Structure-based drug design has often been restricted by the rather static picture of protein-ligand complexes presented by crystal structures, despite the widely accepted importance of protein flexibility in biomolecular recognition. Here we report a detailed experimental and computational study of the drug target, human heat shock protein 90, to explore the contribution of protein dynamics to the binding thermodynamics and kinetics of drug-like compounds. We observe that their binding properties depend on whether the protein has a loop or a helical conformation in the binding site of the ligand-bound state. Compounds bound to the helical conformation display slow association and dissociation rates, high-affinity and high cellular efficacy, and predominantly entropically driven binding. An important entropic contribution comes from the greater flexibility of the helical relative to the loop conformation in the ligand-bound state. This unusual mechanism suggests increasing target flexibility in the bound state by ligand design as a new strategy for drug discovery.

Electronic devices fabricated from SiC/Si epitaxial wafers will need surface passivation and insulating coatings. For solar cell applications – and in MOS systems – Al-oxide thin film coatings have some strong advocates, not the least due to the advances of the ALD process. We have grown SiC/Si, formed by a remote CH4 plasma interacting with Si surfaces in UHV. After growing the SiC/Si system (SiC thickness between 0.5 and 5 nm; polycrystalline) a self-limiting Si-oxide layer was grown on the surface, with a thickness of around 1 nm, at 7000C. On top of this layer we deposited approximately 1 nm of Al with a Knudsen atomic source (all steps in UHV) and then reacted it thermally (at 6000C) with the Si-oxide. We monitored all the process steps and the resulting structures of the layers and the interface using synchrotron radiation induced core level photoemission at ASTRID, Aarhus, Denmark. We found similar qualities with this procedure, as for Si, i.e. an atomically sharp interface between Al-oxide and SiC, and this reaction scheme offers self-limiting behavior both of the oxidation to create Si-oxide, and to the conversion into Al-oxide, which only needs a sufficient amount of Al to affect the total conversion of the Si-oxide, while excess Al will leave the system at sufficiently elevated temperatures.

Abnormal trinucleotide repeat expansions alter protein conformation causing malfunction and contribute to a significant number of incurable human diseases. Scarce structural insights available on disease-related homorepeat expansions hinder the design of effective therapeutics. Here, we present the dynamic structure of human PHOX2B C-terminal fragment, which contains the longest polyalanine segment known in mammals. The major α-helical conformation of the polyalanine tract is solely extended by polyalanine expansions in PHOX2B, which are responsible for most congenital central hypoventilation syndrome cases. However, polyalanine expansions in PHOX2B additionally promote nascent homorepeat conformations that trigger length-dependent phase transitions into solid condensates that capture wild-type PHOX2B. Remarkably, HSP70 and HSP90 chaperones specifically seize PHOX2B alternative conformations preventing phase transitions. The precise observation of emerging polymorphs in expanded PHOX2B postulates unbalanced phase transitions as distinct pathophysiological mechanisms in homorepeat expansion diseases, paving the way towards the search of therapeutics modulating biomolecular condensates in central hypoventilation syndrome.

Parkinson's Disease (PD) is a common neurodegenerative disorder affecting millions of people worldwide for which there are only symptomatic therapies. Small molecules able to target key pathological processes in PD have emerged as interesting options for modifying disease progression. We have previously shown that a (poly)phenol-enriched fraction (PEF) of Corema album L. leaf extract modulates central events in PD pathogenesis, namely α-synuclein (αSyn) toxicity, aggregation and clearance. PEF was now subjected to a bio-guided fractionation with the aim of identifying the critical bioactive compound. We identified genipin, an iridoid, which relieves αSyn toxicity and aggregation. Furthermore, genipin promotes metabolic alterations and modulates lipid storage and endocytosis. Importantly, genipin was able to prevent the motor deficits caused by the overexpression of αSyn in a Drosophila melanogaster model of PD. These findings widens the possibility for the exploitation of genipin for PD therapeutics.

In this study, the aqueous mixture viscosities of two phenolic DESs, consisting of (1 ChCl: 3 phenol) and (1 ChCl: 4 phenol), were measured at atmospheric pressure over the temperature range of 293.15–333.15 K. According to the measured data, the values of viscosity deviations for the investigated aqueous systems were calculated to indicate deviating viscosity behavior with respect to ideality. Both aqueous systems showed negative viscosity deviations over the entire composition range and at all of the investigated temperatures. The Redlich-Kister model was applied to estimate the viscosity deviations of both aqueous systems at different compositions and temperatures, while the viscosity behavior, itself, was modeled by different literature models, consisting of the Grunberg-Nissan, Jouyban-Acree, McAllister, Preferential Solvation, and an Arrhenius-like viscosity model. All of the models presented satisfactory agreement, however the Preferential Solvation and the Jouyban-Acree models succeeded to achieve more reliable results as compared to the others. In addition to the mixture viscosity estimation models, the Jones-Dole viscosity model was applied to both of the aqueous systems to suggest the interactions in the mixture. By calculating and analyzing the values of the B-coefficients of this model, possibly stronger interactions among the DESs and water molecules in the mixture were suggested, as compared to the self-species interactions.

Dihydroartemisinin-piperaquine (DHA-PPQ) is being recommended in Africa for the management of uncomplicated Plasmodium falciparum malaria and for chemoprevention strategies, based on the ability of piperaquine to delay re-infections. Although therapeutic resistance to piperaquine has been linked to increased copy number in plasmepsin-coding parasite genes (pfpm), their effect on the duration of the post-treatment prophylactic period remains unclear. Here, we retrospectively analyzed data from a randomized clinical trial, where patients received either DHA-PPQ or artesunate-amodiaquine for recurrent malaria episodes over two years. We observed an increase in the relative risk of re-infection among patients receiving DHA-PPQ compared to artesunate-amodiaquine after the first malaria season. This was driven by shorter average times to reinfection and coincided with an increased frequency of infections comprising pfpm3 multi-copy parasites. The decline in post-treatment protection of DHA-PPQ upon repeated use in a high transmission setting raises concerns for its wider use for chemopreventive strategies in Africa.

UV-Vis reflectance spectroscopy has been widely used as a non-invasive method for the study of cultural heritage materials for several decades. In particular, FORS, introduced in the 1980s, allows to acquire hundreds of reflectance spectra in situ in a short time, contributing to the identification of artist's materials. More recently, microspectrofluorimetry has also been proposed as a powerful non-invasive method for the identification of dyes and lake pigments that provides high sensitivity and selectivity. In this chapter, the concepts behind these spectroscopic methodologies will be discussed, as well as the instrumentation and measurement modes used. Case studies related with different cultural heritage materials (paintings and manuscripts, textiles, carpets and tapestries, glass, metals, and minerals), which show the usefulness of UV-Vis reflectance spectroscopy and microspectrofluorimetry applied to the study of artworks, will also be presented.

Classification of defects in ordered systems, based on the homotopy theory, conceived by Gérard Toulouse and Maurice Kléman has a very wide range of applications. We illustrate its modus operandi with three experimental examples. We deal first with dislocations in a dissipative periodic pattern of convection rolls in a shear flow instability in nematics. As the second example we chose the captive disclination loops threaded on polymer fibers immersed in nematics. Third, we focus on objects with double topological character defined for the first time in the generic article coauthored by Gérard Toulouse: the “double et tripple anneau” Hopf links made of interlaced dislocation loops in cholesterics. Finally, we report on the recent discovery of their generalised, beads necklace version made of many minimal dislocation loops threaded, like pearls, on a string-like dislocation loops.

The authors wish to clarify and acknowledge the context of previously published work relevant to this study. In particular, the work by Garcia et al. (Sci. Adv., 2022, 8, eadd4614), cited in the original article, not only reports vacuum ultraviolet circular dichroism measurements of propylene oxide but also includes time-dependent density functional theory calculations of its electronic excited states, in particular vertical excitation energies and rotatory strengths. The present work focuses on high-resolution VUV photoabsorption cross sections over an extended energy range and provides a more detailed characterization of the excited states based on TDDFT calculations, including excitation energies, oscillator strengths, and assignments derived from natural transition orbital (NTO) analysis. In addition, the evolution of the excited-state character along selected nuclear coordinates is explored, revealing Rydberg–valence mixing effects. The authors acknowledge that the relationship between these studies could have been more clearly stated in the original manuscript and regret any lack of clarity in this regard. The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.