Special Glass Structures for First Principles Studies of Bulk Metallic Glasses

The atomic-level structure of bulk metallic glasses is a key determinant of their properties. An accurate representation of amorphous systems in computational studies has traditionally required large supercells that are unfortunately computationally demanding to handle using the most accurate ab initio calculations. To address this, we propose to specifically design small-cell structures that best reproduce the local geometric descriptors (e.g., pairwise distances or bond angle distributions) of a large-cell simulation. We rely on molecular dynamics (MD) driven by empirical potentials to generate the target descriptors, while we use reverse Monte Carlo (RMC) methods to optimize the small-cell structure. The latter can then be used to determine mechanical and electronic properties using more accurate electronic structure calculations. The method is implemented in the Metallic Amorphous Structures Toolkit (MAST) software package.Comment: 10 pages, 4 figure

Fasudil attenuates aggregation of α-synuclein in models of Parkinson’s disease

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, yet disease-modifying treatments do not currently exist. Rho-associated protein kinase (ROCK) was recently described as a novel neuroprotective target in PD. Since alpha-synuclein (alpha-Syn) aggregation is a major hallmark in the pathogenesis of PD, we aimed to evaluate the anti-aggregative potential of pharmacological ROCK inhibition using the isoquinoline derivative Fasudil, a small molecule inhibitor already approved for clinical use in humans. Fasudil treatment significantly reduced alpha-Syn aggregation in vitro in a H4 cell culture model as well as in a cell-free assay. Nuclear magnetic resonance spectroscopy analysis revealed a direct binding of Fasudil to tyrosine residues Y133 and Y136 in the C-terminal region of alpha-Syn. Importantly, this binding was shown to be biologically relevant using site-directed mutagenesis of these residues in the cell culture model. Furthermore, we evaluated the impact of long-term Fasudil treatment on alpha-Syn pathology in vivo in a transgenic mouse model overexpressing human alpha-Syn bearing the A53T mutation (alpha-Syn(A53T) mice). Fasudil treatment improved motor and cognitive functions in alpha-Syn(A53T) mice as determined by Catwalk (TM) gait analysis and novel object recognition (NOR), without apparent side effects. Finally, immunohistochemical analysis revealed a significant reduction of alpha-Syn pathology in the midbrain of alpha-Syn(A53T) mice after Fasudil treatment. Our results demonstrate that Fasudil, next to its effects mediated by ROCK-inhibition, directly interacts with alpha-Syn and attenuates alpha-Syn pathology. This underscores the translational potential of Fasudil as a disease-modifying drug for the treatment of PD and other synucleinopathies

Livelihoods, conflict and aid programming: Is the evidence base good enough?

In conflict-affected situations, aid-funded livelihood interventions are often tasked with a dual imperative: to generate material welfare benefits and to contribute to peacebuilding outcomes. There may be some logic to such a transformative agenda, but does the reality square with the rhetoric? Through a review of the effectiveness of a range of livelihood promotion interventions—from job creation to microfinance—this paper finds that high quality empirical evidence is hard to come by in conflict-affected situations. Many evaluations appear to conflate outputs with impacts and numerous studies fail to include adequate information on their methodologies and datasets, making it difficult to appraise the reliability of their conclusions. Given the primary purpose of this literature—to provide policy guidance on effective ways to promote livelihoods— this silence is particularly concerning. As such, there is a strong case to be made for a restrained and nuanced handling of such interventions in conflict-affected settings.Department for International Development - PO511