Pediatric neurological disorders are a diverse group of conditions affecting the nervous system in children, often challenging to diagnose due to their nonspecific and overlapping clinical features. Advances in molecular diagnostics, particularly whole exome sequencing (WES), have significantly improved the identification of genetic causes, enabling precise diagnoses and personalized treatments. This study explores the application of WES in diagnosing pediatric neurological disorders within Moroccan childrens with undiagnosed or challenging pediatric neurological conditions to uncover genetic causes of complex pediatric neurological conditions unresolvable by traditional diagnostic methods. The study included 188 pediatric patients with complex neurological conditions from the Children’s Hospital of Rabat who underwent exome sequencing to investigate suspected genetic causes. WES revealed a diagnostic yield of 45%, identifying conditions such as intellectual disabilities, hereditary metabolic disorders and epilepsies. It also uncovered neurodevelopmental and neurodegenerative disorders, neuromuscular diseases, and genetic syndromes. A total of 157 variants were detected: 34% were classified as pathogenic, 28.5% as likely pathogenic, and 37.5% as variants of uncertain significance (VUS). These findings underscore the utility of WES as a robust diagnostic tool, providing insights into genetic causes and enabling tailored treatment strategies. They also highlight the importance of expanding genetic research to improve diagnostic accuracy and clinical management of pediatric neurological disorders.

The re-emergence of monkeypox virus (MPXV) as a global public health concern highlights the urgent need for novel therapeutic strategies targeting viral proteins essential for infection. This study investigates the inhibitory potential of Trans-Cannabitriol (trans-CBT), a minor cannabinoid, against MPXV proteins L1R, H3L, and E8L using an integrative in silico framework. Homology modeling was employed to generate 3D structures of these proteins, followed by molecular docking and 1 µs molecular dynamics (MD) simulations. The trans-CBT demonstrated strong binding affinities for L1R (−10.76 kcal/mol) and E8L (−8.531 kcal/mol), with weaker interactions observed for H3L (−5.739 kcal/mol). Four MD simulations of 1 µs revealed that trans-CBT stabilizes L1R by reducing its flexibility and solvent exposure, potentially inhibiting viral entry into host cells. In contrast, trans-CBT increased the flexibility and conformational changes of E8L, possibly impairing its function in viral attachment and pathogenesis. ADMET and target prediction analyses further supported its drug-likeness and safety, with the absence of strong CB1/CB2 binding suggesting that trans-CBT may exert its antiviral effects independently of classical cannabinoid pathways. These findings provide insights into the diverse mechanisms of action of trans-CBT on MPXV proteins and underscore its potential as a broad-spectrum antiviral agent. While promising, further experimental validation and optimization are necessary to assess the real-world applicability of trans-CBT in combating MPXV infections. This work contributes to the expanding field of cannabinoid-derived antivirals and highlights the importance of exploring under-investigated phytochemicals for therapeutic applications.

Scorpion envenomation, a grave public health concern, is primarily driven by the potent neurotoxins chlorotoxin and leiurotoxin present in Leiurus species venom. Developing effective treatments is crucial to mitigate its impact. Utilizing a drug-repositioning bioinformatics-based approach, potential inhibitors of these neurotoxins were identified from Food and Drug Administration (FDA)-approved drugs. Through virtual screening and subsequent molecular dynamics simulations, their ability to stabilize the peptides over time was evaluated. Among the compounds scrutinized, bolazine emerged as a promising candidate, demonstrating significant affinity for both neurotoxins, indicating potential dual inhibitory activity. Molecular dynamics simulations further corroborated the enhanced stability of bolazine complexes compared to neurotoxins alone. These findings suggest the feasibility of repurposing existing drugs to develop new therapeutic strategies to treat scorpion envenomation. Such interventions hold promise in alleviating the severe health repercussions of scorpion stings and meeting the urgent demand for effective remedies in affected communities.

Autism spectrum disorder (ASD) is genetically heterogeneous, involving rare and common variants that disrupt neurodevelopmental pathways. To explore this complexity, we performed whole-exome sequencing in children with ASD. Clinical phenotypes were systematically recorded, and severity was classified according to DSM-5 criteria. Variants were interpreted using ACMG guidelines, with recurrence analysis to identify genes shared across individuals and cohort enrichment testing against gnomAD. To examine genotype-phenotype relationships, we applied SKAT/SKAT-O across 16 phenotypes after covariate adjustment. Among 25 included individuals, pathogenic or likely pathogenic variants were found in 9, yielding a diagnostic yield of 36%. These involved genes linked to neurodevelopmental, epileptic, metabolic, and syndromic disorders. Recurrence analysis identified 586 genes present in at least two individuals, with PABPC1, GTF2I, PCLO, PKD1, and EP400 being the most frequent. SKAT/SKAT-O revealed the strongest burden associations for motor delay, aggressive behavior, mutism, anxiety, unresponsiveness to spoken voice, digestive disorder, and sleep disturbances, with limited overlap across phenotypes. Several recurrent genes also showed phenotype-specific associations. Overall, this integrative WES study provides clinically actionable diagnoses, highlights recurrent genes, and uncovers phenotype-specific signals, supporting convergent pathways with gene-level heterogeneity.

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer, accounting for 15% to 20% of cases, is often resistant to treatment. Delta-9-tetrahydrocannabinol (THC) disrupts HER2-cannabinoid receptor (2CB2) receptor complexes and inhibits HER2 activation. This study evaluates whether Nabilone, a synthetic cannabinoid, can similarly disrupt HER2-CB2 interactions. A CB2-HER2 complex model was generated via protein-protein docking. Three 1-µs molecular dynamics simulations (CB2-HER2, CB2-HER2-THC, CB2-HER2-Nabilone) were performed using the Schrodinger Desmond with membrane embedding and solvent. Structural stability (root mean square deviation [RMSD] and root mean square fluctuation [RMSF]), binding free energy (molecular mechanics/generalized born surface area [MM/GBSA]), and intracellular/extracellular distances between receptors were analyzed. Intermolecular interactions were assessed using the MAPIYA server. Nabilone induced comparable structural instability to THC, with increased RMSD and RMSF. The MM/GBSA analysis showed Nabilone increased the binding free energy between CB2 and HER2, indicating stronger disruption. Intracellular and extracellular distances between CB2 and HER2 increased, especially intracellularly, with Nabilone. Intermolecular interaction analysis revealed that Nabilone decreased the number of contacts, particularly hydrophobic interactions, between CB2 and HER2. Our in silico model predicts that Nabilone may disrupt the HER2-CB2 complex, suggesting a hypothesis that it could serve as a potential therapeutic agent. These computational findings warrant urgent experimental validation.

Introduction: Immune checkpoint blockade targeting PD-1/PD-L1 has revolutionized cancer treatment; however, resistance remains a major clinical challenge. V-domain Immunoglobulin Suppressor of T cell Activation (VISTA), a B7 family member with high expression in tumor-infiltrating lymphocytes of ovarian cancer, has emerged as a promising alternative target for immunotherapeutic intervention. Materials and Methods: We performed in silico screening of 9,397 DrugBank compounds against PD-L1 and VISTA using AutoDock Vina. The top candidates based on docking scores were assessed through 100 ns molecular dynamics simulations, and binding free energies were calculated via MM-PBSA. Results: DB15637, DB12867, and DB06744 showed the strongest PD-L1 binding affinities (−7.33 to −7.87 kcal/mol) with average RMSD values of 8.89 Å, 8.94 Å, and 7.57 Å, respectively. DB00321 exhibited the highest affinity for VISTA (−7.31 kcal/mol) with an RMSD of 6.18 Å, maintaining stable interactions with key residues throughout the simulation. Discussion: The identified compounds demonstrated favorable docking scores, dynamic stability, and binding free energies, suggesting their potential as PD-L1 and VISTA inhibitors. Dual checkpoint targeting could enhance antitumor immune responses in ovarian cancer, where both proteins contribute to immune evasion. Conclusion: This in silico study identified promising candidates for PD-L1 and VISTA inhibition. These findings provide a computational basis for further experimental validation to confirm their therapeutic potential in the treatment of ovarian cancer.