A strategy for designing inhibitors of alpha-synuclein aggregation and toxicity as a novel treatment for Parkinson's disease and related disorders.

Convergent biochemical and genetic evidence suggests that the formation of alpha-synuclein (alpha-syn) protein deposits is an important and, probably, seminal step in the development of Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). It has been reported that transgenic animals overexpressing human alpha-syn develop lesions similar to those found in the brain in PD, together with a progressive loss of dopaminergic cells and associated abnormalities of motor function. Inhibiting and/or reversing alpha-syn self-aggregation could, therefore, provide a novel approach to treating the underlying cause of these diseases. We synthesized a library of overlapping 7-mer peptides spanning the entire alpha-syn sequence, and identified amino acid residues 64-100 of alpha-syn as the binding region responsible for its self-association. Modified short peptides containing alpha-syn amino acid sequences from part of this binding region (residues 69-72), named alpha-syn inhibitors (ASI), were found to interact with full-length alpha-syn and block its assembly into both early oligomers and mature amyloid-like fibrils. We also developed a cell-permeable inhibitor of alpha-syn aggregation (ASID), using the polyarginine peptide delivery system. This ASID peptide was able to inhibit the DNA damage induced by Fe(II) in neuronal cells transfected with alpha-syn(A53T), a familial PD-associated mutation. ASI peptides without this delivery system did not reverse levels of Fe(II)-induced DNA damage. Furthermore, the ASID peptide increased (P

Welfare Effort and Poverty from the Monetary and Capabilities Approach: A Cross-Country Analysis in Latin American and the Caribbean (1990-2010)

There is abundant empirical evidence on the negative relationship between welfare effort and poverty. However, poverty indicators traditionally used have been representative of the monetary approach, excluding its multidimensional reality from the analysis. Using three regression techniques for the period 1990-2010 and controlling for demographic and cyclical factors, this paper examines the relationship between social spending per capita —as the indicator of welfare effort— and poverty in up to 21 countries of the region. The proportion of the population with an income below its national basic basket of goods and services (PM1) and the proportion of population with an income below 50% of the median income per capita (PM2) were the two poverty indicators considered from the monetarist approach to measure poverty. From the capability approach the proportion of the population with food inadequacy (PC1) and the proportion of the population without access to improved water sources or sanitation facilities (PC2) were used. The fi ndings confi rm that social spending is actually useful to explain changes in poverty (PM1, PC1 and PC2), as there is a high negative and signifi cant correlation between the variables before and after controlling for demographic and cyclical factors. In two regression techniques, social spending per capita did not show a negative relationship with the PM2. Countries with greater welfare effort for the period 1990-2010 were not necessarily those with the lowest level of poverty. Ultimately social spending per capita was more useful to explain changes in poverty from the capability approach.

R-matrix theory of electron molecule scattering

This paper presents an overview of R-matrix theory of electron scattering by diatomic and polyatomic molecules. The paper commences with a detailed discussion of the fixed-nuclei approximation which in recent years has been used as the basis of the most accurate ab initio calculations. This discussion includes an overview of the computer codes which enable electron collisions with both diatomic and polyatomic molecules to be calculated. Nuclear motion including rotational and vibrational excitation and dissociation is then discussed. In non-resonant energy regions, or when the scattered electron energy is not close to thresholds, the adiabatic-nuclei approximation can be successfully used. However, when these conditions are not applicable, non-adiabatic R-matrix theory must be used and a detailed discussion of this theory is given. Finally, recent applications of the theory to treat electron scattering by polyatomic molecules are reviewed and a detailed comparison of R-matrix calculations and experimental measurements for water is presented.