Local impact of perivascular plaques on cerebral blood flow dynamics in a transgenic mouse model of Alzheimer's disease.

Cerebrovascular pathology is closely coupled to cognitive function decline, as indicated by numerous studies at the system level. To better understand the mechanisms of this cognitive decline it is important to resolve how pathological changes in the vasculature - such as perivascular plaques - affect local cerebral blood flow dynamics. This issue is ideally studied in the intact brain at very high spatial resolution. Here, we describe initial results obtained by an approach based on in vivo observation by multi-photon microscopy of vascular plaques and local blood flow measurements in a transgenic mouse model engineered to express the human amyloid precursor protein with the Swedish and Arctic mutations. These mice exhibit a striking abundance of perivascular plaques in the cerebral cortex and are well suited to investigate vascular pathology in Alzheimer's disease

Density variations of TMAO solutions in the kilobar range: Experiments, PC-SAFT predictions, and molecular dynamics simulations

We present measurements, molecular dynamics (MD) simulations, and predictions using Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) of the density of aqueous solutions in a pressure range from 1 bar to 5000 bar, a pressure regime that is highly relevant for both biochemical applications and the fundamental understanding of solvation. The accurate determination of density data of pressurized solutions remains challenging. We determined relative density changes from the variations in X-ray absorption through the sample and developed a new water parameter set for PC-SAFT modeling that is appropriate for high pressure conditions in the kilobar regime. As a showcase, we studied trimethylamine N-oxide (TMAO) solutions and demonstrated that their compressibility decreases with the TMAO content. This result is linked to the stabilizing effect of TMAO on the local H-bond network of water. Experiments and calculations, which represent two independent methods, are in very good agreement and are in accordance with results of force field molecular dynamics simulations of the same systems

Structure and thermodynamics of aqueous urea solutions from ambient to kilobar pressures: From thermodynamic modeling, experiments, and first principles simulations to an accurate force field description

Molecular simulations based on classical force fields are a powerful method for shedding light on the complex behavior of biomolecules in solution. When cosolutes are present in addition to water and biomolecules, subtle balances of weak intermolecular forces have to be accounted for. This imposes high demands on the quality of the underlying force fields, and therefore force field development for small cosolutes is still an active field. Here, we present the development of a new urea force field from studies of urea solutions at ambient and elevated hydrostatic pressures based on a combination of experimental and theoretical approaches. Experimental densities and solvation shell properties from ab initio molecular dynamics simulations at ambient conditions served as the target properties for the force field optimization. Since urea is present in many marine life forms, elevated hydrostatic pressure was rigorously addressed: densities at high pressure were measured by vibrating tube densitometry up to 500 bar and by X-ray absorption up to 5 kbar. Densities were determined by the perturbed-chain statistical associating fluid theory equation of state. Solvation properties were determined by embedded cluster integral equation theory and ab initio molecular dynamics. Our new force field is able to capture the properties of urea solutions at high pressures without further high-pressure adaption, unlike trimethylamine-N-oxide, for which a high-pressure adaption is necessary