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.     

Transport of charge-density waves in the presence of disorder: classical pinning versus quantum localization

We consider the interplay of the elastic pinning and the Anderson localization in the transport properties of a charge-density wave in one dimension, within the framework of the Luttinger model in the limit of strong repulsion. We address a conceptually important issue of which of the two disorder-induced phenomena limits the mobility more effectively. We argue that the interplay of the classical and quantum effects in transport of a very rigid charge-density wave is quite nontrivial: the quantum localization sets in at a temperature much smaller than the pinning temperature, whereas the quantum localization length is much smaller than the pinning length.     

Study of K^ - \to \pi ^0 e^ - \overline \nu _e \gamma decay with ISTRA+ setup

Results of study of the $K^ - \to \pi ^0 e^ - \overline \nu \gamma $ decay at the ISTRA+ setup are presented. We observed 4476 events of this decay. The branching ratio is found to be $R = \frac{{Br(K^ - \to \pi ^0 e^ - \overline \nu _e \gamma )}}{{Br(K^ - \to \pi ^0 e^ - \overline \nu _e )}}$ = (1.81±0.03(stat.)±0.07(syst.)) × 10^?2 for E*_γ > 10 MeV and θ*_eγ > 10°. For comparison with the previous experiment the branching ratio with cuts E*_γ > 10 MeV, 0.6 < cos θ*_eγ < 0.9 is calculated: R = $\frac{{Br(K^ - \to \pi ^0 e^ - \overline \nu _e \gamma )}}{{Br(K^ - \to \pi ^0 e^ - \overline \nu _e )}}$ = (0.47±0.02(stat.) ± 0.03(syst.)) × 10^?2. For the cuts E*_γ > 30 MeV and θ*_eγ > 20°, used in most theoretical papers, Br = (3.06 ± 0.09(stat.) ± 0.14(syst.)) × 10^?4. For the asymmetry we get A _ξ = ?0.015 ± 0.021. At present it is the best estimate of this asymmetry.     

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.     

Magnetic properties of Fe–Ti–O composite films obtained via solid-phase synthesis

The results from investigating the magnetic and magneto-optical properties of Fe–Ti–O composite films with compositions above the percolation threshold, prepared via a solid-phase reaction with oxygen exchange in layered FeO/Ti structures, are presented. Features of the magneto-optical spectra of prepared films are compared to the spectra of continuous metal films.     

Thermodynamic characteristics of ion-exchange sorption of Co2+ cations on Na-vermiculite

The exchange of Na⁺ ions of vermiculite for Co²⁺ cations is measured by sorption-analytical and microcalorimetric methods. The previously revealed growth of the equilibrium constant with a rise in the degree of filling θ of vermiculite exchange sites with Co²⁺ cations is confirmed. This result is explained by the segregation of Co²⁺ and Na⁺ cations being exchanged in separate interlayer regions of vermiculite. The negative heats of exchange of Na⁺ cations for Co²⁺ cations are associated with the energy consumption for the rearrangement of the segregated interlayer regions in vermiculite. The positive entropy changes resulting from the exchange indicate the formation of a more disordered Co-Na-layered “cake” in comparison with the initial Na-form vermiculite. A decrease in the integral molal free-energy change ΔG _m of the mixed form of the mineral is determined by the entropy factor. It is shown that, as θ increases, the ΔG _m(θ) dependence passes from a positive to a negative range of values. This pattern of the curve may be interpreted as a gradual phase transition from the Na-form to the mixed Co-Na-segregated form. The first derivatives of the enthalpy and entropy changes with respect to the degree of filling θ exhibit distinct maxima at θ ～ 0.20 as a result of the transition from the ideal mixing of Co²⁺ and Na⁺ cations being exchanged to their segregation.     

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.     

Infrared sensitivity of unstable vacua

We discover that some unstable vacua have long memory. By that we mean that even in the theories containing only massive particles, there are correllators and expectation values which grow with time. We examine the cases of instabilities caused by the constant electric fields, expanding and contracting universes and, most importantly, the global de Sitter space. In the last case the interaction leads to a remarkable UV/IR mixing and to a large back reaction. This gives reasons to believe that the cosmological constant problem could be resolved by the infrared physics.     

Interaction of Alkyl Radicals with Dihydric Phenol Derivatives in Hexane Solutions under γ-Radiolysis

The influence of structurally different dihydric phenols on the radical reactions of hexane in deaerated solutions under -irradiation was studied. It was found that 4-tert-butylpyrocatechol (I), 3,5-diisopropylpyrocatechol (II), 2,5-di-tert-butylhydroquinone (III), and 4,6-di-tert-butylresorcinol (IV) effectively inhibited the formation of hexyl radical combination products. Using the chromatography–mass spectrometry technique, it was shown that the adducts of alkyl radicals with I–III have the structure of a monoalkyl ether. Phenol IV gave a mixture of dimers with O- and C-alkylation products.