A short isoform of STIM1 confers frequency-dependent synaptic enhancement

Store-operated Ca2+-entry (SOCE) regulates basal and receptor-triggered Ca2+ signaling with STIM proteins sensing the endoplasmic reticulum (ER) Ca2+ content and triggering Ca2+ entry by gating Orai channels. Although crucial for immune cells, STIM1’s role in neuronal Ca2+ homeostasis is controversial. Here, we characterize a splice variant, STIM1B, which shows exclusive neuronal expression and protein content surpassing conventional STIM1 in cerebellum and of significant abundance in other brain regions. STIM1B expression results in a truncated protein with slower kinetics of ER-plasma membrane (PM) cluster formation and ICRAC, as well as reduced inactivation. In primary wild-type neurons, STIM1B is targeted by its spliced-in domain B to presynaptic sites where it converts classic synaptic depression into Ca2+- and Orai-dependent short-term synaptic enhancement (STE) at high-frequency stimulation (HFS). In conjunction with altered STIM1 splicing in human Alzheimer disease, our findings highlight STIM1 splicing as an important regulator of neuronal calcium homeostasis and of synaptic plasticity

Hygroscopic Growth and Deliquescence of NaCl Nanoparticles Mixed with Surfactant SDS

Several complementary experimental and theoretical methodologies were used to explore water uptake on sodium chloride (NaCl) particles containing varying amounts of sodium dodecyl sulfate (SDS) to elucidate the interaction of water with well-defined, environmentally relevant surfaces. Experiments probed the hygroscopic growth of mixed SDS/NaCl nanoparticles that were generated by electrospraying aqueous 2 g/L solutions containing SDS and NaCl with relative NaCl/SDS weight fractions of 0, 5, 11, 23, or 50 wt/wt %. Particles with mobility-equivalent diameters of 14.0(±0.2) nm were size selected and their hygroscopic growth was monitored by a tandem nano-differential mobility analyzer as a function of relative humidity (RH). Nanoparticles generated from 0 and 5 wt/wt % solutions deliquesced abruptly at 79.1(±1.0)% RH. Both of these nanoparticle compositions had 3.1(±0.5) monolayers of adsorbed surface water prior to deliquescing and showed good agreement with the Brunauer−Emmett−Teller and the Frenkel−Halsey−Hill isotherms. Above the deliquescence point, the growth curves could be qualitatively described by Köhler theory after appropriately accounting for the effect of the particle shape on mobility. The SDS/NaCl nanoparticles with larger SDS fractions displayed gradual deliquescence at a RH that was significantly lower than 79.1%. All compositions of SDS/NaCl nanoparticles had monotonically suppressed mobility growth factors (GFm) with increasing fractions of SDS in the electrosprayed solutions. The Zdanovskii−Stokes−Robinson model was used to estimate the actual fractions of SDS and NaCl in the nanoparticles; it suggested the nanoparticles were enhanced in SDS relative to their electrospray solution concentrations. X-ray photoelectron spectroscopy (XPS), FTIR, and AFM were consistent with SDS forming first a monolayer and then a crystalline phase around the NaCl core. Molecular dynamics simulations of water vapor interacting with SDS/NaCl slabs showed that SDS kinetically hinders the initial water uptake. Large binding energies of sodium methyl sulfate (SMS)−(NaCl)4, H2O−(NaCl)4, and SMS−H2O−(NaCl)4 calculated at the MP2/cc-pVDZ level suggested that placing H2O in between NaCl and surfactant headgroup is energetically favorable. These results provide a comprehensive description of SDS/NaCl nanoparticles and their properties

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Einbindung von Speichern für erneuerbare Energien in die Kraftwerkseinsatzplanung : Einfluss auf die Strompreise der Spitzenlast

Das Ziel dieser Arbeit bestand darin, aufzuzeigen, inwieweit die Einbindung von Stromspeichern und Lastmanagement in die Kraftwerkseinsatzplanung die Spitzenlaststrompreise eines Systems mit hohem Anteil erneuerbarer Energien beeinflusst. Mithilfe des auf MATLAB/SIMULINK® basierenden Energiesystemmodells EmSAr erfolgt eine nach ökonomischen Gesichtpunkten ausgerichtete Einsatzoptimierung fossiler Regelkraftwerke, Speichertechnologien sowie der Option Lastmanagement. Es handelt sich dabei um ein lineares Optimierungsmodell, welches als Punktmodell den Elektrizitätsbedarf der Bundesrepublik Deutschland im Jahre 2020 bei hohem Anteil erneuerbarer Energien deckt. Die Einsatzplanung konzentriert sich dabei auf den starke Fluktuationen aufweisenden Spitzenlastbereich. Aus den Ergebnissen der Einsatzplanung leiten sich die Spitzenlaststrompreise des Systems ab. Ergänzt wird das Modell durch ein separates Simulationsmodell, welches das Ladeverhalten der Speichersysteme abbildet

Energy efficiency as a key element of the EU's post-Kyoto strategy : results of an integrated scenario analysis

Under the framework of the UN framework convention on climate change (UNFCCC) and its Kyoto Protocol the targets and strategies for the second and third commitment period ("post-2012") have to be discussed and set in the near future. Regarding the substantial emission reductions that have to be shouldered by the industrialized nations over the next two decades it is evident that all available potentials to mitigate greenhouse gas (GHG) emissions have to be harnessed and that energy efficiency has to play a key role. To substantiate this we developed a comprehensive scenario analysis of the EU 25s energy system and other greenhouse gas emissions until 2020. Our analysis shows which key potentials to mitigate greenhouse gas emissions are available, by which policies and measures they are attainable and which will be benefits of greenhouse gas mitigation measures. By this analysis we show the mayor role of energy efficiency in all sectors and all member states. We demonstrate that a reduction of EU 25 greenhouse gas emissions by more than 30 % by 2020 is feasible, reasonable and - to a large extent - cost effective. We also develop a comprehensive policy package necessary to achieve ambitious Post-Kyoto targets. The scenario analysis results in a clear identification of the needed strategies, policies and measures and especially the relevance of energy efficiency to achieve the necessary ambitious greenhouse gas reduction targets. It also clearly shows the costs and the benefits of such a policy compared to a business as usual case

Einbindung von Speichern für erneuerbare Energien in die Kraftwerkseinsatzplanung

Das Ziel dieser Arbeit bestand darin, aufzuzeigen, inwieweit die Einbindung von Stromspeichern und Lastmanagement in die Kraftwerkseinsatzplanung die Spitzenlaststrompreise eines Systems mit hohem Anteil erneuerbarer Energien beeinflusst. Mithilfe des auf MATLAB/SIMULINK$^\circledR$ basierenden Energiesystemmodells $\it {EmSAr}$ erfolgt eine nach ökonomischen Gesichtpunkten ausgerichtete Einsatzoptimierung fossiler Regelkraftwerke, Speichertechnologien sowie der Option Lastmanagement. Es handelt sich dabei um ein lineares Optimierungsmodell, welches als Punktmodell den Elektrizitätsbedarf der Bundesrepublik Deutschland im Jahre 2020 bei hohem Anteil erneuerbarer Energien deckt. Die Einsatzplanung konzentriert sich dabei auf den starke Fluktuationen aufweisenden Spitzenlastbereich. Aus den Ergebnissen der Einsatzplanung leiten sich die Spitzenlaststrompreise des Systems ab. Ergänzt wird das Modell durch ein separates Simulationsmodell, welches das Ladeverhalten der Speichersysteme abbildet