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Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory impairment, and behavioral alterations. The N-methyl-D-aspartate (NMDA) receptor has emerged as a promising target for AD pharmacotherapy due to its role in the disease's pathogenesis. This study leverages advanced computational methods to screen 80 active constituents of Withania somnifera (Ashwagandha), a traditional herb known for its neuroprotective effects, against the NMDA receptor, using FDA-approved Ifenprodil as a reference. Our blind virtual screening results demonstrated that all tested compounds could bind to various domains of the NMDA receptor, with binding energies ranging from - 4.1 to -11.9 kcal/mol, compared to Ifenprodil's -7.8 kcal/mol. Binding preference analysis revealed 7 compounds bound to the A-chain, 37 to the B-chain, 7 to the C-chain, and 29 to the D-chain of the receptor. Notable binding was observed predominantly at the Amino Terminal Domain (ATD) core site, some at the ATD-Ligand Binding Domain (LBD) interface, and a few at the Transmembrane Domain (TMD). Particularly, 17alpha-hydroxywithanolide D, with a binding energy of -11.9 kcal/mol, emerged as a prime candidate for further investigation. Molecular dynamics simulations of this compound revealed key interactions, including direct hydrogen bonding with residues ASP165, ARG431, THR433, LYS466, and TYR476 on the D-chain, as well as additional hydrophobic and water-bridging interactions. These simulations highlighted the compound's influence on dynamic conformational states of the GluN1b-GluN2B receptor complex, modulating interactions between GluN1b Lys178 and GluN2B Asn184. Furthermore, the compound affected the distance between LBD heterodimers and the tension within the LBD-M30 linker, demonstrating its potential to modulate NMDA receptor activity. This comprehensive study not only underscores the therapeutic promise of Withania somnifera derivatives for AD but also provides a detailed molecular basis for their efficacy, offering valuable insights for targeted drug development and innovative therapeutic strategies against Alzheimer's disease., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

A0A6P1CI42_RHITR, a protein originating from Rhizobium tropici strain CIAT 899, has emerged as a key player in leguminous plant symbiosis and nitrogen fixation processes. Understanding the intricate details of its structure and function holds immense significance for unraveling the molecular mechanisms underlying its biological activities. In this study, we employed molecular modeling and molecular dynamics (MD) simulations to investigate the A0A6P1CI42_RHITR protein, with a specific emphasis on the influence of Fe-atoms, linker structural integrity, and conformational changes within the GAF domain. Our findings unveiled noteworthy conformational changes in the A0A6P1CI42_RHITR protein, particularly within the GAF domain, when Fe-atoms were present compared to its apo form. Significant conformational rearrangements after an initial 20 ns, accompanied by the opening of the ligand substrate accommodating loop in the GAF domain influenced by Fe-atoms was observed. At the residue level, the investigation revealed substantial activity variations in individual residues, particularly in those contributing to the GAF domain from positions 51 to 223. Intriguingly, the presence of Fe-atoms led to controlled movement of conserved cysteine residues at positions 467 and 472, indicating a correlation between interlinker domain motion and the activity of the GAF domain loop responsible for substrate accommodation. Moreover, in the presence of Fe-atoms, the distance between Cys467 and Cys472 residues was maintained, ensuring the overall structural integrity of the interdomain loop necessary for protein activation. Conversely, in the apo form, a sudden flip motion of cysteine residues' thiol groups was observed, leading to a loss of structural integration. Overall, our study utilizing molecular modeling and MD simulations offers valuable insights into the structural dynamics and functional implications of the A0A6P1CI42_RHITR protein.Communicated by Ramaswamy H. Sarma.

The highly spreading virus, COVID-19, created a huge need for an accurate and speedy diagnosis method. The famous RT-PCR test is costly and not available for many suspected cases. This article proposes a neurotrophic model to diagnose COVID-19 patients based on their chest X-ray images. The proposed model has five main phases. First, the speeded up robust features (SURF) method is applied to each X-ray image to extract robust invariant features. Second, three sampling algorithms are applied to treat imbalanced dataset. Third, the neutrosophic rule-based classification system is proposed to generate a set of rules based on the three neutrosophic values < T; I; F>, the degrees of truth, indeterminacy falsity. Fourth, a genetic algorithm is applied to select the optimal neutrosophic rules to improve the classification performance. Fifth, in this phase, the classification-based neutrosophic logic is proposed. The testing rule matrix is constructed with no class label, and the goal of this phase is to determine the class label for each testing rule using intersection percentage between testing and training rules. The proposed model is referred to as GNRCS. It is compared with six state-of-the-art classifiers such as multilayer perceptron (MLP), support vector machines (SVM), linear discriminant analysis (LDA), decision tree (DT), naive Bayes (NB), and random forest classifiers (RFC) with quality measures of accuracy, precision, sensitivity, specificity, and F1-score. The results show that the proposed model is powerful for COVID-19 recognition with high specificity and high sensitivity and less computational complexity. Therefore, the proposed GNRCS model could be used for real-time automatic early recognition of COVID-19., Competing Interests: Conflict of InterestThe authors of this paper declare that there is no conflict of interest regarding its publication., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021.)

Background: Expressed by endothelial cells, CDH5 is a cadherin involved in vascular morphogenesis and in the maintenance of vascular integrity and lymphatic function. The main purpose of our study was to identify distinct variants of the CDH5 gene that could be associated with lymphatic malformations and predisposition for lymphedema. Methods and Results: We performed Next Generation Sequencing of the CDH5 gene in 235 Italian patients diagnosed with lymphedema but who tested negative for variants in known lymphedema genes. We detected six different variants in CDH5 five missense and one nonsense. We also tested available family members of the probands. For family members who carried the same variant as the proband, we performed lymphoscintigraphy to detect any lymphatic system abnormalities. Variants were modeled in silico. The results showed that CDH5 variants may contribute to the onset of lymphedema, although further in vitro studies are needed to confirm this hypothesis. Conclusions: Based on our findings, we propose CDH5 as a new gene that could be screened in patients with lymphedema to gather additional evidence.

Macrophages are considered to be key players in innate immunity and inflammatory responses. Domestic cattle with standard body size quickly reach their heat tolerance limit and are prone to heat stress. The combined effects of high temperature and endotoxemia on bovine monocyte-derived macrophages remain almost undisclosed. This study aims to unravel the molecular and functional responses of bovine monocyte-derived macrophages to thermal cum lipopolysaccharide induced stress challenge in vitro. The cells were incubated at 37 °C or 40 °C with lipopolysaccharide (1.0 μg/mL) for 24 h and 48 h. At the end of each treatment, cell viability, apoptotic rate, mitochondrial membrane potential, oxidative activity, phagocytosis, and autophagy functions were assessed and mRNA abundance of genes related to heat shock (HSP 70), inflammation (IL1β, IL6, IL 12, TNF, INF γ), cell signalling (TLR4), cell viability (Bax, Bcl2), nitric oxide synthesis (NOS2) and natural resistant associated macrophage protein were quantified by quantitative polymerase chain reaction (qPCR). The results revealed the increased apoptosis, reduced mitochondrial membrane potential, and cell viability, decreased oxidative and phagocytosis ability in cells co-stimulated with LPS and thermal stimuli. Upregulation of HSP 70 gene and downregulation of natural resistant associated macrophage protein, cell signalling, and inflammation related genes mRNA expressions were also identified due to these stressors. In conclusion, the observed thermal cum LPS stress induced dysregulation in macrophage functionality may be one facet of the increased disease susceptibility in dairy cattle during thermal stress., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Carbonic anhydrases catalyze the reversible hydration of carbon dioxide to form bicarbonate, a reaction required for many functions such as carbon assimilation, pH acid-base homeostasis, respiration and photosynthesis via a zinc-hydroxide mechanism for carbon dioxide hydration. In earlier studies, it was revealed that Carbonic anhydrases are inactive at pH 7.5 and active at pH 8.4. This steep pH dependence for its activity led us to design this work to understand its mode of action at atomic level detail. In our microsecond simulation based analysis, it was revealed that the interaction between Glu106 and Thr199 plays a critically important role in its activity. Thr199 co-ordinated loop movement was observed to be acting as a lid, with 'open' and 'close' mechanism for substrate entry to the core of the catalytic site, where Zn-ion resides and executes its carbon dioxide hydration mechanism. On the other hand, decline in the total secondary structural elements percentage in the protein was observed in correspondence to the pH condition change. The α-helices between Thr125-Gly145 and Val150-Lys170 residues were especially noticed to be losing their structural integrity responsible for formation of dimer and tetramers. In conclusion, our analysis showed that the interaction between Glu106 and Thr199 is crucial for maintaining the structural integrity of the Thr199 coordinated loop, responsible for allowing substrate towards the catalytic site.Communicated by Ramaswamy H. Sarma.