Chloride Transport Research Articles

The Cl- transporter ClC-7 is essential for phagocytic clearance by microglia.

Microglia, professional phagocytic cells of the brain, rely upon the appropriate activation of lysosomes to execute their immune and clearance functions. Lysosomal activity is, in turn, modulated by a complex network of over 200 membrane and accessory proteins that relay extracellular cues to these key degradation centers. The ClC-7 chloride (Cl-)-proton (H+) antiporter (also known as CLCN7) is localized to the endolysosomal compartments and mutations in CLCN7 lead to osteopetrosis and neurodegeneration. Although the functions of ClC-7 have been extensively investigated in osteoclasts and neurons, its role in microglia in vivo remains largely unexamined. Here, we show that microglia and embryonic macrophages in zebrafish clcn7 mutants cannot effectively process extracellular debris in the form of apoptotic cells and β-amyloid. Despite these functional defects, microglia develop normally in clcn7 mutants and display normal expression of endosomal and lysosomal markers. We also find that mutants for ostm1, which encodes the β-subunit of ClC-7, have a phenotype that is strikingly similar to that of clcn7 mutants. Together, our observations uncover a previously unappreciated role of ClC-7 in microglia and contribute to the understanding of the neurodegenerative phenotypes that accompany mutations in this channel.

The Lucigenin Assay: Measuring Anion Transport in Lipid Vesicles

AbstractInvited for this month′s cover are the collaborating groups of the Université libre de Bruxelles and Masaryk University. The cover picture shows liposomes with a fluorescent probe encapsulated to study the transmembrane transport of chloride by synthetic anion transporters via quenching of the fluorescence. More information can be found in the Concept article by Hennie Valkenier and co‐workers.

Mimicking the Shape and Function of the ClC Chloride Channel Selective Pore by Combining a Molecular Hourglass Shape with Anion-π Interactions.

ClC is the main family of natural chloride channel proteins that transport Cl- across the cell membrane with high selectivity. The chloride transport and selectivity are determined by the hourglass-shaped pore and the filter located in the central and narrow region of the pore. Artificial unimolecular channel that mimics both the shape and function of the ClC selective pore is attractive, because it could provide simple molecular model to probe the intriguing mechanism and structure-function relevance of ClC. Here we elaborated upon the concept of molecular hourglass plus anion-π interactions for this purpose. The concept was validated by experimental results of molecular hourglasses using shape-persistent 1,3-alternate tetraoxacalix[2]arene[2]triazine as the central macrocyclic skeleton to control the conductance and selectivity, and anion-π interactions as the driving force to facilitate the chloride dehydration and movement along the channel.

Developmental loss of NMDA receptors results in supernumerary forebrain neurons through delayed maturation of transit-amplifying neuroblasts

Developmental neurogenesis is a tightly regulated spatiotemporal process with its dysregulation implicated in neurodevelopmental disorders. NMDA receptors are glutamate-gated ion channels that are widely expressed in the early nervous system, yet their contribution to neurogenesis is poorly understood. Notably, a variety of mutations in genes encoding NMDA receptor subunits are associated with neurodevelopmental disorders. To rigorously define the role of NMDA receptors in developmental neurogenesis, we used a mutant zebrafish line (grin1−/−) that lacks all NMDA receptors yet survives to 10 days post-fertilization, offering the opportunity to study post-embryonic neurodevelopment in the absence of NMDA receptors. Focusing on the forebrain, we find that these fish have a progressive supernumerary neuron phenotype confined to the telencephalon at the end of embryonic neurogenesis, but which extends to all forebrain regions during postembryonic neurogenesis. This enhanced neuron population does not arise directly from increased numbers or mitotic activity of radial glia cells, the principal neural stem cells. Rather, it stems from a lack of timely maturation of transit-amplifying neuroblasts into post-mitotic neurons, as indicated by a decrease in expression of the ontogenetically-expressed chloride transporter, KCC2. Pharmacological blockade with MK-801 recapitulates the grin1−/− supernumerary neuron phenotype, indicating a requirement for ionotropic signaling. Thus, NMDA receptors are required for suppression of indirect, transit amplifying cell-driven neurogenesis by promoting maturational termination of mitosis. Loss of suppression results in neuronal overpopulation that can fundamentally change brain circuitry and may be a key factor in pathogenesis of neurodevelopmental disorders caused by NMDA receptor dysfunction.

Cystic Fibrosis Lung Disease: A Narrative Literature Review

Cystic fibrosis (CF) is caused by mutations in autosomal recessive genes that code for proteins cystic fibrosis transmembrane conductance regulator (CFTR) which is located on chromosome seven. The CFTR protein under normal conditions acts as a chloride channel and helps the movement of sufficient electrolytes and water across the membrane. Mutations in CFTR cause abnormalities in chloride ion transport through epithelial cells and impaired sodium and water transport resulting in viscous secretions with low water content. This thick and sticky secretion will inhibit the normal function of various organs, although pulmonary complications are the most common cause of death. Cystic fibrosis has wide genotypic and phenotypic variations. There are six categories of mutations based on their effect on the CFTR protein, where these categories are not only used to predict the phenotype but also to determine better therapeutic strategies based on the identified mutations.

Mesoscopic statistics-based probability characteristics of chloride transport and reliability-based corrosion initiation life of bridge tower

Chloride-induced corrosion involves multiple factors and uncertainties. This study focuses on the probabilistic and multifactorial prediction model for the reliability and service life of reinforced concrete structures in marine environments. We present a new probabilistic framework to quantify the uncertainty of chloride transport by mesoscopic statistics and Spearman correlation analysis and develop a modified chloride transport model, incorporating multi-factors such as time dependence, admixture usage, temperature, relative humidity, stress level, freeze-thaw cycles, chloride binding capacity, aggregate volume fraction, aggregate particle size, and concrete deterioration. Taking the Shenzhen-Zhongshan Bridge as an example, by considering the chloride diffusion coefficient, concrete cover thickness, convection zone thickness, critical chloride concentration, and surface chloride concentration as random variables, the first-order reliability method (FORM) was employed to determine the time-variant reliability index and service life of the example bridge in different environmental conditions, encompassing atmospheric, splashing, tidal, and submerged zones. The sensitivity of the time-variant reliability to these random variables and the impact of the non-random variables on the reliability index were investigated quantitatively and comparatively. The findings reveal significant temporal and spatial variability in chloride diffusion coefficients due to the random arrangement of aggregates within concrete. The study demonstrates that concrete cover thickness and chloride diffusion coefficient are the most influential variables on structural reliability and emphasizes the substantial impact of admixtures, concrete deterioration, and environmental factors on the time-variant reliability. This research offers a significant reference in the reliability design, safety assessment, and maintenance of concrete structures in chloride-rich environments.

Interaction and Transport of Benzalkonium Chlorides by the Organic Cation and Multidrug and Toxin Extrusion Transporters.

Humans are chronically exposed to benzalkonium chlorides (BACs) from environmental sources. The U.S. Food and Drug Administration (FDA) has recently called for additional BAC safety data, as these compounds are cytotoxic and have great potential for biochemical interactions. Biodistribution studies revealed that BACs extensively distribute to many tissues and accumulate at high levels, especially in the kidneys, but the underlying mechanisms are unclear. In this study, we characterized the interactions of BACs of varying alkyl chain length (C8 to C14) with the human organic cation transporters (hOCT1-3) and multidrug and toxin extrusion proteins (hMATE1/2K) with the goal to identify transporters that could be involved in BAC disposition. Using transporter-expressing cell lines, we showed that all BACs are inhibitors of hOCT1-3 and hMATE1/2K (IC50 ranging 0.83-25.8 μM). Further, the short-chain BACs (C8 and C10) were identified as substrates of these transporters. Interestingly, although BAC C8 displayed typical Michaelis-Menten kinetics, C10 demonstrated a more complex substrate-inhibition profile. Transwell studies with transfected Madin-Darby canine kidney cells revealed that intracellular accumulation of basally applied BAC C8 and C10 was substantially higher (8.2- and 3.7-fold, respectively) in hOCT2/hMATE1 double-transfected cells in comparison with vector-transfected cells, supporting a role of these transporters in mediating renal accumulation of these compounds in vivo. Together, our results suggest that BACs interact with hOCT1-3 and hMATE1/2K as both inhibitors and substrates and that these transporters may play important roles in tissue-specific accumulation and potential toxicity of short-chain BACs. Our findings have important implications for understanding human exposure and susceptibility to BACs due to environmental exposure. SIGNIFICANCE STATEMENT: Humans are systemically exposed to benzalkonium chlorides (BACs). These compounds broadly distribute through tissues, and their safety has been questioned by the FDA. Our results demonstrate that hOCT2 and hMATE1 contribute to the renal accumulation of BAC C8 and C10 and that hOCT1 and hOCT3 may be involved in the tissue distribution of these compounds. These findings can improve our understanding of BAC disposition and toxicology in humans, as their accumulation could lead to biochemical interactions and deleterious effects.

Phase-field chemo-mechanical modelling of corrosion-induced cracking in reinforced concrete subjected to non-uniform chloride-induced corrosion

A model for corrosion-induced cracking of reinforced concrete subjected to non-uniform chloride-induced corrosion is presented. The gradual corrosion initiation of the steel surface is investigated by simulating chloride transport considering binding. The transport of iron from the steel surface, its subsequent precipitation into rust, and the associated precipitation-induced pressure are explicitly modelled. Model results, obtained through finite element simulations, agree very well with experimental data, showing significantly improved accuracy over uniform corrosion modelling. The results obtained from case studies reveal that crack-facilitated transport of chlorides cannot be neglected, that the size of the anodic region must be considered, and that precipitate accumulation in pores can take years.

Mesoscopic characteristics and spatiotemporal variability of chloride transport in concrete

Chloride-induced corrosion is the leading cause of structural performance deterioration and life decay in marine environments. This paper delves into the mesoscopic characteristics and spatiotemporal variability of chloride transport in concrete. We conducted extensive mesoscopic simulations to reveal the effects of ITZ and aggregate volume fraction, morphology, size, and particle quantity on chloride transport. We identified the probability characteristics of chloride concentration and diffusion coefficient based on statistical analysis of the mesoscopic simulation results. We proposed a novel probabilistic framework and predictive model for chloride diffusion coefficients incorporating aggregate parameters like volume fraction and particle size. The findings of this study demonstrate that the chloride transport shows noteworthy spatiotemporal variability; the aggregate size effect, aggregate particle quantity effect, and the local effect of large aggregates are all significant characteristics of the chloride transport in addition to the pre-discovered dilution effect, tortuosity effect, and ITZ effect. The chloride diffusion coefficient approximately follows a log-normal distribution, whereas the chloride concentration roughly follows a normal or log-normal distribution. The findings in this work are instrumental in predicting the probabilistic chloride transport and service life of reinforced concrete structures.

Raman Spectroscopy and Cystic Fibrosis Disease: An Alternative Potential Tool for Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulator Response Differentiation-A Pilot Study Based on Serum Samples.

Cystic fibrosis (CF) is a genetic disorder that alters chloride transport in mucous membranes. Recent studies have demonstrated that treatment with modulators of the chloride channel reduces inflammatory markers, restoring, among others, the imbalance of lipids. In this study, we analyzed the serum samples of treated and non-treated patients with modulators with Raman spectroscopy. Nineteen (eight treated an eleven non-treated) patients were considered. The main difference between the two groups appeared in the 3020-2800 cm-1 range. A Voigt deconvolution fit was performed, and nine sub-bands were identified. To distinguish between treated and non-treated patients, the area ratio between the CH3 and CH2 vibration modes was calculated for each patient. The results were validated using statistical analyses. In particular, receiver operating characteristic (ROC) curves and Youden index (Y) were calculated (Area Under Curve (AUC): 0.977; Y: 3.30). An ROC curve represents the performance of the classification, illustrating the diagnostic ability of Raman spectroscopy. It was demonstrated that Raman spectroscopy is able to highlight peculiar differences between elexacaftor/tezacaftor/ivacaftor (ETI)-treated and non-treated patients, in relation with lipids biomarkers.

Effect of ITZ on chloride ion transport in recycled aggregate concrete: Analytical and numerical studies

The weaker ITZ is one of the significant differences between recycled concrete and ordinary concrete. How the weaker ITZ between recycled aggregate and mortar in recycled concrete affects the transport mechanism of chloride ions has become the main obstacle to the large-scale promotion and recycling of demolished building waste. To tackle this issue, a novel equivalent single-phase analytical method was proposed and a series of numerical simulations with different ITZ distributions and characteristics were carried out. The research results indicated that the transport of chloride ions in recycled aggregate concrete was primarily controlled by the diffusion coefficient, volume, and distribution of the ITZ (mainly affected by recycled aggregates). The current analytical methods effectively described the aggregate blocking effect and ITZ effect. The research results revealed that the addition of recycled aggregate within a certain range had little effect on chloride ion transport (the difference in the effect of 30 % and 35 % recycled aggregates addition on chloride ion transport was within 5 %). However, once the volume fraction of aggregates exceeded the threshold, the transfer rate of chloride ions increased sharply. Furthermore, the uniform mixing of recycled aggregates was crucial. As the ITZ non-uniformity coefficient increased, the ITZ diffusion coefficient increased. The weaker ITZ of recycled concrete amplified the impact of concrete cracks, ITZ-crack channels of chloride ions were formed even if minor cracks developed. Current research provided technical support for the durability design of recycled concrete structures.

Probing and evaluating transmembrane chloride ion transport in double walled trifluorophenyl/phthalimide extended calix[4]pyrrole-based supramolecular receptors.

Therapeutic applications have sparked increased interest in the use of synthetic anion receptors for ion transport across lipid membranes. In this context, the construction of synthetic transmembrane transporters for the physiologically important chloride ion is currently of enormous interest. As a result, considerable effort is being devoted to the design and synthesis of artificial transmembrane chloride ion transporters. However, only inadequate progress has been made in developing macrocyclic chloride ion transporters using the fundamental principles of supramolecular chemistry, and hence this field entails fostering investigations. In this investigation, the synthesis of two new double walled trifluorophenyl/phthalimide extended calix[4]pyrrole (C4P) receptors (3 and 7) has been successfully reported. 1H-NMR titration and HRMS studies confirmed the 1 : 1 binding stoichiometry of the chloride ion with these receptors in the solution phase (only receptor 3b was studied by 1H-NMR). Regarding ion transport of 3b and 7, when studied in the HPTS-based vesicular system, 3b showed better activity with an EC50 value of 0.39 μM. The detailed ion transport studies on 3b have revealed that ion transport occurs through the Cl-/NO3- antiport mode.

Platinum-based metal complexes as chloride transporters that trigger apoptosis.

In this paper we demonstrate that Pt(ii) complexes can function as efficient transmembrane chloride transporters. A series of Pt(ii) metal complexes with urea-appended isoquinoline ligands were synthesised and operate via classical hydrogen bonding interactions rather than ligand exchange. A number of the complexes exhibited potent transmembrane chloride activity in vesicle studies, while also showing strong antiproliferative activity in cisplatin-resistant cell lines via induction of apoptosis and inhibition of intracellular ROS.

Assessment of Progression Markers for Cirrhosis in Cystic Fibrosis Patients

Cystic Fibrosis is an autosomal dominant disease that affects the CFTR gene, which is responsible for producing a protein that regulates the transport of chloride ions across the cell membrane. This alteration results in obstruction in the body's ducts and channels, primarily affecting the pulmonary system. Additionally, other systems can be affected. Cystic Fibrosis-related liver disease is a common complication that can lead to steatosis, fibrosis, and multifocal biliary cirrhosis; however, there are no well-established diagnostic criteria yet. The present study was conducted at the Cystic Fibrosis Outpatient Clinic of the Hospital de Clínicas, Federal University of Paraná, examining 98 medical records of patients with cystic fibrosis for at least 10 years. Patients with hepatitis B, hepatitis C, alcohol consumption, or pregnancy were excluded. The objective was to determine the best predictor for the outcome of cirrhosis, and for this purpose, demographic parameters, laboratory tests, and imaging were collected. The statistical analysis was performed using SPSS® software, with quantitative variables described as mean ± standard deviation and categorical variables presented as the number of observations and percentage. ROC curves were adjusted to determine the best predictor, using the Youden index to establish the optimal cutoff point and the corresponding area under the curve to determine the model's efficacy. The study included 80 patients, and 10 of them (12.5%) were diagnosed with Cystic Fibrosis-related cirrhosis. The average age of the cirrhosis group was 21.6 years, with a predominance of males. The most accurate parameter for predisposition to cirrhosis was the APRI score, with a cutoff value of 0.27. Univariate analysis showed that gender, hepatic changes on ultrasound, splenomegaly, increased portal vein diameter, presence of vomiting, levels of alanine transaminase, aspartate transaminase, platelet count, and FIB-4 score were significantly associated with an APRI score value greater than 0.27. This study suggests the hypothesis that the APRI score is the most sensitive and specific tool for defining cirrhosis in patients with cystic fibrosis.

Rational design of chloride ion transport channels in an open borate framework

La-doped Ca2B5O9Cl exhibits one-dimensional chloride-ion transport defined by the dimensionality of the borate framework. Theoretical calculations indicate an unusual interstitialcy mechanism involving complex association between Cl and La atoms.

Randomness and time-varying characteristics of chloride ion transport in existing harbor concrete structures

This paper presents a study on the durability testing of a concrete facility located within the North Bay Port region, which has been in service for 200 months. Based on the results of 20 sets of concrete samples, an improved Kolmogorov-Smirnov (K-S) test method and gross error discrimination method are proposed to analyze the random distribution functions of the apparent chloride diffusion coefficient (Dapp) and the apparent surface chloride concentration (Cs), and further explore the time-varying characteristics of chloride ion transmission in concrete. The research shows that the improved K-S method presented in this paper can effectively reduce the probability of type II errors by selecting a rational sample size, which can also improve detection efficiency. When the sample size does not exceed 10, the 2σ criterion proposed in this paper can effectively identify and eliminate gross errors. In general, Dapp and Cs follow the log-normal distribution, while the time factor (m) follows a normal distribution parameter. The value of Cs basically stabilized after exposure to 80 months, whereas Dapp tended to stabilize after exposure to 100 months. The value of m obtained through fitting short-term experimental data is typically overestimated, and its value decreases as the exposure time prolongs. Therefore, m should also be considered a time-varying parameter that decreases with time. The tested RC structure will begin to experience rebar corrosion after 48.5-60 years of exposure to the marine environment based on the probabilistic assessment.

Solute Carrier Family 26 Member 4 (SLC26A4), A Potential Therapeutic Target for Asthma.

Asthma is a prevalent respiratory condition with multifaceted pathomechanisms, presenting challenges for therapeutic development. The SLC (Solute Carrier) gene family, encompassing diverse membrane transport proteins, plays pivotal roles in various human diseases by facilitating solute movement across biological membranes. These solutes include ions, sugars, amino acids, neurotransmitters, and drugs. Mutations in these ion channels have been associated with numerous disorders, underscoring the significance of SLC gene families in physiological processes. Among these, the SLC26A4 gene encodes pendrin, an anion exchange protein involved in transmembrane transport of chloride, iodide, and bicarbonate. Mutations in SLC26A4 are associated with Pendred syndrome. Elevated SLC26A4 expression has been linked to airway inflammation, hyperreactivity, and mucus production in asthma. Here, we review novel insights from SLC gene family members into the mechanisms of substrate transport and disease associations, with specific emphasis on SLC26A4. We explore triggers inducing SLC26A4 expression and its contributions to the pathogenesis of pulmonary diseases, particularly asthma. We summarize the inhibitors of SLC26A4 that have shown promise in the treatment of different phenotypes of diseases. While SLC26A4 inhibitors present potential treatments for asthma, further research is imperative to delineate their precise role in asthma pathogenesis and develop efficacious therapeutic strategies targeting this protein.

Graphene oxide-DNA/graphene oxide-PDDA sandwiched membranes with neuromorphic function.

The behavior of polyelectrolytes in confined spaces has direct relevance to the protein mediated ion transport in living organisms. In this paper, we govern lithium chloride transport by the interface provided by polyelectrolytes, polycation, poly(diallyldimethylammonium chloride) (PDDA) and, polyanion, double stranded deoxyribonucleic acid (dsDNA), in confined graphene oxide (GO) membranes. Polyelectrolyte-GO interfaces demonstrate neuromorphic functions that were successfully applied with nanochannel ion interactions contributed, resulting in ion memory effects. Excitatory and inhibitory post-synaptic currents were tuned continuously as the number of pulses applied increased accordingly, increasing decay times. Furthermore, we demonstrated the short-term memory of a trained vs untrained device in computation. On account of its simple and safe production along with its robustness and stability, we anticipate our device to be a low dimensional building block for arrays to embed artificial neural networks in hardware for neuromorphic computing. Additionally, incorporating such devices with sensing and actuating parts for a complete feedback loop produces robotics with its own ability to learn by modifying actuation based on sensing data.

A photocaged, pH-sensitive anion transporter with AND logic dual-stimuli activation.

A pH-switchable anion transporter 1 was photocaged with two photolabile groups to enhance spatiotemporal control over its chloride transport activity. Simultaneous application of light irradiation and acidic pH restores the activity of 1, while either stimulus alone results in no or very low activity. The double activation strategy described herein has potential to yield more selectively cytotoxic anionophores for future medical applications.

Impact of Stone Powder Content on Corrosion Resistance in Reinforced Concrete under Stray Current and Chloride Interactions.

Manufactured sand, known for its artificial production, eco-friendliness, cost-effectiveness, and sustainability, serves as an excellent alternative to natural sand. Stone powder content plays a crucial role in determining the performance of manufactured sand, significantly enhancing concrete compaction and its ability to withstand environmental degradation. This study aims to explore the feasibility of using environmentally and economically advantageous manufactured sand in the construction of subway tunnel segments in coastal areas. It investigates the impact of stone powder content on the corrosion resistance of concrete made with manufactured sand under the combined influence of chloride salts and stray currents. The analysis covers corrosion tendencies, the post-rusting performance of reinforcement bars, the resistance of concrete to chloride transport, and microstructure properties, which are assessed through electron microscope scanning and mercury compression testing. The findings indicate that the corrosion resistance of manufactured sand concrete generally surpasses that of river sand concrete. Furthermore, stone powder content within the 3-8% range leads to a denser concrete microstructure, reduced porosity, lower free-chloride ion levels, increased polarization resistance of post-corrosion reinforcements, lower corrosion current density, and reduced mass loss of reinforcing bars. This research provides valuable theoretical support for promoting the use of environmentally friendly manufactured sand concrete in subway construction projects.