Modification of amyloid-beta peptide aggregation via photoactivation of strained Ru(ii) polypyridyl complexes

Alzheimer''s disease (AD) is a chronic neurodegenerative disorder characterized by progressive and irreversible damage to the brain. One of the hallmarks of the disease is the presence of both soluble and insoluble aggregates of the amyloid beta (Aβ) peptide in the brain, and these aggregates are considered central to disease progression. Thus, the development of small molecules capable of modulating Aβ peptide aggregation may provide critical insight into the pathophysiology of AD. In this work we investigate how photoactivation of three distorted Ru(ii) polypyridyl complexes (Ru1–3) alters the aggregation profile of the Aβ peptide. Photoactivation of Ru1–3 results in the loss of a 6,6′-dimethyl-2,2′-bipyridyl (6,6′-dmb) ligand, affording cis-exchangeable coordination sites for binding to the Aβ peptide. Both Ru1 and Ru2 contain an extended planar imidazo[4,5-f][1,10]phenanthroline ligand, as compared to a 2,2′-bipyridine ligand for Ru3, and we show that the presence of the phenanthroline ligand promotes covalent binding to Aβ peptide His residues, and in addition, leads to a pronounced effect on peptide aggregation immediately after photoactivation. Interestingly, all three complexes resulted in a similar aggregate size distribution at 24 h, forming insoluble amorphous aggregates as compared to significant fibril formation for peptide alone. Photoactivation of Ru1–3 in the presence of pre-formed Aβ_1–42 fibrils results in a change to amorphous aggregate morphology, with Ru1 and Ru2 forming large amorphous aggregates immediately after activation. Our results show that photoactivation of Ru1–3 in the presence of either monomeric or fibrillar Aβ_1–42 results in the formation of large amorphous aggregates as a common endpoint, with Ru complexes incorporating the extended phenanthroline ligand accelerating this process and thereby limiting the formation of oligomeric species in the initial stages of the aggregation process that are reported to show considerable toxicity.

Photoactivation of a series of Ru(ii) polypyridyl complexes leads to ligand exchange and modulation of amyloid-beta peptide aggregation of relevance to Alzheimer''s disease.     

Catalytic stereoselective alkene aziridination with sulfonimidamides

Diastereoselective copper-catalyzed alkene aziridination has been investigated using chiral nitrenes generated from sulfonimidamides in the presence of an iodine(III) oxidant. Starting from a stoichiometric amount of the substrates, the corresponding aziridines were isolated with excellent yields of up to 96%. Good levels of asymmetric induction were obtained in the case of electron-poor olefins, with an optimal de of 94% being reached starting from tert-butyl acrylate. Matching and mismatching effects were also observed upon the use of chiral copper catalysts for the aziridination of styrene.     

New Procedure for the Preparation of the Tetrazole Analogue of GABA

The hydrochloride of the tetrazolyl bioisostere of the neurotransmitter GABA can be easily prepared by means of three simple steps: a Gabriel-type substitution on 4-bromobutyronitrile with Boc₂NH, a tetrazole formation by action of azidotributyltin on the cyano group and a deprotection step using gaseous HCl.     

Comparative Metabolomic Analysis of Four Fabaceae and Relationship to In Vitro Nematicidal Activity against Xiphinema index

The grapevine fanleaf virus (GFLV), responsible for fanleaf degeneration, is spread in vineyards by the soil nematode Xiphinema index. Nematicide molecules were used to limit the spread of the disease until they were banned due to negative environmental impacts. Therefore, there is a growing interest in alternative methods, including plant-derived products with antagonistic effects to X. index. In this work, we evaluated the nematicidal potential of the aerial parts and roots of four Fabaceae: sainfoin (Onobrychis viciifolia), birdsfoot trefoil (Lotus corniculatus), sweet clover (Melilotus albus), and red clover (Trifolium pratense), as well as that of sainfoin-based commercial pellets. For all tested plants, either aerial or root parts, or both of them, exhibited a nematicidal effect on X. index in vitro, pellets being as effective as freshly harvested plants. Comparative metabolomic analyses did not reveal molecules or molecule families specifically associated with antagonistic properties toward X. index, suggesting that the nematicidal effect is the result of a combination of different molecules rather than associated with a single compound. Finally, scanning electron microscope observations did not reveal the visible impact of O. viciifolia extract on X. index cuticle, suggesting that alteration of the cuticle may not be the primary cause of their nematicidal effect.     

Cutting-edge molecular modelling to unveil new microscopic insights into the guest-controlled flexibility of metal–organic frameworks

Metal–organic frameworks are a class of porous solids that exhibit intriguing flexibility under stimuli, leading often to reversible giant structural changes upon guest adsorption. DUT-49(Cu) and MIL-53(Cr) are fascinating flexible MOFs owing to their guest-induced breathing and negative gas adsorption behaviors respectively. Molecular simulation is one of the most relevant tools to examine these phenomena at the atomistic scale and gain a unique understanding of the physics behind them. Although molecular dynamics and Monte Carlo simulations are widely used in the field of porous materials, these methods hardly consider the structural deformation of a soft material upon guest adsorption. In this work, a cutting-edge osmotic molecular dynamics approach is developed to consider simultaneously the fluid adsorption process and material flexibility. We demonstrate that this newly developed computational strategy offers a unique opportunity to gain unprecedented molecular insights into the flexibility of this class of materials.

Osmotic Molecular Dynamics simulation is developed to consider simultaneously the fluid adsorption and material flexibility to gain molecular insights into the flexibility of MOFs such as DUT-49(Cu) which shows a negative gas adsorption behaviour upon exposure to CH₄.     

Oxygenated Metabolites of n‐3 Polyunsaturated Fatty Acids as Potential Oxidative Stress Biomarkers: Total Synthesis of 8‐F3t‐IsoP, 10‐F4t‐NeuroP and [D4]‐10‐F4t‐NeuroP

A wide variety of metabolic products of polyunsaturated fatty acids is of paramount importance for improving our medical knowledge in the field of oxidized lipids. Two novel metabolites of n‐3 polyunsaturated fatty acids, 8‐F_3t‐IsoP and 10‐F_4t‐NeuroP as well as a deuterated derivative thereof were synthesized based on an acetylenic intermediate. An original approach achieved lateral chain insertion of 8‐F_3t‐IsoP by a ring‐closing alkyne metathesis/semi‐reduction strategy together with a temporary tether.     

Micro-level reserving for general insurance claims using a long short-term memory network

Detailed information about individual claims are completely ignored when insurance claims data are aggregated and structured in development triangles for loss reserving. In the hope of extracting predictive power from the individual claims characteristics, researchers have recently proposed to use micro-level loss reserving approaches. We introduce a discrete-time individual reserving framework incorporating granular information in a deep learning approach named Long Short-Term Memory (LSTM) neural network. At each time period, the network has two tasks: first, classifying whether there is a payment or a recovery, and second, predicting the corresponding non-zero amount, if any. Based on a generalized Pareto model for excess payments over a threshold, we adjust the LSTM reserve prediction to account for extreme payments. We illustrate the estimation procedure on a simulated and a real general insurance dataset. We compare our approach with the chain-ladder aggregate method using the predictive outstanding loss estimates and their actual values.     

On the stability of the state 1 in the non-local Fisher–KPP equation in bounded domains

We consider the non-local Fisher–KPP equation on a bounded domain with Neumann boundary conditions. Thanks to a Lyapunov function, we prove that, under a general hypothesis on the kernel involved in the non-local term, the homogenous steady state 1 is globally asymptotically stable. This assumption happens to be linked to some conditions given in the literature, which ensure that travelling waves link 0 to 1.