The Cytotoxic Effect of α-Synuclein Aggregates

Parkinson's disease is a neurodegenerative disorder involving a functional protein, α-synuclein, whose primary function is related to vesicle trafficking. However, α-synuclein is prone to form aggregates, and these inclusions, known as Lewy bodies, are the hallmark of Parkinson's disease. α-synuclein can alter its conformation and acquire aggregating capacity, forming aggregates containing β-sheets. This protein's pathogenic importance is based on its ability to form oligomers that impair synaptic transmission and neuronal function by increasing membrane permeability and altering homeostasis, generating a deleterious effect over cells. First, we establish that oligomers interfere with the mechanical properties of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) membrane, as demonstrated by nanoindentation curves. In contrast, nanoindentation revealed that the α-synuclein monomer's presence leads to a much more resistant lipid bilayer. Moreover, the oligomers’ interaction with cell membranes can promote lactate dehydrogenase (LDH) release, suggesting the activation of cytotoxic events.     

NMR spectral analysis of strongly second-order 6-, 8-, 9- and 10- spin-systems (1H─19F, 19F─19F,and 13C─19F) in perfluorotoluyl- and tetrafluoro-pyridyl-aromatics using the lineshape method ANATOLIA

A simple to use nuclear magnetic resonance analysis method has been tested on complex ¹H, ¹⁹F, and ¹³C multiplets. This open-source line-shape analysis method analysis of total lineshape (ANATOLIA)¹ provides some significant advantages over traditional assign-iterate methods of NMR spectral analysis by avoiding false minima and progressing optimisation to the global minimum. The target molecules are 1-perfluorotol-4-yl-2-perfluorotol-4-yl-oxymethyl-1H-benzimidazole (molecule-I) and 1-tetrafluoropyrid-4-yl-2-tetrafluoropyrid-4-yl-thio-1H-benzimidazole (molecule-II) which were produced as part of a family of fluorinated drug scaffolds prepared for anticancer and antiparasitic screening. Spectra display significant second-order effects with ¹H Δδ = 3.68 and 4.67 Hz for the aromatic hydrogen “triplets”, with ¹⁹F ⁴J_AA', ⁴J_BB', ⁴J_XX', and ⁴J_YY' coupling constants range from +4.8 to −14.0 Hz and for ¹³C-isotopomers ¹⁹F Δδ of up to 111.56 Hz. A spin-system of six coupling nuclei (H_aH_bH_cH_d F_YF_Y') was analysed in 12 s, a spin-system of nine coupling fluorine nuclei (AA'BB'CCC-YY') was analysed within 2 min, and 10 coupling nuclei (XX'YY'ZZZ-BB'-H_d) was optimised in 6 min using a laptop computer. ANATOLIA was also robust enough to be able to yield accurate spectral values from inaccurate input values. In both compounds, a fluorine–fluorine coupling constant was identified between the two fluoro-aromatic rings (F_BB' and F_YY') of +4.05 and +4.67 Hz and attributed to a through-space interaction. Ab initio structure optimisations and coupling constant calculations provided useful input data for spectral analysis. A modern ¹⁹F nuclear magnetic resonance spectrum of perfluorotoluene (octafluorotoluene) and analysis from 1975 was used as a test data set to assess ANATOLIA.     

A new study of associating inhomogeneous fluids with classical density functional theory

ABSTRACT

A new density functional for the study of associating inhomogeneous fluids based on Wertheim's first-order thermodynamic perturbation theory is presented and compared to the most currently used associating density functionals. This functional is developed using the weighted density approximation in the range of association of hard spheres. We implement this functional within the framework of classical density functional theory together with modified fundamental measure theory to account for volume exclusion of hard spheres. This approach is tested against molecular simulations from literature of pure associating hard spheres and mixtures of non-associationg and associating hard spheres with different number of bonding sites close to a hard uniform wall. Furthermore, we compare and review our results with the performance of associating functionals from literature, one based on fundamental measure theory and the inhomogeneous version of Wertheim's perturbation theory. Results obtained with classical DFT and the three functionals show excellent agreement with molecular simulations in systems with one hard wall. For the cases of small pores where only one or two layers of fluid are allowed discrepancies between results with classical DFT and molecular simulations were found.     

Sets of reflections defining twisted Bruhat orders

Twisted Bruhat orders are certain partial orders on a Coxeter system (W,S) associated to initial sections of reflection orders, which are certain subsets of the set of reflections T of a Coxeter system. We determine which subsets of T give rise to a partial order on W in the same way.