Search

The BCR‐ABL tyrosine kinase which is responsible for the pathogenesis of chronic myeloid leukemia (CML), has emerged as a promising therapeutic target. To address this issue, we employed a comprehensive computational approach integrating virtual screening, molecular dynamics (MD) simulations, and MM‐GBSA (Molecular Mechanics/Generalized Born Surface Area) analysis to identify potential inhibitors and elucidate their binding mechanisms. Initially, virtual screening was conducted on 994 compounds from the ZINC database and, these compounds were docked against wildtype and T315I mutant ABL1 for the Type I and Type II ABL1 kinase inhibition mechanisms. In our molecular docking analysis for Type I inhibition, compound 911 demonstrated notable affinity towards the wildtype ABL1, with a binding energy of −14.91 kcal/mol, while compound 972 showed significant binding affinity towards the mutant ABL1, with a binding energy of −14.27 kcal/mol. In the Type II inhibition mechanism, the compounds with the highest binding affinity were compound 261 in wildtype ABL1 with −17.05 kcal/mol binding energy and compound 966 to the mutant ABL1 with a binding energy of −16.29 kcal/mol. Furthermore, analyses of MD simulations and MM/GBSA binding free energy (ΔG) were performed for target proteins with compounds, that exhibited the most favorable binding affinities with target proteins. The selected hit compounds showed ΔG scores ranging from −118.09 to −74.85 kJ/mol in both wildtype and mutant ABL1. Considering all in silico studies performed, it can be inferred that the identified molecules hold promise as potential candidates for drug design aimed at targeting CML. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are a major cause of mortality worldwide. Long-term monitoring of nighttime heart rate (HR) and heart rate variability (HRV) may be useful in identifying latent cardiovascular risk. The Oura Ring has shown excellent correlation only with ECG-derived HR, but not HRV. We thus assessed if stringent data quality filters can improve the accuracy of time-domain and frequency-domain HRV measures. 92 younger (<45 years) and 22 older (≥45 years) participants from two in-lab sleep studies with concurrent overnight Oura and ECG data acquisition were analyzed. For each 5 min segment during time-in-bed, the validity proportion (percentage of interbeat intervals rated as valid) was calculated. We evaluated the accuracy of Oura-derived HR and HRV measures against ECG at different validity proportion thresholds: 80%, 50%, and 30%; and aggregated over different durations: 5 min, 30 min, and Night-level. Strong correlation and agreements were obtained for both age groups across all HR and HRV metrics and window sizes. More stringent validity proportion thresholds and averaging over longer time windows (i.e., 30 min and night) improved accuracy. Higher discrepancies were found for HRV measures, with more than half of older participants exceeding 10% Median Absolute Percentage Error. Accurate HRV measures can be obtained from Oura's PPG-derived signals with a stringent validity proportion threshold of around 80% for each 5 min segment and aggregating over time windows of at least 30 min. [ABSTRACT FROM AUTHOR]

This study aimed to determine whether a relationship exists between middle school teachers' emotional intelligence levels, teaching styles, and self-efficacy. A correlational research model was used in the research. The participants of the study consisted of 321 teachers working in middle schools. Data were collected using a personal information form, a teaching style scale, a teacher self-efficacy scale, and the Rotterdam Emotional Intelligence Scale. SPSS software was used for data analysis. As a result of the research, it was determined that teachers had high levels of teaching style, self-efficacy, and emotional intelligence. A positive and moderate correlation was found between teachers' teaching styles and self-efficacy levels, teaching styles and emotional intelligence levels, and emotional intelligence levels and self-efficacy. The study also revealed that the teaching style and self-efficacy variables predicted 31% of the emotional intelligence level. Given these findings, educational practitioners and policymakers should incorporate emotional intelligence and self-efficacy enhancement into teacher professional development strategies to refine teaching styles and elevate educational quality. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is the most common type of diabetes and has become a serious public health problem in over the world. There are various antidiabetic drugs on the market, but most of these drugs cause many side effects such as diarrhea, kidney failure, musculoskeletal pain, and enlarged urinary system infections in the clinical treatment of T2DM. Therefore, there is a need for new antidiabetic drugs that can be used orally, are safe with improved efficacy, and reduced side effects. Today, drugs targeting alpha-glucosidase (a-glucosidase), peroxisome proliferator activating receptor gamma (PPAR-γ), and aldose reductase have an important role in the treatment of T2DM. This study is aimed to develop new antidiabetic agents with molecular modeling methods that are more effective, and specific and have fewer side effects than existing drug molecules for a-glucosidase, PPAR-γ, and aldose reductase. Herein, enzyme-ligand interaction mechanisms between target enzymes and 45 hydrazone compounds were examined by using molecular docking and molecular dynamics simulation methods. In addition, the ADME properties of these compounds and their pharmacokinetic suitability according to Lipinski and Veber's rules were evaluated. Compound 2 has shown the best binding affinity against a-glucosidase, compound 27 for aldose reductase, and compound 4 for PPAR-γ and these compounds exhibited good ADME properties. Also, the best active hydrazone compounds have been observed to interact with key amino acid residues on target enzymes via hydrogen bonds. This information can guide the development of new antidiabetic agents by making important contributions to experimental studies. [ABSTRACT FROM AUTHOR]