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The 2TM domain family of K channels are also known as the inward-rectifier K channel family. This family includes the strong inward-rectifier K channels (Kir2.x) that are constitutively active, the G-protein-activated inward-rectifier K channels (Kir3.x) and the ATP-sensitive K channels (Kir6.x, which combine with sulphonylurea receptors (SUR1-3)). The pore-forming α subunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. Kir3.2 with Kir3.3).

NMR thermometers are a convenient way to determine the temperature inside the sample of an NMR spectrometer. They rely on signals with strongly temperature-dependent chemical shifts, often of OH groups; 99.8% perdeuterated methanol is an established example which is particularly well suited for modern, high-sensitivity spectrometers, but it is so far calibrated only in the range of 282 to 330 K. In this work, we extend this calibration to the entire liquid range of methanol, 175 to 338 K. Additionally, we use a temperature sensor calibrated traceably to the International Temperature Scale (ITS-90) and accounted for the magnetic field effect on the sensor, yielding a more accurate calibration curve with an uncertainty (2σ) varying between 25 and 190 mK.

Paramagnetic NMR constraints are very useful to study protein interdomain motion, but their interpretation is not always straightforward. On the example of the particularly flexible complex Calmodulin/Munc13-1, we present a new approach to characterize this motion with pseudocontact shifts and residual dipolar couplings. Using molecular mechanics, we sampled the conformational space of the complex and used a genetic algorithm to find ensembles that are in agreement with the data. We used the Bayesian information criterion to determine the ideal ensemble size. This way, we were able to make an accurate, unambiguous, reproducible model of the interdomain motion of Calmodulin/Munc13-1 without prior knowledge about the domain orientation from crystallography.

Anisotropic NMR has gained increasing popularity to determine the structure and specifically the configuration of small, flexible, non-crystallizable molecules. However, it suffers from the necessity to dissolve the analyte in special media such as liquid crystals or polymer gels. Generally, small degrees of alignment are also caused by an anisotropic magnetic susceptibility of the molecule, for example, induced by aromatic moieties. For this mechanism, the alignment can be predicted via density functional theory. Here we show that both residual dipolar couplings and residual chemical shift anisotropies can be acquired from natural products without special sample preparation using magnetically induced alignment. On the two examples of the novel natural product gymnochrome G and the alkaloid strychnine, these data, together with the predicted alignment, yield the correct configuration with high certainty.

The 2TM domain family of K channels are also known as the inward-rectifier K channel family. This family includes the strong inward-rectifier K channels (Kir2.x) that are constitutively active, the G-protein-activated inward-rectifier K channels (Kir3.x) and the ATP-sensitive K channels (Kir6.x, which combine with sulphonylurea receptors (SUR1-3)). The pore-forming α subunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. Kir3.2 with Kir3.3).

Introduction Reticulated or immature Platelets are pro-thrombotic RNA-rich young platelets, which have been reported to correlate with adverse events in several pathological settings including coronary artery disease. However, the predictive value of this subgroup of platelets in patients with acute coronary syndrome treated with the potent novel P2Y12 inhibitors prasugrel or ticagrelor has not been investigated yet. Moreover, their role as predictors of major bleeding is unclear. Purpose The primary aim of this prespecified reticulated platelet ISAR-REACT-5 substudy was to evaluate the immature platelet fraction (IPF%) in peripheral blood as a predictor of the composite primary endpoint consisting of death, myocardial infarction, or stroke at one year after randomization in patients with acute coronary syndrome. Methods IPF was assessed in the first 24h after randomization using a fully automated system and correlated to the incidence of the primary endpoint. All patients with available IPF values were included. The Sysmex system uses two fluorescent dyes to stain platelet RNA and a computer algorithm (Sysmex IPF Master) discriminates immature from mature platelets by the intensity of forward scattered light and fluorescence. The immature platelet fraction is displayed as percentage of the total optical platelet count (IPF%). Results IPF values within the first 24h after randomization were available in a total of 506 randomized patients. Baseline characteristics and IPF (median [IQR]) values did not differ between the 2 study groups (IPF: prasugrel 3.9% [2.7–5.8] ticagrelor 3.4% [2.5–5.6] p=0.56). Significantly higher IPF values were observed in patients reaching the primary endpoint (n=55 of 506) independent from the study group (p for interaction= 0.28). ROC-curve analysis revealed a cut-of value of IPF 3.6% for the prediction of death, myocardial infarction or stroke with a Hazard ratio (HR) according to cox-regression analysis of 1.98 (95% CI, 1.15–3.44), P=0.01 (Figure 1A). Interestingly, we also detected a trend for higher major bleedings (BARC 3–5) in patients with elevated IPF values above IPF>4.8% according to ROC-curve analysis (Figure 1B). Conclusion IPF was significantly associated with the primary endpoint in the ISAR-REACT 5 substudy independent from the treatment group and therefore is a promising novel biomarker for the prediction of adverse cardiovascular events in patients with acute coronary syndrome. Figure 1 Funding Acknowledgement Type of funding source: None

Introduction The recently published randomized multicenter open label ISAR REACT 5 trial showed that prasugrel was superior to ticagrelor with respect to the composite primary end point of death, myocardial infarction, or stroke at one year after randomization in patients with acute coronary syndrome with planned invasive evaluation. The reasons for this finding are speculative. Purpose The aim of this prespecified platelet aggregation substudy was to assess platelet aggregation induced by adenosine-diphosphate (ADP) in patients who received prasugrel or ticagrelor treatment and underwent PCI. Methods We assessed all patients who underwent PCI and who had valid ADP-induced platelet aggregation values at hospital admission and at 2–24 hours after administration of prasugrel or ticagrelor loading dose followed by maintenance dose. ADP-induced platelet aggregation values were measured using the Mulitplate Analyzer®. Patients were recruited in the German Heart Center, Munich, Germany or in Klinikum rechts der Isar, Munich, Germany, Technical University of Munich. Results A total of 608 patients were analyzed. Patients in the prasugrel group were slightly but significantly older than patients in the ticagrelor group (66,5 years versus 64,6 years, P=0,048). The remaining baseline characteristics did not significantly differ between the two treatment groups. ADP-induced platelet aggregation (median [IQR]) at baseline did not differ between prasgurel- and ticagrelor treated patients (809 [556; 1057] AU x min versus 797 [534–1095] AU x min. At 2–24 hours after study drug administration ADP-induced platelet aggregation was significantly lower in patients who had received prasugrel in comparison to ticagrelor (105 [57–176] AU x min versus 138 [77–207] AU x min (Figure 1). Conclusion ADP-induced platelet aggregation was significantly lower in patients who received prasugrel in comparison to patients who received ticagrelor, which could have influenced patients' outcome in the ISAR-REACT 5 trial. Figure 1 Funding Acknowledgement Type of funding source: None

Advanced biomass conversion plants can replace fossil resources in the electricity, heat, transportation fuels and chemicals sectors, but they face specific challenges with regard to their economic operation. When choosing a capacity for a biomass conversion plant, economies of scale must be weighed against the transportation costs for the widely-distributed input materials. Here, we model the problem of determining the optimal capacity for plants with a single product or a fixed set of products using a single optimization variable and two alternative economic objective functions. To identify the factors that most strongly influence economic plant operation, we perform a sensitivity analysis of various model parameters to determine their impact on the optimal solution using the Envelope Theorem. We also present an optimization approach for simultaneously planning the capacity and configuration of multi-product plants. By modeling economies of scale on a process-specific level, our nonlinear optimization approach makes it possible to determine the optimal configurations, and thus ranges of products, for changing plant capacities. An examination of the obtained feasible solutions shows that the optimization problem is neither convex nor concave.

Nuclear magnetic resonance (NMR) is a fundamental spectroscopic technique for the study of biological systems and materials, molecular imaging and the analysis of small molecules. It detects interactions at very low energies and is thus non-invasive and applicable to a variety of targets, including animals and humans. However, one of its most severe limitations is its low sensitivity, which stems from the small interaction energies involved. Here, we report that dynamic nuclear polarization in liquid solution and at room temperature can enhance the NMR signal of 13C nuclei by up to three orders of magnitude at magnetic fields of ∼3 T. The experiment can be repeated within seconds for signal averaging, without interfering with the sample magnetic homogeneity. The method is therefore compatible with the conditions required for high-resolution NMR. Enhancement of 13C signals on various organic compounds opens up new perspectives for dynamic nuclear polarization as a general tool to increase the sensitivity of liquid NMR.