Orchestrated increase of dopamine and PARK mRNAs but not miR-133b in dopamine neurons in Parkinson's disease

AbstractProgressive loss of substantia nigra dopamine neurons (SN DA) is a hallmark of aging and of Parkinson's disease (PD). Mutations in PARK genes cause familial PD forms. Increased expression of alpha-synuclein (PARK4) is a disease-triggering event in familial PD and also observed in SN DA neurons in sporadic PD but related transcriptional changes are unknown. With optimized single-cell quantitative real-time polymerase chain reaction analysis, we compared messenger RNA and microRNA levels in SN DA neurons from sporadic PD patients and controls. Non-optimally matched donor ages and RNA integrities are common problems when analyzing human samples. We dissected the influence of distinct ages and RNA integrities of our samples by applying a specifically-optimized, linear-mixed-effects model to quantitative real-time polymerase chain reaction-data. We identified that elevated alpha-synuclein messenger RNA levels in SN DA neurons of human PD brains were positively correlated with corresponding elevated levels of mRNAs for functional compensation of progressive SN DA loss and for enhanced proteasomal (PARK5/UCHL1) and lysosomal (PARK9/ATPase13A2) function, possibly counteracting alpha-synuclein toxicity. In contrast, microRNA miR-133b levels, previously implicated in transcriptional dysregulation in PD, were not altered in SN DA neurons in PD

New approaches in order to enlarge the grain size of bulk CdZnTe (CZT) crystals

For the few decades, II-VI compound semiconductors are gaining attention because of its numerous applications in the field of detector technology, photovoltaic, nuclear medicine, astronomy etc. In the recent past, materials scientists focused their attention for the growth of CdTe/CdZnTe single crystals because it doesn\u27t require any specialized cooling and detects higher energy photos as in comparison with the existing Ge, Si and Hgl(2) detectors. In the present study, we are going to discuss five main approaches in order to get good quality CZT crystal and we have successfully grown the CZT crystal by adopting these approaches. They are: i) oscillatory Bridgman technique previous to the growth process, ii) modifying the thermal environments in a Bridgman geometry using a Pt tube as a cold finger in order to reduce the growth velocity iii) growth from the vapour phase using Bridgman geometry with a pyrolitic boron nitride (PBN) crucible to locate the feed material, and with a special temperature profile, iv) microgravity experiments in the FOTON M3 mission using magnetic field prior to the growth process and v) growth by a boron oxide encapsulation. The detailed discussions are given in the following sections

Dewetting During Crystal Growth of (Cd,Zn)Te:In under Microgravity

The phenomenon of "Dewetting" during crystal growth has been observed in several microgravity experiments for different semiconductor crystals. The results of these experiments showed an improvement of the material quality due to the contact-less growth of the crystals. A number of crystal growth techniques have been used to grow CZT. The most widely used is the growth from the melt by the Bridgman method. However the crucible, which is generally made of carbon-layered silica glass, causes a number of problems: solid-liquid interface curvature, spurious nucleation of grains and twins, thermal stresses during the cooling of the crystal. This work is concentrated on the growth of high resistivity (Cd,Zn)Te:In (CZT) crystals by using the phenomenon of dewetting and its application in the processing of CZT detectors. Two Cd0.9Zn0.1Te:In crystals were grown under microgravity on the Russian FOTON satellite in the Polizon facility in September 2007. One crystal was grown under a rotating magnetic field during the phase of homogenization to destroy the typical tellurium clusters in the melt. The other crystal was superheated with 20 K above the melting point. A third crystal has been grown on the ground in similar thermal conditions. Inspection of the surface of the space grown crystals gave the evidence of successful dewetting during the crystal growth. The influence of the dewetting on the material properties is shown by the results of optical and electrical characterization methods. Finally, CZT detectors have been processed from the grown part of the different crystals. The influence of dewetting on their performance will be studied by means of the detector measurements with X- and Gamma-ray sources

Characterization of Structural Defects in (Cd,Zn)Te Crystals Grown by the Travelling Heater Method

Structural defects and compositional uniformity remain the major problems affecting the performance of (Cd, Zn)Te (CZT) based detector devices. Understanding the mechanism of growth and defect formation is therefore fundamental to improving the crystal quality. In this frame, space experiments for the growth of CZT by the Travelling Heater Method (THM) under microgravity are scheduled. A detailed ground-based program was performed to determine experimental parameters and three CZT crystals were grown by the THM. The structural defects, compositional homogeneity and resistivity of these ground-based crystals were investigated. A ZnTe content variation was observed at the growth interface and a high degree of stress associated with extensive dislocation networks was induced, which propagated into the grown crystal region according to the birefringence and X-ray White Beam Topography (XWBT) results. By adjusting the growth parameters, the ZnTe variations and the resulting stress were efficiently reduced. In addition, it was revealed that large inclusions and grain boundaries can generate a high degree of stress, leading to the formation of dislocation slip bands and subgrain boundaries. The dominant defects, including grain boundaries, dislocation networks and cracks in the interior of crystals, led to the resistivity variation in the crystals. The bulk resistivity of the as-grown crystals ranged from 109 Ωcm to 1010 Ωcm

Modulation of neutrophil activity by soluble complement cleavage products — an in-depth analysis

The cellular and fluid phase-innate immune responses of many diseases predominantly involve activated neutrophil granulocytes and complement factors. However, a comparative systematic analysis of the early impact of key soluble complement cleavage products, including anaphylatoxins, on neutrophil granulocyte function is lacking. Neutrophil activity was monitored by flow cytometry regarding cellular (electro-)physiology, cellular activity, and changes in the surface expression of activation markers. The study revealed no major effects induced by C3a or C4a on neutrophil functions. By contrast, exposure to C5a or C5a des-Arg stimulated neutrophil activity as reflected in changes in membrane potential, intracellular pH, glucose uptake, and cellular size. Similarly, C5a and C5a des-Arg but no other monitored complement cleavage product enhanced phagocytosis and reactive oxygen species generation. C5a and C5a des-Arg also altered the neutrophil surface expression of several complement receptors and neutrophil activation markers, including C5aR1, CD62L, CD10, and CD11b, among others. In addition, a detailed characterization of the C5a-induced effects was performed with a time resolution of seconds. The multiparametric response of neutrophils was further analyzed by a principal component analysis, revealing CD11b, CD10, and CD16 to be key surrogates of the C5a-induced effects. Overall, we provide a comprehensive insight into the very early interactions of neutrophil granulocytes with activated complement split products and the resulting neutrophil activity. The results provide a basis for a better and, importantly, time-resolved and multiparametric understanding of neutrophil-related (patho-)physiologies

Overview of GaAs und CdTe Pixel Detectors Using Medipix Electronics

GaAs and CdTe pixel detectors have been developed over the last few decades. The applications of these detectors include X- and gamma-ray detectors working at room temperature. Fundamental properties such as detection efficiency and noise are determined by the material properties of the sensor material. Different materials have been evaluated over the years in search of the best choice for different types of radiation. This article describes the properties of GaAs and CdTe materials for single photon processing pixel detectors using the Medipix electronics.

Block of Voltage-Gated Sodium Channels by Aripiprazole in a State-Dependent Manner

Aripiprazole is an atypical antipsychotic drug, which is prescribed for many psychiatric diseases such as schizophrenia and mania in bipolar disorder. It primarily acts as an agonist of dopaminergic and other G-protein coupled receptors. So far, an interaction with ligand- or voltage-gated ion channels has been classified as weak. Meanwhile, we identified aripiprazole in a preliminary test as a potent blocker of voltage-gated sodium channels. Here, we present a detailed analysis about the interaction of aripiprazole with the dominant voltage-gated sodium channel of heart muscle (hNav1.5). Electrophysiological experiments were performed by means of the patch clamp technique at human heart muscle sodium channels (hNav1.5), heterologously expressed in human TsA cells. Aripiprazole inhibits the hNav1.5 channel in a state- but not use-dependent manner. The affinity for the resting state is weak with an extrapolated Kr of about 55 µM. By contrast, the interaction with the inactivated state is strong. The affinities for the fast and slow inactivated state are in the low micromolar range (0.5–1 µM). Kinetic studies indicate that block development for the inactivated state must be described with a fast (ms) and a slow (s) time constant. Even though the time constants differ by a factor of about 50, the resulting affinity constants were nearly identical (in the range of 0.5 µM). Besides this, aripirazole also interacts with the open state of the channel. Using an inactivation deficit mutant, an affinity of about 1 µM was estimated. In summary, aripiprazole inhibits voltage-gated sodium channels at low micromolar concentrations. This property might add to its possible anticancer and neuroprotective properties