegenerative diseases due to altered protein conformation such as Alzheimer's and Huntington's diseases.

Nurses' confidence in starting a new venture, startup or project in the context of nurse-led hackathons: Results of prehackathon survey.

BACKGROUND: A hackathon framework has been successfully applied to solving health care challenges, including COVID-19, without much documented evidence of nurses' baseline or acquired confidence. PURPOSE: To understand differences in baseline confidence levels in starting a new venture, startup or project in the context of nurse-led hackathons. METHOD: A retrospective secondary analysis of a presurvey of hackathon participants from two NurseHack4Health (NH4H) events held in 2021. DISCUSSION: Male nurses and international nurses were more confident than the U.S.-based nurses. When comparing the 75% of participants who had not attended a hackathon previously to the 25% of participants who had, there was an increased confidence level among non-nurses and among participants with the previous hackathon, datathon, and ideation experience. CONCLUSION: If hackathons can help nurses identify strengths, add new expertise and boost confidence, it may empower nurses to pursue their ideas more effectively, aid professional growth, and provide affirmation of innovator self-identity.