In Vivo Generation of Neurotoxic Prion Protein: Role for Hsp70 in Accumulation of Misfolded Isoforms

Prion diseases are incurable neurodegenerative disorders in which the normal cellular prion protein (PrPC) converts into a misfolded isoform (PrPSc) with unique biochemical and structural properties that correlate with disease. In humans, prion disorders, such as Creutzfeldt-Jakob disease, present typically with a sporadic origin, where unknown mechanisms lead to the spontaneous misfolding and deposition of wild type PrP. To shed light on how wild-type PrP undergoes conformational changes and which are the cellular components involved in this process, we analyzed the dynamics of wild-type PrP from hamster in transgenic flies. In young flies, PrP demonstrates properties of the benign PrPC; in older flies, PrP misfolds, acquires biochemical and structural properties of PrPSc, and induces spongiform degeneration of brain neurons. Aged flies accumulate insoluble PrP that resists high concentrations of denaturing agents and contains PrPSc-specific conformational epitopes. In contrast to PrPSc from mammals, PrP is proteinase-sensitive in flies. Thus, wild-type PrP rapidly converts in vivo into a neurotoxic, protease-sensitive isoform distinct from prototypical PrPSc. Next, we investigated the role of molecular chaperones in PrP misfolding in vivo. Remarkably, Hsp70 prevents the accumulation of PrPSc-like conformers and protects against PrP-dependent neurodegeneration. This protective activity involves the direct interaction between Hsp70 and PrP, which may occur in active membrane microdomains such as lipid rafts, where we detected Hsp70. These results highlight the ability of wild-type PrP to spontaneously convert in vivo into a protease-sensitive isoform that is neurotoxic, supporting the idea that protease-resistant PrPSc is not required for pathology. Moreover, we identify a new role for Hsp70 in the accumulation of misfolded PrP. Overall, we provide new insight into the mechanisms of spontaneous accumulation of neurotoxic PrP and uncover the potential therapeutic role of Hsp70 in treating these devastating disorders

Recombinant Human Growth Hormone and Rosiglitazone for Abdominal Fat Accumulation in HIV- Infected Patients with Insulin Resistance: A Randomized, Double-Blind, Placebo-Controlled, Factorial Trial

Background: Recombinant human growth hormone (rhGH) reduces visceral adipose tissue (VAT) volume in HIV-infected patients but can worsen glucose homeostasis and lipoatrophy. We aimed to determine if adding rosiglitazone to rhGH would abrogate the adverse effects of rhGH on insulin sensitivity (SI) and subcutaneous adipose tissue (SAT) volume. Methodology/Principal Findings: Randomized, double-blind, placebo-controlled, multicenter trial using a 262 factorial design in which HIV-infected subjects with abdominal obesity and insulin resistance were randomized to rhGH 3 mg daily, rosiglitazone 4 mg twice daily, combination rhGH + rosiglitazone, or double placebo (control) for 12 weeks. The primary endpoint was change in SI by frequently sampled intravenous glucose tolerance test from entry to week 12. Body composition was assessed by whole body magnetic resonance imaging (MRI) and dual Xray absorptiometry (DEXA). Seventy-seven subjects were randomized of whom 72 initiated study drugs. Change in SI from entry to week 12 differed across the 4 arms by 1-way ANCOVA (P = 0.02); by pair-wise comparisons, only rhGH (decreasing SI; P = 0.03) differed significantly from control. Changes from entry to week 12 in fasting glucose and glucose area under the curve on 2- hour oral glucose tolerance test differed across arms (1-way ANCOVA P = 0.004), increasing in the rhGH arm relative to control. VAT decreased significantly in the rhGH arms (217.5% in rhGH/rosiglitazone and 222.7% in rhGH) but not in the rosiglitazone alone (22.5%) or control arms (21.9%). SAT did not change significantly in any arm. DEXA results were consistent with the MRI data. There was no significant rhGH x rosiglitazone interaction for any body composition parameter. Conclusions/Significance: The addition of rosiglitazone abrogated the adverse effects of rhGH on insulin sensitivity and glucose tolerance while not significantly modifying the lowering effect of rhGH on VAT

Considering Soil Potassium Pools with Dissimilar Plant Availability

Soil potassium (K) has traditionally been portrayed as residing in four functional pools: solution K, exchangeable K, interlayer (sometimes referred to as “fixed” or “nonexchangeable”) K, and structural K in primary minerals. However, this four-pool model and associated terminology have created confusion in understanding the dynamics of K supply to plants and the fate of K returned to the soil in fertilizers, residues, or waste products. This chapter presents an alternative framework to depict soil K pools. The framework distinguishes between micas and feldspars as K-bearing primary minerals, based on the presence of K in interlayer positions or three-dimensional framework structures, respectively; identifies a pool of K in neoformed secondary minerals that can include fertilizer reaction products; and replaces the “exchangeable” K pool with a pool defined as “surface-adsorbed” K, identifying where the K is located and the mechanism by which it is held rather than identification based on particular soil testing procedures. In this chapter, we discuss these K pools and their behavior in relation to plant K acquisition and soil K dynamics

Progress toward bridging from atomistic to continuum modeling to predict nuclear waste glass dissolution.

This report summarizes research performed for the Nuclear Energy Advanced Modeling and Simulation (NEAMS) Subcontinuum and Upscaling Task. The work conducted focused on developing a roadmap to include molecular scale, mechanistic information in continuum-scale models of nuclear waste glass dissolution. This information is derived from molecular-scale modeling efforts that are validated through comparison with experimental data. In addition to developing a master plan to incorporate a subcontinuum mechanistic understanding of glass dissolution into continuum models, methods were developed to generate constitutive dissolution rate expressions from quantum calculations, force field models were selected to generate multicomponent glass structures and gel layers, classical molecular modeling was used to study diffusion through nanopores analogous to those in the interfacial gel layer, and a micro-continuum model (K{mu}C) was developed to study coupled diffusion and reaction at the glass-gel-solution interface

The Implementation of Participatory Democracy in French Communes

The purpose of the article is to analyze how participatory democracy has been implemented in French communes. The question of neighbourhood democracy is a norm of political speech as local representatives need to legitimize their role in public space by getting closer to their electors. Does the implementation of participatory tools depend on the ideology and the socialization of the mayors or on the structure of the commune (size, territorial configuration)?The paper will mainly use a quantitative investigation made on communes above 5 000 inhabitants as well as interviews conducted in specific communes which were known for their participatory culture