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Using the basolaterally permeabilized, microperfused native human sweat duct, we have discovered that CFTR in the apical membrane can be activated by the exogenous addition of low mM levels of three distinct 5 carbon chain carboxylic acids: α-keto glutarate, glutamate, and glutamine. Activation of CFTR by these substances alone induces a Cl permeable, HCO impermeable state in this tissue that is comparable in magnitude to that elicited by classical activation with cAMP and ATP via protein kinase A phosphorylation. Including mM levels of ATP with these substances appears to induce or to allow a change of state in CFTR that is permeable to both Cl and HCO. Thus, we find the first evidence of an induced dynamic change in ion selectivity of an active anion channel. This novel activation appears to be independent of phosphorylation, but the change in selectivity appears to be dependent on ATP hydrolysis. Evidence that these responses are properties of CFTR is derived from tissues from cystic fibrosis patients that show CFTR mutation (genotype) specific responses. The physiological role of glutamate activation remains to be defined, but we speculate that it may involve controls of cellular energy charge, cell volume, and/or intracellular pH.

The typical CF symptoms with viscous and trapped mucus are still lacking a full explanation. Here we suggest that the CF mucus become sticky and adherent to the epithelial cells by a covalent attachment of MUC2 and MUC5AC. We also suggest that the expression of MUC2 in the lungs could contribute to the CF phenotype. However, there are several unanswered questions before these suggestions can be proved. Among the most urgent ones are to show to what molecules the generated anhydride can attach or if the anhydride only has been hydrolyzed. Once this and other questions have been answered, one can start to address potential therapeutic approaches using recent advances in mucin knowledge.

Using the basolaterally permeabilized, microperfused native human sweat duct, we have discovered that CFTR in the apical membrane can be activated by the exogenous addition of low mM levels of three distinct 5 carbon chain carboxylic acids: α-keto glutarate, glutamate, and glutamine. Activation of CFTR by these substances alone induces a Cl permeable, HCO impermeable state in this tissue that is comparable in magnitude to that elicited by classical activation with cAMP and ATP via protein kinase A phosphorylation. Including mM levels of ATP with these substances appears to induce or to allow a change of state in CFTR that is permeable to both Cl and HCO. Thus, we find the first evidence of an induced dynamic change in ion selectivity of an active anion channel. This novel activation appears to be independent of phosphorylation, but the change in selectivity appears to be dependent on ATP hydrolysis. Evidence that these responses are properties of CFTR is derived from tissues from cystic fibrosis patients that show CFTR mutation (genotype) specific responses. The physiological role of glutamate activation remains to be defined, but we speculate that it may involve controls of cellular energy charge, cell volume, and/or intracellular pH.

The typical CF symptoms with viscous and trapped mucus are still lacking a full explanation. Here we suggest that the CF mucus become sticky and adherent to the epithelial cells by a covalent attachment of MUC2 and MUC5AC. We also suggest that the expression of MUC2 in the lungs could contribute to the CF phenotype. However, there are several unanswered questions before these suggestions can be proved. Among the most urgent ones are to show to what molecules the generated anhydride can attach or if the anhydride only has been hydrolyzed. Once this and other questions have been answered, one can start to address potential therapeutic approaches using recent advances in mucin knowledge.

The overall impact of marketing activities on firm performance constitutes one of the most fundamental questions in our discipline. Naturally, marketing’s provision of demand-related information (DRI) constitutes a major pillar in this context. Almost “by default“ exists the presumption that provision and usage of DRI leads to more satisfied consumers, more products, and, subsequently, higher profits. Remarkably, very little research has investigated the overall effects of DRI. Further, few pieces of research have empirically investigated the impact of DRI on competition.

To explore the effects of DRI, I collect primary, experimental data. The results indicate that DRI indeed leads to more products, a higher primary demand and a higher satisfaction of customer preferences. Also, firms provided with DRI set prices which correspond less to a product’s quality. Surprisingly and more importantly, however, I do not find significant impacts of DRI on firms’ profitability.

These findings suggest that managers tend to over-act. By over-acting I mean that managers pursue too many new product activities that only seemingly amount to new product opportunities. Importantly, such over-acting diminishes firm profits and marketing productivity. This occurs even though those new products do have a positive profit. Furthermore, the often applauded ideal of “segment size one” may turn out to be a myth as managers may over-segment and, thus, cause marketing’s productivity to decline. The relationship between DRI and competition requires a clear definition and measure of competition. Comparing several alternative measures of competitive intensity, I find ambiguous results regarding the relationship between DRI and competition. Managerial and interesting research opportunities conclude this paper.

Using the basolaterally permeabilized, microperfused native human sweat duct, we have discovered that CFTR in the apical membrane can be activated by the exogenous addition of low mM levels of three distinct 5 carbon chain carboxylic acids: α-keto glutarate, glutamate, and glutamine. Activation of CFTR by these substances alone induces a Cl permeable, HCO impermeable state in this tissue that is comparable in magnitude to that elicited by classical activation with cAMP and ATP via protein kinase A phosphorylation. Including mM levels of ATP with these substances appears to induce or to allow a change of state in CFTR that is permeable to both Cl and HCO. Thus, we find the first evidence of an induced dynamic change in ion selectivity of an active anion channel. This novel activation appears to be independent of phosphorylation, but the change in selectivity appears to be dependent on ATP hydrolysis. Evidence that these responses are properties of CFTR is derived from tissues from cystic fibrosis patients that show CFTR mutation (genotype) specific responses. The physiological role of glutamate activation remains to be defined, but we speculate that it may involve controls of cellular energy charge, cell volume, and/or intracellular pH.

The typical CF symptoms with viscous and trapped mucus are still lacking a full explanation. Here we suggest that the CF mucus become sticky and adherent to the epithelial cells by a covalent attachment of MUC2 and MUC5AC. We also suggest that the expression of MUC2 in the lungs could contribute to the CF phenotype. However, there are several unanswered questions before these suggestions can be proved. Among the most urgent ones are to show to what molecules the generated anhydride can attach or if the anhydride only has been hydrolyzed. Once this and other questions have been answered, one can start to address potential therapeutic approaches using recent advances in mucin knowledge.

The typical CF symptoms with viscous and trapped mucus are still lacking a full explanation. Here we suggest that the CF mucus become sticky and adherent to the epithelial cells by a covalent attachment of MUC2 and MUC5AC. We also suggest that the expression of MUC2 in the lungs could contribute to the CF phenotype. However, there are several unanswered questions before these suggestions can be proved. Among the most urgent ones are to show to what molecules the generated anhydride can attach or if the anhydride only has been hydrolyzed. Once this and other questions have been answered, one can start to address potential therapeutic approaches using recent advances in mucin knowledge.

The effects of inositol polyphosphates on ion flux in CF mucosa described here suggest a novel therapeutic approach to the treatment of cystic fibrosis. These studies indicate that transient exposure to an inositol polyphosphate analog, INO-4995, causes long lasting but ultimately reversible changes in therapeutically relevant electrophysiological properties of CF human nasal epithelia. This avoids a major problem encountered with other ion channel regulators that have been advanced as potential CF treatments, limited duration of action.

The typical CF symptoms with viscous and trapped mucus are still lacking a full explanation. Here we suggest that the CF mucus become sticky and adherent to the epithelial cells by a covalent attachment of MUC2 and MUC5AC. We also suggest that the expression of MUC2 in the lungs could contribute to the CF phenotype. However, there are several unanswered questions before these suggestions can be proved. Among the most urgent ones are to show to what molecules the generated anhydride can attach or if the anhydride only has been hydrolyzed. Once this and other questions have been answered, one can start to address potential therapeutic approaches using recent advances in mucin knowledge.