Variations in Discharge Volumes for Hydropower Generation in Switzerland

This study analyses the way climatic variations over the last century impacted the volumes of water available for hydropower production in Switzerland. The analysis relied on virtual intakes located all over Switzerland, which were assumed to be fed by water from mesoscale catchments. Intake capacities were designed using flow duration curves. The results show that the overall warming and increased winter precipitation observed in recent decades have led to more balanced discharge behaviours in rivers and more favourable conditions for electricity production than most periods in the past. In lower-altitude regions of Switzerland, the annual volume of water available for electricity production has not changed significantly; however, significantly more water is available in winters, while less is available during summers. In higher-altitude regions like the Swiss Alps, especially in glaciated catchment areas, significantly more water is available in both seasons; in other words, the annual volume of water available for hydropower production is significantly higher in these areas when compared to earlier periods. Comparison of these results with the actual amount of hydroelectricity produced over the same period reveals that hydrological variations cannot fully explain the variations in power production observed. Plant-specific analyses are needed of the impact of climatic changes on water managemen

Cysteine residues 244 and 458-459 within the catalytic subunit of Na,K-ATPase control the enzyme's hydrolytic and signaling function under hypoxic conditions

Our previous findings suggested that reversible thiol modifications of cysteine residues within the actuator (AD) and nucleotide binding domain (NBD) of the Na,K-ATPase may represent a powerful regulatory mechanism conveying redox- and oxygen-sensitivity of this multifunctional enzyme. S-glutathionylation of Cys244 in the AD and Cys 454-458-459 in the NBD inhibited the enzyme and protected cysteines' thiol groups from irreversible oxidation under hypoxic conditions. In this study mutagenesis approach was used to assess the role these cysteines play in regulation of the Na,K-ATPase hydrolytic and signaling functions. Several constructs of mouse α1 subunit of the Na,K-ATPase were produced in which Cys244, Cys 454-458-459 or Cys 244-454-458-459 were replaced by alanine. These constructs were expressed in human HEK293 cells. Non-transfected cells and those expressing murine α1 subunit were exposed to hypoxia or treated with oxidized glutathione (GSSG). Both conditions induced inhibition of the wild type Na,K-ATPase. Enzymes containing mutated mouse α1 lacking Cys244 or all four cysteines (Cys 244-454-458-459) were insensitive to hypoxia. Inhibitory effect of GSSG was observed for wild type murine Na,K-ATPase, but was less pronounced in Cys454-458-459Ala mutant and completely absent in the Cys244Ala and Cys 244-454-458-459Ala mutants. In cells, expressing wild type enzyme, ouabain induced activation of Src and Erk kinases under normoxic conditions, whereas under hypoxic conditions this effect was inversed. Cys454-458-459Ala substitution abolished Src kinase activation in response to ouabain treatment, uncoupled Src from Erk signaling, and interfered with O2-sensitivity of Na,K-ATPase signaling function. Moreover, modeling predicted that S-glutathionylation of Cys 458 and 459 should prevent inhibitory binding of Src to NBD. Our data indicate for the first time that cysteine residues within the AD and NBD influence hydrolytic as well as receptor function of the Na,K-ATPase and alter responses of the enzyme to hypoxia or upon treatment with cardiotonic steroids

Keep dementia in mind, but forget memory formation : plasticity of the N-methyl-D-aspartate receptor in erythroid cells and its potential for the treatment of sickle cell anemia

Zusammenfassung Das Projekt basiert auf einer Pilotstudie die zeigte, dass N-methyl-D-aspartat Rezeptoren in erythropoietischen Zellen von Ratten und Menschen zu finden sind. Zudem wurde festgestellt, dass Patienten mit einer erhöhten intrazellulären Kalzium Konzentration in den Erythrozyten eine gesteigerte Aktivität der Rezeptoren aufweisen. Das Ziel der vorliegenden Arbeit war es, die Zusammensetzung und die Eigenschaften der Rezeptoren während der Erythropoiese von gesunden Probanden und Sichelzellenanämie-Patienten zu untersuchen. Die Ergebnisse wurden anschliessend mit den Daten über die Struktur und die Funktion des Rezeptors aus den roten Blutkörperchen verknüpft. Die Ergebnisse zeigten, dass sich die Zusammensetzung der Rezeptoruntereinheiten während der Differenzierung der Erythrozyten verändert. Es konnte gezeigt werden, dass die N-methyl-D-aspartat Rezeptoren vor allem für das Überleben der Proerythroblasten und der basophilen Erythroblasten entscheidend sind. Ebenfalls wurde gezeigt, dass sich die Rezeptorexpression während der Erythropoiese in gesunden Probanden nicht massgeblich von Sichelzellenanämie-Patienten unterscheidet. Nichtsdestotrotz wurde klar beobachtet, dass in roten Blutkörperchen von Patienten die Anzahl von aktiven Rezeptoren fünf bis zehn mal grösser ist als im Vergleich zu gesunden Probanden. Die Inhibition dieser aktiven Rezeptoren mit dem Antagonisten Memantin bewirkte eine Reduktion der Dehydration und die damit assoziierte typischen Verformung der Erythrozyten. Gleichzeitig wurde gezeigt, dass die erythropoietischen Vorläuferzellen von Patienten, im Gegensatz zu den Zellen von gesunden Probanden, weniger sensitiv auf Rezeptorantagonisten reagieren. Diese Ergebnisse legen nahe, dass sich die Inhibition dieser N-methyl-D-aspartat Rezeptoren in Erythrozyten positiv auf den Kalziumspiegel der roten Blutkörperchen auswirkt und damit nicht nur die Lebensdauer der Zellen, sondern auch die gesundheitliche Situation der Patient erheblich verbessert werden kann. Basierend auf diesen Resultaten ist eine klinische Studie mit den Rezeptorantagonisten Memantin als neue Therapie für Sichelzellenanämie in Planung. Summary This project was based on a pilot study indicating that N-methyl-D-aspartate receptors (NMDARs) are expressed in rat erythroid precursor cells (EPCs) and present in both, circulating rat and human red blood cells (RBCs). Furthermore, assessment of this receptor’s activity in RBCs of sickle cell disease (SCD) patients revealed that calcium (Ca2+) overload is likely to be due to the pathological up-regulation of receptor abundance and activity in them. The present study was focused on the characterization of NMDARs on the molecular and functional level during erythropoietic maturation. EPCs of healthy humans and SCD patients were studied ex vivo. These findings were then bridged with the data obtained from the NMDARs in mature RBCs. The data revealed the changes in the NMDAR subunit composition mirrored by the change of the functional properties during differentiation. Functional NMDARs were shown to be required for survival of the erythroid precursor cells. They prevented cells from undergo apoptosis. In particular, this protecting effect was present at the proerythroblastic stage. Furthermore, no significant difference was observed in the expression of NMDAR subunits during differentiation of the precursor cells of healthy humans and SCD patients. However, in the circulating RBCs of asymptomatic patients, the number of active receptors exceeded that in cells of healthy donors by 5 to 10-fold. Inhibition of the receptors with pore-targeting antagonist Memantine substantially reduced the dehydration of RBCs and decreased the risk of sickle cell transformation. At the same time, EPCs of SCD patients were less sensitive to Memantine than proerythroblasts of healthy humans. These results suggested that inhibition of the NMDARs in RBCs of SCD patients may be beneficial. The reduction of Ca2+ uptake could decrease dehydration, increase RBC life span, and reduce the risk of thrombosis. Based on these findings, a clinical trial in which Memantine is to be used for treatment of a small cohort of patients is in preparation