Svenstrupfrench6051

The ability of G protein-coupled receptor (GPCR) kinases (GRKs) to regulate the desensitization of GPCRs has made GRK2 and GRK5 attractive targets for treating diseases such as heart failure and cancer. Previously, our work showed that Cys474, a GRK5 subfamily-specific residue located on a flexible loop adjacent to the active site, can be used as a covalent handle to achieve selective inhibition of GRK5 over GRK2 subfamily members. However, the potency of the most selective inhibitors remained modest. Herein, we describe a successful campaign to adapt an indolinone scaffold with covalent warheads, resulting in a series of 2-haloacetyl-containing compounds that react quickly and exhibit three orders of magnitude selectivity for GRK5 over GRK2 and low nanomolar potency. They however retain a similar selectivity profile across the kinome as the core scaffold, which was based on Sunitinib.Orthosilicates adopt the zircon structure types (I41/amd), consisting of isolated SiO4 tetrahedra joined by A-site metal cations, such as Ce and U. They are of significant interest in the fields of geochemistry, mineralogy, nuclear waste form development, and material science. Stetindite (CeSiO4) and coffinite (USiO4) can be formed under hydrothermal conditions despite both being thermodynamically metastable. Water has been hypothesized to play a significant role in stabilizing and forming these orthosilicate phases, though little experimental evidence exists. To understand the effects of hydration or hydroxylation on these orthosilicates, in situ high-temperature synchrotron and laboratory-based X-ray diffraction was conducted from 25 to ∼850 °C. Stetindite maintains its I41/amd symmetry with increasing temperature but exhibits a discontinuous expansion along the a-axis during heating, presumably due to the removal of water confined in the [001] channels, which shrink against thermal expansion along the a-axis. Additional in situ high-temperature Raman and Fourier transform infrared spectroscopy also confirmed the presence of the confined water. Coffinite was also found to expand nonlinearly up to 600 °C and then thermally decompose into a mixture of UO2 and SiO2. A combination of dehydration and dehydroxylation is proposed for explaining the thermal behavior of coffinite synthesized hydrothermally. Additionally, we investigated high-temperature structures of two coffinite-thorite solid solutions, uranothorite (U x Th1-xSiO4), which displayed complex variations in composition during heating that was attributed to the negative enthalpy of mixing. Lastly, for the first time, the coefficients of thermal expansion of CeSiO4, USiO4, U0.46Th0.54SiO4, and U0.9Th0.1SiO4 were determined to be αV = 14.49 × 10-6, 14.29 × 10-6, 17.21 × 10-6, and 17.23 × 10-6 °C-1, respectively.Drug-induced rhabdomyolysis (DIR) is a rare and potentially life-threatening muscle injury that is characterized by low incidence and high risk. To our best knowledge, the performance of the current predictive models for the early detection of DIR is suboptimal because of the scarcity and dispersion of DIR cases. Therefore, on the basis of the curated drug information from the Drug-Induced Rhabdomyolysis Atlas (DIRA) database, we proposed a random forest (RF) model to predict the DIR severity of the marketed drugs. Compared with the state-of-art methods, our proposed model outperformed extreme gradient boosting, support vector machine, and logistic regression in distinguishing the Most-DIR concern drugs from the No-DIR concern drugs (Matthews correlation coefficient (MCC) and recall rate of our model were 0.46 and 0.81, respectively). Our model was subsequently applied to predicting the potentially serious DIR for 1402 drugs, which were reported to cause DIR by the postmarketing DIR surveillance data in the FDA Spontaneous Adverse Events Reporting System (FAERS). As a result, 62.7% (94) of drugs ranked in the top 150 drugs with the Most-DIR concerns in FAERS can be identified by our model. learn more The top four drugs (odds ratio >30) including acepromazine, rapacuronium, oxyphenbutazone, and naringenin were correctly predicted by our model. In conclusion, the RF model can well predict the Most-DIR concern drug only based on the chemical structure information and can be a facilitated tool for early DIR detection.Protein oligomerization and protein-protein interaction are crucial to regulate protein functions and biological processes. p73 protein is a very important transcriptional factor and can promote apoptosis and cell cycle arrest, and its transcriptional activity is regulated by p73 oligomerization and p73-MDM2 interaction. Although extracellular studies on p73 oligomerization and p73-MDM2 interaction have been carried out, it is unclear how p73 oligomerization and p73-MDM2 interaction occur in living cells. In our study, we described an in situ method for studying p73 oligomerization and p73-MDM2 interaction in living cells by combining fluorescence cross-correlation spectroscopy with a fluorescent protein labeling technique. Lentiviral transfection was used to transfect cells with a plasmid for either p73 or MDM2, each fused to a different fluorescent protein. p73 oligomerization was evaluated using brightness per particle, and the p73-MDM2 interaction was quantified using the cross-correlation value. We constructed a series of p73 mutants in three domains (transactivation domain, DNA binding domain, and oligomerization domain) and MDM2 mutants. We systematically studied p73 oligomerization and the effects of p73 oligomerization and the p73 and MDM2 structures on the p73-MDM2 interaction in single living cells. We have found that the p73 protein can form oligomers and that the p73 structure changes in the oligomerization domain significantly influence its oligomerization. p73 oligomerization and the structure changes significantly affect the p73-MDM2 interaction. Furthermore, the effects of inhibitors on p73 oligomerization and p73-MDM2 interaction were studied.Kesterite-based thin-film solar cells (TFSCs) have recently gained significant attention in the photovoltaic (PV) sector for their elemental earth abundance and low toxicity. An inclusive study from the past reveals basic knowledge about the grain boundary (GB) and grain interior (GI) interface. However, the compositional dependency of the surface potential within GBs and GIs remains unclear. The present work provides insights into the surface potential of the bulk and GB interfaces. The tin (Sn) composition is sensitive to the absorber morphology, and therefore, it significantly impacts absorber and device properties. The absorber morphology improves with the formation of larger grains as the Sn content increases. Additionally, the presence of Sn(S,Se)2 and increased [ZnCu + VCu] A-type defect cluster density are observed, validated through Raman analysis. The secondary ion mass spectroscopy analysis reveals the altered distribution of sulfur (S) and sodium (Na) with higher near-surface accumulation. The synergistic outcome of the increased density of defects and the accumulation of S near the interface provides a larger GB and GI difference and expedites carrier separation improvement.