Search Results (72)

The axon initial segment (AIS) is a specialized subcellular domain that plays an essential role in action potential initiation and the diffusion barrier. A key organizer of the AIS is Ankyrin-G, a scaffolding protein responsible for clustering voltage-gated ion channels, cell adhesion molecules (CAMs), and cytoskeletal components at this critical neuronal domain. Recent proteomic analyses have revealed a complex network of proteins in the AIS, emphasizing Ankyrin-G’s central role in its molecular architecture. This review discusses new findings in the study of AIS-associated proteins. It explains how Ankyrin-G and its binding partners (such as ion channels, CAMs, spectrins, actin, and microtubule-associated proteins including end-binding protein 3, tripartite motif-containing protein 46, and calmodulin-regulated spectrin-associated protein 2) organize their structure. Understanding the dynamic regulation and molecular interactions within the AIS offers insights into neuronal excitability and reveals potential therapeutic targets for axonal dysfunction–related diseases. Through these dynamic interactions, Ankyrin-G ensures the proper alignment and dense clustering of key channel complexes, thereby maintaining the AIS’s distinctive molecular and functional identity. By further unraveling the complexity of Ankyrin-G’s interactome, our understanding of AIS formation, maintenance, and plasticity will be considerably enhanced, contributing to the elucidation of the pathogenesis of neurological and neuropsychiatric disorders. Full article

Steel fiber-reinforced concrete structures designed for marine environments can become compromised by the ingress of water and ions. Water and ion transport through the pores between steel fibers and concrete gels significantly affects the durability of such structures, but the mechanisms of this transport are not sufficiently understood. Reported here is a molecular dynamics-based investigation of the transport of water, NaCl, Na₂SO₄, and mixed solutions of NaCl and Na₂SO₄ through γ–FeOOH/CSH pores. The effect of pore width on the capillary transport of NaCl + Na₂SO₄ solutions was also investigated and reported. It is shown that the depth of water penetration in NaCl solution increases parabolically with time. It is further shown that the CSH surface forms bonds with different ions to form Na–O_CSH, Cl–Ca_CSH, and S–Ca_CSH compounds, which results in reduced rates of solution transport. The mixed NaCl + Na₂SO₄ solution was found to have the lowest transport rate. A reduction in pore width was found to reduce the transport rate of water molecules and diminish the transport of ions. In pores smaller than 2.5 nm in width, the immobilized ions aggregate into clusters, occupying pore inlets and blocking more ions from entering the channels. Compared with the matrix on both sides, solutions are transported significantly faster along the CSH side than along the γ–FeOOH side, indicating that the addition of steel fibers can effectively slow down the transport of water molecules and ions in concrete. These data on the difference in the transport of solutions along the two sides of the matrix may provide molecular-level insights to support studies on the durability of concrete materials. Full article

The SCN9A gene, a critical regulator of pain perception, encodes the voltage-gated sodium channel Nav1.7, a key mediator of pain signal transmission. This study conducts a multimodal assessment of SCN9A, integrating genetic variation, structural architecture, and molecular dynamics to elucidate its role in pain regulation. Using advanced computational methods, I-TASSER simulations generated structural decoys of the SCN9A homology domain, producing an ensemble of conformational states. SPICKER clustering identified five representative models with a C-score of −3.19 and TM-score of 0.36 ± 0.12, reflecting moderate structural similarity to experimental templates while highlighting deviations that may underpin functional divergence. Validation via ProSA-web supported model reliability, yielding a Z-score of −1.63, consistent with native-like structures. Central to the analysis was the R1150W non-synonymous variant, a potential pathogenic variant. Structural modeling revealed localized stability in the mutant conformation but disrupted hydrogen bonding and altered charge distribution. Its pathogenicity was underscored by a high MetaRNN score (0.7978498) and proximity to evolutionarily conserved regions, suggesting functional importance. Notably, the variant lies within the Sodium-Ion-Transport-Associated Domain, where perturbations could impair ion conductance and channel gating—mechanisms critical for neuronal excitability. These findings illuminate how SCN9A variants disrupt pain signaling, linking genetic anomalies to molecular dysfunction. While computational insights advance mechanistic understanding, experimental validation is essential to confirm the variant’s impact on Nav1.7 dynamics and cellular physiology. By refining SCN9A’s molecular blueprint and highlighting its therapeutic potential as a target for precision analgesics, this work provides a roadmap for mitigating pain-related disorders through channel-specific modulation. Integrating structural bioinformatics with functional genomics, this study deciphers SCN9A’s role in pain biology, laying the groundwork for novel strategies to manage pathological pain. Full article

In the presence of cellular mutations and impaired mechanisms of energy transmission to the attached cells and tissues, excess energy is available to upregulate some of the mechanotransduction pathways that maintain cell and tissue structure and function. The ability to transfer applied energy through integrin-mediated pathways, cell ion channels, cell membrane, cytoskeleton–nucleoskeleton connections, cell junctions, and cell–extracellular matrix attachments provides an equilibrium for energy storage, transmission, and dissipation in tissues. Disruption in energy storage, transmission, or dissipation via genetic mutations blocks mechanical communication between cells and tissues and impairs the mechanical energy equilibrium that exists between cells and tissues. This results in local structural changes through altered regulatory pathways, which produce cell clustering, collagen encapsulation, and an epithelial–mesenchymal transition (EMT), leading to increased cellular motility along newly reorganized collagen fibers (fibrosis). The goal of this review is to postulate how changes in energy transfer between cells and the extracellular matrix may alter local energy equilibrium and mechanotransduction pathways. The changes along with cellular mutations lead to cell and ECM changes reported in cancer, which is postulated to modify mechanical equilibria between cells and their ECM. This leads to uncontrolled cancer cellular proliferation and collagen remodeling. Full article

Primary aldosteronism is characterised by the excessive production of aldosterone, which is a key regulator of salt metabolism, and is the most common cause of secondary hypertension. Studies have investigated the association between primary aldosteronism and genetic alterations, with pathogenic mutations being identified. This includes a glycine-to-arginine substitution at position 151 (G151R) of the G protein-activated inward rectifier potassium (K⁺) channel 4 (GIRK4), which is encoded by the KCNJ5 gene. Mutations in GIRK4 have been found to reduce the selectivity for K⁺ ions, resulting in membrane depolarisation, the activation of voltage-gated Ca²⁺ channels, and an increase in aldosterone secretion. As a result, there is an interest in identifying and exploring the mechanisms of action of small molecule modulators of wildtype (WT) and mutant channels. In order to investigate the potential modulation of homotetrameric GIRK4^WT and GIRK4^G151R channels, homology models were generated. Molecular dynamics (MD) simulations were performed, followed by a cluster analysis to extract starting structures for molecular docking. The central cavity has been previously identified as a binding site for small molecules, including natural compounds. The OliveNet^TM database, which consists of over 600 compounds from Olea europaea, was subsequently screened against the central cavity. The binding affinities and interactions of the docked ligands against the GIRK4^WT and GIRK4^G151R channels were then examined. Based on the results, luteolin-7-O-rutinoside, pheophorbide a, and corosolic acid were identified as potential lead compounds. The modulatory activity of olive-derived compounds against the WT and mutated forms of the GIRK4 channel can be evaluated further in vitro. Full article

Time-dependent deformation in nuclear graphite is influenced by the creation and migration of radiation-induced defects in the reactor environment. This study investigates the role of pre-existing defects such as point defect clusters and Mrozowski cracks in nuclear graphite IG-110. Separate specimens were irradiated with a 2.8 MeV Au²⁺ beam with a fluence of 4.38 × 10¹⁴ cm⁻² and an 8 MeV C²⁺ beam with a fluence of 1.24 × 10¹⁶ cm⁻². Microscopic specimens were either mechanically loaded inside a transmission electron microscope (TEM) or subjected to ex situ indentation-based creep loading. In situ TEM tests showed significant plasticity in regions highly localized around the Mrozowski cracks, resembling slip or ripplocation bands. Slip bands were also seen near regions without pre-existing defects but at very high stresses. Ex situ self-ion irradiation embrittled the specimens and decreased the creep displacement and rate, while heavy ion irradiation resulted in the opposite behavior. We hypothesize that the large-sized gold ions (compared to the carbon atoms) induced interplanar swelling as well as cross-plane channels for increased defect mobility. These findings illustrate the role of pre-existing defects in the dynamic relaxation of stresses during irradiation and the need for more studies into the radiation environment’s impact on the mechanical response of nuclear graphite. Full article

The human louse (Pediculus humanus) is an obligatory blood feeding ectoparasite with two ecotypes: the human body louse (Pediculus humanus humanus), a competent vector of several bacterial pathogens, and the human head louse (Pediculus humanus capitis), responsible for pediculosis and affecting millions of people around the globe. GABA (γ-aminobutyric acid) receptors, members of the cys-loop ligand gated ion channel superfamily, are among the main pharmacological targets for insecticides. In insects, there are four subunits of GABA receptors: resistant-to-dieldrin (RDL), glycin-like receptor of drosophila (GRD), ligand-gated chloride channel homologue3 (LCCH3), and 8916 are well described and form distinct phylogenetic clades revealing orthologous relationships. Our previous studies in the human body louse confirmed that subunits Phh-RDL, Phh-GRD, and Phh-LCCH3 are well clustered in their corresponding clades. In the present work, we cloned and characterized a putative new GABA receptor subunit in the human body louse that we named HoCas, for Homologous to Cys-loop α like subunit. Extending our analysis to arthropods, HoCas was found to be conserved and clustered in a new (fifth) phylogenetic clade. Interestingly, the gene encoding this subunit is ancestral and has been lost in some insect orders. Compared to the other studied GABA receptor subunits, HoCas exhibited a relatively higher expression level in all development stages and in different tissues of human body louse. These findings improved our understanding of the complex nature of GABA receptors in Pediculus humanus and more generally in arthropods. Full article

Na_1.36(Si_0.86Ga_0.14)₂As_2.98 and Li_1.5Ga_0.9Si_3.1As₄ were synthesized by heating mixtures of the elements at 950 °C. The crystal structures were determined by single crystal X-ray diffraction (Na_1.36(Si_0.86Ga_0.14)₂As_2.98: I4₁/a, Z = 100, a = 19.8772(4) Å, c = 37.652(1) Å; Li_1.5Ga_0.9Si_3.1As₄: C2/c, Z = 8, a = 10.8838(6) Å, b = 10.8821(6) Å, c = 13.1591(7) Å). Na_1.36(Si_0.86Ga_0.14)₂As_2.98 crystallizes similar to NaSi₂P₃ with interpenetrating networks of vertex-sharing T4 and T5 supertetrahedra. Gallium substitution at the silicon sites increases the charge of the cluster network, which is compensated for by a 36% higher sodium content. Since in contrast to NaSi₂P₃, all sodium sites are now fully occupied, there is no significant ion mobility, as indicated by ²³Na-NMR. Consequently, the total sodium-ion conductivity of Na_1.36(Si_0.86Ga_0.14)₂As_2.98 amounts to only 1.6(1) × 10⁻⁷ S cm⁻¹ and is therefore three orders of magnitude lower than in NaSi₂P₃. Li_1.5Ga_0.9Si_3.1As₄ crystallizes in a new structure type with layers of edge-sharing (Si_1−xGa_x)As₄ tetrahedra alternating with layers that contain infinite Si_n zigzag chains. Lithium ions reside in channels between the chains, and thus, the structure does not provide three dimensional pathways for ion conduction and the measured total Li-ion conductivity amounts to only 1.3(1) × 10⁻⁷ S cm⁻¹. Full article

During mammalian heart development, the clustered genes encoding peptide hormones, Natriuretic Peptide A (NPPA; ANP) and B (NPPB; BNP), are transcriptionally co-regulated and co-expressed predominately in the atrial and ventricular trabecular cardiomyocytes. After birth, expression of NPPA and a natural antisense transcript NPPA-AS1 becomes restricted to the atrial cardiomyocytes. Both NPPA and NPPB are induced by cardiac stress and serve as markers for cardiovascular dysfunction or injury. NPPB gene products are extensively used as diagnostic and prognostic biomarkers for various cardiovascular disorders. Membrane-localized guanylyl cyclase receptors on many cell types throughout the body mediate the signaling of the natriuretic peptide ligands through the generation of intracellular cGMP, which interacts with and modulates the activity of cGMP-activated kinase and other enzymes and ion channels. The natriuretic peptide system plays a fundamental role in cardio-renal homeostasis, and its potent diuretic and vasodilatory effects provide compensatory mechanisms in cardiac pathophysiological conditions and heart failure. In addition, both peptides, but also CNP, have important intracardiac actions during heart development and homeostasis independent of the systemic functions. Exploration of the intracardiac functions may provide new leads for the therapeutic utility of natriuretic peptide-mediated signaling in heart diseases and rhythm disorders. Here, we review recent insights into the regulation of expression and intracardiac functions of NPPA and NPPB during heart development, homeostasis, and disease. Full article

Both pandemic and seasonal influenza are major health concerns, causing significant mortality and morbidity. Current influenza drugs primarily target viral neuraminidase and RNA polymerase, which are prone to drug resistance. Polyoxometalates (POMs) are metal cation clusters bridged by oxide anions. They have exhibited potent anti-tumor, antiviral, and antibacterial effects. They have remarkable activity against various DNA and RNA viruses, including human immunodeficiency virus, herpes simplex virus, hepatitis B and C viruses, dengue virus, and influenza virus. In this study, we have identified sodium polyoxotungstate (POM-1) from an ion channel inhibitor library. In vitro, POM-1 has been demonstrated to have potent antiviral activity against H1N1, H3N2, and oseltamivir-resistant H1N1 strains. POM-1 can cause virion aggregation during adsorption, as well as endocytosis. However, the aggregation is reversible; it does not interfere with virus adsorption and endocytosis. Our results suggest that POM-1 exerts its antiviral activity by inhibiting the nuclear import of viral ribonucleoprotein (vRNP). This distinct mechanism of action, combined with its wide range of efficacy, positions POM-1 as a promising therapeutic candidate for influenza treatment and warrants further investigation. Full article

Nanostructure formation on Co(110) surfaces was studied by using irradiation with cluster ion beams with oblique incidence and an energy of 250 eV/atom. In this work, the effect of the mass of the cluster projectiles on the process was analyzed. The launched clusters were formed by different types of charged atoms: He, Ne, Ar, Kr, and Xe. Due to the different collision processes, the formed surface patterns stand out more if the mass of the projectile atoms is greater, regardless of the angle of incidence of the clusters. Two processes control the morphological evolution of the surface during the bombardment phase: sputtering erosion and surface atomic redistribution. At grazing angles, the contribution of sputtering is greater during the process. In fact, heavier species give greater sputtering, and the redistribution factor becomes lower. The weight of redistribution is greater for intermediate angles above the critical angle (50° and 60°), since the displacement is greater for heavier species, and the redistribution factor takes substantially higher values. The experimental results point to a shift in the critical angle with the mass of the projectile atom. In the case of He, a very light ion, the results are marked by channeling and vertical displacements. Full article

In this report we present seven lines of bioinformatic evidence supporting the conclusion that the Pentameric Ligand-gated Ion Channel (pLIC) Family is a member of the Voltage-gated Ion Channel (VIC) Superfamily. In our approach, we used the Transporter Classification Database (TCDB) as a reference and applied a series of bioinformatic methods to search for similarities between the pLIC family and members of the VIC superfamily. These include: (1) sequence similarity, (2) compatibility of topology and hydropathy profiles, (3) shared domains, (4) conserved motifs, (5) similarity of Hidden Markov Model profiles between families, (6) common 3D structural folds, and (7) clustering analysis of all families. Furthermore, sequence and structural comparisons as well as the identification of a 3-TMS repeat unit in the VIC superfamily suggests that the sixth transmembrane segment evolved into a re-entrant loop. This evidence suggests that the voltage-sensor domain and the channel domain have a common origin. The classification of the pLIC family within the VIC superfamily sheds light onto the topological origins of this family and its evolution, which will facilitate experimental verification and further research into this superfamily by the scientific community. Full article

Dendritic structures play a pivotal role in the computational processes occurring within neurons. Signal propagation along dendrites relies on both passive conduction and active processes related to voltage-dependent ion channels. Among these channels, extrasynaptic N-methyl-D-aspartate channels (exNMDA) emerge as a significant contributor. Prior studies have mainly concentrated on interactions between synapses and nearby exNMDA (100 nm–10 µm from synapse), activated by presynaptic membrane glutamate. This study concentrates on the correlation between synaptic inputs and distal exNMDA (>100 µm), organized in clusters that function as signal amplifiers. Employing a computational model of a dendrite, we elucidate the mechanism underlying signal amplification in exNMDA clusters. Our findings underscore the pivotal role of the optimal spatial positioning of the NMDA cluster in determining signal amplification efficiency. Additionally, we demonstrate that exNMDA subunits characterized by a large conduction decay constant. Specifically, NR2B subunits exhibit enhanced effectiveness in signal amplification compared to subunits with steeper conduction decay. This investigation extends our understanding of dendritic computational processes by emphasizing the significance of distant exNMDA clusters as potent signal amplifiers. The implications of our computational model shed light on the spatial considerations and subunit characteristics that govern the efficiency of signal amplification in dendritic structures, offering valuable insights for future studies in neurobiology and computational neuroscience. Full article

The expansion of copper mining on the hyper-arid pacific slope of Southern Peru has precipitated growing concern for scarce water resources in the region. Located in the headwaters of the Torata river, in the department of Moquegua, the Cuajone mine, owned by Southern Copper, provides a unique opportunity in a little-studied region to examine the relative impact of the landscape-scale mining on water resources in the region. Principal component and cluster analyses of the water chemistry data from 16 sites, collected over three seasons during 2017 and 2018, show distinct statistical groupings indicating that, above the settlement of Torata, water geochemistry is a function of chemical weathering processes acting upon underlying geological units, and confirming that the Cuajone mine does not significantly affect water quality in the Torata river. Impact mitigation strategies that firstly divert channel flow around the mine and secondly divert mine waste to the Toquepala river and tailings dam at Quebrada Honda remove the direct effects on the water quality in the Torata river for the foreseeable future. In the study area, our results further suggest that water quality has been more significantly impacted by urban effluents and agricultural runoff than the Cuajone mine. The increase in total dissolved solids in the waters of the lower catchment reflects the cumulative addition of dissolved ions through chemical weathering of the underlying geological units, supplemented by rapid recharge of surface waters contaminated by residues associated with agricultural and urban runoff through the porous alluvial aquifer. Concentrations in some of the major ions exceeded internationally recommended maxima for agricultural use, especially in the coastal region. Occasionally, arsenic and manganese contamination also reached unsafe levels for domestic consumption. In the lower catchment, below the Cuajone mine, data and multivariate analyses point to urban effluents and agricultural runoff rather than weathering of exposed rock units, natural or otherwise, as the main cause of contamination. Full article

Piezo1 is a mechanosensitive ion channel required for various biological processes, but its regulation remains poorly understood. Here, we used erythrocytes to address this question since they display Piezo1 clusters, a strong and dynamic cytoskeleton and three types of submicrometric lipid domains, respectively enriched in cholesterol, GM1 ganglioside/cholesterol and sphingomyelin/cholesterol. We revealed that Piezo1 clusters were present in both the rim and the dimple erythrocyte regions. Upon Piezo1 chemical activation by Yoda1, the Piezo1 cluster proportion mainly increased in the dimple area. This increase was accompanied by Ca²⁺ influx and a rise in echinocytes, in GM1/cholesterol-enriched domains in the dimple and in cholesterol-enriched domains in the rim. Conversely, the effects of Piezo1 activation were abrogated upon membrane cholesterol depletion. Furthermore, upon Piezo1-independent Ca²⁺ influx, the above changes were not observed. In healthy donors with a high echinocyte proportion, Ca²⁺ influx, lipid domains and Piezo1 fluorescence were high even at resting state, whereas the cytoskeleton membrane occupancy was lower. Accordingly, upon decreases in cytoskeleton membrane occupancy and stiffness in erythrocytes from patients with hereditary spherocytosis, Piezo1 fluorescence was increased. Altogether, we showed that Piezo1 was differentially controlled by lipid domains and the cytoskeleton and was favored by the stomatocyte–discocyte–echinocyte transformation. Full article