E46K Parkinson's-linked mutation enhances C-terminal-to-N-terminal contacts in alpha-synuclein

Parkinson's disease (PD) is associated with the deposition of fibrillar aggregates of the protein alpha-synuclein (alphaS) in neurons. Intramolecular contacts between the acidic C-terminal tail of alphaS and its N-terminal region have been proposed to regulate alphaS aggregation, and two originally described PD mutations, A30P and A53T, reportedly reduce such contacts. We find that the most recently discovered PD-linked alphaS mutation E46K, which also accelerates the aggregation of the protein, does not interfere with C-terminal-to-N-terminal contacts and instead enhances such contacts. Furthermore, we do not observe a substantial reduction in such contacts in the two previously characterized mutants. Our results suggest that C-terminal-to-N-terminal contacts in alphaS are not strongly protective against aggregation, and that the dominant mechanism by which PD-linked mutations facilitate alphaS aggregation may be altering the physicochemical properties of the protein such as net charge (E46K) and secondary structure propensity (A30P and A53T)

Cycles of Police Reform in Latin America.

yesOver the last quarter century post-conflict and post-authoritarian transitions in Latin America have been accompanied by a surge in social violence, acquisitive crime, and insecurity. These phenomena have been driven by an expanding international narcotics trade, by the long-term effects of civil war and counter-insurgency (resulting in, inter alia, an increased availability of small arms and a pervasive grammar of violence), and by structural stresses on society (unemployment, hyper-inflation, widening income inequality). Local police forces proved to be generally ineffective in preventing, resolving, or detecting such crime and forms of “new violence”3 due to corruption, frequent complicity in criminal networks, poor training and low pay, and the routine use of excessive force without due sanction. Why, then, have governments been slow to prioritize police reform and why have reform efforts borne largely “limited or nonexistent” long-term results? This chapter highlights a number of lessons suggested by various efforts to reform the police in Latin America over the period 1995-2010 . It focuses on two clusters of countries in Latin America. One is Brazil and the Southern Cone countries (Chile, Argentina, and Uruguay), which made the transition to democracy from prolonged military authoritarian rule in the mid- to late 1980s. The other is Central America and the Andean region (principally El Salvador, Guatemala, Honduras, Peru, and Colombia), which emerged/have been emerging from armed conflict since the mid- 1990s. The chapter examines first the long history of international involvement in police and security sector reform in order to identify long-run tropes and path dependencies. It then focuses on a number of recurring themes: cycles of de- and re-militarization of the policing function; the “security gap” and “democratization dilemmas” involved in structural reforms; the opportunities offered by decentralization for more community-oriented police; and police capacity to resist reform and undermine accountability mechanisms

Effect of Spermidine on Misfolding and Interactions of Alpha-Synuclein

Alpha-synuclein (α-Syn) is a 140 aa presynaptic protein which belongs to a group of natively unfolded proteins that are unstructured in aqueous solutions. The aggregation rate of α-Syn is accelerated in the presence of physiological levels of cellular polyamines. Here we applied single molecule AFM force spectroscopy to characterize the effect of spermidine on the very first stages of α-Syn aggregation – misfolding and assembly into dimers. Two α-Syn variants, the wild-type (WT) protein and A30P, were studied. The two protein molecules were covalently immobilized at the C-terminus, one at the AFM tip and the other on the substrate, and intermolecular interactions between the two molecules were measured by multiple approach-retraction cycles. At conditions close to physiological ones at which α-Syn misfolding is a rare event, the addition of spermidine leads to a dramatic increase in the propensity of the WT and mutant proteins to misfold. Importantly, misfolding is characterized by a set of conformations, and A30P changes the misfolding pattern as well as the strength of the intermolecular interactions. Together with the fact that spermidine facilitates late stages of α-Syn aggregation, our data demonstrate that spermidine promotes the very early stages of protein aggregation including α-Syn misfolding and dimerization. This finding suggests that increased levels of spermidine and potentially other polyamines can initiate the disease-related process of α-Syn

La colisión de los derechos individuales en tiempos contemporáneos: estudios sobre la privacidad, la salud, la propiedad, la justicia y la capacidad

El eje de este libro radica en el interés por estudiar los problemas que han encontrado algunos derechos individuales en la unidad de principios entre la Constitución y el Derecho privado, en cuanto a su concreción, causados eventualmente por su noción abstracta y porque en las últimas décadas han desfilado ante nuestros ojos transformaciones o acontecimientos de importante magnitud —como la integración de la tecnología en todas las áreas de la sociedad— que influyen en la desinformación de los ciudadanos frente a cuestiones de salud, cambios en la forma de regular la interacción de las personas en los servicios que brinda la red virtual y la responsabilidad civil, entre otras cuestiones, de lo que surgen exigencias de adecuación para el Derecho de cara a los nuevos problemas que asisten en el derecho privado.Introducción. Capítulo 1. Habeas data y derechos de los niños, las niñas y los adolescentes. Capítulo 2. El derecho de la privacidad en los Estados Unidos. Un análisis de los efectos de una nueva política de la privacidad. Capítulo 3. El consentimiento informado: síntesis de una ponderación entre la libertad de decisión del paciente y la tutela de la salud. Capítulo 4. El influjo de la sinalagmaticidad en la compraventa: el riesgo. Capítulo 5. Las asistencias en favor de las personas con discapacidad en el derecho peruano. Conclusiones generales. Referencias

Identification of a helical intermediate in trifluoroethanol-induced alpha-synuclein aggregation

Because oligomers and aggregates of the protein α-synuclein (αS) are implicated in the initiation and progression of Parkinson’s disease, investigation of various αS aggregation pathways and intermediates aims to clarify the etiology of this common neurodegenerative disorder. Here, we report the formation of short, flexible, β-sheet-rich fibrillar species by incubation of αS in the presence of intermediate (10–20% v/v) concentrations of 2,2,2-trifluoroethanol (TFE). We find that efficient production of these TFE fibrils is strongly correlated with the TFE-induced formation of a monomeric, partly helical intermediate conformation of αS, which exists in equilibrium with the natively disordered state at low [TFE] and with a highly α-helical conformation at high [TFE]. This partially helical intermediate is on-pathway to the TFE-induced formation of both the highly helical monomeric conformation and the fibrillar species. TFE-induced conformational changes in the monomer protein are similar for wild-type αS and the C-terminal truncation mutant αS1-102, indicating that TFE-induced structural transitions involve the N terminus of the protein. Moreover, the secondary structural transitions of three Parkinson’s disease-associated mutants, A30P, A53T, and E46K, are nearly identical to wild-type αS, but oligomerization rates differ substantially among the mutants. Our results add to a growing body of evidence indicating the involvement of helical intermediates in protein aggregation processes. Given that αS is known to populate both highly and partially helical states upon association with membranes, these TFE-induced conformations imply relevant pathways for membrane-induced αS aggregation both in vitro and in vivo

Private Financing of the Military: A Local Political Economy Approach

The article of record as published may be located at http://dx.doi.org/10.1007/s12116-012-9119-2In developing countries that are democratizing after military rule, and undergoing liberalizing economic reforms that encourage a shrinking of the state, what missions are the armed forces performing, who funds those missions, who benefits from military services, and why? This article analyzes security provision by the armed forces for paying clients—especially private companies in extractive industries—in accordance with negotiations between clients and commanders of the local military units that directly provide the security. The analysis identifies two paths toward local military–client relations. First, weak state capacity may mean that government control of military finances brought by democratization and economic reform remains limited to the national level, promoting local military–client exchanges. Second, amid minimal government control of military finances, even in the capital city, demand from companies in the powerful extractive industries and from recently endowed subnational governments can encourage local military–client contracting