Nouri, S. | Search bioRxiv

bioRxiv2024

Gliflozins, sucrose and flavonoids are allosteric activators of lecithin:cholesterol acyltransferase

Lecithin:cholesterol acyltransferase (LCAT) serves as a pivotal enzyme in preserving cholesterol homeostasis via reverse cholesterol transport, a process closely associated with the onset of atherosclerosis. Impaired LCAT function can lead to severe LCAT deficiency disorders for which no pharmacological treatment exists. LCAT-based therapies, such as small molecule positive allosteric modulators (PAMs), against LCAT deficiencies and atherosclerosis hold promise, although their efficacy against atherosclerosis remains challenging. Herein we utilized a quantitative in silico metric to predict the activity of novel PAMs and tested their potencies with in vitro enzymatic assays. As predicted, sodium-glucose cotransporter 2 (SGLT2) inhibitors (gliflozins), sucrose and flavonoids activate LCAT. This has intriguing implications for the mechanism of action of gliflozins, which are commonly used in the treatment of type 2 diabetes, and for the endogenous activation of LCAT. Our results underscore the potential of molecular dynamics simulations in rational drug design.

biochemistry↗

bioRxiv2024

Microsaccade Selectivity as Discriminative Feature for Object Decoding

Microsaccades, a form of fixational eye movements, maintain visual stability during stationary observations. Previous studies have provided valuable insights into the relationship between microsaccade characteristics and external stimuli. However, the dynamic nature of microsaccades provides an opportunity to explore the mechanisms of information processing, particularly object decoding. This study examines the modulation of microsaccadic rates by different stimulus categories. Our experimental approach involves an analysis of microsaccade characteristics in monkeys and human subjects engaged in a passive viewing task. The stimulus categories comprised four primary categories: human, animal, natural, and man-made. We identified distinct microsaccade patterns across different stimulus categories, successfully decoding the stimulus category based on the microsaccade rate post-stimulus distribution. Our experiments demonstrate that stimulus categories can be classified with an average accuracy and recall of up to 85%. Our study found that microsaccade rates are independent of pupil size changes. Neural data showed that category classification in the inferior temporal (IT) cortex peaks earlier than microsaccade rates, suggesting a feedback mechanism from the IT cortex that influences eye movements after stimulus discrimination. These results exhibit potential for advancing neurobiological models, developing more effective human-machine interfaces, optimizing visual stimuli in experimental designs, and expanding our understanding of the capability of microsaccades as a feature for object decoding.

neuroscience↗