Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery

Aminoacyl-tRNA synthetases (aaRSs) catalyze the esterification of tRNA with a cognate amino acid and are essential enzymes in all three kingdoms of life. Due to their important role in the translation of the genetic code, aaRSs have been recognized as suitable targets for the development of small molecule anti-infectives. In this review, following a concise discussion of aaRS catalytic and proof-reading activities, the various inhibitory mechanisms of reported natural and synthetic aaRS inhibitors are discussed. Using the expanding repository of ligand-bound X-ray crystal structures, we classified these compounds based on their binding sites, focusing on their ability to compete with the association of one, or more of the canonical aaRS substrates. In parallel, we examined the determinants of species-selectivity and discuss potential resistance mechanisms of some of the inhibitor classes. Combined, this structural perspective highlights the opportunities for further exploration of the aaRS enzyme family as antimicrobial targets.     

Enhancing the Yield Stress in Liquid Polydimethylsiloxane to Allow Its 3D Printing: Hydrogels as Removable Fillers

For manufacturing parts of very soft materials by liquid deposition modeling (e.g., to mimic living soft tissues), formulations of 3D-printable polydimethylsiloxane have been developed, with the aim of increasing the yield stress of the liquid and reducing the final mechanical modulus. In the present work, suspensions of solid-like hydrogel particles, which are easily 3D-printable, are prepared in order to generate yield stress, and the suspended phase is removed after manufacturing by taking advantage of the thermo-reversibility of the hydrogel behavior, resulting in porosity, which reduces the final rigidity. The reported approach is even more efficient than a previous approach based on emulsion formulations.     

Models for circular data from time series spectra

Circular data are those for which the natural support is the unit circle and its toroidal extensions. Numerous constructions have been proposed which can be used to generate models for such data. We propose a new, very general, one based on the normalization of the spectra of complex-valued stationary processes. As illustrations of the new construction's application, we study models for univariate circular data obtained from the spectra of autoregressive moving average models and relate them to existing models in the literature. We also propose and investigate multivariate circular models obtained from the high-order spectra of stationary stochastic processes generated using linear filtering with an autoregressive moving average response function. A new family of distributions for a Markov process on the circle is also introduced. Results for asymptotically optimal inference for dependent observations on the circle are presented which provide a new paradigm for inference with circular models. The application of one of the new families of spectra-generated models is illustrated in an analysis of wind direction data.     

Triethanolamine Stabilization of Methotrexate-β-Cyclodextrin Interactions in Ternary Complexes

The interaction of methotrexate (MTX) with beta-cyclodextrin (β-CD) in the presence of triethanolamine (TEA) was investigated with the aim to elucidate the mechanism whereby self-assembly cyclodextrin systems work in association with this third component. Solubility diagram studies showed synergic increment of the MTX solubility to be about thirty-fold. Experiments using 2D ROESY and molecular modeling studies revealed the inclusion of aromatic ring III of the drug into β-CD cavity, in which TEA contributes by intensifying MTX interaction with β-CD and stabilizes MTX:β-CD:TEA ternary complex by electrostatic interaction. The maintenance of these interactions in solid phase was also studied in ternary MTX:β-CD:TEA and comparisons were made with freeze dried binary MTX:β-CD and physical mixtures. FTIR studies evidenced that MTX–β-CD interaction remained in solid ternary complexes, which was also supported by thermal (differential scanning calorimetry (DSC), thermogravimetric analysis (TG)/first derivative of TG analysis (DTG) and C,N,H elementary analysis) and structural (X-ray diffraction analysis, (XRD)) studies, mainly regarding the increment of drug stability. The efficient in vitro drug dissolution studies successfully demonstrated the contribution of ternary complexes, which highlights the importance of this possible new raw material for further applications in drug delivery systems.     

Developing an Irreversible Inhibitor of Human DDAH‐1, an Enzyme Upregulated in Melanoma

Inhibitors of the human enzyme dimethylarginine dimethylaminohydrolase‐1 (DDAH‐1) can raise endogenous levels of asymmetric dimethylarginine (ADMA) and lead to a subsequent inhibition of nitric oxide synthesis. In this study, N⁵‐(1‐imino‐2‐chloroethyl)‐L ‐ornithine (Cl‐NIO) is shown to be a potent time‐ and concentration‐dependent inhibitor of purified human DDAH‐1 (K_I=1.3±0.6 μM ; k_inact=0.34±0.07 min^?1), with >500‐fold selectivity against two arginine‐handling enzymes in the same pathway. An activity probe is used to measure the “in cell” IC₅₀ value (6.6±0.2 μM ) for Cl‐NIO inhibition of DDAH‐1 artificially expressed within cultured HEK293T cells. A screen of diverse melanoma cell lines reveals that a striking 50/64 (78 %) of melanoma lines tested showed increased levels of DDAH‐1 relative to normal melanocyte control lines. Treatment of the melanoma A375 cell line with Cl‐NIO shows a subsequent decrease in cellular nitric oxide production. Cl‐NIO is a promising tool for the study of methylarginine‐mediated nitric oxide control and a potential therapeutic lead compound for other indications with elevated nitric oxide production, such as septic shock and idiopathic pulmonary fibrosis.     

Oxidation Behavior of γ′-Ni3Al-Based Ni–20Al–5Cr Alloys With and Without Reactive Elements Under Different Heating Conditions

Oxidation of Metals - High-temperature oxidation of a model γ′-Ni3Al-based Ni–20Al–5Cr alloy and versions of this alloy doped with Y, Hf, or Si, or some combination of these,...     

Natural ventilation in buildings: measurement in a wind tunnel and numerical simulation with large-eddy simulation

Natural ventilation in buildings can create a comfortable and healthy indoor environment, and can save energy compared to mechanical ventilation systems. In building design the prediction of ventilation can be difficult; cases of wind-driven single-sided ventilation, where the effects of turbulence dominate, are particularly problematic to simulate. In order to investigate the mechanism of natural ventilation driven by wind force, large-eddy simulation (LES) is used. In the meanwhile, detailed airflow fields, such as mean and fluctuating velocity and pressure distribution inside and around building-like models were measured by wind tunnel tests and compared to LES results for model validation. Three ventilation cases, single-sided ventilation with an opening in windward wall, single-sided ventilation with an opening in leeward wall, and cross ventilation, are studied. In the wind tunnel, a laser Doppler anemometry was used to provide accurate and detailed velocity data. In LES calculations, two subgrid-scale (SS) models, a Smagorinsky SS model and a filtered dynamic SS model, were used. The numerical results from LES are in good agreement with the experimental data, in particular with the predicted airflow patterns and velocities around and within, and the surface pressures over, the models. This is considered to establish confidence in the application of the LES methods to the calculation of ventilation in buildings, in particular for single-sided ventilation cases.     

Regional competitive advantage and growth in national interindustry markets

A region's producing sectors compete in national markets with other regions, and its output growth therefore depends on changes in the region's sectoral input costs relative to those in other regions. In this model, production costs are taken as dependent upon wages and other payments to local factors and upon costs of interindustry inputs, the producers of which pay wages and other factor costs locally or, if the inputs are imported, in other regions. After consideration of conditions by which regional commodity supply functions can be aggregated, sectoral commodity prices and the regional production of national and local goods are endogenously determined in a computable equilibrium system within a balanced regional model framework.