A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.     

Dynamic probe of ZnTe(110) surface by scanning tunneling microscopy

The reconstructed surface structure of the II–VI semiconductor ZnTe (110), which is a promising material in the research field of semiconductor spintronics, was studied by scanning tunneling microscopy/spectroscopy (STM/STS). First, the surface states formed by reconstruction by the charge transfer of dangling bond electrons from cationic Zn to anionic Te atoms, which are similar to those of IV and III–V semiconductors, were confirmed in real space. Secondly, oscillation in tunneling current between binary states, which is considered to reflect a conformational change in the topmost Zn–Te structure between the reconstructed and bulk-like ideal structures, was directly observed by STM. Third, using the technique of charge injection, a surface atomic structure was successfully fabricated, suggesting the possibility of atomic-scale manipulation of this widely applicable surface of ZnTe.     

Distribution of carbon contamination in MgAl2O4 spinel occurring during spark-plasma-sintering (SPS) processing: I – Effect of heating rate and post-annealing

Carbon contamination from the carbon paper/dies during spark-plasma-sintering (SPS) processing was examined in the MgAl₂O₄ spinel. The carbon contamination sensitively changes with the heating rate during the SPS processing. At the high heating rate of 100 °C/min, the carbon contamination having organized structures occurred over almost the entire area from the surface to deep inside the SPSed spinel disk. In contrast, at the slow heating rate of 10 °C/min, the carbon contamination having disordered structures occurred only around the surface area. The carbon phases transform into high pressure CO/CO₂ gases by post-annealing in air and lead to pore formation along the grain junctions. The pore formation significantly occurs at the high heating rate due to the large amount of the contaminant carbon phases. This suggests that if once the carbon contamination was formed in the materials, it is very difficult to remove the carbon phases from the materials.     

Matrix influence on the piezoelectric properties of piezoelectric ceramic/polymer composite exhibiting particle alignment

This study was addressed to the influence of an electric field strength applied at fabrication process and matrix properties, such as the dielectric constant and the Young's modulus, on “pseudo‐1‐3 piezoelectric ceramic/polymer composite” in order to further enhance the piezoelectricity of that. The pseudo‐1‐3 piezoelectric ceramic/polymer composite consists of linearly ordered piezoelectric ceramic particles in polymer material. Silicone gel, silicone rubber, urethane rubber, and poly‐methyl‐methacrylate, which exhibit different dielectric constants and Young's modulus, were used as matrices to evaluate the matrix influence. The piezoelectricity of the pseudo‐1‐3 piezoelectric ceramic/polymer composite was evaluated using the piezoelectric strain constant d₃₃. The d₃₃ is one of the indices of the piezoelectric properties for piezoelectric materials. As a result, it was confirmed that d₃₃ of the pseudo‐1‐3 piezoelectric ceramic/polymer composite increased with the increase of the electric filed strength applied at fabrication process, though, it reached a constant value at a certain strength value. Further it was confirmed that dielectric constant of the matrix had a small influence on d₃₃ of the pseudo‐1‐3 piezoelectric ceramic/polymer composite, however, in case of matrix of lower Young's modulus, d₃₃ was increase. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41817.     

Serum vanadium levels in chronic hemodialysis patients

Serum vanadium, aluminum, silicon and beta 2-microglobulin levels as well as the red cell count, hemoglobin and systolic blood pressure were simultaneously measured in 80 chronic hemodialysis patients. The serum vanadium level was positively correlated with the serum levels of aluminum, silicon and beta 2-microglobulin as well as the systolic blood pressure, and was inversely correlated with the red cell count and hemoglobin. The mean serum vanadium level was 18.4 +/- 7.6 ng/ml before hemodialysis and decreased to 13.0 +/- 5.30 ng/ml at the completion of dialysis. The dialysate vanadium level increased from 0.4 +/- 0.2 (inflow) to 1.0 +/- 0.4 ng/ml (outflow). It was concluded that vanadium was transferred from blood to dialysate when purified water was used in the preparation of the dialysate.     

Estramustine and estrone analogs rapidly and reversibly inhibit deoxyribonucleic acid synthesis and alter morphology in cultured human glioblastoma cells

Estramustine is an estradiol-based agent that has been shown to accumulate in human glioma cells, resulting in a concentration-dependent alteration in cell size and shape within minutes and an inhibition of proliferation over 3 to 6 days. We evaluated human glioblastoma cultures with [3H]thymidine incorporation assays to determine estramustine's early effects on deoxyribonucleic acid synthesis in these tumors. Because estramustine shares a common structural motif with other antimicrotubule drugs, we synthesized four A-ring conjugates of estrone that contained a carbamate moiety but lacked nitrogen mustard. These analogs were examined by [3H]thymidine incorporation and compared with vinblastine. Greater than 70% inhibition of [3H]thymidine incorporation occurred within 1 hour of treatment with estramustine at 10(-5) mol/L, which increased to 80% inhibition at 4 hours. Ethyl carbamate JE208 was nearly as effective as estramustine in inhibiting deoxyribonucleic acid synthesis, and both were more effective than vinblastine. The inhibitory effects of estramustine and estrone analogs were reversible; vinblastine was not reversible. Although estramustine and JE208 induced similar antiproliferative and morphological changes in glioblastoma cells that persisted for at least 4 days, there was a modest recovery of morphology and thymidine incorporation with JE208 after prolonged treatment. The common findings with estramustine and JE208 suggest that these agents may have a similar mechanism of action and form the basis for the investigation of new agents that may rapidly and reversibly inhibit glioblastoma.