Structure-based pharmacophore modeling for precision inhibition of mutant ESR2 in breast cancer: A systematic computational approach.

BACKGROUND: Breast cancer, a leading cause of female mortality, is closely linked to mutations in estrogen receptor beta (ESR2), particularly in the ligand-binding domain, which contributed to altered signaling pathways and uncontrolled cell growth. OBJECTIVES/AIMS: This study investigates the molecular and structural aspects of ESR2 mutant proteins to identify shared pharmacophoric regions of ESR2 mutant proteins and potential therapeutic targets aligned within the pharmacophore model. METHODS: This study was initiated by establishing a common pharmacophore model among three mutant ESR2 proteins (PDB ID: 2FSZ, 7XVZ, and 7XWR). The generated shared feature pharmacophore (SFP) includes four primary binding interactions: Hydrogen bond donors (HBD), hydrogen bond acceptors (HBA), hydrophobic interactions (HPho), and Aromatic interactions (Ar), along with halogen bond donors (XBD) and totalling 11 features (HBD: 2, HBA: 3, HPho: 3, Ar: 2, XBD: 1). By employing an in-house Python script, these 11 features distributed into 336 combinations, which were used as query to isolate a drug library of 41,248 compounds and subjected to virtual screening through the generated SFP. RESULTS: The virtual screening demonstrated 33 hits showing potential pharmacophoric fit scores and low RMSD value. The top four compounds: ZINC94272748, ZINC79046938, ZINC05925939, and ZINC59928516 showed a fit score of more than 86% and satisfied the Lipinski rule of five. These four compounds and a control underwent molecular (XP Glide mode) docking analysis against wild-type ESR2 protein (PDB ID: 1QKM), resulting in binding affinity of -8.26, -5.73, -10.80, and -8.42 kcal/mol, respectively, along with the control -7.2 kcal/mol. Furthermore, the stability of the selected candidates was determined through molecular dynamics (MD) simulations of 200 ns and MM-GBSA analysis. CONCLUSION: Based on MD simulations and MM-GBSA analysis, our study identified ZINC05925939 as a promising ESR2 inhibitor among the top four hits. However, it is essential to conduct further wet lab evaluation to assess its efficacy.

Exploring Bryophyllum pinnatum compounds as potential inhibitors for Vespula vulgaris allergen proteins: A systematic computational approach.

Vespula vulgaris (V. vulgaris), commonly known as the common wasp, poses a significant health threat due to its venom-induced allergic reactions. This research focused on the exploration of bioactive compounds from Bryophyllum pinnatum as potential inhibitors for V. vulgaris allergen proteins, including Phospholipase A1 (Ves V1), Hyaluronoglucosaminidase (Ves V2), and Antigen 5 (Ves V5). Through a multidisciplinary approach involving literature reviews, molecular docking analyses, ADMET assessments and Molecular Dynamics Simulations (MDS) of 100ns we identified two promising drug candidates from four bioactive compounds- Bryophyllin A, Bryophyllin B, Bryotoxin A, and Bryotoxin B of Bryophyllum pinnatum. Molecular docking results revealed strong binding interactions, with Bryophyllin B and Bryotoxin A consistently exhibiting the highest affinity (-9.6 kcal/mol and -10.0 kcal/mol) across the allergen proteins. ADMET analyses highlighted Bryophyllin B as a favorable candidate, showing high absorption (HIA: 92.1 %), minimal metabolic interactions (CYP1A2: No), and a low toxicity profile (LD50 (rat): 2.431). MDS analysis revealed Bryophyllin B and Bryotoxin A as promising drug inhibitors, exhibiting the highest binding stability with the allergen proteins of V. vulgaris, as indicated by the lowest Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of Gyration (RG) values and highest protein-ligand contacts. Our study provides valuable insights into the therapeutic potential of Bryophyllum pinnatum compounds as inhibitors for V. vulgaris allergen proteins having two promising candidates- Bryophyllin B and Bryotoxin A.

Computational approach for identifying immunogenic epitopes and optimizing peptide vaccine through in-silico cloning against Mycoplasma genitalium.

Mycoplasma genitalium is a pathogenic microorganism linked to a variety of severe health conditions including ovarian cancer, prostate cancer, HIV transmission, and sexually transmitted diseases. A more effective approach to address the challenges posed by this pathogen, given its high antibiotic resistance rates, could be the development of a peptide vaccine. In this study, we used experimentally validated 13 membrane proteins and their immunogenicity to identify suitable vaccine candidates. Thus, based on immunogenic properties and high conservation among other Mycoplasma genitalium sub-strains, the P110 surface protein is considered for further investigation. Later on, we identified T-cell epitopes and B-cell epitopes from the P110 protein to construct a multiepitope-based vaccine. As a result, the 'NIAPISFSFTPFTAA' T-cell epitope and 'KVKYESSGSNNISFDS' B-cell epitope have shown 99.53% and 87.50% population coverage along with 100% conservancy among the subspecies, and both epitopes were found to be non-allergenic. Furthermore, focusing on molecular docking analysis showed the lowest binding energy for MHC-I (-137.5 kcal/mol) and MHC-II (-183.3 kcal/mol), leading to a satisfactory binding strength between the T-cell epitopes and the MHC molecules. However, the constructed multiepitope vaccine (MEV) consisting of 54 amino acids demonstrates favorable characteristics for a vaccine candidate, including a theoretical pI of 4.25 with a scaled solubility of 0.812 and high antigenicity probabilities. Additionally, structural analyses reveal that the MEV displays substantial alpha helices and extended strands, vital for its immunogenicity. Molecular docking with the human Toll-like receptors TLR1/2 heterodimer shows strong binding affinity, reinforcing its potential to elicit an immune response. Our immune simulation analysis demonstrates immune memory development and robust immunity, while codon adaptation suggests optimal expression in E. coli using the pET-28a(+) vector. These findings collectively highlight the MEV's potential as a valuable vaccine candidate against M. genitalium.

Distance learning in higher education during COVID-19: The role of basic psychological needs and intrinsic motivation for persistence and procrastination-a multi-country study.

Due to the COVID-19 pandemic, higher educational institutions worldwide switched to emergency distance learning in early 2020. The less structured environment of distance learning forced students to regulate their learning and motivation more independently. According to self-determination theory (SDT), satisfaction of the three basic psychological needs for autonomy, competence and social relatedness affects intrinsic motivation, which in turn relates to more active or passive learning behavior. As the social context plays a major role for basic need satisfaction, distance learning may impair basic need satisfaction and thus intrinsic motivation and learning behavior. The aim of this study was to investigate the relationship between basic need satisfaction and procrastination and persistence in the context of emergency distance learning during the COVID-19 pandemic in a cross-sectional study. We also investigated the mediating role of intrinsic motivation in this relationship. Furthermore, to test the universal importance of SDT for intrinsic motivation and learning behavior under these circumstances in different countries, we collected data in Europe, Asia and North America. A total of N = 15,462 participants from Albania, Austria, China, Croatia, Estonia, Finland, Germany, Iceland, Japan, Kosovo, Lithuania, Poland, Malta, North Macedonia, Romania, Sweden, and the US answered questions regarding perceived competence, autonomy, social relatedness, intrinsic motivation, procrastination, persistence, and sociodemographic background. Our results support SDT's claim of universality regarding the relation between basic psychological need fulfilment, intrinsic motivation, procrastination, and persistence. However, whereas perceived competence had the highest direct effect on procrastination and persistence, social relatedness was mainly influential via intrinsic motivation.

Effectiveness and outcomes of a nurse practitioner-run chest pain evaluation unit.

BACKGROUND: Every year, more than 5 million patients seek medical care for chest pain. OBJECTIVE: The goal of this study was to evaluate test utilization and outcomes of a nurse practitioner (NP)-based chest pain unit and compare results to data previously reported from our institution. DESIGN, SETTING, AND PARTICIPANTS: The records from 814 consecutive patients with chest pain admitted to the NP-run unit were compared to the outcomes of 250 patients admitted to a separate hospitalist-run unit at a New York City hospital. RESULTS: Forty-four percent of patients in the NP unit underwent stress myocardial perfusion imaging (MPI) as the primary diagnostic test (compared to 22% in the hospitalist unit, p < .0001). The average length of stay was shorter for patients in the NP unit (2.7 ± 3.6 days compared to 3.9 ± 3.4 days, p < .0001). Additionally, the 90-day readmission rate was less for patients in the NP unit (2.7% vs. 3.9%, p < .0006). CONCLUSIONS: An NP-run chest pain unit resulted in decreased length of stay and reduced readmission rates compared to a hospitalist-based unit.

Mortality in the coronary care unit.

OBJECTIVES: Currently, there are limited data on mortality or predictors of survival for patients admitted to the coronary care unit (CCU). The purpose of this study was to provide data on mortality in the modern-day CCU and to better define factors influencing patient survival. METHODS: A survey was conducted of all patients admitted to CCUs in New York City metropolitan academic hospitals in 2011, followed by a retrospective analysis comparing clinical data from 59 nonsurvivors with those from 897 survivors at two representative institutions. RESULTS: The weighted average mortality in the CCU across all hospitals was 5.6% (range 2.2-9.2%). The average age of the patients admitted to the CCU was 67 years, with 68% being male. Acute coronary syndromes accounted for 57% of all CCU admissions. Survival was worse in patients admitted for cardiac arrest (P=0.000), sepsis (P=0.002), primary respiratory failure (P=0.031), and systolic heart failure (P=0.003). Excluding patients who were made 'do not resuscitate' during their CCU stay, patients receiving treatments such as defibrillation after in-CCU cardiac arrest, right heart invasive monitoring, mechanical ventilation, inotropic support, emergent dialysis, or placement of an intra-aortic balloon pump had higher rates of in-CCU mortality. The most frequent causes of death were intractable cardiogenic shock, brain death, respiratory failure, multiorgan failure, or hypotension. CONCLUSION: This study provides additional mortality information for the modern-day CCU and should help identify factors that may predict survival.

Microcystins (cyanobacterial toxins) in surface waters of rural Bangladesh: pilot study.

In Bangladesh the exposure of millions of inhabitants to water from (shallow) tube wells contaminated with high geogenic loads of arsenic is a major concern. As an alternative to the costly drilling of deep wells, the return to the use of surface water as a source of drinking water is considered. In addition to the well-known hazards of water borne infectious diseases associated with the use of surface water, recently the potential public health implications of toxic cyanobacteria have been recognized. As a first step towards a risk assessment for cyanotoxins in Bangladesh surface waters, seston samples of 79 ponds were analysed in late summer 2002 for the presence of cyanobacteria and microcystins (MCYST), the most frequently detected cyanobacterial toxins worldwide. Microcystins could be detected in 39 ponds, mostly together with varying abundance of potentially microcystin-producing genera such as Microcystis, Planktothrix and Anabaena. Total microcystin concentrations ranged between <0.1 and > 1,000 microg l(-1), and more than half of the positive samples contained high concentrations of more than 10 microg l(-1). The results clearly show that concentrations of microcystins well above the provisional WHO guideline value of 1 microg l(-1) MCYST-LR can be frequently detected in Bangladesh ponds. Thus, an increasing use of surface water for human consumption introduces a risk of replacing one health hazard by another and therefore needs to be accompanied by cyanotoxin hazard assessments.