Identification and Optimization of the First Highly Selective GLUT1 Inhibitor BAY‐876

Despite the long‐known fact that the facilitative glucose transporter GLUT1 is one of the key players safeguarding the increase in glucose consumption of many tumor entities even under conditions of normal oxygen supply (known as the Warburg effect), only few endeavors have been undertaken to find a GLUT1‐selective small‐molecule inhibitor. Because other transporters of the GLUT1 family are involved in crucial processes, these transporters should not be addressed by such an inhibitor. A high‐throughput screen against a library of ～3 million compounds was performed to find a small molecule with this challenging potency and selectivity profile. The N‐(1H‐pyrazol‐4‐yl)quinoline‐4‐carboxamides were identified as an excellent starting point for further compound optimization. After extensive structure–activity relationship explorations, single‐digit nanomolar inhibitors with a selectivity factor of >100 against GLUT2, GLUT3, and GLUT4 were obtained. The most promising compound, BAY‐876 [N⁴‐[1‐(4‐cyanobenzyl)‐5‐methyl‐3‐(trifluoromethyl)‐1H‐pyrazol‐4‐yl]‐7‐fluoroquinoline‐2,4‐dicarboxamide], showed good metabolic stability in vitro and high oral bioavailability in vivo.     

Structured Raney Nickel Catalysts for Liquid‐Phase Hydrogenation

Structured catalysts consisting of metal sheets on which Raney nickel was deposited by the thermal spraying method were tested for the liquid‐phase hydrogenation of glucose to sorbitol and 2‐nitrotoluene to 2‐methylaniline, used as model reactions. Catalytic tests performed in a bench‐scale (1 L) reactor showed that the catalytic activity of Raney Ni sheets is significantly higher than the one of the pellets used for fixed‐bed applications, but lower than the activity of the powder catalyst used in slurry mode. The activity could be significantly improved when applying a two‐phase co‐current flow through a monolith. In this case, the activity was superior to the one obtained with the slurry catalyst. These results confirm the potential of Raney Ni monoliths as structured catalysts.     

Entropy‐Based Optimal Sensor Placement for Model Identification of Periodic Structures Endowed with Bolted Joints

The number of sensors and the corresponding locations are very important for the information content obtained from the measured data, which is a recognized challenging problem for large‐scale structural systems. This article pays special attention to the sensor placement issues on a large‐scale periodically articulated structure representing typical pipelines to extract the most information from measured data for the purpose of model identification. The minimal model parameter estimation uncertainties quantified by the information entropy (IE) measure is taken as the optimality criterion for sensors placement. By utilizing the inherent periodicity property of this type of structure together with the Bloch theorem, a novel tailor‐made modeling approach is proposed and the computational cost required for dynamic analysis to form the IE with respect to the entire periodic structure can be dramatically reduced regardless of the number of contained periodic units. In addition, to avoid the error of dynamic modeling induced by conventional finite element method based on static shape function, the spectral element method, a highly accurate dynamic modeling method, is employed for modeling the periodic unit. Moreover, a novel discrete optimization method is developed, which is very efficient in terms of the number of function evaluations. The proposed methodology is demonstrated by both numerical and laboratory experiments conducted for a bolt‐connected periodic beam model.     

A decomposition-based approach for the selection of standardized modular containers

The standardisation of packaging and containers for product handling has potential benefits from transportation, material handling and environmental perspectives. Likewise, standardised modular containers play an important role in the Physical Internet (PI). To support implementation of standard modular containers, we introduce a mathematical model to select a requisite number of modular containers to pack a set of products to maximise space utilisation. A decomposition-based solution methodology is developed and presented. Computational results from industry-based problem instances indicate that using standardised modular containers results in increased space utilisation at the unit load level. This finding substantiates the use of modular containers in moving toward the PI.     

Injection of Microporous Annealing Particle (MAP) Hydrogels in the Stroke Cavity Reduces Gliosis and Inflammation and Promotes NPC Migration to the Lesion

With the number of deaths due to stroke decreasing, more individuals are forced to live with crippling disability resulting from the stroke. To date, no therapeutics exist after the first 4.5 h after the stroke onset, aside from rest and physical therapy. Following stroke, a large influx of astrocytes and microglia releasing proinflammatory cytokines leads to dramatic inflammation and glial scar formation, affecting brain tissue's ability to repair itself. Pathological conditions, such as a stroke, trigger neural progenitor cells (NPCs) proliferation and migration toward the damaged site. However, these progenitors are often found far from the cavity or the peri‐infarct tissue. Poststroke tissue remodeling results in a compartmentalized cavity that can directly accept a therapeutic material injection. Here, this paper shows that the injection of a porous hyaluronic acid hydrogel into the stroke cavity significantly reduces the inflammatory response following stroke while increasing peri‐infarct vascularization compared to nonporous hydrogel controls and stroke only controls. In addition, it is shown that the injection of this material impacts NPCs proliferation and migration at the subventricular zone niche and results, for the first time, in NPC migration into the stroke site.     

Electrochemical investigations on amorphous Fe-base alloys for alkaline water electrolysis

In this work different amorphous melt-spun Fe-alloys (Fe₈₂B₁₈, Fe₈₀Si₁₀B₁₀, Fe₆₀Co₂₀Si₁₀B₁₀) were investigated as cathode materials for the alkaline electrolysis of water. In particular, the influence of cobalt as well as the metalloids boron and silicon on the activity for the hydrogen evolution reaction (HER) was studied in 1 M KOH at 298 K using cyclic voltammetric, galvanostatic and polarization techniques. The electrocatalytic activity was evaluated in the view of the overpotential. It was found that cyclic voltammetric techniques can be used to activate the melt-spun Fe-alloys strongly. Different cyclic voltammetric activation procedures are discussed and the influence of the sweep rate and the potential window on the HER activity was elucidated. The experimental data indicate that the addition of metalloids and, most importantly, of cobalt improves the HER activity of the materials. Thus, the overpotential can be reduced by 200 mV compared to polycrystalline Ni.     

The mutual influence of surface energy and substrate temperature on the saturation mobility in organic semiconductors

We report on a mutual correlation between the substrate temperature during semiconductor deposition and the surface energy of the gate dielectric on the charge carrier mobility in bottom gate top contact organic field effect transistors (OFETs) with N,N′-diphenyl-3,4,9,10-perylene tetracarboxylic diimide (DP-PDI) as organic semiconductor.     

Rogue components: their effect and control using logical analysis of data

There is a small subset of any repairable component population that can develop a failure mode outside the scope of the standard repair and overhaul procedures, which makes them “rogue”. When this happens, a Darwinian-like “natural selection” phenomenon ensures that they will be placed in the most disadvantageous position in the asset management program, negatively affecting multiple aspects of the operational and maintenance organizations. Rogue components have long plagued the airline industry and created havoc in their asset management programs. In this paper, we describe how these rogues develop, outline the natural selection process that leads to their hampering the asset management program, and examine some of the negative impacts that ensue. Then we propose a Condition based maintenance approach to control the development of these components. We explore the use of a supervised learning data mining technique called Logical analysis of data (LAD) in CBM for the purpose of detecting rogues within a population of repairable components. We apply the resulting LAD based decision model on an inventory of turbo compressors belonging to an airline fleet. Finally, we evaluate the applicability of LAD to the rogue component detection problem and review its efficiency as a decision model for this type of problem.     

Extruded linseed and rapeseed both influenced fatty acid composition of total lipids and their polar and neutral fractions in longissimus thoracis and semitendinosus muscles of finishing Normand cows

The effects of extruded linseed and rapeseed on lipids and FA composition of total, polar and neutral lipids of longissimus thoracis (LT) and semitendinosus (ST) muscles were investigated in 21 Normand cull cows. Animals were assigned in a 100d finishing period to straw (30%) and concentrate (70%) based (C) or the same diet supplemented with linseed (L) or with rapeseed (66%) plus linseed (33%) (RL). Beef polar and neutral lipids were purified by liquid chromatography and their FA analysed by GLC. Trans and cis 18:1, purified by HPLC from total FA methyl esters, were analysed by GLC–MS. L and LR diets did not increase beef lipid deposition, but had modified FA composition of both LT and ST muscles in favouring deposition of 18:3n-3 and 9cis,11tr 18:2 (CLA), mainly to the detriment of 18:1?9 cis (neutral lipids) and 18:2n-6 (polar lipids). However, they did not favour deposition of LC n-3 PUFA in the two muscles, but had increased deposition of trans 18:1 significantly, especially of ?13tr to ?16tr isoforms to the detriment of ?10tr 18:1 (L diet) and of ?11tr 18:1 (RL diet).