Design, synthesis and biological evaluation of novel aminopyrazole- and 7-azaindole-based Nek1 inhibitors and their effects on zebrafish kidney development.

NIMA-related protein kinase Nek1 is crucially involved in cell cycle regulation, DNA repair and microtubule regulation and dysfunctions of Nek1 play key roles in amyotrophic lateral sclerosis (ALS), polycystic kidney disease (PKD) and several types of radiotherapy resistant cancer. Targeting of Nek1 could reveal a new class of radiosensitizing substances and provide useful tools to better understand the aforementioned diseases. In this report we explore substituted aminopyrazoles and 7-azaindoles as potent inhibitors for the Nek1 kinase domain and examine their effect on kidney organogenesis in Danio rerio.

Functionally Gradient Macroporous Polymers: Emulsion Templating Offers Control over Density, Pore Morphology, and Composition.

Gradient macroporous polymers were produced by polymerization of emulsion templates comprising a continuous monomer phase and an internal aqueous template phase. To produce macroporous polymers with gradient composition, pore size, and foam density, we varied the template formulation, droplet size, and internal phase ratio of emulsion templates continuously and stacked those prior to polymerization. Using the outlined approach, it is possible to vary one property along the resulting macroporous polymer while retaining the other properties. The elastic moduli and crush strengths change along the gradient of the macroporous polymers; their mechanical properties are dominated by those of the weakest layers in the gradient. Macroporous polymers with gradient chemical composition and thus stiffness provide both high impact load and energy adsorption, rendering the gradient foam suitable for impact protective applications. We show that dual-dispensing and simultaneous blending of two different emulsion formulations in various ratios results in a fine, bidirectional change of the template composition, enabling the production of true gradient macroporous polymers with a high degree of design freedom.

Characterisation of thermally treated beech and birch by means of quasi-static tests and ultrasonic waves.

Wood, being renewable and highly abundant material, with excellent high specific strength and stiffness, has received increasing attention to be used in high performance applications such as the structural element of a battery case in an electric vehicle. For a successful implementation of wood in the automotive sector, it is, therefore, crucial to understand the behaviour of wood during and after temperature exposure and in the event of fire with the presence/absence of oxygen. In this study, the mechanical properties of thermally modified and unmodified European beech and birch in air and nitrogen environments at six different treatment intensities were characterised using compression tests, tensile tests, shear tests and Poisson's ratio tests. Further, the elastic properties of these wood species were quantified using the ultrasound measurements. The obtained strength and stiffness exhibited mild improvement upon moderate temperature treatment (200 °C), followed by a decrease at elevated temperature levels. This improvement was somewhat more pronounced under nitrogen treatment than under air treatment conditions. Nevertheless, a more noticeable decrease in the material performance was observed in beech compared to birch, occurring at earlier stages of modifications. This study confirms the tension-compression asymmetry of beech and birch where higher Young's moduli were obtained from tensile than from compression tests for reference and thermally treated beech and birch. The shear moduli obtained from ultrasound for birch were comparable to those obtained from quasi-static tests, whereas there was an overestimation of approximately 11-59% for the shear modulus of beech compared to quasi-static tests. Poisson's ratios from ultrasound tests corresponded well with those from quasi-static tests for untreated beech and birch, but not for thermally modified samples. The Saint-Venant model can satisfactorily predict the shear moduli of untreated and treated beech wood.

Illuminating a Dark Kinase: Structure-Guided Design, Synthesis, and Evaluation of a Potent Nek1 Inhibitor and Its Effects on the Embryonic Zebrafish Pronephros.

NIMA-related kinase 1 (Nek1) has lately garnered attention for its widespread function in ciliogenesis, apoptosis, and the DNA-damage response. Despite its involvement in various diseases and its potential as a cancer drug target, no directed medicinal chemistry efforts toward inhibitors against this dark kinase are published. Here, we report the structure-guided design of a potent small-molecule Nek1 inhibitor, starting from a scaffold identified by kinase cross-screening analysis. Seven lead compounds were identified in silico and evaluated for their inhibitory activity. The top compound, 10f, was further profiled for efficacy, toxicity, and bioavailability in a zebrafish polycystic kidney disease model. Administration of 10f caused the expansion of fluorescence-labeled proximal convoluted tubules, supporting our hypothesis that Nek1-inhibition causes cystic kidneys in zebrafish embryos. Compound 10f displayed insignificant inhibition in 48 of 50 kinases in a selectivity test panel. The findings provide a powerful tool to further elucidate the function and pharmacology of this neglected kinase.

On the Development of a Release Mechanism for a Split Hopkinson Tension and Compression Bar.

Split Hopkinson bars are used for the dynamic mechanical characterisation of materials under high strain rates. Many of these test benches are designed in such a way that they can either be used for compressive or tensile loading. The goal of the present work is to develop a release mechanism for an elastically pre-stressed Split Hopkinson bar that can be universally used for tensile or compressive loading. The paper describes the design and dimensioning of the release mechanism, including the brittle failing wear parts from ultra-high strength steel. Additionally, a numerical study on the effect of the time-to-full-release on the pulse-shape and pulse-rising time was conducted. The results of the analytical dimensioning approaches for the release mechanism, including the wear parts, were validated against experimental tests. It can be demonstrated that the designed release concept leads to sufficiently short and reproducible pulse rising times of roughly 0.11 ms to 0.21 ms, depending on the pre-loading level for both the tension and compression wave. According to literature, the usual pulse rising times can range from 0.01 ms to 0.35 ms, which leads to the conclusion that a good average pulse rising time was achieved with the present release system.

On the Dynamic Electro-Mechanical Failure Behavior of Automotive High-Voltage Busbars Using a Split Hopkinson Pressure Bar.

High-voltage busbars are important electrical components in today's electric vehicle battery systems. Mechanical deformations in the event of a vehicle crash could lead to electrical busbar failure and hazardous situations that pose a threat to people and surroundings. In order to ensure a safe application of busbars, this study investigated their mechanical behavior under high strain rate loading using a split Hopkinson pressure bar. Two different types of high-voltage busbars, consisting of a polyamide 12 and a glass-fiber-reinforced (30%) polyamide 6 insulation layer, were tested. Additionally, the test setup included a 1000 V electrical short circuit measurement to link the electrical with the mechanical failure. It was found that the polyamide 12 insulated busbars' safety regarding insulation failure increases at high loading speed compared to quasi-static measurements. On the contrary, the fiber-reinforced polyamide 6 insulated busbar revealed highly brittle material behavior leading to reduced bearable loads and intrusions. Finally, the split Hopkinson pressure bar tests were simulated. Existing material models for the thermoplastics were complemented with an optimized generalized incremental stress state-dependent model (GISSMO) with strain rate dependency. A good agreement with the experimental behavior was achieved, although the absence of viscoelasticity in the underlying material models was notable.

A Comparative Study on the Temperature Effect of Solid Birch Wood and Solid Beech Wood under Impact Loading.

In order to use wood for structural and load-bearing purposes in mechanical engineering, basic information on the impact behaviour of the material over a wide temperature range is needed. Diffuse porous hardwoods such as solid birch wood (Betula pendula) and solid beech wood (Fagus sylvatica) are particularly suited for the production of engineered wood products (EWPs) such as laminated veneer lumber (LVL) or plywood due to their processability in a veneer peeling process. In the frame of this study, solid birch wood and solid beech wood samples (300 × 20 × 20 mm3) were characterised by means of an impact pendulum test setup (working capacity of 150 J) at five temperature levels, ranging from -30 °C to +90 °C. The pendulum hammer (mass = 15 kg) was equipped with an acceleration sensor in order to obtain the acceleration pulse and deceleration force besides the impact bending energy. In both solid birch wood and solid beech wood, the deceleration forces were highest at temperatures at and below zero. While the average impact bending energy for solid birch wood remained almost constant over the whole considered temperature range, it was far less stable and prone to higher scattering for solid beech wood.

Temperature-Related Properties of Solid Birch Wood under Quasi-Static and Dynamic Bending.

The project WoodC.A.R. investigates the capabilities of wood and engineered wood-products (EWPs) for their application as a load-bearing material in automotive applications. For crash-relevant components, materials have to provide a high impact bending energy over a wide range of climatic conditions. This study investigates the effect of temperature on the bending behavior of solid birch wood beams (800 × 90 × 43 mm3) under quasi-static and dynamic loading. Specimens were exposed to a three-point bending test with lateral confinement, replicating the hypothetical installation environment in a car, at five temperature levels: -30 °C, 0 °C, +30 °C, +60 °C, and +90 °C. A cylindrical impactor (D = 254 mm, m = 91 kg) was propelled against the center of the beam with an initial velocity of 8.89 m/s (dynamic) and at a constant velocity of 10 mm/min (quasi-static), respectively. Specimens were conditioned in a freezer and a climate chamber, respectively. Temperature was monitored prior and during testing. Bulk density and global fiber deviation were determined afterwards. In both, the dynamic and the quasi-static load case maximum force slightly decreased with increasing temperature, but remained almost constant at temperatures exceeding +30 °C. On average, the maximum dynamic peak force level was twice as high as in quasi-static tests. In the quasi-static tests, the energy absorption remained constant at elevated temperatures (+30 °C to +90 °C) but decreased by about 50% at lower temperatures -30 °C and 0 °C. In the dynamic tests, the energy absorption remained almost constant throughout the entire temperature range.