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Abstract: This study aims to understand possible effects of flavour compounds on the structure and conformation of endogenous proteins. Using methyl anthranilate (a grape flavour compound added to drinks, confectionery, and vape-liquids) and bovine serum albumin (BSA, a model serum protein) we designed experimental investigations using analytical ultracentrifugation, size exclusion chromatography small angle X-ray scattering, and fluorescence spectroscopy to reveal that methyl anthranilate spontaneously binds to BSA (ΔG°, ca. −21 KJ mol−1) which induces a conformational compactness (ca. 10 %) in the monomer structure. Complementary molecular modelling and dynamics simulations suggested the binding occurs at Sudlow II of BSA via establishment of hydrogen bonds with arginine409, lysine413 and serine488 leading to an increased conformational order in domains IA, IIB and IIIB. This work aims to set the foundation for future research on flavour-protein interactions and offer new sets of opportunities for understanding the effects of small compounds on protein structure.

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Abstract: Synchrotron X-ray diffraction computed tomography (XRD-CT) was employed to study a commercial 18650 cylindrical LiNi0.8Co0.15Al0.5O2 (NCA) battery under operating conditions and during seven cycles. The analysis of the spatially-resolved diffraction patterns revealed multiple chemical heterogeneities related to the lithium distribution in both the cathode and the anode. It is shown that during the charging of the battery, the anode exhibits different degrees of activity regarding the lithiation process. Explicitly, the following three regions were identified: a uniform/homogenous lithiation, a delayed lithiation and an inactive-to-lithiation region. The inactive-to-lithiation anode region was a result of the specific cell geometry (i.e. due to lack of cathode tape opposite these anode areas) and throughout the cycling experiments remained present in the form of LiC30-30+. The delayed lithiation region was seen to have a direct impact on the properties of NCA in its close proximity during the battery discharging, preventing its full lithiation. Further to this, the aluminum tab negatively affected the NCA in direct contact with it, leading to different lattice parameter a and c evolution compared to the rest of the cathode.

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Abstract: While human poly-ADP-ribose chain generating poly-ARTs, PARP1 and 2 and TNKS1 and 2, have been widely characterized, less is known on the pathophysiological roles of the mono-ADP-ribosylating mono-ARTs, partly due to the lack of selective inhibitors. In this context, we have focused on the development of inhibitors for the mono-ART PARP10, whose overexpression is known to induce cell death. Starting from OUL35 (1) and its 4-(benzyloxy)benzamidic derivative (2) we herein report the design and synthesis of new analogues from which the cyclobutyl derivative 3c rescued cells most efficiently from PARP10 induced apoptosis. Most importantly, we also identified 2,3-dihydrophthalazine-1,4-dione as a new suitable nicotinamide mimicking PARP10 inhibitor scaffold. When it was functionalized with cycloalkyl (8a-c), o-fluorophenyl (8h), and thiophene (8l) rings, IC50 values in the 130–160 nM range were obtained, making them the most potent PARP10 inhibitors reported to date. These compounds also inhibited PARP15 with low micromolar IC50s, but none of the other tested poly- and mono-ARTs, thus emerging as dual mono-ART inhibitors. Compounds 8a, 8h and 8l were also able to enter cells and rescue cells from apoptosis. Our work sheds more light on inhibitor development against mono-ARTs and identifies chemical probes to study the cellular roles of PARP10 and PARP15.

Open Access

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Abstract: Four different structural models, which all fit the same X-ray powder pattern, were obtained in the structure determination of 4,11-di­fluoro­quinacridone (C20H10N2O2F2) from unindexed X-ray powder data by a global fit. The models differ in their lattice parameters, space groups, Z, Z′, molecular packing and hydrogen bond patterns. The molecules form a criss-cross pattern in models A and B, a layer structure built from chains in model C and a criss-cross arrangement of dimers in model D. Nevertheless, all models give a good Rietveld fit to the experimental powder pattern with acceptable R-values. All molecular geometries are reliable, except for model D, which is slightly distorted. All structures are crystallochemically plausible, concerning density, hydrogen bonds, intermolecular distances etc. All models passed the checkCIF test without major problems; only in model A a missed symmetry was detected. All structures could have probably been published, although 3 of the 4 structures were wrong. The investigation, which of the four structures is actually the correct one, was challenging. Six methods were used: (1) Rietveld refinements, (2) fit of the crystal structures to the pair distribution function (PDF) including the refinement of lattice parameters and atomic coordinates, (3) evaluation of the colour, (4) lattice-energy minimizations with force fields, (5) lattice-energy minimizations by two dispersion-corrected density functional theory methods, and (6) multinuclear CPMAS solid-state NMR spectroscopy (1H, 13C, 19F) including the comparison of calculated and experimental chemical shifts. All in all, model B (perhaps with some disorder) can probably be considered to be the correct one. This work shows that a structure determination from limited-quality powder data may result in totally different structural models, which all may be correct or wrong, even if they are chemically sensible and give a good Rietveld refinement. Additionally, the work is an excellent example that the refinement of an organic crystal structure can be successfully performed by a fit to the PDF, and the combination of computed and experimental solid-state NMR chemical shifts can provide further information for the selection of the most reliable structure among several possibilities.

Open Access

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Abstract: Three-dimensional X-ray diffraction (3DXRD) is shown to be feasible at the I12 Joint Engineering, Environmental and Processing (JEEP) beamline of Diamond Light Source. As a demonstration, a microstructually simple low-carbon ferritic steel was studied in a highly textured and annealed state. A processing pipeline suited to this beamline was created, using software already established in the 3DXRD user community, enabling grain centre-of-mass positions, orientations and strain tensor elements to be determined. Orientations, with texture measurements independently validated from electron backscatter diffraction (EBSD) data, possessed a ∼0.1° uncertainty, comparable with other 3DXRD instruments. The spatial resolution was limited by the far-field detector pixel size; the average of the grain centre of mass position errors was determined as ±∼80 µm. An average per-grain error of ∼1 × 10−3 for the elastic strains was also measured; this could be reduced in future experiments by improving sample preparation, geometry calibration, data collection and analysis techniques. Application of 3DXRD onto I12 shows great potential, where its implementation is highly desirable due to the flexible, open architecture of the beamline. User-owned or designed sample environments can be used, thus 3DXRD could be applied to previously unexplored scientific areas.