Biochemometry-Based Discovery of Phenylpropanoids from Azadirachta indica Fruits as Inhibitors of In Vitro Osteoclast Formation

(1) Background: Inhibition of osteoclast differentiation is the key approach in treating osteoporosis. However, using state-of-the-art treatments such as bisphosphonates and estrogen-based therapy is usually accompanied by many side effects. As opposed to this, the use of natural products as an osteoporotic remedy delivers promising outcomes with minimal side effects. (2) Methods: In the present study, we implemented a biochemometric workflow comprising (i) chemometric approaches using NMR and mass spectrometry and (ii) cell biological approaches using an osteoclast cytochemical marker (TRAP). The workflow serves as a screening tool to pursue potential in vitro osteoclast inhibitors. (3) Results: The workflow allowed for the selective isolation of two phenylpropanoids (coniferyl alcohol and sinapyl alcohol) from the fruits of neem tree (Azadirachta indica). These two isolated phenylpropanoids showed a very promising dose-dependent inhibition of osteoclast differentiation with negligible effects in terms of cell viability. (4) Conclusion: The presented workflow is an effective tool in the discovery of potential candidates for osteoclast inhibition from complex extracts. The used biochemometric approach saves time, effort and costs while delivering precise hints to selectively isolate bioactive constituents.     

Design Platform for Sustainable Catalysis with Radicals: Electrochemical Activation of Cp2TiCl2 for Catalysis Unveiled

The combination of synthesis, rotating ring-disk electrode (RRDE) and cyclic voltammetry (CV) measurements, and computational investigations with the aid of DFT methods shows how a thiourea, a squaramide, and a bissulfonamide as additives affect the E_qC_r equilibrium of Cp₂TiCl₂. We have, for the first time, provided quantitative data for the E_qC_r equilibrium and have determined the stoichiometry of adduct formation of [Cp₂Ti(III)Cl₂]⁻, [Cp₂Ti(III)Cl] and [Cp₂Ti(IV)Cl₂] and the additives. By studying the structures of the complexes formed by DFT methods, we have established the Gibbs energies and enthalpies of complex formation as well as the adduct structures. The results not only demonstrate the correctness of our use of the E_qC_r equilibrium as predictor for sustainable catalysis. They are also a design platform for the development of novel additives in particular for enantioselective catalysis.     

Development of Red-Shifted and Fluorogenic Nucleoside and Oligonucleotide Diarylethene Photoswitches

The reversible modulation of fluorescence signals by light is of high interest for applications in super-resolution microscopy, especially on the DNA level. In this article we describe the systematic variation of the core structure in nucleoside-based diarylethenes (DAEs), in order to generate intrinsically fluorescent photochromes. The introduction of aromatic bridging units resulted in a bathochromic shift of the visible absorption maximum of the closed-ring form, but caused reduced thermal stability and switching efficiency. The replacement of the thiophene aryl unit by thiazol improved the thermal stability, whereas the introduction of a benzothiophene unit led to inherent and modulatable turn-off fluorescence. This feature was further optimized by introducing a fluorescent indole nucleobase into the DAE core, resulting in an effective photoswitch with a fluorescence quantum yield of 0.0166 and a fluorescence turn-off factor of 3.2. The site-specific incorporation into an oligonucleotide resulted in fluorescence-switchable DNA with high cyclization quantum yields and switching efficiency, which may facilitate future applications.     

Antiferromagnetic Alkali Metal Oxohydroxoferrates(III) with Correlated Hydrogen Bonding Systems

The oxohydroxoferrates(III) A₂[Fe₂O₃(OH)₂] (A=K, Rb, Cs) were synthesized under hydroflux conditions. Approximately equimolar mixtures of the alkali metal hydroxides and water were reacted with Fe(NO₃)₃ ⋅ 9H₂O at about 200 °C. The product formation depends on the hydroxide concentration, therefore also other reaction products, such as KFeO₂, K_2−x[Fe₄O_7−x(OH)_x] or α-Fe₂O₃, are obtained. The crystal structures of the oxohydroxoferrates(III) A₂[Fe₂O₃(OH)₂] follow the same structural principle, yet differ in their layer stacking or/and their hydrogen bonding systems depending on A and temperature. In the resulting four different orthorhombic structure types, [FeO₃OH]⁴⁻ tetrahedra share their oxide corners to create folded Fe₂O₃(OH)₂]²⁻ layers. The terminal hydroxide ligands form hydrogen bonds between and/or within the layers. The positions of the hydrogen atoms in these networks are correlated. The A⁺ cations are located between the folded anionic layers as well as in their trenches. Under reaction conditions, the potassium compound crystallizes in the space group Cmce (Pearson symbol oC88), showing a bimodal disorder of the hydrogen atoms in hydrogen bridges. In a virtually hysteresis-less first-order transition at 340(2) K, the structure slightly distorts into the room-temperature modification with the subgroup Pbca (oP88), and the hydrogen atoms order. The rubidium and caesium compounds are isostructural to each other but not to the potassium compound, and are always obtained as mixtures of two modifications with space groups Cmce (oC88′) and Immb (oI88). Upon heating, the oxohydroxoferrates decompose into their anhydrides AFeO₂ and water. The type of hydrogen bonding network influences the decomposition temperature, the structure and the morphology of the crystals. Despite the presence of iron(III), which was confirmed by ⁵⁷Fe-Mössbauer spectroscopy, K₂[Fe₂O₃(OH)₂] is diamagnetic in the investigated temperature range between 1.8 and 300 K. Neutron diffraction revealed strong antiferromagnetic coupling of the magnetic moments, which are inverted in neighboring tetrahedra.     

Selective ortho‐Functionalization of Adamantylarenes Enabled by Dispersion and an Air‐Stable Palladium(I) Dimer

Contrary to the general belief that Pd‐catalyzed cross‐coupling at sites of severe steric hindrance are disfavored, we herein show that the oxidative addition to C?Br ortho to an adamantyl group is as favored as the corresponding adamantyl‐free system due to attractive dispersion forces. This enabled the development of a fully selective arylation and alkylation of C?Br ortho to an adamantyl group, even if challenged with competing non‐hindered C?OTf or C?Cl sites. The method makes use of an air‐stable Pd^I dimer and enables straightforward access to diversely substituted therapeutically important adamantylarenes in 5–30 min.     

Car path tracking in traffic flow networks with bounded buffers at junctions

This article deals with the modeling for an individual car path through a road network, where the dynamics is driven by a coupled system of ordinary and partial differential equations. The network is characterized by bounded buffers at junctions that allow for the interpretation of roundabouts or on-ramps while the traffic dynamics is based on first-order macroscopic equations of Lighthill-Whitham-Richards (LWR) type. Trajectories for single drivers are then influenced by the surrounding traffic and can be tracked by appropriate numerical algorithms. The computational experiments show how the modeling framework can be used as navigation device.     

Correction to: Globalized inexact proximal Newton-type methods for nonconvex composite functions

Computational Optimization and Applications -     

pH Transients in hydroxyapatite chromatography columns—Experimental evidence and phenomenological modeling

Hydroxyapatite (HAP) columns, widely used for chromatographic separation of proteins and other biomolecules because of their unique selectivity and ability to resolve complex mixtures, exhibit limited stability at acidic conditions requiring careful control of pH. Even with buffered solutions, however, unintended pH transients can occur when the salt concentration varies. For example, the pH temporarily decreases below the feed value when the salt concentration increases and increases above the feed value when the salt concentration is decreased. The intensity and duration of these transients depend on the particular buffer used and the magnitude of the salt concentration step, but in extreme cases the pH can drop by as much as 1.5 pH units creating conditions where the HAP stability is potentially compromised. This work examines the mechanisms leading to pH transients in HAP columns generated by salt steps. The pH excursions are similar to those observed for weak cation exchange columns, but are accompanied by a transient evolution of phosphate which temporarily decreases below the feed value when the salt concentration is increased and increases sharply when the salt concentration is reduced before returning to the feed value. A phenomenological model is developed to describe this behavior by considering the reversible uptake of sodium ions by the P-sites and binding of phosphate ions by the C-sites. The interplay of these two adsorption mechanisms results in complex pH patterns that are consistent with those observed experimentally. In addition to helping understand the underlying mechanisms, the model also provides a useful tool to predict the effects of different buffers and salt concentration and develop corrective measures that can reduce the intensity and duration of the pH transients such as the addition of unretained co-buffers.     

Giga-bit optical receiver for plastic optical fibre

An optical receiver with high sensitivity and linearity specially designed for Giga-bit communications over small-bandwidth high-attenuation multimode plastic optical fiber is presented. An automatic gain control transimpedance amplifier and linear post amplifiers are used to maintain a good performance with multilevel modulation. Using multilevel signaling and large-diameter integrated photodiodes make the presented optical receiver suitable for large core plastic optical fiber. For a wavelength of 675 nm, a sensitivity of −26.3 dB m (BER = 10⁻⁹) at 500 Mb/s is presented by a binary signal. A data rate of 1 Gb/s and a sensitivity of −19.8 dB m (BER = 10⁻⁹) are achieved with four-level pulse amplitude modulation.