No abstract

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common form of genetic stroke and vascular dementia syndrome resulting from mutations in NOTCH3. To elucidate molecular mechanisms of the condition and identify drug targets, we established a patient-specific induced pluripotent stem cell (iPSC) model and demonstrated for the first time a failure of the patient iPSC-derived vascular mural cells (iPSC-MCs) in engaging and stabilizing endothelial capillary structures. The patient iPSC-MCs had reduced platelet-derived growth factor receptor b, decreased secretion of the angiogenic factor vascular endothelial growth factor (VEGF), were highly susceptible to apoptotic insults, and could induce apoptosis of adjacent endothelial cells. Supplementation of VEGF significantly rescued the capillary destabilization. Small interfering RNA knockdown of NOTCH3 in iPSC-MCs revealed a gain-of-function mechanism for the mutant NOTCH3. These disease mechanisms likely delay brain repair after stroke in CADASIL, contributing to the brain hypoperfusion and dementia in this condition, and will help to identify potential drug targets.

Cerebral small vessel disease (SVD) is a major contributor to stroke, cognitive impairment and dementia with limited therapeutic interventions. There is a critical need to provide mechanistic insight and improve translation between pre-clinical research and the clinic. A 2-day workshop was held which brought together experts from several disciplines in cerebrovascular disease, dementia and cardiovascular biology, to highlight current advances in these fields, explore synergies and scope for development. These proceedings provide a summary of key talks at the workshop with a particular focus on animal models of cerebral vascular disease and dementia, mechanisms and approaches to improve translation. The outcomes of discussion groups on related themes to identify the gaps in knowledge and requirements to advance knowledge are summarized.

Silver nanoparticles (Ag NPs) have been used widely for antibacterial applications; however, the effects of their sizes on antibacterial activities and toxicities to human cells, particularly for the laser-generated Ag NPs, are not fully understood. In this study, sucrose gradient centrifugation was used to separate laser-generated Ag NPs into different fractions by size. Transmission electron microscopy was used to analyze the size distribution of the Ag NPs, and well diffusion method was used to evaluate the antibacterial activity of the Ag NP fractions against the Escherichia coli. Results showed that the antibacterial effects of laser-generated Ag NPs inversely correlated to the particle size. Among Ag NP fractions with average sizes ranging 19-47 nm, the 19-nm Ag NPs presented the highest bactericidal effect. The smaller sized laser Ag NPs also significantly induced the generation of reactive oxygen species when applied to E. coli, compared with that of the larger sized laser Ag NPs. Cytotoxicity analysis revealed that the different sized laser-generated Ag NPs were not significantly toxic to the human fibroblasts and lung epithelial cells in a 72-h in vitro cell culture period. Understanding the size-dependent functional properties of the laser-generated Ag NPs helps informing the designs for future applications of the laser-generated Ag NPs.