Covalent targeting of non-cysteine residues in PI4KIIIβ

The synthesis and characterisation of fluorosulfate covalent inhibitors of the lipid kinase PI4KIIIβ is described. The conserved lysine residue located within the ATP binding site was targeted, and optimised compounds based upon reversible inhibitors with good activity and physicochemical profile showed strong reversible interactions and slow onset times for the covalent inhibition, resulting in an excellent selectivity profile for the lipid kinase target. X-Ray crystallography demonstrated a distal tyrosine residue could also be targeted using a fluorosulfate strategy. Combination of this knowledge showed that a dual covalent inhibitor could be developed which reveals potential in addressing the challenges associated with drug resistant mutations

The Influence of Reproductive Experience on Milk Energy Output and Lactation Performance in the Grey Seal (Halichoerus grypus)

Although evidence from domestic and laboratory species suggests that reproductive experience plays a critical role in the development of aspects of lactation performance, whether reproductive experience may have a significant influence on milk energy transfer to neonates in wild populations has not been directly investigated. We compared maternal energy expenditures and pup growth and energy deposition over the course of lactation between primiparous and fully-grown, multiparous grey seal (Halichoerus grypus) females to test whether reproductive experience has a significant influence on lactation performance. Although there was no difference between primiparous females in milk composition and, thus, milk energy content at either early or peak lactation primiparous females had a significantly lower daily milk energy output than multiparous females indicating a reduced physiological capacity for milk secretion

DeepSportradar-v1: Computer Vision Dataset for Sports Understanding with High Quality Annotations

With the recent development of Deep Learning applied to Computer Vision, sport video understanding has gained a lot of attention, providing much richer information for both sport consumers and leagues. This paper introduces DeepSportradar-v1, a suite of computer vision tasks, datasets and benchmarks for automated sport understanding. The main purpose of this framework is to close the gap between academic research and real world settings. To this end, the datasets provide high-resolution raw images, camera parameters and high quality annotations. DeepSportradar currently supports four challenging tasks related to basketball: ball 3D localization, camera calibration, player instance segmentation and player re-identification. For each of the four tasks, a detailed description of the dataset, objective, performance metrics, and the proposed baseline method are provided. To encourage further research on advanced methods for sport understanding, a competition is organized as part of the MMSports workshop from the ACM Multimedia 2022 conference, where participants have to develop state-of-the-art methods to solve the above tasks. The four datasets, development kits and baselines are publicly available at https://github.com/DeepSportRadar

Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA₂ Inhibitor

We describe the incorporation of a bicyclo[1.1.1]­pentane moiety within two known LpPLA₂ inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]­butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile

Discovery of novel irreversible inhibitors of IL-2 inducible tyrosine kinase (Itk) by targeting cysteine 442 in the ATP pocket

IL-2 inducible tyrosine kinase (Itk) plays a key role in antigen receptor signalling in T cells and is considered an important target for anti-inflammatory drug discovery. In order to generate inhibitors with the necessary potency and selectivity, a compound that targeted Cysteine442 in the ATP binding pocket and with an envisaged irreversible mode of action was designed. We incorporated a high degree of molecular recognition and specific design features making the compound suitable for inhaled delivery. This study confirms the irreversible covalent binding of the inhibitor to the kinase by X-ray crystallography and enzymology, whilst demonstrating potency, selectivity, and prolonged duration of action in in vitro biological assays. The biosynthetic turnover of the kinase was also examined as a critical factor when designing irreversible inhibitors for extended duration of action. The exemplified Itk inhibitor demonstrated inhibition of both TH1 and TH2 cytokines, was additive with fluticasone propionate and inhibited cytokine release from human lung fragments. Finally, we describe an in vivo pharmacodynamic assay that allows rapid preclinical development without animal efficacy models