Amin Akbari Ahangar

The gating and function of γ-aminobutyric acid type A receptors (GABA_ARs) depend on their hetero-pentameric subunit composition, yet the rules guiding subunit selection remain unclear. We show that a conserved N-linked glycan in α subunits, uniquely positioned within the extracellular pore, acts as a structural constraint that limits the functional viability of α-containing assemblies. A total of 32 µs of molecular dynamics simulations of native and hypothetical non-canonical assemblies show that adding a third pore-facing glycan or placing two glycans on adjacent subunits disrupts key interactions at the β⁺/α^- interface containing the GABA-binding site. These perturbations propagate allosterically, alter extracellular-transmembrane domain coupling, and promote deep gate closure. Systems with three pore-facing glycans consistently adopt deep-closed conformations, whereas native assemblies with two glycans preserve interfacial integrity and pore hydration. These results identify the pore-facing glycan as a structural constraint on functionally viable GABA_AR architecture and gating.

Voltage-gated sodium (Nav) channels are pivotal for cellular signaling, and mutations in Nav channels can lead to excitability disorders in cardiac, muscular, and neural tissues. A major cluster of pathological mutations localizes in the voltage-sensing domains (VSDs), resulting in either gain-of-function, loss-of-function effects, or both. However, the mechanism behind this functional diversity of mutations at equivalent positions remains elusive. Through hotspot analysis, we identified three gating charges (R1, R2, and R3) as major mutational hotspots in VSDs. The same amino acid substitutions at equivalent gating-charge positions in VSDI and VSDII of the cardiac sodium channel Nav1.5 show differential gating property impacts in electrophysiology measurements. We conducted molecular dynamics (MD) simulations on wild-type channels and six mutants to elucidate the structural basis of their differential impacts. Our 120-µs MD simulations with applied external electric fields captured VSD state transitions and revealed the differential structural dynamics between equivalent R-to-Q mutants. Notably, we observed transient leaky conformations in some mutants during structural transitions, offering a detailed structural explanation for gating-pore currents. Our salt-bridge network analysis uncovered VSD-specific and state-dependent interactions among gating charges, countercharges, and lipids. This detailed analysis revealed how mutations disrupt critical electrostatic interactions, thereby altering VSD permeability and modulating gating properties. By demonstrating the crucial importance of considering the specific structural context of each mutation, our study advances our understanding of structure–function relationships in Nav channels. Our work establishes a robust framework for future investigations into the molecular basis of ion channel–related disorders.

Voltage-gated sodium (Na _v ) channels are pivotal for cellular signaling and mutations in Na _v channels can lead to excitability disorders in cardiac, muscular, and neural tissues. A major cluster of pathological mutations localizes in the voltage-sensing domains (VSDs), resulting in either gain-of-function (GoF), loss-of-function (LoF) effects, or both. However, the mechanism behind this functional divergence of mutations at equivalent positions remains elusive. Through hotspot analysis, we identified three gating charges (R1, R2, and R3) as major mutational hotspots in VSDs. The same amino-acid substitutions at equivalent gating-charge positions in VSD _I and VSD _II of the cardiac sodium channel Na _v 1.5 show differential gating-property impacts in electrophysiology measurements. We conducted 120 µs molecular dynamics (MD) simulations on wild-type and six mutants to elucidate the structural basis of their differential impacts. Our μs-scale MD simulations with applied external electric fields captured VSD state transitions and revealed the differential structural dynamics between equivalent R-to-Q mutants. Notably, we observed transient leaky conformations in some mutants during structural transitions, offering a detailed structural explanation for gating-pore currents. Our salt-bridge network analysis uncovered VSD-specific and state-dependent interactions among gating charges, countercharges, and lipids. This detailed analysis elucidated how mutations disrupt critical electrostatic interactions, thereby altering VSD permeability and modulating gating properties. By demonstrating the crucial importance of considering the specific structural context of each mutation, our study represents a significant leap forward in understanding structure- function relationships in Na _v channels. Our work establishes a robust framework for future investigations into the molecular basis of ion channel-related disorders.

Optimal glucose control is crucial for maintaining brain health and preventing metabolic and cognitive disorders in the general population. Glycosylated hemoglobin (HbA1c) serves as a key marker for assessing glucose intolerance and its impact on brain structure and function in healthy individuals. However, existing literature presents conflicting findings, necessitating a systematic review to consolidate current knowledge in this domain. This systematic review examines 26 English‐language studies involving participants aged 15 years and above, investigating the relationship between HbA1c levels and brain health. Studies focusing on normal/general populations and utilizing magnetic resonance imaging (MRI) as the imaging modality were included. Exclusion criteria encompassed review articles, abstracts, letters, animal studies, and research involving neuropsychiatric or metabolic diseases. Data were gathered from PubMed, Scopus, and Web of Science databases up to November 2023. Analysis reveals significant associations between HbA1c levels and various brain metrics, including volume, cortical thickness, fractional anisotropy, mean diffusivity, activity, and connectivity. However, findings exhibit inconsistency, likely attributed to disparities in sample characteristics and study sizes. Notably, hippocampal volume, white matter hyperintensity, and ventral attention network connectivity emerge as frequently affected structures and functions, mirroring trends observed in diabetic populations. Despite inconclusive evidence, glucose intolerance appears to exert considerable influence on select brain structures and functions in individuals without diagnosed metabolic disorders. Understanding these associations is critical for mitigating the risk of cognitive decline and dementia in healthy populations. Future investigations should aim to elucidate the intricate relationship between HbA1c concentrations and brain health parameters in normoglycemic individuals.

Purpose The COVID-19 pandemic has sparked concerns about weight management because of the changes in population lifestyle. As previous studies suggest, these changes can affect adolescents to a greater degree, especially as schools shut down. Designing a method for weight management that accounts for the specific conditions of the pandemic can help students attend to their physical conditions during the pandemic. Method An online gamified peer pressure group on WhatsApp was employed to help 10th-grade boys in a high school in Tehran, Iran. The available sample consisted of 15 main group students and 13 control students. A paired t-test examined the difference between each group’s initial and final state as well as the group’s final state. Additionally, an ANCOVA test was done to ensure that the observed effect was because of the intervention. Results The initial BMI for the intervention group (µ = 30.68, δ = 3.23) and the control group (µ = 29.73, δ = 3.23) were the same (p = 0.468). Two dropouts in the intervention group were found after forty days. A significant difference between the intervention group’s steady and final states (p = 0.027) was detected; however, this difference was not significant in the control group (p = 0.634). Conclusion Online gamified social groups can play a key role in adolescents’ weight management during the COVID-19 pandemic.

Thousands of voltage-gated sodium (Nav) channel variants contribute to a variety of disorders, including epilepsy, autism, cardiac arrhythmia, and pain disorders. Yet variant effects of more mutations remain unclear. The conventional gain-of-function (GoF) or loss-of-function (LoF) classifications is frequently employed to interpret of variant effects on function and guide precision therapy for sodium channelopathies. Our study challenges this binary classification by analyzing 525 mutations associated with 34 diseases across 366 electrophysiology studies, revealing that diseases with similar phenotypic effects can stem from unique molecular mechanisms. Our results show a high biophysical agreement (86%) between homologous disease-associated variants in different Na _v genes, significantly surpassing the 60% phenotype (GoF _o /LoF _o ) agreement among homologous mutants, suggesting the need for more nuanced disease categorization and treatment based on specific gating-property changes. Using UniProt data, we mapped over 2,400 disease-associated missense variants across nine human Nav channels and identified three clusters of mutation hotspots. Our findings indicate that mutations near the selectivity filter generally diminish the maximal current amplitude, while those in the fast inactivation region lean towards a depolarizing shift in half-inactivation voltage in steady-state activation, and mutations in the activation gate commonly enhance persistent current. In contrast to mutations in the PD, those within the VSD exhibit diverse impacts and subtle preferences on channel activity. This study shows great potential to enhance prediction accuracy for variant effects based on the structural context, laying the groundwork for targeted drug design in precision medicine.

Purpose Defining a standard norm is critical in nutritional cognitive-behavioral interventions. These norms can be derived from a statistical or value-based point of view. Religion and subsequent cultural values can have significant effects on social behaviors, especially on eating habits. In this study, the authors quantify the presence of religio-cultural nutritional behavior norms in Abrahamic scriptures. Methods Qualitative content analysis and descriptive analysis were applied to these texts to provide a better understanding of the subject. Results The extracted norms were categorized into nine main behavioral domains, and most of the observed value-based norms were in agreement with previous experimental researches. Conclusion There is strong emphasis on nutritional habits in value-based religio-cultural sources. The use of these norms in later policies and practices is advised. This approach can lead to healthier nutritional choices and a decrease in non-communicable diseases.

Background: Stachys lavandulifolia Vahl is an herbaceous perennial plant which its flowering aerial parts are used traditionally as gastrotonic, spasmolytic, sedative and for the treatment of gastrointestinal disorders. In the present study the aerial parts of this medicinal plant was investigated for its flavonoid glycosides content. Methods: n-butanol fraction derived from hydroalcoholic extract of S. lavandulifolia was subjected to phytochemical analysis using chromatography on Sephadex LH-20 and RP-18 silica gel columns. The structures of isolated compounds were identified using ¹H-NMR, ¹³C-NMR and UV spectral analysis. Results: Four flavone glycosides, chrysoeriol-7-O-β-D-glucopyranoside (1), apigenin-7-O-(6″-O-acetyl)-β-D-glucopyranoside (2), luteolin-7-O-β-D-glucopyranoside (3), apigenin-7-O-β-D-glucopyranoside (4), along with apigenin (5) and chlorogenic acid (6) were isolated from S. lavandulifolia aerial parts. Conclusion: Identification of these phenolic compounds with some known biological activities in S. lavandulifolia explains some medicinal properties reported for this species and make scientific rationale for its traditional uses.