One Question,Multiple Answers: Biochemical and Biophysical Screening Methods Retrieve Deviating Fragment Hit Lists

Fragment‐based lead discovery is gaining momentum in drug development. Typically, a hierarchical cascade of several screening techniques is consulted to identify fragment hits which are then analyzed by crystallography. Because crystal structures with bound fragments are essential for the subsequent hit‐to‐lead‐to‐drug optimization, the screening process should distinguish reliably between binders and non‐binders. We therefore investigated whether different screening methods would reveal similar collections of putative binders. First we used a biochemical assay to identify fragments that bind to endothiapepsin, a surrogate for disease‐relevant aspartic proteases. In a comprehensive screening approach, we then evaluated our 361‐entry library by using a reporter‐displacement assay, saturation‐transfer difference NMR, native mass spectrometry, thermophoresis, and a thermal shift assay. While the combined results of these screening methods retrieve 10 of the 11 crystal structures originally predicted by the biochemical assay, the mutual overlap of individual hit lists is surprisingly low, highlighting that each technique operates on different biophysical principles and conditions.     

Mesoscopic Monte Carlo simulations of interfacial films in ZnO-Bi2O3 ceramics

This paper reports mesoscopic Monte Carlo simulations (in which a ‘mesoscopic particle’ corresponds to a group of atoms or molecules) of interfacial films in ZnO-Bi₂O₃ binary ceramics. We observe the formation of Bi₂O₃-rich interfacial phases at the surface of ZnO grains (surface amorphous films) or at the grain-boundary between ZnO grains (intergranular films). In qualitative agreement with the experimental results reported on premelting of ceramics, the thickness of these films increases as the temperature increases up to the eutectic temperature. Moreover, the Bi₂O₃ concentration in the surficial or intergranular films is found to be larger than in the bulk. These surficial films exhibit both some layering and lateral ordering.     

Selection of an adsorbent for lead removal from drinking water by a point-of-use treatment device

The removal of lead from drinking water was investigated to develop a point-of-use water filter that could meet the regulation imposed by the new European Directive 98-83 lowering lead concentration in drinking water below 10 μg L⁻¹. The objective of this research was to assess the potential of different adsorbents (zeolites, resins, activated carbon, manganese oxides, cellulose powder) to remove lead from tap water with a very short contact time. To begin, the repartition of the lead species in a tap water and a mineral water was computed with the computer model CHESS. It showed that in bicarbonated waters lead is mainly under lead carbonate form, either in the aqueous or in the mineral phase. Batch experiments were then conducted to measure the equilibrium adsorption isotherms of the adsorbents. Then, for five of them, dynamic experiments in micro-columns were carried out to assess the outlet lead concentration level. Three adsorbents gave rise to a leakage concentration lower than 10 μg L⁻¹ and were then selected for prototypes experiments: chabasite, an activated carbon coated with a synthetic zeolite and a natural manganese oxide. The proposed method clearly showed that the measurement of equilibrium isotherms is not sufficient to predict the effectiveness of an adsorbent, and must be coupled with dynamic experiments.     

Human-robot synchrony: flexible assistance using adaptive oscillators

We propose a novel method for movement assistance that is based on adaptive oscillators, i.e., mathematical tools that are capable of extracting the high-level features (amplitude, frequency, and offset) of a periodic signal. Such an oscillator acts like a filter on these features, but keeps its output in phase with respect to the input signal. Using a simple inverse model, we predicted the torque produced by human participants during rhythmic flexion-extension of the elbow. Feeding back a fraction of this estimated torque to the participant through an elbow exoskeleton, we were able to prove the assistance efficiency through a marked decrease of the biceps and triceps electromyography. Importantly, since the oscillator adapted to the movement imposed by the user, the method flexibly allowed us to change the movement pattern and was still efficient during the nonstationary epochs. This method holds promise for the development of new robot-assisted rehabilitation protocols because it does not require prespecifying a reference trajectory and does not require complex signal sensing or single-user calibration: the only signal that is measured is the position of the augmented joint. In this paper, we further demonstrate that this assistance was very intuitive for the participants who adapted almost instantaneously.