Understanding the Reshaping of Fluorinated Polyester Vitrimers by Kinetic and DFT Studies of the Transesterification Reaction

Vitrimers are a third class of polymers gathering the mechanical properties and solvent resistance of 3D thermosets and the reprocessability of thermoplastics. This unique behaviour is due to the triggering of certain covalent exchange reactions that allow the network to rearrange upon application of a stimulus. The constitutive feature of vitrimers is the adoption of a glass-like viscosity during the rearrangement of the network, often due to an associative mechanism for the exchange reaction. Transesterification networks are one of the most studied type of vitrimers that usually require the incorporation of a catalyst, implying the associated drawbacks. Following up on a recent report on catalyst-free transesterification vitrimers in which the ester functions are particularly reactive thanks to the presence of fluorine atoms in α- or β-position, parallel DFT calculations and an experimental kinetic study on model molecules are presented in order to quantitatively assess the effect of neighbouring fluorinated groups on the transesterification reaction rate.     

An improved capillary electrophoresis method for in vitro monitoring of the challenging early steps of Aβ1–42 peptide oligomerization: Application to anti‐Alzheimer's drug discovery

We report an improved CE method to monitor in vitro the self‐assembly of monomeric amyloid β‐peptide (42 amino acids amyloid β‐peptide, Aβ_1–42) and in particular the crucial early steps involved in the formation of the neurotoxic oligomers. In order to start the kinetics from the beginning, sample preparation was optimized to provide samples containing exclusively the monomeric form. The CE method was also improved using a dynamic coating and by reducing the separation distance. Using this method, the disappearance of the monomer as well as the progressive formation of four species during the self‐assembly process can now be monitored and quantified over time. The hydrodynamic radius of the species present at the initial kinetics step was estimated around 1.8 nm by Taylor dispersion analysis while SDS‐PAGE analyses showed the predominance of the monomer. These results confirmed that the Aβ_1–42 species present at this initial time was the monomer. Methylene blue, an anti‐Alzheimer disease candidate, was then evaluated. In spite of an oligomerization inhibition, the enhanced disappearance of the Aβ_1–42 monomer provoked by methylene blue was demonstrated for the first time. This method, allowing the monomeric and smallest oligomeric species to be monitored, represents a new accurate and precise way to evaluate compounds for drug discovery.     

Inhibition of Thiol-Mediated Uptake with Irreversible Covalent Inhibitors

Thiol-mediated uptake is emerging as method of choice to penetrate cells. This study focuses on irreversible covalent inhibitors of thiol-mediated uptake. High-content high-throughput screening of the so far largest collection of hypervalent iodine reagents affords inhibitors that are more than 250 times more active than Ellman’s reagent and rival the best dynamic covalent inhibitors. Comparison with other irreversible reagents reveals that inhibition within one series follows reactivity, whereas inhibition across series deviates from reactivity. These trends support that molecular recognition, besides dynamic covalent exchange, contributes significantly to thiol-mediated uptake. The most powerful inhibitors besides the best hypervalent iodine reagents were Fukuyama’s nosyl protecting group and super-cinnamaldehydes that have been introduced as irreversible activators of the pain receptor TRPA1. Considering that several viruses use different forms of thiol-mediated uptake to enter cells, the identification of new irreversible inhibitors of thiol-mediated uptake is of general interest for the discovery of new antivirals.     

Density functional and spectroscopic studies of nitrogen inversion in substituted dizocilpines

While developing a synthesis towards tagged dizocilpine (MK‐801) analogues, we observed highly restricted inversion of a nitrogen centre in a number hydroxylamines obtained as key intermediates. These compounds are shown to possess some of the structural elements which are expected to significantly hinder the nitrogen inversion, potentially leading to hydroxylamines with a chiral nitrogen centre. Free energy barriers (ΔG^≠) of the nitrogen inversion were estimated to be ca. 22 kcal mol^?1 at temperatures near 420 K using variable temperature NMR measurements in DMSO‐d₆. Further density functional studies of a number model systems were undertaken in order to better rationalize the measured inversion barriers and follow the role of various structural factors in raising the barrier height of the nitrogen inversion process. Copyright © 2008 John Wiley & Sons, Ltd.     

Fluidization of Nano-size Particles

Fluidization and collapsing bed experiments were performed with 'Tullanox', 10nm diameter fumed silica. The minimum fluidization velocity was determined to be 0.0115m/s at the unusually low volume fraction of solids of 0.0077. The solids volume fraction was measured using a -ray densitometer. Fluidization was without large bubbles, with a high bed expansion ratio. The highest granular temperature was of the order of that of Geldart B particles, as measured by Cody et al. (1996). The sedimentation process was simulated using a two-fluid hydrodynamic model. The input into the model was a measured solids stress modulus and an agglomerate size determined from the settling curves. With these two rheological parameters, there was good agreement between the sedimentation theory and the experiment. This study shows that the standard collapse bed experiment used in industry is a good test of rheological properties of particles.     

A Note on Error Bounds for Convex and Nonconvex Programs

Given a single feasible solution and a single infeasible solution of a mathematical program, we provide an upper bound to the optimal dual value. We assume that satisfies a weakened form of the Slater condition. We apply the bound to convex programs and we discuss its relation to Hoffman-like bounds. As a special case, we recover a bound due to Mangasarian [11] on the distance of a point to a convex set specified by inequalities.     

The string coupling accelerates the expansion of the universed

Generic cosmological models in non-critical string theory have a time-dependent dilaton background at a late epoch. The cosmological deceleration parameter q ₀ is given by the square of the string coupling, g _s ², up to a negative sign. Hence the expansion of the Universe must accelerate eventually, and the observed value of q ₀ corresponds to g _s ² ∼ 0.6. In this scenario, the string coupling is asymptotically free at large times, but its present rate of change is imperceptibly small. First Award in the 2005 Essay Competition of the Gravity Research Foundation. - Ed.