The Antibacterial Drug Candidate SBC3 is a Potent Inhibitor of Bacterial Thioredoxin Reductase

Antibiotic resistance is a growing problem for public health and associated with increasing economic costs and mortality rates. Silver and silver-related compounds have been used for centuries due to their antimicrobial properties. In this work, we show that 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene silver(I) acetate/NHC*-Ag-OAc (SBC3) is a reversible, high affinity inhibitor of E. coli thioredoxin reductase (TrxR; K_i=10.8±1.2 nM). Minimal inhibition concentration (MIC) tests with different E. coli and P. aeruginosa strains demonstrated that SBC3 can efficiently inhibit bacterial cell growth, especially in combination with established antibiotics like gentamicin. Our results show that SBC3 is a promising antibiotic drug candidate targeting bacterial TrxR.     

Tropfenbewegung und Stofftransport in technischen Flüssig/flüssig-Systemen. Teil 2: Auswirkung von Grenzflächeneffekten und Verunreinigungen

The design of a liquid/liquid contact apparatus necessitates the knowledge of fluid dynamics and mass transfer in the dispersion. Prediction of process parameters is challenging due to swarm and interfacial effects. Single drop investigations are suitable to enable a sophisticated dimensioning based on few simple experiments combined with published theories and correlations. In the first part of this article, the fundamentals of fluid dynamics and mass transfer in absence of interfacial effects were explained. Here, an overview of relevant interfacial phenomena and the influence of different substances typically occurring in technical applications as impurities or accompanying components is given.     

Experimentelle Untersuchung des Abwälzverhaltens von Beveloidverzahnungen mit lokal angepassten Verzahnungsdaten entlang der Zahnbreite

Forschung im Ingenieurwesen - Zur Übertragung von Drehmoment und Drehzahl in beliebiger Achsanordnung eignen sich bei kleinem Achswinkel bis 30° Beveloidverzahnungen. Besonders...     

Anisotropy Effects in the Shape-Memory Performance of Polymer Foams

Isotropic and anisotropic shape-memory polymer foams are prepared by supercritical carbon dioxide foaming from a multiblock copolymer (PDLCL) consisting of poly(ω-pentadecalactone) and poly(ε-caprolactone) segments. Analysis by micro-computed tomography reveals for the anisotropic PDLCL foam cells a high shape anisotropy ratio of R = 1.72 ± 0.62 with a corresponding Young's compression moduli ratio between longitudinal and transversal direction of 4.3. The experimental compression data in the linear elastic range can be well described by the anisotropic open foam model of Gibson and Ashby. A micro-morphological analysis for single pores using scanning electron microscopy images permits the correlation between the macroscopic stress-compression behavior and microscale structural changes.     

Two Methods,One Goal: Structural Differences between Cocrystallization and Crystal Soaking to Discover Ligand Binding Poses

In lead optimization, protein crystallography is an indispensable tool to analyze drug binding. Binding modes and non-covalent interaction inventories are essential to design follow-up synthesis candidates. Two protocols are commonly applied to produce protein–ligand complexes: cocrystallization and soaking. Because of its time and cost effectiveness, soaking is the more popular method. Taking eight ligand hinge binders of protein kinase A, we demonstrate that cocrystallization is superior. Particularly for flexible proteins, such as kinases, and larger ligands cocrystallization captures more reliable the correct binding pose and induced protein adaptations. The geometrical discrepancies between soaking and cocrystallization appear smaller for fragment-sized ligands. For larger flexible ligands that trigger conformational changes of the protein, soaking can be misleading and underestimates the number of possible polar interactions due to inadequate, highly impaired positions of protein amino-acid side and main chain atoms. Thus, if applicable cocrystallization should be the gold standard to study protein–ligand complexes.     

Synthesis and Initial Characterization of a Selective,Pseudo-irreversible Inhibitor of Human Butyrylcholinesterase as PET Tracer

The enzyme butyrylcholinesterase (BChE) represents a promising target for imaging probes to potentially enable early diagnosis of neurodegenerative diseases like Alzheimer's disease (AD) and to monitor disease progression in some forms of cancer. In this study, we present the design, facile synthesis, in vitro and preliminary ex vivo and in vivo evaluation of a morpholine-based, selective inhibitor of human BChE as a positron emission tomography (PET) tracer with a pseudo-irreversible binding mode. We demonstrate a novel protecting group strategy for ¹⁸F radiolabeling of carbamate precursors and show that the inhibitory potency as well as kinetic properties of our unlabeled reference compound were retained in comparison to the parent compound. In particular, the prolonged duration of enzyme inhibition of such a morpholinocarbamate motivated us to design a PET tracer, possibly enabling a precise mapping of BChE distribution.     

Novel BQCA- and TBPB-Derived M1 Receptor Hybrid Ligands: Orthosteric Carbachol Differentially Regulates Partial Agonism

Recently, investigations of the complex mechanisms of allostery have led to a deeper understanding of G protein-coupled receptor (GPCR) activation and signaling processes. In this context, muscarinic acetylcholine receptors (mAChRs) are highly relevant due to their exemplary role in the study of allosteric modulation. In this work, we compare and discuss two sets of putatively dualsteric ligands, which were designed to connect carbachol to different types of allosteric ligands. We chose derivatives of TBPB [1-(1′-(2-tolyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one] as M₁-selective putative bitopic ligands, and derivatives of benzyl quinolone carboxylic acid (BQCA) as an M₁ positive allosteric modulator, varying the distance between the allosteric and orthosteric building blocks. Luciferase protein complementation assays demonstrated that linker length must be carefully chosen to yield either agonist or antagonist behavior. These findings may help to design biased signaling and/or different extents of efficacy.     

科帕卡格拉纳建筑 奥地利维亚纳

正科帕卡格拉纳位于新多瑙河12.5公里处,毗邻Reichsbrücke大桥。出于同旧有设计保持协调性考虑,力求能让大楼融入当地环境,迎合自身功能性需要,GERNER GERNER PLUS团队充分考虑现有周边环境,对大楼重新规划设计。新的设计突显建筑的特殊性和重要性,面向河流的立面是科帕卡格拉纳大楼最重要的部分,所以设计的重点也放在了这里。现有的城市中轴线是一个参照物,为了视觉上和氛围上形成一体化城市的感     

Uncertainties in the determination of pyrrolizidine alkaloid levels in naturally contaminated honeys and comparison of results obtained by different analytical approaches

The contamination of honey with hepatotoxic pyrrolizidine alkaloids (PAs) is a well-known hazard for food safety. While management strategies and controls of the honey industry aim to reduce the PA levels, uncertainties remain with regard to the safety of regionally produced and marketed honey. In addition, a previous study showed large differences of results obtained after various periods of storage and apparent differences between the analytical results of different laboratories. Therefore, this study aimed at examining these uncertainties by monitoring the impact of storage on the PA and PA N-oxide (PANO) content of two freshly harvested honeys and on possible demixing effects caused by pollen settling. Additionally, three analytical approaches – target analysis with matrix-matched calibration or standard addition and a sum parameter method – were applied for a comparative analysis of 20 honeys harvested in summer 2016. All samples originated from Schleswig-Holstein in Northern Germany where the PA plant Jacobaea vulgaris is currently observed on a massive scale. The results of the time series analyses showed that PANO levels markedly decreased within a few weeks and practically reached the LOD 16 weeks after harvest. Tertiary PAs, by contrast, remained stable and did not increase as a consequence of PANO decrease. The experiments on a putative demixing, which may result in a heterogeneous distribution of PAs/PANOs, revealed that there was no such effect during storage of up to 12 weeks. A comparison of the PA/PANO levels obtained by different analytical approaches showed that in some cases the sum parameter method yielded much higher levels than the target approaches, whereas in other cases, the target analysis with standard addition found higher levels than the other two methods. In summary, the results of this study highlight uncertainties regarding the validity and comparability of analytical results and consequently regarding health risk assessment.     

Effect of load reduction mechanisms on loads and blade bearing movements of wind turbines

The power control of wind turbines is usually realized via a change in the pitch angle of the rotor blades. Pitching facilitates the exact control of the turbines and the reliable deceleration of the rotor when required. Pitch movements can moreover be used for load control. One of these methods is called individual pitch control (IPC). IPC controls the blades individually and brings about a significant reduction in the fatigue loads and extreme loads placed on the structural components, while at the same time reducing the yield of the turbine only slightly. The lower loads reduce material costs, and thus, the cost of energy (CoE) is reduced, despite the slight reduction in yield. The method is nevertheless not used everywhere since the additional movement cycles put the rotor blade bearings in particular under stress. Special attention must be paid to small amplitude oscillating movements, which carry a high risk of inducing surface damage in the rolling contacts of the blade bearings. This paper uses a cycle analysis of the IWT7.5‐164 reference turbine to illustrate the differences in the movement patterns of wind turbine blade bearings with and without IPC. Moreover, model calculations with single contacts are used to show which of the movement patterns carries a risk of inducing surface damage. The use of IPC leads to the expected load reduction at the blade root. In current literature, IPC is usually assumed to have a negative influence on the life expectancy of blade bearings, but the findings of this study contradict this. The summed blade bearing movement is increased, although the number of very small pitch angles occurring is reduced. This reduction reduces the risk of wear in the blade bearings.