Analyzing molecular signatures in preeclampsia and fetal growth restriction: Identifying key genes, pathways, and therapeutic targets for preterm birth.

Background: Intrauterine growth restriction (IUGR) and preeclampsia (PE) are intricately linked with specific maternal health conditions, exhibit shared placental abnormalities, and play pivotal roles in precipitating preterm birth (PTB) incidences. However, the molecular mechanism underlying the association between PE and IUGR has not been determined. Therefore, we aimed to analyze the data of females with PE and those with PE + IUGR to identify the key gene(s), their molecular pathways, and potential therapeutic interactions. Methods: In this study, a comprehensive relationship analysis of both PE and PE + IUGR was conducted using RNA sequence datasets. Using two datasets (GSE148241 and GSE114691), differential gene expression analysis via DESeq2 through R-programming was performed. Gene set enrichment analysis was performed using ClusterProfiler, protein‒protein interaction (PPI) networks were constructed, and cluster analyses were conducted using String and MCODE in Cytoscape. Functional enrichment analyses of the resulting subnetworks were performed using ClueGO software. The hub genes were identified under both conditions using the CytoHubba method. Finally, the most common hub protein was docked against a library of bioactive flavonoids and PTB drugs using the PyRx AutoDock tool, followed by molecular dynamic (MD) simulation analysis. Pharmacokinetic analysis was performed to determine the ADMET properties of the compounds using pkCSM. Results: We identified eight hub genes highly expressed in the case of PE, namely, PTGS2, ENG, KIT, MME, CGA, GAPDH, GPX3, and P4HA1, and the network of the PE + IUGR gene set demonstrated that nine hub genes were overexpressed, namely, PTGS2, FGF7, FGF10, IL10, SPP1, MPO, THBS1, CYBB, and PF4. PTGS2 was the most common hub gene found under both conditions (PE and PEIUGR). Moreover, the greater (-9.1 kcal/mol) molecular binding of flavoxate to PTGS2 was found to have satisfactory pharmacokinetic properties compared with those of other compounds. The flavoxate-bound PTGS2 protein complex remained stable throughout the simulation; with a ligand fit to protein, i.e., a RMSD ranging from ∼2.0 to 4.0 Å and a RMSF ranging from ∼0.5 to 2.9 Å, was observed throughout the 100 ns analysis. Conclusion: The findings of this study may be useful for treating PE and IUGR in the management of PTB.

Genetic insights into obesity: in silico identification of pathogenic SNPs in MBOAT4 gene and their structural molecular dynamics consequences.

Membrane Bound O-Acyltransferase Domain-Containing 4 (MBOAT4) protein catalyzes ghrelin acylation, leading to prominent ghrelin activity, hence characterizing its role as an anti-obesity target. We extracted 625 exonic SNPs from the ENSEMBL database and one phenotype-based missense mutation associated with obesity (A46T) from the HGMD (Human Gene Mutation Database). These were differentiated on deleterious missense SNPs of the MBOAT4 gene through MAF (minor allele frequency: <0.01) cut-off criteria in relation to some bioinformatics-based supervised machine learning tools. We found 8 rare-coding and harmful missense SNPs. The consensus classifier (PredictSNP) tool predicted that the SNP (G57S, C: rs561065025) was the most pathogenic. Several trained in silico algorithms have predicted decreased protein stability [ΔΔG (kcal/mol)] function in the presence of these rare-coding pathogenic mutations in the MBOAT4 gene. Then, a stereochemical quality check (i.e. validation and assessment) of the 3D model was performed, followed by a blind cavity docking approach, used to search for druggable cavities and molecular interactions with citrus flavonoids of the Rutaceae family, ranked with energetic estimations. Significant interactions with Phloretin 3',5'-Di-C-Glucoside were also observed at R304, W306, N307, A311, L314 and H338 with (iGEMDOCK: -95.82 kcal/mol and AutoDock: -7.80 kcal/mol). The RMSD values and other variables of MD simulation analyses on this protein further validated its significant interactions with the above flavonoids. The MBOAT4 gene and its molecular interactions could serve as an interventional future anti-obesity target. The current study's findings will benefit future prospects for large population-based studies and drug development, particularly for generating personalized medicine.Communicated by Ramaswamy H. Sarma.

Transcript-Level In Silico Analysis of Alzheimer's Disease-Related Gene Biomarkers and Their Evaluation with Bioactive Flavonoids to Explore Therapeutic Interactions.

Alzheimer's disease (AD) is a progressive brain disorder that can significantly affect the quality of life. We used a variety of in silico tools to investigate the transcript-level mutational impact of exonic missense rare variations (single nucleotide polymorphisms, SNPs) on protein function and to identify potential druggable protein cavities that correspond to potential therapeutic targets for the management of AD. According to the NIA-AA (National Institute on Aging-Alzheimer's Association) framework, we selected three AD biomarker genes (APP, NEFL, and MAPT). We systematically screened transcript-level exonic rare SNPs from these genes with a minor allele frequency of 1% in 1KGD (1000 Genomes Project Database) and gnomAD (Genome Aggregation Database). With downstream functional effect predictions, a single variation (rs182024939: K > N) of the MAPT gene with nine transcript SNPs was identified as the most pathogenic variation from the large dataset of mutations. The machine learning consensus classifier predictor categorized these transcript-level SNPs as the most deleterious variations, resulting in a large decrease in protein structural stability (ΔΔG kcal/mol). The bioactive flavonoid library was screened for drug-likeness and toxicity risk. Virtual screening of eligible flavonoids was performed using the MAPT protein. Identification of druggable protein-binding cavities showed VAL305, GLU655, and LYS657 as consensus-interacting residues present in the MAPT-docked top-ranked flavonoid compounds. The MM/PB(GB)SA analysis indicated hesperetin (-5.64 kcal/mol), eriodictyol (-5.63 kcal/mol), and sakuranetin (-5.60 kcal/mol) as the best docked flavonoids with the near-native binding pose. The findings of this study provide important insights into the potential of hesperetin as a promising flavonoid that can be utilized for further rational drug design and lead optimization to open new gateways in the field of AD therapeutics.

In Silico Characterization of Withania coagulans Bioactive Compounds as Potential Inhibitors of Hydroxymethylglutaryl (HMG-CoA) Reductase of Mus musculus.

Hypercholesterolemia is a mediator for the etiology of cardiovascular diseases, which are characterized as the global leading cause of mortality. We aimed to investigate the inhibitory activity of Withania coagulans compounds against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) of Mus musculus using an extensive in silico approach. The 3D structure of the Hmgcr protein is not yet known, so we performed the homology modeling using MODELLER and SWISS-MODEL tools, followed with structural validation and assessment. The PROCHECK web server showed that the top-ranked homology model from SWISS-MODEL has 93.4% of residues in the most-favorable region, the quality factor was 98%, and the Verify3D score was 91.43%, compared to the other generated models. The druggable protein-binding cavities in a 3D model of Hmgcr were investigated with the aid of commonly prescribed statin compounds using the CB-dock approach. We compiled a 3D compound library of W. coagulans, followed by drug-likeness evaluation, and found 20 eligible compounds. The pattern of consensus residues obtained from the CB-dock procedure was then used for grid-box docking of W. coagulans compounds and statin drugs using AutoDock 4.2, respectively. The results showed that withanolide R (-10.77 kcal/mol), withanolide Q (-10.56 kcal/mol), withanolide J (-10.52 kcal/mol), atorvastatin (-8.99 kcal/mol), simvastatin (-8.66 kcal/mol), and rosuvastatin (-8.58 kcal/mol) were promising candidates that bind Hmgcr protein. The key residues involved in protein-ligand (withanolide R) interactions were Y516, C526, V529, I530, M533, I535, and V537, and the formation of a H-bond was at C526, M533, and I535 residues. M533 was the consensus residue having a tendency to form a H-bond with withanolide Q, too. Molecular dynamics simulations were used to validate the top-ranked docked complexes for the stability of the modeled protein. We also predicted the pharmacokinetic properties of binding affinity-based top-ranked compounds and concluded that they could be used as potential inhibitors of Hmgcr. However, further in vitro and in vivo studies are essential to completing the drug development process.

Effects of nomophobia on anxiety, stress and depression among Saudi medical students in Jeddah, Saudi Arabia.

OBJECTIVE: To assess the prevalence of depression, anxiety and stress in medical students, and to analyse effects of demographics and nomophobia on depression, anxiety and stress. METHOD: The descriptive cross-sectional study was conducted at the College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia, from April 1 to May 23, 2019, and comprised male and female medical students aged 19-25 years. Data was collected using a demographic information form, the 21-item depression, anxiety and stress scale and the 20-item nomophobia questionnaire. Data was analysed using SPSS 20. RESULTS: Of the 230 students, 108(47%) were boys and 122 (53%) were girls. The overall mean age was 21.93±1.80 years. Anxiety, depression and stress was reported in 168 (74.6%), 158 (70.2%) and 127 (55.9%) of the students. Extremely severe anxiety, depression and stress were self-reported by 92 (40.9%), 38 (16.8%) and 16 (7.04%) students. There was a significant difference in the distribution of subjects within different levels of anxiety across gender (p<0.05). Higher anxiety and stress scores were observed in 78 (33.9%) students with severe nomophobia. Differences in the levels of anxiety and stress with regards to type of residence and nomophobia levels were significant (p<0.05). CONCLUSIONS: There was high prevalence of depression, anxiety and stress associated with gender, nomophobia levels and residence type.

Experiences of expatriate university teachers in a health science university in Saudi Arabia-A Qualitative study.

BACKGROUND AND OBJECTIVE: A large number of university teachers in Saudi Arabia comprise of expatriates. Their experiences are unique in context of the challenges and benefits of academic expatriation. The purpose of this study was to describe the experiences of expatriate university teachers in Saudi Arabia. METHODS: A qualitative descriptive design was used based on in-depth interviews with academic expatriates, recruited through snowball sampling in a Health Science University in Saudi Arabia. The study was conducted from 12 September 2019 to 20 October 2019 after IRB approval. Graneheimian inductive approach was used for content analysis of the data. Standard principles of trustworthiness were applied. RESULTS: Three major themes emerged as 'conscious venture', 'spirit at work' and 'coping strategies'. Each theme had 2-3 subthemes, populated by 14-23 statements. CONCLUSION: Expatriate faculty members described antecedents for their motivations at work. They shared their experiences regarding job adjustments, work environment and professional commitment.