α-Synuclein Suppression by Targeted Small Interfering RNA in the Primate Substantia Nigra

The protein α-synuclein is involved in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. Its toxic potential appears to be enhanced by increased protein expression, providing a compelling rationale for therapeutic strategies aimed at reducing neuronal α-synuclein burden. Here, feasibility and safety of α-synuclein suppression were evaluated by treating monkeys with small interfering RNA (siRNA) directed against α-synuclein. The siRNA molecule was chemically modified to prevent degradation by exo- and endonucleases and directly infused into the left substantia nigra. Results compared levels of α-synuclein mRNA and protein in the infused (left) vs. untreated (right) hemisphere and revealed a significant 40–50% suppression of α-synuclein expression. These findings could not be attributable to non-specific effects of siRNA infusion since treatment of a separate set of animals with luciferase-targeting siRNA produced no changes in α-synuclein. Infusion with α-synuclein siRNA, while lowering α-synuclein expression, had no overt adverse consequences. In particular, it did not cause tissue inflammation and did not change (i) the number and phenotype of nigral dopaminergic neurons, and (ii) the concentrations of striatal dopamine and its metabolites. The data represent the first evidence of successful anti-α-synuclein intervention in the primate substantia nigra and support further development of RNA interference-based therapeutics

Innovation and growth in the UK pharmaceuticals: the case of product and marketing introductions

New drug introductions are key to growth for pharmaceutical firms. However, not all innovations are the same and they may have differential effects that vary by firm size. We use quarterly sales data on UK pharmaceuticals in a dynamic panel model to estimate the impact of product (new drugs) and marketing (additional pack varieties) innovations within a therapeutic class on a firm’s business unit growth. We find that product innovations lead to substantial growth in both the short and long run, whereas a new pack variety only produces short-term effects. The strategies are substitutes but the marginal effects are larger for product innovations relative to additional packs, and the effects are larger for smaller business units. Nonetheless, pack introductions offer a viable short-term growth strategy, especially for small- and medium-sized businesses

Determinação das curvas de secagem das sementes de andiroba em secador solar

The oil of crabwood is commonly extracted in Amazon by traditional or by pressing method. The extraction efficiency is related to the heating and water content of the seeds. Thus, the determination of a drying model that represent satisfactorily the experimental data is of paramount importance to minimize the changes introduced by the process, consequently obtaining a quality product. The objective of this study was to describe the drying kinetics of seeds of crabwood as well as adjust the mathematical models to the experimental data, using solar dryer. The coefficient of determination, the magnitude of the mean relative error and standard deviation of the estimate was used as the criterion of fit of mathematical models. Drying in a shorter period of time (14 days) of Carapa surinamensis to reach the water equilibrium content (12.28%) may be attributed to the smaller size of the seeds and the greater amount of oil compared to Carapa guianensis. Logarithmic and Midilli et al. were the model that best fitted the experimental data for seeds of both species of Andiroba. © 2015, Departamento de Engenharia Agricola - UFCG/Cnpq. All rights reserved

Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes

On-orbit performance of the MIPS instrument

The Multiband Imaging Photometer for Spitzer (MIPS) provides long wavelength capability for the mission, in imaging bands at 24, 70, and 160 microns and measurements of spectral energy distributions between 52 and 100 microns at a spectral resolution of about 7%. By using true detector arrays in each band, it provides both critical sampling of the Spitzer point spread function and relatively large imaging fields of view, allowing for substantial advances in sensitivity, angular resolution, and efficiency of areal coverage compared with previous space far-infrared capabilities. The Si:As BIB 24 micron array has excellent photometric properties, and measurements with rms relative errors of 1% or better can be obtained. The two longer wavelength arrays use Ge:Ga detectors with poor photometric stability. However, the use of 1.) a scan mirror to modulate the signals rapidly on these arrays, 2.) a system of on-board stimulators used for a relative calibration approximately every two minutes, and 3.) specialized reduction software result in good photometry with these arrays also, with rms relative errors of less than 10%

The number of nigral dopaminergic neurons is not affected by siRNA-induced α-synuclein suppression.

<p>Squirrel monkeys received a unilateral nigral infusion of siRNA targeting α-synuclein. Both the number of TH-immunoreactive cells and the total number of dopaminergic neurons were counted stereologically in the substantia nigra. Values (mean ± SEM) were not different between the right (untreated) and left (siRNA-infused) hemisphere.</p

Effect of α-synuclein siRNA on α-synuclein protein in the monkey substantia nigra.

<p>α-Synuclein or luciferase siRNA was unilaterally infused into the left substantia nigra. Midbrain sections were immunostained with an antibody against α-synuclein. Representative images from an animal receiving α-synuclein siRNA show more robust α-synuclein immunoreactivity within the neuropil of the right (untreated, <b>A</b>) <i>vs.</i> left (siRNA-infused, <b>B</b>) substantia nigra. Scale bar = 5 µm. (<b>C</b>) Optical density measurements of nigral α-synuclein immunoreactivity. Data are expressed as percent of the control value in the right (untreated) substantia nigra and represent mean ± SEM. A significant decrease is caused by α-synuclein but not luciferase siRNA in the left (siRNA-infused) hemisphere. *p<0.03.</p

Levels of striatal dopamine, DOPAC and HVA are unaffected by α-synuclein siRNA infusion.

<p>α-Synuclein siRNA was unilaterally infused into the left substantia nigra. Values are expressed as ng/mg protein. Data are shown as mean ± SEM. LC, lateral caudate; MC, medial caudate; DP, dorsal putamen; VP, ventral putamen.</p