Modifying the 5-position of thieno[2,3-d][1,2,3]thiadiazole-6-carboxylate derivatives

Thieno[2,3-d][1,2,3]thiadiazole-6-carboxylates 3 belong to a new group of plant protecting agents as highly potent inducers of systemic acquired resistance (SAR). In order to obtain an enhanced basis set for structure activity relationship studies several modifications of the heteroaromatic core were performed by introduction of various substituents. One approach utilizing metallation techniques led to several 5-substituted derivatives 4a – h of the title compound. Using the chloro-compound 5 obtained via this route the ability to undergo nucleophilic substitution reactions was investigated, representing a complementary strategy towards derivatives 6a – c .     

Optimization of electro-blown polysulfone nanofiber mats for air filtration applications

Durable, robust, and hydrophobic air filtration media was produced via electro-blow spinning (EBS) technique using polysulfone (PSU) due to its superior properties. To our knowledge, this is the first optimization study of PSU nanofiber production via EBS technique for air filtration applications. Concentration, air pressure, and voltage were determined as independent variables for the optimization based on “smaller is the better” approach of Taguchi Design of Experiment. The optimized values which supplied the smallest average fiber diameter (AFD) possible were obtained as 13 wt% PSU, 3 bar, and 7.5 kV. The AFD of the sample obtained from the confirmation experiment was calculated as 105 ± 34 nm. Surface morphologies, porosity values, and wettability behaviors of the samples were investigated by using scanning electron microscopy, gravimetric method, and water contact angle measurements, respectively. PSU nanofiber mats exhibited superhydrophobic behavior (water contact angle values up to 159.8°) which is important for various separation processes. Samples prepared at different deposition times (15, 30, 45, and 60 min) were investigated in terms of particle capture efficiency and pressure drop. The 0.3 μm particle filtration efficiency was found to be 98.09% at an expense of 202 Pa pressure drop which would be suitable for various respiratory and HVAC filter applications.     

Human iPSC-Derived Proinflammatory Macrophages cause Insulin Resistance in an Isogenic White Adipose Tissue Microphysiological System

Chronic white adipose tissue (WAT) inflammation has been recognized as a critical early event in the pathogenesis of obesity-related disorders. This process is characterized by the increased residency of proinflammatory M1 macrophages in WAT. However, the lack of an isogenic human macrophage-adipocyte model has limited biological studies and drug discovery efforts, highlighting the need for human stem cell-based approaches. Here, human induced pluripotent stem cell (iPSC) derived macrophages (iMACs) and adipocytes (iADIPOs) are cocultured in a microphysiological system (MPS). iMACs migrate toward and infiltrate into the 3D iADIPOs cluster to form crown-like structures (CLSs)-like morphology around damaged iADIPOs, recreating classic histological features of WAT inflammation seen in obesity. Significantly more CLS-like morphologies formed in aged and palmitic acid-treated iMAC-iADIPO-MPS, showing the ability to mimic inflammatory severity. Importantly, M1 (proinflammatory) but not M2 (tissue repair) iMACs induced insulin resistance and dysregulated lipolysis in iADIPOs. Both RNAseq and cytokines analyses revealed a reciprocal proinflammatory loop in the interactions of M1 iMACs and iADIPOs. This iMAC-iADIPO-MPS thus successfully recreates pathological conditions of chronically inflamed human WAT, opening a door to study the dynamic inflammatory progression and identify clinically relevant therapies.     

Prioritizing Small Sets of Molecules for Synthesis through in-silico Tools: A Comparison of Common Ranking Methods

Prioritizing molecules for synthesis is a key role of computational methods within medicinal chemistry. Multiple tools exist for ranking molecules, from the cheap and popular molecular docking methods to more computationally expensive molecular-dynamics (MD)-based methods. It is often questioned whether the accuracy of the more rigorous methods justifies the higher computational cost and associated calculation time. Here, we compared the performance on ranking the binding of small molecules for seven scoring functions from five docking programs, one end-point method (MM/GBSA), and two MD-based free energy methods (PMX, FEP+). We investigated 16 pharmaceutically relevant targets with a total of 423 known binders. The performance of docking methods for ligand ranking was strongly system dependent. We observed that MD-based methods predominantly outperformed docking algorithms and MM/GBSA calculations. Based on our results, we recommend the application of MD-based free energy methods for prioritization of molecules for synthesis in lead optimization, whenever feasible.     

Selective Monovalent Galectin-8 Ligands Based on 3-Lactoylgalactoside

Galectin-8 has gained attention as a potential new pharmacological target for the treatment of various diseases, including cancer, inflammation, and disorders associated with bone mass reduction. To that end, new molecular probes are needed in order to better understand its role and its functions. Herein we aimed to improve the affinity and target selectivity of a recently published galectin-8 ligand, 3-O-[1-carboxyethyl]-β-d -galactopyranoside, by introducing modifications at positions 1 and 3 of the galactose. Affinity data measured by fluorescence polarization show that the most potent compound reached a K_D of 12 μM. Furthermore, reasonable selectivity versus other galectins was achieved, making the highlighted compound a promising lead for the development of new selective and potent ligands for galectin-8 as molecular probes to examine the protein's role in cell-based and in vivo studies.     

Verhalten von hochduktilem Beton unter Impaktbelastung

In diesem Aufsatz wird das Materialverhalten von Hochduktilem Beton (engl.: Strain Hardening Cementitious Composite – SHCC) bei Impaktbelastung beschrieben. Dazu werden Ergebnisse aus hochdynamischen Spallations‐Experimenten an einem Hopkinson‐ Bar mit Dehnraten > 140 1/s den Resultaten aus quasi‐statischen, zentrischen Zugversuchen mit Dehnraten von 0,001 1/s gegenübergestellt. Die Auswirkungen hoher Dehnraten auf das Materialverhalten erfolgt anhand eines Vergleiches der zentrischen Zugfestigkeit, des E‐Moduls sowie der Bruchenergie. Die experimentellen Ergebnisse werden zudem mit den Kennwerten anderer Betone in Beziehung gesetzt. Unterschiede im Materialverhalten werden auf Grundlage von Phänomenen der Rissbildung und des Faserauszuges erklärt. Mechanical Behaviour of SHCC under Impact This paper describes the material behaviour of Strain Hardening Cementitious Composite (SHCC) at high strain rates. The results of high dynamic spall experiments using a Hopkinson Bar at strain rates > 140/sec were arrayed against the results of quasistatic, centric tensile tests at strain rates of 0,001/sec. This comparison is based on the parameters of tensile strength, elastic modulus, and fracture energy of the specimens. In addition, the experimental results of SHCC are related to the characteristic values of other concrete types. Differences in material behaviour are explained by the phenomena of crack formation and fibre pullout force.     

Analysis of light scattering in amorphous Si:H solar cells by a one‐dimensional semi‐coherent optical model

A one‐dimensional semi‐coherent optical model for thin‐film solar cells is presented. The optical circumstances at flat interfaces are addressed and the situation at rough interfaces in the model is described for the case of direct (coherent) incident and scattered (incoherent) incident light. After the model has been experimentally verified, analysis of the light scattering process in hydrogenated amorphous silicon (a‐Si:H) p–i–n solar cells is carried out. The influence of the interface root‐mean‐square roughness and the effect of different angular distribution functions of diffused light on quantum efficiency and short‐circuit current are investigated by the optical model. Copyright © 2002 John Wiley & Sons, Ltd.     

An Intriguing Array of Extrudate Patterns in Long-Chain Branched Polymers During Extrusion

The present study highlights a range of surface and volume extrudate patterns that can be detected during the extrusion flow of long-chain branched polymers. Thus, four linear low-density polyethylenes (LDPEs) have been extruded using a single-screw extruder coupled to an inline optical imaging system. The selected LDPEs are selected to outline the influence of molecular weight and long-chain branching on the types of melt flow extrusion instabilities (MFEI). Through the inline imaging system, space–time diagrams are constructed and analyzed via Fourier-transformation using a custom moving window procedure. Based on the number of characteristic frequencies, peak broadness, and whether they are surface or volume distortions, three main MFEI types, distinct from those typically observed in linear and short-chain branched polymers, are identified. The higher molecular weight, low long-chain branching LDPEs exhibited all three instability types, including a special type volume instability. Independently of the molecular weight, higher long-chain branching appeared to have a stabilizing effect on the transition sequences by suppressing volume extrudate distortions or limiting surface patters to a form of weak intensity type.