Chloride Ion Conductance Research Articles

Land use-land cover effects on surface flowing water quality: a statistical approach

The drainage basin surrounding River Kaduna within the middle stretch is known to have numerous land uses and land covers. Several researchers have investigated the water quality of the river with respect to season and surrounding geology. However, none or little on the water quality of the river have been investigated with respect to land use and land cover (LULC). Hence, this paper examined the water quality of the middle stretch of the river in relation to the different land uses and land covers present using statistical techniques. This was achieved by monthly analyzing 10 physicochemical parameters from water samples collected in 15 sampling stations for a period of 12 calendar months using standard methods. The physicochemical parameters considered include; turbidity, total dissolved solids, pH, chloride ion and electrical conductivity. Others include dissolved oxygen, 5-days biochemical oxygen demand, chemical oxygen demand, total nitrogen and total phosphorus. The different LULC of the watershed obtained via ArcGIS 10.5 were agricultural, vegetation, built-up, industrial, water body and bare surface. Spearman’s correlation analysis between laboratory results and the different LULCs determined via SPSS version 20 revealed that Built-up, industrial, and agricultural land uses contributes significantly to the impairment of River Kaduna water quality as the correlation coefficients between these LULCs and water quality deterioration ranged from 0.0281 to 0.6901. Nevertheless, a significant negative correlation (-0.1482 to -0.5490) exist between vegetation (forest coverage) and water quality deterioration, suggesting that forest cover can mitigate the deterioration of water quality to a certain degree.Keywords: Runoff water, Correlation Coefficient, LULC, Water quality, Sampling frequency

Use of oil shale ash in road construction: results of follow-up environmental monitoring.

Oil shale ash (OSA) was used for road construction in a pristine swamp area in East-Estonia during 2013-2014. OSA was used as a binder both in mass stabilization of soft peat soil and in the upper layer. Use of OSA in civil engineering always raises questions about the environmental safety of such activities. Post-construction environmental monitoring of the pilot section was carried out in 2014 and 2015. The monitoring program involved surface water and soil sampling campaigns. Samples were analyzed for selected constituents and parameters of environmental concern. The paper gives data for assessing the environmental impact and evaluation of potential risks associated with construction of roads using OSA. Leaching of hazardous compounds from the pilot section to surrounding aqueous environment was not observed during the monitoring program. Still, the road construction affected the concentration of sulfates in surrounding surface water. Also, the water-soluble content of barium in surface water correlated significantly with the concentrations of chloride and sulfate ion and electric conductivity of the surface water. Therefore, it is recommended to monitor the electric conductivity, concentrations of sulfates, chlorides, and barium in nearby surface water when OSA is used in road construction.

Identifying Inhibitors of the Hsp90-Aha1 Protein Complex, a Potential Target to Drug Cystic Fibrosis, by Alpha Technology

Deletion of a single phenylalanine residue at position 508 of the protein CFTR (cystic fibrosis transmembrane conductance regulator), a chloride channel in lung epithelium, is the most common cause for cystic fibrosis. As a consequence, folding of the CFTRΔF508 protein and delivery to the cell surface are compromised, resulting in degradation of the polypeptide. Accordingly, decreased surface presence of CFTRΔF508 causes impaired chloride ion conductivity and is associated with mucus accumulation, a hallmark of cystic fibrosis. Molecular chaperones such as Hsp90 and its co-chaperone partner Aha1 are thought to play a key role in targeting folding-deficient CFTRΔF508 for degradation. Thus, pharmacologic manipulation to inhibit Hsp90-Aha1 chaperone complex formation appears beneficial to inhibit proteolysis of CFTRΔF508 and rescue its residual chloride channel activity. Therefore, we have screened a collection of 14,400 druglike chemical compounds for inhibitors of the Hsp90-Aha1 complex by amplified luminescence proximity homogeneous assay (Alpha). We identified two druglike molecules that showed promising results when we tested their ability to restore chloride channel activity in culture cells expressing the mutant CFTRΔF508 protein. The two molecules were most effective in combination with the corrector VX-809 and may therefore serve as a lead compound that can be further developed into a drug to treat cystic fibrosis patients.

热水器加热管载荷下腐蚀研究

用电化学线性极化电阻法研究了在载荷工况下，不同电力密度、氯离子浓度、碳酸氢根浓度、电导率对加热管310S不锈钢的腐蚀性能影响。从实验结果来看，水质对腐蚀的影响主要体现在加热和保温阶段。研究结果表明影响加热管使用寿命的环境影响因子由强到弱的排序为Cl− > HCO3(结垢因子) > 电力密度，电导率对加热管腐蚀影响轻微。 The electrochemical linear polarization resistance method was used to study the effects of different power density, chloride ion concentration, bicarbonate concentration and conductivity on the corrosion performance of heating tube 310S stainless steel under loading state. From the experimental results, the impact of water quality on corrosion is mainly reflected in the heating and insulation stage. The results show that the order of environmental impact factors affecting the service life of heating tube is as follows: Cl− > HCO3(scale factor) > power density (strong to weak), Conductivity has a slight effect on corrosion of the heating tube.

Polystyrene-Block-Poly(ethylene-ran-butylene)-Block-Polystyrene Triblock Copolymer Separators for a Vanadium-Cerium Redox Flow Battery

A series of polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene (SEBS)-based anion exchange membranes (AEMs) were synthesized via chloromethylation of SEBS followed by quaternization with trimethylamine (TMA). AEMs functionalized with TMA+ cations exhibited high chloride ion conductivity of 33.6 mS/cm at 70°C. A V-Ce RFB employing the SEBS-based AEM as the separator yielded an energy efficiency of 86% at a current density of 50 mA/cm2 with a 10% drop in capacity over 20 charge/discharge cycles. In contrast, a V-Ce RFB using Nafion212 as the separator had an energy efficiency of 80% and a 40% drop in capacity over 20 charge/discharge cycles. The observed capacity fade was primarily due to cation intermixing between the anodic and cathodic compartments – much better permselectivity was obtained with the AEM separator. After 60 charge-discharge cycles (350 hours of operation), the ion exchange capacity and ionic conductivity of the AEM dropped by about 20%. There was no observed change in mechanical properties. The oxidative stability of the AEM was evaluated ex situ by immersion in 1.5 M VO2+ + 3 M H2SO4 for 500 hours - the ionic conductivity remained constant over this timeframe. The chemical and mechanical stability and high conductivity of SEBS-based AEMs make them promising separator candidates for electrode-decoupled RFBs.

MicroRNA Dysregulation in Cystic Fibrosis.

The cystic fibrosis lung is a complex milieu comprising multiple factors that coordinate its physiology. MicroRNAs are regulatory factors involved in most biological processes and it is becoming increasingly clear that they play a key role in the development and manifestations of CF lung disease. These small noncoding RNAs act posttranscriptionally to inhibit protein production. Their involvement in the pathogenesis of CF lung disease stems from the fact that their expression is altered in vivo in the CF lung due to intrinsic and extrinsic factors; to date defective chloride ion conductance, endoplasmic reticulum stress, inflammation, and infection have been implicated in altering endogenous miRNA expression in this setting. Here, the current state-of-the-art and biological consequences of altered microRNA expression in cystic fibrosis are reviewed.

교류 피복아크 용접에 의한 해수 배관 용접부위의 부식 특성 평가

A seawater pipe of the engine room in the ships is being surrounded with severely corrosive environments caused by fast flowing of the seawater, containing aggressive chloride ion and high conductivity etc.. Therefore, the leakage of the seawater from its pipe have been often occurred due to its local corrosion by aggressive chloride ions. Subsequently, its leakage area is usually welded by AC shielded metal arc welding with various electrodes. In this study, when the sea water pipe is welded with several types of electrodes such as E4301, E4311, E4313 and E4316, a difference of the corrosion resistance on the welding metal zones was investigated using an electrochemical method, observing microstructure, measuring polarization behaviors and hardness. The weld metal zone welded with E4313 electrode exhibited the lowest value of hardness compared to other weld metal zones. In addition, its zone indicated also the best corrosion resistance than those of other weld metal zones. Furthermore, all of the weld metal zones revealed a relatively better corrosion resistance than those of the base metal zones. and also showed higher hardness than the base metal zones.

Regulation of Cystic Fibrosis Transmembrane Conductance Regulator by MicroRNA-145, -223, and -494 Is Altered in ΔF508 Cystic Fibrosis Airway Epithelium

Expression of the cystic fibrosis transmembrane conductance regulator (CFTR) is altered in individuals with the ΔF508 CFTR mutation. We previously reported differential expression of microRNA (miRNA) in CF airway epithelium; however, the role of miRNA in regulation of CFTR expression here remains unexplored. In this study, we investigated the role of upregulated miRNAs in CFTR regulation in vivo in bronchial brushings from individuals homozygous or heterozygous for ΔF508 CFTR, validated our observations in vitro, and assessed the impact of defective chloride ion conductance, genotype, and colonization status on miRNA expression. miRNA target prediction was performed in silico, and expression of miRNA and target genes were measured by quantitative real-time PCR and/or Western blotting. Overexpression and inhibition studies were performed with pre-miRs or antimiRs, respectively, and a luciferase reporter gene was used to elucidate direct miRNA-target interactions. miR-145, miR-223, and miR-494 were upregulated in CF versus non-CF bronchial brushings and cell lines; in ΔF508 CFTR homozygotes versus heterozygotes; in subjects positive for P. aeruginosa; and in cells treated with a CFTR inhibitor or IL-1β. Reciprocal downregulation or upregulation of CFTR gene and/or protein expression was observed after miRNA manipulation and direct miRNA-target relationships demonstrated via a reporter system containing a wild type or mutated full-length CFTR 3' untranslated region. Increased expression of miR-145, miR-223, and miR-494 in vivo in bronchial epithelium of individuals carrying the ΔF508 CFTR mutation correlates with decreased CFTR expression. Defective CFTR function, Pseudomonas colonization, and inflammation may affect miRNA expression and contribute to the regulation of ΔF508 CFTR.

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

Cystic fibrosis (CF) is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine.

Influence of Bound Ion on the Morphology and Conductivity of Anion-Conducting Block Copolymers

Anion-conducting membranes are important for several applications including fuel cells and artificial photosynthesis. In this study such membranes were made by quaternizing polystyrene-block-polychloromethylstyrene (PS-b-PCMS) copolymers. PS-b-PCMS copolymers with molecular weights ranging from 4 to 60 kg/mol were synthesized by nitroxide-mediated controlled radical polymerization. Separate aliquots of the PS-b-PCMS samples were quaternized to transform the PCMS block. This resulted in block copolymers with ionizable blocks containing either trimethylammonium chloride or n-butylimidazolium chloride. We refer to ion-containing block copolymers synthesized from the same precursor as matched pairs: SAM (containing trimethylammonium chloride) and SIM (containing n-butylimidazolium chloride). The volume fraction of the ion-containing block, ϕ, ranges from 0.26 to 0.50 for the case of SAM and from 0.35 to 0.60 for the case of SIM. Self-assembly in these copolymers resulted in the formation of lamellar phases regardless of ϕ, chemical formula of the bound ion, and chain length. Chloride ion conductivity and water uptake measurements on one of the matched pairs led to similar results. Preliminary experiments wherein the chloride ions in this matched pair were replaced by hydroxide ions were performed, and the changes in conductivity due to this are reported.

Molecular Dynamics Simulations of CFTR Gating and Conductance

The crystal structure of CFTR, the chloride ion channel defective in cystic fibrosis, has not yet been solved. Here we present two new homology models of human CFTR based on template structures from related ABC transporters. The first is based on the bacterial transporter Sav1866 and is representative of the open channel state of CFTR. Unlike previous Sav1866-based homology models of CFTR, our model incorporates several key structural features expected from experiment, including the proper positioning of pore-lining residues and important salt bridges. The second is based on the crystal structure of murine P-glycoprotein and models the closed state of CFTR. We performed targeted molecular dynamics simulations using these two models as end states, in order to gain insight into the conformational changes that CFTR undergoes during its gating cycle. Our simulations reveal that CFTR gating involves a conformational wave that is initiated at the nucleotide-binding domains, and propagates through interactions in the intracellular loops to the membrane-spanning domains. Analysis of our simulations also led to a better understanding of the relative motions of the twelve transmembrane helices in CFTR, and how they alter pore structure during gating. Our MD simulations allowed identification of key inter-residue interactions that stabilize the end states as well as transient interactions that may exist in the intermediate stages in gating. Charting the progression of these interactions provides a timeline of events likely to occur during gating, and may prove invaluable in furthering our understanding of structure-function relationships in CFTR. Finally, we report on preliminary simulations of chloride ion conduction in the open CFTR channel, which reveal key interactions of pore-lining residues with passing ions, as well as identifying the putative narrow region in the pore that may form a selectivity filter in this channel. (NIH-2R56DK056481-07)

41 Corrector effect of resveratrol on refractory adrenergic pathway in saliva secretion of cystic fibrosis mice

Objectives: Expression of the cystic fibrosis transmembrane conductance regulator is altered in individuals with the DF508 CFTR mutation. MicroRNA (miRNA) are differentially expressed in the CF airway epithelium, however their role in regulation of CFTR expression here remains unexplored. Herein we investigated the role of up regulated miRNAs in CFTR regulation in vivo in bronchial brushings from individuals homozygous or heterozygous for DF508 CFTR, validated our observations in vitro and assessed the impact of defective chloride ion conductance, genotype and Pseudomonas status on miRNA expression. Methods: MiRNA target prediction was performed in silico, expression of miRNAs and target genes was measured by qRT-PCR and/or western blotting. Modulation of miRNA was carried out using pre-miRs or antagomirs and a luciferase reporter gene employed to elucidate miRNA/CFTR interaction. MiR-145, -223 and 494 were up regulated in CF versus non-CF bronchial brushings and cell lines, in DF508 homovs. heterozygotes, in subjects positive for P. aeruginosa and in 16HBE14o− cells treated with a CFTR inhibitor. Reciprocal down or up regulation of CFTR gene and/or protein expression was observed following miRNA manipulation and direct miRNA/target relationship demonstrated via a luciferase reporter system containing the full length 3’-untranslated region of CFTR. Conclusions: Increased expression of miR-145, -223 and -494 in vivo in bronchial epithelium of individuals carrying the DF508 CFTR mutation correlates with decreased CFTR expression. Defective CFTR function and Pseudomonas colonisation may affect miRNA expression and contribute to the regulation of DF508 CFTR mutation.

Hot Topic: [How Can We Target Pulmonary Inflammation in Cystic Fibrosis? (Guest Editor: Catherine M. Greene)

With each year our enhanced understanding of the pathogenesis of cystic fibrosis (CF) is challenged by new discoveries related to the increasingly complex nature of this disorder. Originally described as a genetic disorder principally due to defective chloride ion conductance at epithelial surfaces and a predisposition to bacterial colonization have been moved into the category of an inflammatory disorder because of increasing research efforts. As our knowledge of the molecular and cellular events associated with CF has burgeoned, we now have a greater appreciation of its protean inflammatory manifestations. This Mini-Hot Topic on “Mechanisms of Pulmonary Inflammation in Cystic Fibrosis” presents a series of comprehensive review articles in which the authors describe novel mechanisms regulating inflammation in the CF lung and propose and dissect the potential benefits and side-effects of diverse treatments aimed at ameliorating the inflammatory consequences of CF lung disease.

Editorial: How Can We Target Pulmonary Inflammation in Cystic Fibrosis?

With each year our enhanced understanding of the pathogenesis of cystic fibrosis (CF) is challenged by new discoveries related to the increasingly complex nature of this disorder. Originally described as a genetic disorder principally due to defective chloride ion conductance at epithelial surfaces and a predisposition to bacterial colonization have been moved into the category of an inflammatory disorder because of increasing research efforts. As our knowledge of the molecular and cellular events associated with CF has burgeoned, we now have a greater appreciation of its protean inflammatory manifestations. This Mini-Hot Topic on “Mechanisms of Pulmonary Inflammation in Cystic Fibrosis” presents a series of comprehensive review articles in which the authors describe novel mechanisms regulating inflammation in the CF lung and propose and dissect the potential benefits and side-effects of diverse treatments aimed at ameliorating the inflammatory consequences of CF lung disease.

Chloride ion conduction without water coordination in the pore of ClC protein

In the present work, we have found by an atomistic molecular dynamics simulation that hydrogen atoms originating from the residues of a prokaryotic ClC protein (EcClC) stabilize the chloride ion without water molecules in the pore of ClC protein. When the chloride ion conduction is simulated by pulling a chloride ion along the pore axis, the free energy barrier for chloride ion conduction is calculated to be low (4 kcal/mol), although the chloride ion is stripped of its hydration shell as it passes through the dehydrated pore region. The calculation of the number of hydrogen atoms surrounding the chloride ion reveals that water molecules hydrating the chloride ion are replaced by polar and non-polar hydrogen atoms protruding from the protein residues. From the analysis of the pair interaction energy between the chloride ion and these hydrogen atoms, it is realized that the hydrogen atoms from the protein residues stabilize the chloride ion at the dehydrated region instead of water molecules, by which the energetic penalty for detaching water molecules from the permeating ion is compensated.

Myotonic disorders

Myotonia reflects a state of muscle fiber hyperexcitability. Impaired transmembrane conductance of either chloride or sodium ions results in myotonia. Myotonic disorders include the myotonic dystrophies and nondystrophic myotonias. Mutations in the genes encoding chloride (ClC-1) or sodium (SCN4A) channels expressed exclusively in skeletal muscle cause nondystrophic myotonias. Genetic defects in the myotonic dystrophies do not involve ion channel or its regulator proteins. Recent research supports a novel RNA-mediated disease mechanism of myotonia in the myotonic dystrophies. Myotonic dystrophy Type 1 is caused by CTG repeat expansion in the 3' untranslated region in the Dystrophia Myotonica Protein Kinase (DMPK) gene. Myotonic dystrophy Type 2 is caused by CCTG repeat expansion in the first intron in Zinc Finger Protein 9 (ZNF9) gene. The expanded repeat is transcribed in RNA and forms discrete inclusions in nucleus in both types of myotonic dystrophies. Mutant RNA sequesters MBNL1, a splice regulator protein and depletes MBNL1 from the nucleoplasm. Loss of MBNL1 results in altered splicing of ClC-1 mRNA. Altered splice products do not encode functional ClC-1 protein. Subsequent loss of chloride conductance in muscle membrane causes myotonia in the myotonic dystrophies. The purpose of this review is to discuss the clinical presentation, recent advances in understanding the disease mechanism with particular emphasis on myotonic dystrophies and potential therapy options in myotonic disorders.

Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy

In myotonic dystrophy (dystrophia myotonica [DM]), an increase in the excitability of skeletal muscle leads to repetitive action potentials, stiffness, and delayed relaxation. This constellation of features, collectively known as myotonia, is associated with abnormal alternative splicing of the muscle-specific chloride channel (ClC-1) and reduced conductance of chloride ions in the sarcolemma. However, the mechanistic basis of the chloride channelopathy and its relationship to the development of myotonia are uncertain. Here we show that a morpholino antisense oligonucleotide (AON) targeting the 3' splice site of ClC-1 exon 7a reversed the defect of ClC-1 alternative splicing in 2 mouse models of DM. By repressing the inclusion of this exon, the AON restored the full-length reading frame in ClC-1 mRNA, upregulated the level of ClC-1 mRNA, increased the expression of ClC-1 protein in the surface membrane, normalized muscle ClC-1 current density and deactivation kinetics, and eliminated myotonic discharges. These observations indicate that the myotonia and chloride channelopathy observed in DM both result from abnormal alternative splicing of ClC-1 and that antisense-induced exon skipping offers a powerful method for correcting alternative splicing defects in DM.

Cystic Fibrosis Transmembrane Conductance Regulator-independent Phagosomal Acidification in Macrophages

It was reported recently that the cystic fibrosis transmembrane conductance regulator (CFTR) is required for acidification of phagosomes in alveolar macrophages (Di, A., Brown, M. E., Deriy, L. V., Li, C., Szeto, F. L., Chen, Y., Huang, P., Tong, J., Naren, A. P., Bindokas, V., Palfrey, H. C., and Nelson, D. J. (2006) Nat. Cell Biol. 8, 933-944). Here we determined whether the CFTR chloride channel is a generalized pathway for chloride entry into phagosomes in macrophages and whether mutations in CFTR could contribute to alveolar macrophage dysfunction. The pH of mature phagolysosomes in macrophages was measured by fluorescence ratio imaging using a zymosan conjugate containing Oregon Green(R) 488 and tetramethylrhodamine. Acidification of phagolysosomes in J774A.1 macrophages (pH approximately 5.1 at 45 min), murine alveolar macrophages (pH approximately 5.3), and human alveolar macrophages (pH approximately 5.3) was insensitive to CFTR inhibition by the thiazolidinone CFTR(inh)-172. Acidification of phagolysosomes in alveolar macrophages isolated from mice homozygous for DeltaF508-CFTR, the most common mutation in cystic fibrosis, was not different compared with that in alveolar macrophages isolated from wild-type mice. We also measured the kinetics of phagosomal acidification in J774A.1 and murine alveolar macrophages using a zymosan conjugate containing fluorescein and tetramethylrhodamine. Phagosomal acidification began within 3 min of zymosan binding and was complete within approximately 15 min of internalization. The rate of phagosomal acidification in J774A.1 cells was not slowed by CFTR(inh)-172 and was not different in alveolar macrophages from wild-type versus DeltaF508-CFTR mice. Our data indicate that phagolysosomal acidification in macrophages is not dependent on CFTR channel activity and do not support a proposed mechanism for cystic fibrosis lung disease involving defective phagosomal acidification and bacterial killing in alveolar macrophages.

Modelling the restoration of wild-type dynamic behaviour in ΔF508-CFTR NBD1 by 8-cyclopentyl-1,3-dipropylxanthine

Cystic fibrosis (CF) is the most frequently occurring severe, genetic disease in western populations with an incidence as high as 1 in 2500. The principal biochemical defect in CF is a mutation in a membrane transport protein, namely the cystic fibrosis transmembrane conductance regulator (CFTR), which is responsible for the conductance of chloride ions across cell membranes. In 70% of cases a single mutation in CFTR, namely the deletion of amino acid 508 (called ΔF508) is sufficient to cause severe disease. This mutation manifests as a failure of the protein to be effectively targeted to the membrane. Recently, it has been shown that small molecule drug therapy can restore the membrane-targeting of ΔF508-CFTR, where the mutant channel functions adequately. We have created models of the first nucleotide-binding domain (NBD1) region (which houses the proposed binding site of these restorative drugs) of the wild-type and mutant forms of human CFTR. We have simulated the dynamical behaviour of these proteins in the presence of drugs that restore trafficking of the protein. Our results indicate that there are particular modes of dynamic motion that are distinguishable between wild-type and mutant CFTR. These regions of motion are localized in the regions of the ΔF508 mutation and the drug-binding regions. The simulations of drug binding indicate that wild-type dynamic motions are restored in these regions. We conclude therefore that these drugs are able to alter the dynamic properties of ΔF508-CFTR such that the drug-bound mutant protein more closely resembles the wild-type protein dynamic behaviour, and hence we hypothesize that it is this that allows for correct targeting to the membrane.

Regulation of chloride ion conductance during skeletal muscle development and in disease. Focus on “Chloride channelopathy in myotonic dystrophy resulting from loss of posttranscriptional regulation for CLCN1”

productive investigations of disease mechanisms that also reveal new information about normal regulation elicit a particularly satisfying sense of a two-for-one deal. In the case of Lueck et al. (Ref. [13][1]; see page 1291 of this issue), a detailed study of the molecular basis for the myotonia (