Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors

Indoles are privileged structures in medicinal and bioorganic chemistry that are particularly well suited to serve as platforms for diversity. Among many other therapeutic areas, the indole scaffold has been used to design aromatic compounds useful to interfere with enzymes engaged in the regulation of substrate acylation status, such as sirtuins. However, the planarity of the indole ring is not necessarily optimal for all target enzymes, especially when functionalization with aromatic side chains is required. Replacement of flat scaffolds by nonplanar molecular cores dominated by sp³ hybridization is a common strategy to avoid the disadvantages associated with poor solubility and high promiscuity, while covering less-well-explored areas of chemical space. Thus, we synthesized fragment-like tetrahydroindoles suitable for fragment-based drug discovery as well as a well-characterized small library intended as multipurpose screening compounds. For proof of principle, these compounds were screened against sirtuins 1–3, enzymes known to be addressable by indoles. We found that 2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamides are potent and selective SIRT2 inhibitors. Compound 16 t displayed an IC₅₀ value of 0.98 μm and could serve as exquisite starting point for hit-to-lead profiling.     

Linear friction welding of Ti6Al4V: experiments and modelling

Linear friction welding of the Ti6Al4V alloy is studied. A new definition of the energy input rate is proposed, based on an integration over time of the in-plane force and velocity; a strong correlation with the upset rate is then found. The effective friction coefficient is estimated to be 0·5±0·1 for varying frequencies and amplitudes, with only a weak dependence on the processing conditions displayed. A model is proposed that accounts for both the conditioning and equilibrium stages of the process, which is shown to be in good agreement with the experimental data. The model is used to study the mechanism by which the flash is formed. A criterion is proposed by which the rippled nature of its morphology can be predicted.     

Matrix Transformation in Boron Containing High-Temperature Co–Re–Cr Alloys

An addition of boron largely increases the ductility in polycrystalline high-temperature Co–Re alloys. Therefore, the effect of boron on the alloy structural characteristics is of high importance for the stability of the matrix at operational temperatures. Volume fractions of ε (hexagonal close-packed—hcp), γ (face-centered cubic—fcc) and σ (Cr₂Re₃ type) phases were measured at ambient and high temperatures (up to 1500 °C) for a boron-containing Co–17Re–23Cr alloy using neutron diffraction. The matrix phase undergoes an allotropic transformation from ε to γ structure at high temperatures, similar to pure cobalt and to the previously investigated, more complex Co–17Re–23Cr–1.2Ta–2.6C alloy. It was determined in this study that the transformation temperature depends on the boron content (0–1000 wt. ppm). Nevertheless, the transformation temperature did not change monotonically with the increase in the boron content but reached a minimum at approximately 200 ppm of boron. A probable reason is the interplay between the amount of boron in the matrix and the amount of σ phase, which binds hcp-stabilizing elements (Cr and Re). Moreover, borides were identified in alloys with high boron content.     

Proton-Detected Solid-State NMR of the Cell-Free Synthesized α-Helical Transmembrane Protein NS4B from Hepatitis C Virus

Proton-detected 100 kHz magic-angle-spinning (MAS) solid-state NMR is an emerging analysis method for proteins with only hundreds of microgram quantities, and thus allows structural investigation of eukaryotic membrane proteins. This is the case for the cell-free synthesized hepatitis C virus (HCV) nonstructural membrane protein 4B (NS4B). We demonstrate NS4B sample optimization using fast reconstitution schemes that enable lipid-environment screening directly by NMR. 2D spectra and relaxation properties guide the choice of the best sample preparation to record 2D ¹H-detected ¹H,¹⁵N and 3D ¹H,¹³C,¹⁵N correlation experiments with linewidths and sensitivity suitable to initiate sequential assignments. Amino-acid-selectively labeled NS4B can be readily obtained using cell-free synthesis, opening the door to combinatorial labeling approaches which should enable structural studies.     

Cultivation and downstream processing of microalgae and cyanobacteria to generate protein-based technofunctional food ingredients

Abstract

Microalgae are unicellular microorganisms that can be rich in proteins and are therefore a valuable ingredient in different foods. So far microalgae are mainly utilized in foods in low concentrations as a whole-cell ingredient even though it is known that proteins extracted from microalgae can possibly posess various technofunctional properties, such as high protein solubility, emulsification, foaming, and gelation properties. The widespread usage of protein-rich ingredients obtained from microalgae is for the most part prevented by the high price of the biomass, the lack of efficient downstream processes, and the adverse taste. The aim of this review is to give insights into the fundamental properties of the growth and processing of microalgae, highlight the advantages of microalgae ingredients and show potential applications based on the technofunctional, nutritional and sensory properties that were reported. Moreover, the existing challenges and knowledge gaps that hinder the application of microalgal proteins in foods are discussed.     

Malic acid production from renewables: a review

Malic acid derived from fossil resources is currently applied in the food and beverage industries with a medium global production capacity. However, in the transition from a fossil-based to a bio-based economy, biotechnologically produced l -malic acid may become an important platform chemical with many new applications, especially in the field of biopolymers. In this review, currently used petrochemical production routes to dl -malic acid are outlined and insights into possible bio-based alternatives for microbial l -malic acid production are provided. Besides ecological reasons, the possibility to produce enantiopure l -malic acid by microbial fermentation is the biggest advantage over chemical synthesis. State-of-the-art and open challenges concerning production host engineering, substrate choice and downstream processing are addressed. With regard to production hosts, a literature overview is given covering the leading natural production strains of Aspergillus, Ustilago and Aureobasidium, as well as Escherichia coli as the most important engineered recombinant host. The utilization of renewable substrates as an alternative to glucose is emphasized in particular as a key aspect for a competitive bio-based production. Out of the alternative substrates discussed in this review, the industrial side-streams crude glycerol and molasses seem to be most promising for large-scale l -malic acid production. © 2019 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.     

Atomistic simulations of grain boundary migration in copper

While the motion of twist boundaries can be readily studied by atomistic simulations with molecular dynamics (MD) under the action of an elastic driving force, the approach fails for tilt boundaries. This is due to the interaction of the elastic stress with the grain boundary (GB) structure, which causes plastic strain by GB sliding. A novel concept, the orientation correlated driving force, is introduced to circumvent this problem. It is shown that this concept can be successfully applied to the study of the migration of tilt boundaries. The migration behavior of several twist and tilt GBs was investigated. The transition from low-to high-angle boundaries can be captured, and a structural transition of tilt boundaries was found at high temperatures, which also affected the migration behavior. The results compare well with experimental results of the motion high-angle boundaries, but for low-angle boundaries, the agreement is poor. This article is based on a presentation made in the “Hillert Symposium on Thermodynamics & Kinetics of Migrating Interfaces in Steels and Other Complex Alloys,” December 2–3, 2004, organized by The Royal Institute of Technology in Stockholm, Sweden.     

Efficient Low Dissipative High Order Schemes for Multiscale MHD Flows, II: Minimization of ∇·B Numerical Error

An adaptive numerical dissipation control in a class of high order filter methods for compressible MHD equations is systematically discussed. The filter schemes consist of a divergence-free preserving high order spatial base scheme with a filter approach which can be divergence-free preserving depending on the type of filter operator being used, the method of applying the filter step, and the type of flow problem to be considered. Some of these filter variants provide a natural and efficient way for the minimization of the divergence of the magnetic field (∇·B) numerical error in the sense that commonly used divergence cleaning is not required. Numerical experiments presented emphasize the performance of the ∇·B numerical error. Many levels of grid refinement and detailed comparison of the filter methods with several commonly used compressible MHD shock-capturing schemes will be illustratedA condensed version appears in the Proceedings of the International Conference on High Performance Scientific Computing, March 10-14, 2003, Hanoi, Vietnam. This is a revised version of a longer internal report, Feb. 19, 2004. The longer internal report was published as a RIACS Technical Report TR03.10, July 2003, NASA Ames Research Center