α-Synuclein induces both positive mean curvature and negative Gaussian curvature in membranes

Using a combination of X-ray scattering, fluorescence correlation spectroscopy, coarse-grained molecular dynamics (MD) simulations and potential of mean force calculations, we have explored the membrane remodeling effects of monomeric α-synuclein (αS). Our initial findings from multiple approaches are that αS (1) causes a significant thinning of the bilayer and (2) stabilizes positive mean curvature, such that the maximum principle curvature matches that of synaptic vesicles, αS-induced tubules, and the synthetic lipid vesicles to which the protein binds most tightly. This suggests that αS binding to synaptic vesicles likely stabilizes their intrinsic curvature. We then show that αS induces local negative Gaussian curvature, an effect that occurs in regions of αS shown previously via NMR and corroborated by MD simulation to have significant conformational flexibility. The induction of negative Gaussian curvature, which has implications for all curvature-sensing and curvature-generating amphipathic α-helices, supports a hypothesis that connects helix insertion to fusion and fission of vesicles, processes that have recently been linked to αS function. Then, in an effort to explain these biophysical properties of αS, we promote an intrinsic curvature-field model that recasts long-range protein-protein interactions in terms of the interactions between the local curvature fields generated by lipid-protein complexes.     

Bifunctional compounds for controlling metal-mediated aggregation of the aβ42 peptide

Abnormal interactions of Cu and Zn ions with the amyloid β (Aβ) peptide are proposed to play an important role in the pathogenesis of Alzheimer's disease (AD). Disruption of these metal-peptide interactions using chemical agents holds considerable promise as a therapeutic strategy to combat this incurable disease. Reported herein are two bifunctional compounds (BFCs) L1 and L2 that contain both amyloid-binding and metal-chelating molecular motifs. Both L1 and L2 exhibit high stability constants for Cu(2+) and Zn(2+) and thus are good chelators for these metal ions. In addition, L1 and L2 show strong affinity toward Aβ species. Both compounds are efficient inhibitors of the metal-mediated aggregation of the Aβ(42) peptide and promote disaggregation of amyloid fibrils, as observed by ThT fluorescence, native gel electrophoresis/Western blotting, and transmission electron microscopy (TEM). Interestingly, the formation of soluble Aβ(42) oligomers in the presence of metal ions and BFCs leads to an increased cellular toxicity. These results suggest that for the Aβ(42) peptide-in contrast to the Aβ(40) peptide-the previously employed strategy of inhibiting Aβ aggregation and promoting amyloid fibril dissagregation may not be optimal for the development of potential AD therapeutics, due to formation of neurotoxic soluble Aβ(42) oligomers.     

Glycosidically-Bound Volatile Phenols Linked to Smoke Taint: Stability during Fermentation with Different Yeasts and in Finished Wine

When wine grapes are exposed to smoke, there is a risk that the resulting wines may possess smoky, ashy, or burnt aromas, a wine flaw known as smoke taint. Smoke taint occurs when the volatile phenols (VPs) largely responsible for the aroma of smoke are transformed in grape into a range of glycosides that are imperceptible by smell. The majority of VP-glycosides described to date are disaccharides possessing a reducing β-d-glucopyranosyl moiety. Here, a two-part experiment was performed to (1) assess the stability of 11 synthesized VP-glycosides towards general acid-catalyzed hydrolysis during aging, and (2) to examine whether yeast strains differed in their capacity to produce free VPs both from these model glycosides as well as from grapes that had been deliberately exposed to smoke. When fortified into both model and real wine matrices at 200 ng/g, all VP-disaccharides were stable over 12 weeks, while (42–50 ng/g) increases in free 4-ethylphenol and p-cresol were detected when these were added to wine as their monoglucosides. Guaiacol and phenol were the most abundantly produced VPs during fermentation, whether originating from natural VP-precursors in smoked-exposed Pinot Noir must, or due to fortification with synthetic VP-glycosides. Significant yeast strain-specific differences in glycolytic activities were observed for phenyl-β-d-glycopyranoside, with two strains (RC212 and BM45) being unable to hydrolyze this model VP, albeit both were active on the guaiacyl analogue. Thus, differences in Saccharomyces cerevisiae β-glucosidase activity appear to be influenced by the VP moiety.     

Hagedorn Wavepackets in Time-Frequency and Phase Space

The Hermite functions are an orthonormalbasis of the space of square integrable functions with favourable approximation properties. Allowing for a flexible localization in position and momentum, the Hagedorn wavepackets generalize the Hermite functions also to several dimensions. Using Hagedorn’s raising and lowering operators, we derive explicit formulas and recurrence relations for the Wigner and FBI transform of the wavepackets and show their relation to the Laguerre polyomials.     

Omnibus Sequences, Coupon Collection, and Missing Word Counts

In this paper, we study the properties of k-omnisequences of length n, defined to be strings of length n that contain all strings of smaller length k embedded as (not necessarily contiguous) subsequences. We start by proving an elementary result that relates our problem to the classical coupon collector problem. After a short survey of relevant results in coupon collection, we focus our attention on the number M of strings (or words) of length k that are not found as subsequences of an n string, showing that there is a gap between the probability threshold for the emergence of an omnisequence and the zero-infinity threshold for ${\mathbb E}(M)$ .     

On Universal Central Extensions of Leibniz Algebras

We construct the endofunctor 𝔲𝔠𝔢 between the category of Leibniz algebras which assigns to a perfect Leibniz algebra its universal central extension, and we obtain the isomorphism 𝔲𝔠𝔢_Lie(𝔮_Lie) ? (𝔲𝔠𝔢_Leib(𝔮))_Lie, where 𝔮 is a perfect Leibniz algebra satisfying the condition [x, [x, y]] + [[x, y], x] = 0, for all x, y ∈ 𝔮. Moreover, we obtain several results concerning the lifting of automorphisms and derivations in a covering. We also study the relationship between the universal central extension of a semidirect product of perfect Leibniz algebras and the semidirect product of the universal central extension of both of them.     

Actor of a Precrossed Module

Applying the equivalence of the category of precrossed modules with the category of groups with two additional unary operations satisfying the corresponding conditions, the construction of an actor is given in terms of Whitehead group of generalized regular derivations, defined in the article, and the automorphism group of a precrossed module. The analogous approach to this problem in the case of crossed modules leads to the well-known construction given in the works of Lue and Norrie.     

Gas-phase reactions of halogenated radical carbene anions with sulfur and oxygen containing species

The reactivities of mono- and dihalocarbene anions (CHCl⁻, CHBr⁻, CF₂⁻, CCl₂⁻, and CBrCl⁻) were studied using a tandem flowing afterglow-selected ion flow tube instrument. Reaction rate constants and product branching ratios are reported for the reactions of these carbene anions with six neutral reagents (CS₂, COS, CO₂, O₂, CO, and N₂O). These anions were found to demonstrate diverse chemistry as illustrated by formation of multiple product ions and by the observed reaction trends. The reactions of CHCl⁻ and CHBr⁻ occur with similar efficiencies and reactivity patterns. Substitution of a Cl atom for an H atom to form CCl₂⁻ and CBrCl⁻ decreases the rate constants; these two anions react with similar efficiencies and reactivity trends. The CF₂⁻ anion displays remarkably different reactivity; these differences are discussed in terms of its lower electron binding energy and the effect of the electronegative fluorine substituents. The results presented here are compared to the reactivity of the CH₂⁻ anion, which has previously been reported.