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Frontiers in Molecular Neuroscience 2024Binge drinking in adolescence can disrupt myelination and cause brain structural changes that persist into adulthood. Alcohol consumption at a younger age increases the...
INTRODUCTION
Binge drinking in adolescence can disrupt myelination and cause brain structural changes that persist into adulthood. Alcohol consumption at a younger age increases the susceptibility of these changes. Animal models to understand ethanol's actions on myelin and white matter show that adolescent binge ethanol can alter the developmental trajectory of oligodendrocytes, myelin structure, and myelin fiber density. Oligodendrocyte differentiation is epigenetically regulated by H3K9 trimethylation (H3K9me3). Prior studies have shown that adolescent binge ethanol dysregulates H3K9 methylation and decreases H3K9-related gene expression in the PFC.
METHODS
Here, we assessed ethanol-induced changes to H3K9me3 occupancy at genomic loci in the developing adolescent PFC. We further assessed ethanol-induced changes at the transcription level with qPCR time course approaches in oligodendrocyte-enriched cells to assess changes in oligodendrocyte progenitor and oligodendrocytes specifically.
RESULTS
Adolescent binge ethanol altered H3K9me3 regulation of synaptic-related genes and genes specific for glutamate and potassium channels in a sex-specific manner. In PFC tissue, we found an early change in gene expression in transcription factors associated with oligodendrocyte differentiation that may lead to the later significant decrease in myelin-related gene expression. This effect appeared stronger in males.
CONCLUSION
Further exploration in oligodendrocyte cell enrichment time course and dose response studies could suggest lasting dysregulation of oligodendrocyte maturation at the transcriptional level. Overall, these studies suggest that binge ethanol may impede oligodendrocyte differentiation required for ongoing myelin development in the PFC by altering H3K9me3 occupancy at synaptic-related genes. We identify potential genes that may be contributing to adolescent binge ethanol-related myelin loss.
PubMed: 38840776
DOI: 10.3389/fnmol.2024.1389100 -
The Journal of Biological Chemistry Jun 2024Hearing crucially depends on cochlear ion homeostasis as evident from deafness elicited by mutations in various genes encoding cation or anion channels and transporters....
Hearing crucially depends on cochlear ion homeostasis as evident from deafness elicited by mutations in various genes encoding cation or anion channels and transporters. Ablation of ClC‑K/barttin chloride channels causes deafness by interfering with the positive electrical potential of the endolymph, but roles of other anion channels in the inner ear have not been studied. Here we report the intracochlear distribution of all five LRRC8 subunits of VRAC, a volume-regulated anion channel that transports chloride, metabolites, and drugs such as the ototoxic anti-cancer drug cisplatin, and explore its physiological role by ablating its subunits. Sensory hair cells express all LRRC8 isoforms, whereas only LRRC8A, D and E were found in the potassium-secreting epithelium of the stria vascularis. Cochlear disruption of the essential LRRC8A subunit, or combined ablation of LRRC8D and E, resulted in cochlear degeneration and congenital deafness of Lrrc8a mice. It was associated with a progressive degeneration of the organ of Corti and its innervating spiral ganglion. Like disruption of ClC-K/barttin, loss of VRAC severely reduced the endocochlear potential. However, the mechanism underlying this reduction seems different. Disruption of VRAC, but not ClC-K/barttin, led to an almost complete loss of Kir4.1 (KCNJ10), a strial K channel crucial for the generation of the endocochlear potential. The strong downregulation of Kir4.1 might be secondary to a loss of VRAC-mediated transport of metabolites regulating inner ear redox potential such as glutathione. Our study extends the knowledge of the role of cochlear ion transport in hearing and ototoxicity.
PubMed: 38838775
DOI: 10.1016/j.jbc.2024.107436 -
Science Advances Jun 2024Unlike aquaporins or potassium channels, ammonium transporters (Amts) uniquely discriminate ammonium from potassium and water. This feature has certainly contributed to...
Unlike aquaporins or potassium channels, ammonium transporters (Amts) uniquely discriminate ammonium from potassium and water. This feature has certainly contributed to their repurposing as ammonium receptors during evolution. Here, we describe the ammonium receptor Sd-Amt1, where an Amt module connects to a cytoplasmic diguanylate cyclase transducer module via an HAMP domain. Structures of the protein with and without bound ammonium were determined to 1.7- and 1.9-Ångstrom resolution, depicting the ON and OFF states of the receptor and confirming the presence of a binding site for two ammonium cations that is pivotal for signal perception and receptor activation. The transducer domain was disordered in the crystals, and an AlphaFold2 prediction suggests that the helices linking both domains are flexible. While the sensor domain retains the trimeric fold formed by all Amt family members, the HAMP domains interact as pairs and serve to dimerize the transducer domain upon activation.
Topics: Ammonium Compounds; Cation Transport Proteins; Signal Transduction; Models, Molecular; Binding Sites; Crystallography, X-Ray; Protein Domains; Protein Binding; Amino Acid Sequence
PubMed: 38838143
DOI: 10.1126/sciadv.adm9441 -
Nature Communications Jun 2024Intracellular potassium (K) homeostasis is fundamental to cell viability. In addition to channels, K levels are maintained by various ion transporters. One major family...
Intracellular potassium (K) homeostasis is fundamental to cell viability. In addition to channels, K levels are maintained by various ion transporters. One major family is the proton-driven K efflux transporters, which in gram-negative bacteria is important for detoxification and in plants is critical for efficient photosynthesis and growth. Despite their importance, the structure and molecular basis for K-selectivity is poorly understood. Here, we report ~3.1 Å resolution cryo-EM structures of the Escherichia coli glutathione (GSH)-gated K efflux transporter KefC in complex with AMP, AMP/GSH and an ion-binding variant. KefC forms a homodimer similar to the inward-facing conformation of Na/H antiporter NapA. By structural assignment of a coordinated K ion, MD simulations, and SSM-based electrophysiology, we demonstrate how ion-binding in KefC is adapted for binding a dehydrated K ion. KefC harbors C-terminal regulator of K conductance (RCK) domains, as present in some bacterial K-ion channels. The domain-swapped helices in the RCK domains bind AMP and GSH and they inhibit transport by directly interacting with the ion-transporter module. Taken together, we propose that KefC is activated by detachment of the RCK domains and that ion selectivity exploits the biophysical properties likewise adapted by K-ion-channels.
Topics: Cryoelectron Microscopy; Escherichia coli; Escherichia coli Proteins; Glutathione; Molecular Dynamics Simulation; Potassium; Potassium-Hydrogen Antiporters; Protein Domains
PubMed: 38834573
DOI: 10.1038/s41467-024-49082-7 -
Heliyon Jun 2024A complete model for estimating the electric conductivity of combustion product gases, with added cesium (Cs) or potassium (K) vapor for ionization, is presented....
A complete model for estimating the electric conductivity of combustion product gases, with added cesium (Cs) or potassium (K) vapor for ionization, is presented. Neutral carrier gases serve as the bulk fluid that carries the seed material, as well as the electrons generated by the partial thermal (equilibrium) ionization of the seed alkali metal. The model accounts for electron-neutral scattering, as well as electron-ion and electron-electron scattering. The model is tested through comparison with published data. The model is aimed at being utilized for the plasma within magnetohydrodynamic (MHD) channels, where direct power extraction from passing electrically conducting plasma gas enables electric power generation. The thermal ionization model is then used to estimate the electric conductivity of seeded combustion gases under complete combustion of three selected fuels, namely: hydrogen (H), methane (CH), and carbon (C). For each of these three fuels, two options for the oxidizer were applied, namely: air (21 % molecular oxygen, 79 % molecular nitrogen by mole), and pure oxygen (oxy-combustion). Two types of seeds (with 1 % mole fraction, based on the composition before ionization) were also applied for each of the six combinations of (fuel-oxidizer), leading to a total of 12 different MHD plasma cases. For each of these cases, the electric conductivity was computed for a range of temperatures from 2000 K to 3000 K. The smallest estimated electric conductivity was 0.35 S/m for oxy-hydrogen combustion at 2000 K, with potassium seeding. The largest estimated electric conductivity was 180.30 S/m for oxy-carbon combustion at 3000 K, with cesium seeding. At 2000 K, replacing potassium with cesium causes a gain in the electric conductivity by a multiplicative gain factor of about 3.6 regardless of the fuel and oxidizer. This gain factor declines to between 1.77 and 2.07 at 3000 K. Based on the findings of this research study, the four analyzed factors to increase the electric conductivity of MHD plasma can be listed by their significance (descending order) as (1) type of additive seed type (cesium is better than potassium), (2) temperature (the higher the better), (3) carbon-to-hydrogen ratio of the fuel (the higher the better), and finally (4) the oxidizer type (air is generally better than pure oxygen). The relative size of the two electric conductivity components (due to neutrals scattering and Coulomb scattering) at various plasma conditions are discussed, and a threshold of 10 (0.001 %) electrons mole fraction is suggested to safely neglect Coulomb scattering.
PubMed: 38832275
DOI: 10.1016/j.heliyon.2024.e31697 -
Nature Communications Jun 2024Artificial photosynthesis using carbon nitride (g-CN) holds a great promise for sustainable and cost-effective HO production, but the high carrier recombination rate...
Artificial photosynthesis using carbon nitride (g-CN) holds a great promise for sustainable and cost-effective HO production, but the high carrier recombination rate impedes its efficiency. To tackle this challenge, we propose an innovative method involving multispecies iodine mediators (I/I) intercalation through a pre-photo-oxidation process using potassium iodide (suspected deteriorated "KI") within the g-CN framework. Moreover, we introduce an external electric field by incorporating cationic methyl viologen ions to establish an auxiliary electron transfer channel. Such a unique design drastically improves the separation of photo-generated carriers, achieving an impressive HO production rate of 46.40 mmol g h under visible light irradiation, surpassing the most visible-light HO-producing systems. Combining various advanced characterization techniques elucidates the inner photocatalytic mechanism, and the application potential of this photocatalytic system is validated with various simulation scenarios. This work presents a significative strategy for preparing and applying highly efficient g-CN-based catalysts in photochemical HO production.
PubMed: 38830881
DOI: 10.1038/s41467-024-49046-x -
Oncotarget Jun 2024Ibrutinib was the first Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of patients with chronic lymphocytic leukemia (CLL). While producing durable... (Review)
Review
Ibrutinib was the first Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of patients with chronic lymphocytic leukemia (CLL). While producing durable responses and prolonging survival, roughly 20-25% of patients experience dose limiting side effects, mostly consisting of cardiovascular toxicities like severe hypertension and atrial fibrillation. While clinical predictors of BTK inhibitor-related cardiotoxicity have been proposed and may aid in risk stratification, there is no routine risk model used in clinical practice today to identify patients at highest risk. A recent study investigating genetic predictors of ibrutinib-related cardiotoxicity found that single nucleotide polymorphisms in KCNQ1 and GATA4 were significantly associated with cardiotoxic events. If replicated in larger studies, these biomarkers may improve risk stratification in combination with clinical factors. A clinicogenomic risk model may aid in identifying patients at highest risk of developing BTK inhibitor-related cardiotoxicity in which further risk mitigation strategies may be explored.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Protein Kinase Inhibitors; Cardiotoxicity; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Adenine; Risk Assessment; Pyrimidines; Pyrazoles; Biomarkers; Polymorphism, Single Nucleotide; KCNQ1 Potassium Channel; Tyrosine Kinase Inhibitors
PubMed: 38829647
DOI: 10.18632/oncotarget.28589 -
Frontiers in Cellular Neuroscience 2024Voltage-gated ion channels are essential for membrane potential maintenance, homeostasis, electrical signal production and controlling the Ca flow through the membrane.... (Review)
Review
Voltage-gated ion channels are essential for membrane potential maintenance, homeostasis, electrical signal production and controlling the Ca flow through the membrane. Among all ion channels, the key regulators of neuronal excitability are the voltage-gated potassium channels (K), the largest family of K channels. Due to the ROS high levels in the aging brain, K channels might be affected by oxidative agents and be key in aging and neurodegeneration processes. This review provides new insight about channelopathies in the most studied neurodegenerative disorders, such as Alzheimer Disease, Parkinson's Disease, Huntington Disease or Spinocerebellar Ataxia. The main affected K channels in these neurodegenerative diseases are the K1, K2.1, K3, K4 and K7. Moreover, in order to prevent or repair the development of these neurodegenerative diseases, previous K channel modulators have been proposed as therapeutic targets.
PubMed: 38827782
DOI: 10.3389/fncel.2024.1406709 -
Frontiers in Psychiatry 2024Anxiety and depression in children and adolescents warrant special attention as a public health concern given their devastating and long-term effects on development and...
Anxiety and depression in children and adolescents warrant special attention as a public health concern given their devastating and long-term effects on development and mental health. Multiple factors, ranging from genetic vulnerabilities to environmental stressors, influence the risk for the disorders. This study aimed to understand how environmental factors and genomics affect children and adolescents anxiety and depression across three cohorts: Adolescent Brain and Cognitive Development Study (US, age of 9-10; N=11,875), Consortium on Vulnerability to Externalizing Disorders and Addictions (INDIA, age of 6-17; N=4,326) and IMAGEN (EUROPE, age of 14; N=1888). We performed data harmonization and identified the environmental impact on anxiety/depression using a linear mixed-effect model, recursive feature elimination regression, and the LASSO regression model. Subsequently, genome-wide association analyses with consideration of significant environmental factors were performed for all three cohorts by mega-analysis and meta-analysis, followed by functional annotations. The results showed that multiple environmental factors contributed to the risk of anxiety and depression during development, where early life stress and school support index had the most significant and consistent impact across all three cohorts. In both meta, and mega-analysis, SNP rs79878474 in chr11p15 emerged as a particularly promising candidate associated with anxiety and depression, despite not reaching genomic significance. Gene set analysis on the common genes mapped from top promising SNPs of both meta and mega analyses found significant enrichment in regions of chr11p15 and chr3q26, in the function of potassium channels and insulin secretion, in particular Kv3, Kir-6.2, SUR potassium channels encoded by the KCNC1, KCNJ11, and ABCCC8 genes respectively, in chr11p15. Tissue enrichment analysis showed significant enrichment in the small intestine, and a trend of enrichment in the cerebellum. Our findings provide evidences of consistent environmental impact from early life stress and school support index on anxiety and depression during development and also highlight the genetic association between mutations in potassium channels, which support the stress-depression connection via hypothalamic-pituitary-adrenal axis, along with the potential modulating role of potassium channels.
PubMed: 38827440
DOI: 10.3389/fpsyt.2024.1384298 -
Biochemical and neurophysiological effects of deficiency of the mitochondrial import protein TIMM50.BioRxiv : the Preprint Server For... May 2024TIMM50, an essential TIM23 complex subunit, is suggested to facilitate the import of ∼60% of the mitochondrial proteome. In this study, we characterized a disease...
TIMM50, an essential TIM23 complex subunit, is suggested to facilitate the import of ∼60% of the mitochondrial proteome. In this study, we characterized a disease causing mutation in human fibroblasts, and noted significant decreases in TIM23 core protein levels (TIMM50, TIMM17A/B, and TIMM23). Strikingly, TIMM50 deficiency had no impact on the steady state levels of most of its substrates, challenging the currently accepted import dogma of the essential general import role of TIM23 and suggesting that fully functioning TIM23 complex is not essential for maintaining the steady state level of the majority of mitochondrial proteins. As TIMM50 mutations have been linked to severe neurological phenotypes, we aimed to characterize TIMM50 defects in manipulated mammalian neurons. TIMM50 knockdown in mouse neurons had a minor effect on the steady state level of most of the mitochondrial proteome, supporting the results observed in patient fibroblasts. Amongst the few affected TIM23 substrates, a decrease in the steady state level of components of the intricate oxidative phosphorylation and mitochondrial ribosome complexes was evident. This led to declined respiration rates in fibroblasts and neurons, reduced cellular ATP levels and defective mitochondrial trafficking in neuronal processes, possibly contributing to the developmental defects observed in patients with TIMM50 disease. Finally, increased electrical activity was observed in TIMM50 deficient mice neuronal cells, which correlated with reduced levels of KCNJ10 and KCNA2 plasma membrane potassium channels, likely underlying the patients' epileptic phenotype.
PubMed: 38826427
DOI: 10.1101/2024.05.20.594480