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Sestrin2 (SESN2) is a highly conserved stress-inducible protein that serves as a central hub for integrating cellular responses to nutrient availability, oxidative stress, and endoplasmic reticulum (ER) stress. A key function of SESN2 is its role as a direct sensor for the branched-chain amino acid (BCAA) leucine, which modulates the activity of the mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of cell growth and metabolism. While the functional link between leucine and SESN2 is well-established, the precise molecular determinants that confer its high specificity for leucine over other BCAAs, such as isoleucine and valine, remain poorly understood. This study employs an integrated computational approach, spanning atomic interactions to global protein dynamics, combining molecular docking, extensive all-atom molecular dynamics (MD) simulations, and binding free energy calculations, to elucidate the structural and dynamic basis of BCAA-SESN2 recognition. Our thermodynamic analysis reveals a distinct binding affinity hierarchy (Leucine > Isoleucine > Valine), which is primarily driven by superior van der Waals interactions and the shape complementarity of leucine’s isobutyl side chain within the protein’s hydrophobic pocket. Critically, a quantitative analysis of the conformational ensemble reveals that leucine induces a dramatic collapse of the protein’s structural heterogeneity. This “conformational locking” mechanism funnels the flexible, high-entropy unbound protein—which samples 35 distinct conformations—into a sharply restricted ensemble of just 9 stable states. This four-fold reduction in conformational freedom is accompanied by a kinetic trapping effect, which significantly lowers the rate of transitions between states. This process of conformational selection stabilizes a well-defined, signaling-competent structure, providing a comprehensive, atom-to-global-scale model of SESN2’s function. In the context of these findings, this work provides a critical framework for understanding SESN2’s complex role in disease and offers a clear rationale for the design of next-generation allosteric therapeutics.

This study delves into the correlation existing between the managerial prowess of CEOs and the performance of sustainability initiatives, drawing insights from the upper echelon theory. Through a comprehensive triple-down analysis, we ascertain whether an augmentation in managerial capabilities expedites the adoption of practices promoting environmental, social and economic sustainability (recognized as the pillars of sustainability). Furthermore, the research delves into the impact of CEOs’ career horizons on the relationship between CEO’s managerial ability and sustainability performance. Employing a panel data methodology on a dataset encompassing Chinese publicly listed companies spanning the years 2010 to 2019, our findings reveal a positive influence of CEOs’ managerial competence on the overall sustainability endeavors of these firms. These outcomes maintain their robustness even after subjecting them to various alternative empirical examinations. The conclusions drawn from these findings substantiate the interconnection between managerial skill and sustainability performance, underscoring the discrete impacts on each facet of the sustainability pillars. The identification of the potential for fostering sustainability practices through the skillful dissemination of management skills stands as a pivotal inference with significant implications for practitioners in the field. JEL Classification: G34, M12, Q56. Plain language summary There are a lot of factors which influence the manager’s decisions and strategy. The study is critical because it investigates the most important requisite of the organization’s leader, “the ability of the CEO.” Moreover, it establishes the stance on how the ability impacts the sustainability practices of the organization. While digging deep, this study presents the triple-down analysis of sustainability performance, that is, three pillars of sustainability, namely social sustainability, economic sustainability, and environmental sustainability. This is the first study that has (1) researched the relation of CEO’s managerial ability with sustainability in developing economy, (2) has classified sustainability into its main pillars and studied each one with CEO’s ability. Using panel data methodology on Chinese listed firms from 2010 to 2019, we report that CEO’s managerial ability impacts the overall sustainability practices of the firms positively. Moreover, we find that social sustainability and economic sustainability also increases with the increase of the CEO’s managerial ability of the firm. We could not reach any significant relationship of environmental sustainability with managerial ability. Our results remain robust after utilizing various methodologies and definitions. Our findings confirm the upper echelon theory’s insights that illustrate that the firm’s top leadership characteristics influence firm-level decisions.

Diabetes mellitus is prevalent worldwide, with vascular complications responsible for over 70% of deaths associated with the condition. Methylglyoxal (MGO), a by-product of glycolysis, is a significant modulator of vascular dysfunction in diabetes. Sestrin2 (SESN2) has been recognized as a vital regulator of cellular homeostasis and stress responses. Although SESN2’s role in cellular defense is gaining recognition, its precise function in endothelial cells under diabetic-like conditions remains poorly understood. This study examines the role of SESN2 in preserving endothelial cell angiogenic function under MGO-induced stress. The study reveals that SESN2 is a vital regulator of multiple protective pathways, as demonstrated by both loss-of-function and gain-of-function approaches in EA.hy926 endothelial cells. Our data showed that SESN2 overexpression significantly maintained tubular network formation, proliferation, and invasive capacity under MGO stress, whereas SESN2 silencing exacerbated MGO-induced impairment of angiogenic capacity. SESN2 was identified as orchestrating NRF2/HO-1 antioxidant pathway activation while simultaneously enhancing VEGF-C expression, offering a dual strategy for cellular protection and angiogenesis. Moreover, SESN2 facilitated a regulated equilibrium of the AKT/mTOR signaling pathway, ensuring synchronized activation during stress conditions. SESN2 also regulated stress-activated MAPK pathways, diminishing P38 and ERK1/2 activation upon MGO exposure. This study highlights SESN2 as a pivotal regulator of endothelial cell homeostasis and angiogenic activity under MGO-induced stress, indicating its potential as a therapeutic target for addressing diabetic vascular complications and improving patient outcomes.

Metabolic syndrome (MetS) poses a substantial health risk, particularly in Qatar. This study aimed to compare the diagnostic accuracy of various indices for MetS identification in a well-characterized Qatari cohort from Qatar Biobank (QBB). This cross-sectional study included 692 adults (≥18 years) from the QBB, categorized into MetS and healthy groups using the International Diabetes Federation (IDF) criteria. We compared the distributions of biochemical, anthropometric, and combined indices between groups. Logistic regression assessed associations with MetS, adjusting for demographics. Receiver Operating Characteristic (ROC) analysis evaluated discriminative performance and identified optimal thresholds. Robustness was tested using a 75/25 train-test split. Stratified analyses examined the influence of age, gender, and nationality. The MetS prevalence was 19.1% among participants. Individuals with MetS displayed significantly higher levels of all indices compared to the healthy group. Triglycerides (adjusted odd ratio (AOR): 4.93), waist circumference (AOR: 3.87), and lipid accumulation product (LAP) (AOR: 14.91) showed the strongest associations within their respective categories. LAP achieved the highest discriminative performance (area under the curve (AUC): 0.896; 95% CI: 0.870-0.923), followed by the visceral adiposity index (VAI) (AUC: 0.877) and TyG × waist circumference (AUC: 0.872). LAP's optimal threshold was 37.1, with a sensitivity of 0.856 and a specificity of 0.789. Combined indices consistently outperformed individual measures. Discriminative accuracy was comparable across genders and nationalities but higher in individuals under 45 years. Combined indices, particularly LAP, demonstrate superior discriminative ability for MetS in this Qatari cohort. Incorporating LAP into routine clinical practice could improve MetS detection and facilitate timely interventions. Further validation in larger, diverse populations is, however, warranted.

Sestrin2 (SESN2) is a stress-inducible protein known for its cytoprotective functions, but its role in diabetic vascular complications remains unclear. This study investigated the impact of SESN2 on methylglyoxal (MGO)-induced endothelial-mesenchymal transition (EndMT). Human endothelial cells were transfected with SESN2 siRNA duplexes to silence SESN2 expression, followed by MGO treatment. SESN2 knockdown significantly exacerbated MGO-induced oxidative stress, as evidenced by the reduced expression of antioxidant markers. Furthermore, SESN2 silencing enhanced the inflammatory response to MGO, demonstrated by the increased levels of pro-inflammatory cytokines. Notably, SESN2 deficiency promoted EndMT, a key process in diabetes-induced cardiovascular complications, as shown by the increased expression of mesenchymal markers and the decreased expression of endothelial markers. These findings suggest that SESN2 plays a critical protective role in endothelial cells against MGO-induced damage. The study provides novel insights into the molecular mechanisms underlying diabetic cardiovascular complications and identifies SESN2 as a potential therapeutic target for preventing endothelial dysfunction in diabetes. Our results indicate that SESN2 downregulation may contribute to the pathogenesis of diabetic vascular complications by promoting EndMT, increased oxidative stress, and inflammation.

Pseudomonas aeruginosa is a Gram-negative pathogenic bacterium that is present commonly in soil and water and is responsible for causing septic shock, pneumonia, urinary tract and gastrointestinal infections, etc. The multi-drug resistance (MDR) phenomenon has increased dramatically in past years and is now considered a major threat globally, so there is an urgent need to develop new strategies to overcome drug resistance by P. aeruginosa. In P. aeruginosa, a major factor of drug resistance is associated to the formation of biofilms by the LasR enzyme, which regulates quorum sensing and has been reported as a new therapeutic target for designing novel antibacterial molecules. In this study, virtual screening and molecular docking were performed against the ligand binding domain (LBD) of LasR by employing a pharmacophore hypothesis for the screening of 2373 FDA-approved compounds to filter top-scoring hit compounds. Six inhibitors out of 2373 compounds were found to have binding affinities close to that of known LasR inhibitors. The binding modes of these compounds to the binding site in LasR-LBD were analyzed to identify the key interactions that contribute to the inhibition of LasR activity. Then, 50 ns simulations of top hit compounds were performed to elucidate the stability of their binding conformations with the LasR-LBD. This study, thus concluded that sulfamerazine showed the highest binding affinity for the LasR-LBD binding pocket exhibiting strong inhibitory binding interactions during molecular dynamics (MD) simulation.

Diabetes mellitus (DM) is recognized as one of the oldest chronic diseases and has become a significant public health issue, necessitating innovative therapeutic strategies to enhance patient outcomes. Traditional treatments have provided limited success, highlighting the need for novel approaches in managing this complex disease. In our study, we employed graph signature-based methodologies in conjunction with molecular simulation and free energy calculations. The objective was to engineer the CA33 monoclonal antibody for effective targeting of the aP2 antigen, aiming to elicit a potent immune response. This approach involved screening a mutational landscape comprising 57 mutants to identify modifications that yield significant enhancements in binding efficacy and stability. Analysis of the mutational landscape revealed that only five substitutions resulted in noteworthy improvements. Among these, mutations T94M, A96E, A96Q, and T94W were identified through molecular docking experiments to exhibit higher docking scores compared to the wild-type. Further validation was provided by calculating the dissociation constant (K ), which showed a similar trend in favor of these mutations. Molecular simulation analyses highlighted T94M as the most stable complex, with reduced internal fluctuations upon binding. Principal components analysis (PCA) indicated that both the wild-type and T94M mutant displayed similar patterns of constrained and restricted motion across principal components. The free energy landscape analysis underscored a single metastable state for all complexes, indicating limited structural variability and potential for high therapeutic efficacy against aP2. Total binding free energy (TBE) calculations further supported the superior performance of the T94M mutation, with TBE values demonstrating the enhanced binding affinity of selected mutants over the wild-type. Our findings suggest that the T94M substitution, along with other identified mutations, significantly enhances the therapeutic potential of the CA33 antibody against DM by improving its binding affinity and stability. These results not only contribute to a deeper understanding of antibody-antigen interactions in the context of DM but also provide a valuable framework for the rational design of antibodies aimed at targeting this disease more effectively.

A timely and adequate response to stress is inherently present in each cell and is important for maintaining the proper functioning of the cell in changing intracellular and extracellular environments. Disruptions in the functioning or coordination of defense mechanisms against cellular stress can reduce the tolerance of cells to stress and lead to the development of various pathologies. Aging also reduces the effectiveness of these defense mechanisms and results in the accumulation of cellular lesions leading to senescence or death of the cells. Endothelial cells and cardiomyocytes are particularly exposed to changing environments. Pathologies related to metabolism and dynamics of caloric intake, hemodynamics, and oxygenation, such as diabetes, hypertension, and atherosclerosis, can overwhelm endothelial cells and cardiomyocytes with cellular stress to produce cardiovascular disease. The ability to cope with stress depends on the expression of endogenous stress-inducible molecules. Sestrin2 (SESN2) is an evolutionary conserved stress-inducible cytoprotective protein whose expression is increased in response to and defend against different types of cellular stress. SESN2 fights back the stress by increasing the supply of antioxidants, temporarily holding the stressful anabolic reactions, and increasing autophagy while maintaining the growth factor and insulin signaling. If the stress and the damage are beyond repair, SESN2 can serve as a safety valve to signal apoptosis. The expression of SESN2 decreases with age and its levels are associated with cardiovascular disease and many age-related pathologies. Maintaining sufficient levels or activity of SESN2 can in principle prevent the cardiovascular system from aging and disease.

Bruton's Tyrosine Kinase (BTK) is an anchor in B-cell receptor signaling and plays an important role in chronic lymphocytic leukemia (CLL). The use of covalent inhibitors of BTK, such as ibrutinib, enhances the survival of patients with CLL. However, mutations at the C481 residue cause resistance to ibrutinib and diminish its clinical efficacy. Recently, super-resistant mutants, i.e., T474M-C481S and T474I-C481S, were reported to cause manifold resistance to the BTK-targeting drug, ibrutinib; however, the mechanism of this resistance is still elusive. Structure-based approaches proved to be effective in deciphering drug resistance mechanisms (s) that could guide the development of novel, effective therapeutics. Therefore, we used molecular modeling combined with biophysical simulation approaches to determine the impact of T474M-C481S and T474I-C481S mutations on the binding of ibrutinib. Our results revealed that essential hydrogen bonds and a covalent interaction with C481 are lost due to these mutations. Using µs simulations, our results revealed that the regions 432-439 and 545-559 demonstrated dynamically unstable behavior with the transition of secondary structure, where a helix to loop and loop to helix transition could be observed. Structural compactness, residue flexibility, and average hydrogen bonds in each trajectory reported significant variations. The binding free energy calculation using MM-GBSA (Molecular Mechanics Generalized Born Surface Area) and MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) approaches revealed that both the vdW and electrostatic energies are reduced in mutants. Using the MM-PBSA approach, the wild type demonstrated a total binding free energy (TBE) of -42.65 ± 0.08 kcal/mol, while T474M-C481S and T474I-C481S had TBE values of -38.81 ± 0.18 kcal/mol, and - 33.04 ± 0.13 kcal/mol, respectively. The MM-GBSA results revealed that the wild type had a TBE of -60.33 ± 0.06 kcal/mol, while the TBE values for T474M-C481S and T474M-C481S mutants were - 53.18 ± 0.12 kcal/mol and - 49.12 ± 0.10 kcal/mol, respectively. PCA and FEL results further revealed the dynamic variations caused by these mutations. These findings underline the significant impact of mutations T474M and C481S on the binding free energy, highlighting the importance of these residues in ibrutinib-BTK interactions.