Lysine-selective molecular tweezers are cell penetrant and concentrate in lysosomes.

Lysine-selective molecular tweezers are promising drug candidates against proteinopathies, viral infection, and bacterial biofilm. Despite demonstration of their efficacy in multiple cellular and animal models, important questions regarding their mechanism of action, including cell penetrance and intracellular distribution, have not been answered to date. The main impediment to answering these questions has been the low intrinsic fluorescence of the main compound tested to date, called CLR01. Here, we address these questions using new fluorescently labeled molecular tweezers derivatives. We show that these compounds are internalized in neurons and astrocytes, at least partially through dynamin-dependent endocytosis. In addition, we demonstrate that the molecular tweezers concentrate rapidly in acidic compartments, primarily lysosomes. Accumulation of molecular tweezers in lysosomes may occur both through the endosomal-lysosomal pathway and via the autophagy-lysosome pathway. Moreover, by visualizing colocalization of molecular tweezers, lysosomes, and tau aggregates we show that lysosomes likely are the main site for the intracellular anti-amyloid activity of molecular tweezers. These findings have important implications for the mechanism of action of molecular tweezers in vivo, explaining how administration of low doses of the compounds achieves high effective concentrations where they are needed, and supporting the development of these compounds as drugs for currently cureless proteinopathies.

Collective self-esteem and perceived stress among the non-infected general public in China during the 2019 coronavirus pandemic: A multiple mediation model.

This study aimed to investigate the multiple mediating effects of perceived social support and anxiety between collective self-esteem and perceived stress during the 2019 coronavirus disease (COVID-19) pandemic. From February 18 to 25, 2020, 1921 participants aged 18-68 were recruited to complete the questionnaire online. The results showed that collective self-esteem reduced the perceived stress by increasing perceived social support and decreasing anxiety, and their chain mediation path. Our findings identified the important factors in reducing perceived stress and their relationship, which can be used to develop interventions to improve the mental health of the general public during the COVID-19 pandemic.