The Development and Design Strategy of Leucine-Rich Repeat Kinase 2 Inhibitors: Promising Therapeutic Agents for Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting millions of people worldwide. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factor for PD. Elevated LRRK2 kinase activity is found in idiopathic and familial PD cases. LRRK2 mutations are involved in multiple PD pathogeneses, including dysregulation of mitochondrial homeostasis, ciliogenesis, etc. Here, we provide a comprehensive overview of the biological function, structure, and mutations of LRRK2. We also examine recent advances and challenges in developing LRRK2 inhibitors and address prospective protein-based targeting strategies. The binding mechanisms, structure-activity relationships, and pharmacokinetic features of inhibitors are emphasized to provide a comprehensive compendium on the rational design of LRRK2 inhibitors. We hope that this publication can serve as a guide for designing novel LRRK2 inhibitors based on the summarized facts and perspectives.

Visual preferences for outdoor space along commercial pedestrian streets under the influence of plant characteristics.

Chinese commercial pedestrian streets have developed rapidly in recent years. However, people's preferences were not sufficiently considered and reflected in the outdoor space and landscape design. With the outdoor landscapes along commercial pedestrian streets in the region south of the Five Ridges as the research objects, this study revealed the public's different preference evaluations of the landscapes under the reciprocal effects of street characteristics. The main results were as follows: (a) When arcade spaces were available, people prefer streets with taller trees and a lower planting density (50 plants/km or less). Conversely, they preferred streets with relatively low trees (3-6 m), a higher planting density (100-200 plants/km) and two or more vertical layers of plants. People did not like the way that plants are lined in the middle of a street. (b) When there were only one or two types of signage hanging, people preferred streets with a moderate planting density (50-100 plants/km); and there were three or more types of signage hanging, people preferred the plants with low linear density (50 plants/km or less) and that were arranged along one or two sides of the street. (c) When benches were available, people preferred streets with plants on one or both sides, fewer plant colours (one or two kind of colours) and better plant growth status. Specifically, the richer the vertical structure and the bigger number of colours were, the higher the preference score. This study provided design schemes to enhance the visual quality of landscapes by improving landscape characteristics in similar outdoor spaces.