On enhanced non-linear free surface flow simulations with a hybrid LBM–VOF model

In this paper, we present extensions, extensive validations and applications of our previously published hybrid volume-of-fluid-based (VOF) model for the simulation of free-surface flow problems. For the solution of the flow field, the lattice Boltzmann method is used, where the free surface is represented by a VOF approach. The advection equation for the VOF fill level is discretized with a finite volume method, on the basis of a 3D Piecewise Linear Interface Reconstruction (PLIC) algorithm. The model is validated for several standard free surface benchmarks, such as breaking dam scenarios and a free falling jet. Finally, the hybrid algorithm is applied to the simulation of a wave breaking by overturning during shoaling, which is considered to be a demanding test case, especially for VOF solvers. In this case, the flow field is initialized early in the shoaling process with a solitary wave solution from inviscid, irrotational potential flow. The wave breaking process is then simulated with the 3D transient and turbulent LBM–VOF solver. All validation and benchmark tests confirm the accuracy of the proposed hybrid model.     

TIME'S ARROW IN PARTICLE PHYSICS

This article gives an introduction into the current understanding of time invariance and evidence of its violation in experimental particle physics. The connection between time invariance and other discrete symmetries, particularly, CP-invariance, is explained. The first experimental determination of CP-violation is explained, and recent experiments on CP-violation and on T-violation are discussed.     

Aliphatic 18F-Radiofluorination: Recent Advances in the Labeling of Base-Sensitive Substrates**

Aliphatic fluorine-18 radiolabeling is the most commonly used method to synthesize tracers for PET-imaging. With an increasing demand for ¹⁸F-radiotracers for clinical applications, new labeling strategies aiming to increase radiochemical yields of established tracers or, more importantly, to enable ¹⁸F-labeling of new scaffolds have been developed. In recent years, increased attention has been focused on the direct aliphatic ¹⁸F-fluorination of base-sensitive substrates in this respect. This minireview gives a concise overview of the recent advances within this field and aims to highlight the advantages and limitations of these methods.     

Nitroreductase-Mediated Release of Inhibitors of Lysine-Specific Demethylase 1 (LSD1) from Prodrugs in Transfected Acute Myeloid Leukaemia Cells

Lysine-specific demethylase 1 (LSD1) has evolved as a promising therapeutic target for cancer treatment, especially in acute myeloid leukaemia (AML). To approach the challenge of site-specific LSD1 inhibition, we developed an enzyme-prodrug system with the bacterial nitroreductase NfsB (NTR) that was expressed in the virally transfected AML cell line THP1-NTR⁺. The cellular activity of the NTR was proven with a new luminescent NTR probe. We synthesised a diverse set of nitroaromatic prodrugs that by design do not affect LSD1 and are reduced by the NTR to release an active LSD1 inhibitor. The emerging side products were differentially analysed using negative controls, thereby revealing cytotoxic effects. The 2-nitroimidazolyl prodrug of a potent LSD1 inhibitor emerged as one of the best prodrug candidates with a pronounced selectivity window between wild-type and transfected THP1 cells. Our prodrugs are selectively activated and release the LSD1 inhibitor locally, proving their suitability for future targeting approaches.     

Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors

Indoles are privileged structures in medicinal and bioorganic chemistry that are particularly well suited to serve as platforms for diversity. Among many other therapeutic areas, the indole scaffold has been used to design aromatic compounds useful to interfere with enzymes engaged in the regulation of substrate acylation status, such as sirtuins. However, the planarity of the indole ring is not necessarily optimal for all target enzymes, especially when functionalization with aromatic side chains is required. Replacement of flat scaffolds by nonplanar molecular cores dominated by sp³ hybridization is a common strategy to avoid the disadvantages associated with poor solubility and high promiscuity, while covering less-well-explored areas of chemical space. Thus, we synthesized fragment-like tetrahydroindoles suitable for fragment-based drug discovery as well as a well-characterized small library intended as multipurpose screening compounds. For proof of principle, these compounds were screened against sirtuins 1–3, enzymes known to be addressable by indoles. We found that 2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamides are potent and selective SIRT2 inhibitors. Compound 16 t displayed an IC₅₀ value of 0.98 μm and could serve as exquisite starting point for hit-to-lead profiling.     

Fouling Detection in an Optically Accessible Microstructured Heat Exchanger

The application of highly effective microstructured devices in continuous production and industrial environments is frequently prone to fouling. A new method is presented to characterize fouling in these microstructures. Thermal fouling of aqueous solutions containing whey protein were used as a test system. Different fouling effects could be observed and distinguished. Integral fouling indicators, such as thermal fouling resistance and pressure drop, as conventional criteria for the occurrence of fouling were compared with direct local optical observation. Low thermal fouling resistances could be detected.     

Nicotinic Acid Increases Adiponectin Secretion from Differentiated Bovine Preadipocytes through G-Protein Coupled Receptor Signaling

The transition period in dairy cows (3 weeks prepartum until 3 weeks postpartum) is associated with substantial mobilization of energy stores, which is often associated with metabolic diseases. Nicotinic acid (NA) is an antilipolytic and lipid-lowering compound used to treat dyslipidaemia in humans, and it also reduces non-esterified fatty acids in cattle. In mice the G-protein coupled receptor 109A (GPR109A) ligand NA positively affects the secretion of adiponectin, an important modulator of glucose and fat metabolism. In cattle, the corresponding data linking NA to adiponectin are missing. Our objective was to examine the effects of NA on adiponectin and AMPK protein abundance and the expression of mRNAs of related genes such as chemerin, an adipokine that enhances adiponectin secretion in vitro. Differentiated bovine adipocytes were incubated with pertussis toxin (PTX) to verify the involvement of GPR signaling, and treated with 10 or 15 µM NA for 12 or 24 h. NA increased adiponectin concentrations (p ≤ 0.001) and the mRNA abundances of GPR109A (p ≤ 0.05) and chemerin (p ≤ 0.01). Pre-incubation with PTX reduced the adiponectin response to NA (p ≤ 0.001). The NA-stimulated secretion of adiponectin and the mRNA expression of chemerin in the bovine adipocytes were suggestive of GPR signaling-dependent improved insulin sensitivity and/or adipocyte metabolism in dairy cows.