| 1. |
- Chen, Zhen, et al.
(författare)
-
Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a "Tail Switching" Strategy on a Piperazinyl Azetidine Skeleton
- 2019
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 62:7, s. 3336-3353
-
Tidskriftsartikel (refereegranskat)abstract
- Monoacylglycerol lipase (MAGL) is a senile hydrolase that degrades 2-arachidonoylglycerol (2-AG) in the endocannabinoid system (eCB). Selective inhibition of MAGL has emerged as a potential therapeutic approach for the treatment of diverse pathological conditions, including chronic pain, inflammation, cancer, and neurodegeneration. Herein, we disclose a novel array of reversible and irreversible MAGL inhibitors by means of "tail switching" on a piperazinyl azetidine scaffold. We developed a lead irreversible-binding MAGL inhibitor 8 and reversible-binding compounds 17 and 37, which are amenable for radiolabeling with C-11 or F-18. [C-11]8 ([C-11]MAGL-2-11) exhibited high brain uptake and excellent binding specificity in the brain toward MAGL. Reversible radioligands [C-11]17 ([C-11]PAD) and [F-18]37 ([F-18]MAGL-4-11) also demonstrated excellent in vivo binding specificity toward MAGL in peripheral organs. This work may pave the way for the development of MAGL-targeted positron emission tomography tracers with tunability in reversible and irreversible binding mechanisms.
|
|
| 2. |
|
|
| 3. |
- Libby, Simon, et al.
(författare)
-
Exploring the impact of fracture interaction on connectivity and flow channelling using grown fracture networks
- 2024
-
Ingår i: Quarterly journal of engineering geology and hydrogeology. - : Geological Society of London. - 1470-9236 .- 2041-4803. ; 57:1
-
Tidskriftsartikel (refereegranskat)abstract
- Quantitative assessment of the flow properties and mechanical stability of naturally fractured rock is frequently practised across the mining, petroleum, geothermal, geological disposal, construction and environmental remediation industries. These fluid and mechanical behaviours are strongly influenced by the connectivity of the fracture system and the size of the intact rock blocks. However, these are amongst the more difficult fracture system properties to characterize and honour in numerical simulations. Nonetheless, they are still the product of interactions between fractures that can be conceptualized as a series of deformation events following geomechanical principles. Generating numerical models of fracture networks by simulating this deformation with a coupled and evolving rock mass and stress field is a significant undertaking. Instead, large-scale fracture network models can be 'grown' dynamically according to rules that mimic the underlying mechanical processes and deformation history. This paper explores a computationally efficient rules-based method to generate fracture networks, demonstrates how different types of fracture patterns can be simulated, and illustrates how inclusion of fracture interactions can affect flow and mechanical properties. Relative to methods without fracture interaction and in contrast to some other rules-based approaches, the method described here regularizes and increases fracture connectivity and decreases flow channelling.
|
|
| 4. |
- Santangelo, James S., et al.
(författare)
-
Global urban environmental change drives adaptation in white clover
- 2022
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 375
-
Tidskriftsartikel (refereegranskat)abstract
- Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural dines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.
|
|
