Long-term, stable, targeted biodelivery and efficacy of GDNF from encapsulated cells in the rat and Goettingen miniature pig brain

Delivering glial cell line-derived neurotrophic factor (GDNF) to the brain is a potential treatment for Parkinson'sDisease (PD). Here we use an implantable encapsulated cell technology that uses modified human clonal ARPE-19cells to deliver of GDNF to the brain. In vivostudies demonstrated sustained delivery of GDNF to the rat striatumover 6 months. Anatomical benefits and behavioral efficacy were shown in 6-OHDA lesioned rats where nigraldopaminergic neurons were preserved in neuroprotection studies and dopaminergicfibers were restored inneurorecovery studies. When larger, clinical-sized devices were implanted for 3 months into the putamen ofG\u20acottingen minipigs, GDNF was widely distributed throughout the putamen and caudate producing a significantupregulation of tyrosine hydroxylase immunohistochemistry. These results are thefirst to provide clear evidencethat implantation of encapsulated GDNF-secreting cells deliver efficacious and biologically relevant amounts ofGDNF in a sustained and targeted manner that is scalable to treat the large putamen in patients with Parkinson'sdiseas

Restructuring of supported Pd by green solvents: an operando Quick EXAFS (QEXAFS) study and implications for the derivation of structure-function relationships in Pd catalysis

Transmission electron microscopy (TEM) is commonly used as an ex-situ technique to determine structural changes by comparing images of catalyst particles before and after a reaction. This requires the use of an alcoholic solvent to disperse the particles on a grid. In this work, we will show that Pd catalysts can be transformed during the procedure, by using EXAFS to determine the structure of Pd catalysts in different environments (as dry or wet samples). Supported palladium nanoparticles exposed to aqueous ethanolic solution (50% w/v) are transformed to a common, reduced, and hydrogen-contaminated state, irrespective of their initial habit or support. Catalysts comprised of nanosize PdO are reduced at ca. 350 K, whereas samples comprised of very small (ca. ≤ 10 atoms) Pd particles react with the solvent at just above room temperature and agglomerating with considerable loss of dispersion. As such any potential benefits to catalysis sought through the synthesis of very highly dispersed metallic Pd supported upon a range of inorganic dispersants will be rapidly erased through the action of such solvents

Effect of retained chlorine in ENCAT™ 30 catalysts on the development of encapsulated Pd: insights from in situ Pd K, L₃ and Cl K-edge XAS

In situ X-ray absorption spectroscopy (XAS) and Pd K, LIII, and Cl K-edges shows that Cl can be present in significant amounts in ENCAT™ 30 catalysts and that it can severely retard Pd nanoparticle (NP) development in flowing solvents. We also show that whilst polymeric encapsulation protects the Pd against solvent induced agglomeration of Pd nanoparticles the evidence suggests it does not prevent the formation PdHx through reaction with the aqeous ethanol solvent, and that, as received, ENCAT™ 30 NP catalysts are not, for the most part, comprised of nanoparticulate Pd0 irrespective of the presence of Cl

The Ly-alpha profile and center-to-limb variation of the quiet Sun

We study the emission of the hydrogen Lyman-a line in the quiet Sun, its center-to-limb variation (CLV), and its radiance distribution. We also compare quasi-simultaneous Ly-a and Ly-b line profiles. We used the high spectral and spatial resolution of the SUMER spectrometer and completed raster scans at various locations along the disk. For the first time, we used a method to reduce the incoming photon flux to a 20%-level by partly closing the aperture door. We also performed a quasi-simultaneous observation of both Ly-a and Ly-b at Sun center in sit-and-stare mode. We infer the flow characteristic in the Ly-a map from variations in the calibrated 1206 Si III line centroids. We present the average profile of Ly-a, its radiance distribution, its CLV behaviour, and the signature of flows on the line profiles. Little CLV and no limb brightening are observed in the profiles of the Ly-a line. In contrast to all other lines of the Lyman series, which have a stronger red-horn, Ly-a has a dominating blue-horn asymmetry. There appears to be a brightness-to-asymmetry relationship. A similar and even clearer trend is observed in the downflow-to-asymmetry relationship. This important result is consistent with predictions from models that include flows. However, the absence of a clear CLV in the profiles may be more indicative of an isotropic field than a radial flow. It appears that the ubiquitous hydrogen behaves similar to a filter that dampens all signatures of the line formation by processes in the chromosphere and transition region.Comment: 4 pages, 4 figure

Crystallographic Phase Transition and High-Tc Superconductivity in LaFeAsO:F

Undoped LaFeAsO, parent compound of the newly found high-Tc superconductor, exhibits a sharp decrease in the temperature-dependent resistivity at ~160 K. The anomaly can be suppressed by F doping and the superconductivity appears correspondingly, suggesting a close associate of the anomaly with the superconductivity. We examined the crystal structures, magnetic properties and superconductivity of undoped (normal conductor) and 14 at.% F-doped LaFeAsO (Tc = 20 K) by synchrotron X-ray diffraction, DC magnetic measurements, and ab initio calculations to demonstrate that the anomaly is associated with a phase transition from tetragonal (P4/nmm) to orthorhombic (Cmma) phases at ~160 K as well as an antiferromagnetic transition at ~140 K. These transitions can be explained by spin configuration-dependent potential energy surfaces derived from the ab initio calculations. The suppression of the transitions is ascribed to interrelated effects of geometric and electronic structural changes due to doping by F- ions.Comment: 22 pages, 8 figures, 2 tables, Supplementary information is included at the end of the document, accepted for publication in Supercond. Sci. Techno

Metabolically stable bradykinin B2 receptor agonists enhance transvascular drug delivery into malignant brain tumors by increasing drug half-life

<p>Abstract</p> <p>Background</p> <p>The intravenous co-infusion of labradimil, a metabolically stable bradykinin B2 receptor agonist, has been shown to temporarily enhance the transvascular delivery of small chemotherapy drugs, such as carboplatin, across the blood-brain tumor barrier. It has been thought that the primary mechanism by which labradimil does so is by acting selectively on tumor microvasculature to increase the local transvascular flow rate across the blood-brain tumor barrier. This mechanism of action does not explain why, in the clinical setting, carboplatin dosing based on patient renal function over-estimates the carboplatin dose required for target carboplatin exposure. In this study we investigated the systemic actions of labradimil, as well as other bradykinin B2 receptor agonists with a range of metabolic stabilities, in context of the local actions of the respective B2 receptor agonists on the blood-brain tumor barrier of rodent malignant gliomas.</p> <p>Methods</p> <p>Using dynamic contrast-enhanced MRI, the pharmacokinetics of gadolinium-diethyltriaminepentaacetic acid (Gd-DTPA), a small MRI contrast agent, were imaged in rodents bearing orthotopic RG-2 malignant gliomas. Baseline blood and brain tumor tissue pharmacokinetics were imaged with the 1^stbolus of Gd-DTPA over the first hour, and then re-imaged with a 2^ndbolus of Gd-DTPA over the second hour, during which normal saline or a bradykinin B2 receptor agonist was infused intravenously for 15 minutes. Changes in mean arterial blood pressure were recorded. Imaging data was analyzed using both qualitative and quantitative methods.</p> <p>Results</p> <p>The decrease in systemic blood pressure correlated with the known metabolic stability of the bradykinin B2 receptor agonist infused. Metabolically stable bradykinin B2 agonists, methionine-lysine-bradykinin and labradimil, had differential effects on the transvascular flow rate of Gd-DTPA across the blood-brain tumor barrier. Both methionine-lysine-bradykinin and labradimil increased the blood half-life of Gd-DTPA sufficiently enough to increase significantly the tumor tissue Gd-DTPA area under the time-concentration curve.</p> <p>Conclusion</p> <p>Metabolically stable bradykinin B2 receptor agonists, methionine-lysine-bradykinin and labradimil, enhance the transvascular delivery of small chemotherapy drugs across the BBTB of malignant gliomas by increasing the blood half-life of the co-infused drug. The selectivity of the increase in drug delivery into the malignant glioma tissue, but not into normal brain tissue or skeletal muscle tissue, is due to the inherent porous nature of the BBTB of malignant glioma microvasculature.</p

The Structure and Dynamics of the Upper Chromosphere and Lower Transition Region as Revealed by the Subarcsecond VAULT Observations

The Very high Angular resolution ULtraviolet Telescope (VAULT) is a sounding rocket payload built to study the crucial interface between the solar chromosphere and the corona by observing the strongest line in the solar spectrum, the Ly-a line at 1216 {\AA}. In two flights, VAULT succeeded in obtaining the first ever sub-arcsecond (0.5") images of this region with high sensitivity and cadence. Detailed analyses of those observations have contributed significantly to new ideas about the nature of the transition region. Here, we present a broad overview of the Ly-a atmosphere as revealed by the VAULT observations, and bring together past results and new analyses from the second VAULT flight to create a synthesis of our current knowledge of the high-resolution Ly-a Sun. We hope that this work will serve as a good reference for the design of upcoming Ly-a telescopes and observing plans.Comment: 28 pages, 11 figure

Qualitative XANES and XPS Analysis of Substrate Effects in VO2 Thin Films: A Route to Improving Chemical Vapor Deposition Synthetic Methods?

Vanadium(IV) oxide thin films were synthesized via atmospheric pressure chemical vapor deposition by the reaction between vanadium(IV) chloride and ethyl acetate at 550 °C. The substrate was varied with films being deposited on glass, SnO2, and F-doped SnO2. The films were characterized by X-ray diffraction, X-ray photoelectron spectroscopy, UV–vis spectroscopy, scanning electron microscopy, and X-ray absorption near-edge structure. The influence of the electronic contribution of the substrate on the deposited VO2 film was found to be key to the functional properties observed. Highly electron-withdrawing substituents, such as fluorine, favored the formation of V5+ ions in the crystal lattice and so reduced the thermochromic properties. By considering both the structural and electronic contributions of the substrate, it is possible to establish the best substrate choices for the desired functional properties of the VO2 thin films synthesized

Pd-LaFeO3 catalysts in aqueous ethanol: Pd reduction, leaching, and structural transformations in the presence of a base

The reactive behavior of three catalysts based on Pd-loaded LaFeO3 was investigated in terms of the reducibility of Pd and its propensity to leaching into the liquid phase in flowing solutions prototypical of C–C coupling catalysis in a continuous flow reactor cell. In situ quick extended X-ray absorption fine structure spectroscopy showed that Pd remains stable and nonreducible in the flowing ethanol/water solvent mixture under heating to 353 K. However, ex situ transmission electron microscopy, high-energy X-ray diffraction, and fluorescence yield Fe K-edge X-ray absorption near-edge structure show that the addition of a significant amount of base (K2CO3, 0.1 M) results in the structural degradation of the perovskite support as well as the mobilization of Pd along the sample bed that is dependent on the structure and crystallite size of the perovskite. The results are discussed in terms of the use of perovskite-type oxides in various areas of research where they are placed in contact with liquid phases of variable temperature and elevated pH