MLN51 and GM-CSF involvement in the proliferation of fibroblast-like synoviocytes in the pathogenesis of rheumatoid arthritis

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease of unclear etiology. This study was conducted to identify critical factors involved in the synovial hyperplasia in RA pathology. We applied cDNA microarray analysis to profile the gene expressions of RA fibroblast-like synoviocytes (FLSs) from patients with RA. We found that the MLN51 (metastatic lymph node 51) gene, identified in breast cancer, is remarkably upregulated in the hyperactive RA FLSs. However, growth-retarded RA FLSs passaged in vitro expressed small quantities of MLN51. MLN51 expression was significantly enhanced in the FLSs when the growth-retarded FLSs were treated with granulocyte – macrophage colony-stimulating factor (GM-CSF) or synovial fluid (SF). Anti-GM-CSF neutralizing antibody blocked the MLN51 expression even though the FLSs were cultured in the presence of SF. In contrast, GM-CSF in SFs existed at a significant level in the patients with RA (n = 6), in comparison with the other inflammatory cytokines, IL-1β and TNF-α. Most RA FLSs at passage 10 or more recovered from their growth retardation when cultured in the presence of SF. The SF-mediated growth recovery was markedly impaired by anti-GM-CSF antibody. Growth-retarded RA FLSs recovered their proliferative capacity after treatment with GM-CSF in a dose-dependent manner. However, MLN51 knock-down by siRNA completely blocked the GM-CSF/SF-mediated proliferation of RA FLSs. Taken together, our results imply that MLN51, induced by GM-CSF, is important in the proliferation of RA FLSs in the pathogenesis of RA

Identification and Characterization of a Dual-Acting Antinematodal Agent against the Pinewood Nematode, Bursaphelenchus xylophilus

The pinewood nematode (PWN), Bursaphelenchus xylophilus, is a mycophagous and phytophagous pathogen responsible for the current widespread epidemic of the pine wilt disease, which has become a major threat to pine forests throughout the world. Despite the availability of several preventive trunk-injection agents, no therapeutic trunk-injection agent for eradication of PWN currently exists. In the characterization of basic physiological properties of B. xylophilus YB-1 isolates, we established a high-throughput screening (HTS) method that identifies potential hits within approximately 7 h. Using this HTS method, we screened 206 compounds with known activities, mostly antifungal, for antinematodal activities and identified HWY-4213 (1-n-undecyl-2-[2-fluorphenyl] methyl-3,4-dihydro-6,7-dimethoxy-isoquinolinium chloride), a highly water-soluble protoberberine derivative, as a potent nematicidal and antifungal agent. When tested on 4 year-old pinewood seedlings that were infected with YB-1 isolates, HWY-4213 exhibited a potent therapeutic nematicidal activity. Further tests of screening 39 Caenorhabditis elegans mutants deficient in channel proteins and B. xylophilus sensitivity to Ca2+ channel blockers suggested that HWY-4213 targets the calcium channel proteins. Our study marks a technical breakthrough by developing a novel HTS method that leads to the discovery HWY-4213 as a dual-acting antinematodal and antifungal compound

Phase stability of a microtron driving a terahertz FEL

The phase stability of bunches accelerated by a magnetron-driven microtron-injector of a terahertz Free Electron Laser (FEL) has been studied to optimize the microtron regimes providing good operation of the FEL. The study is based on a simulation of the beam dynamics in the microtron considering 2-D motion of the electrons in the median plane. This allows the computation of the current loading the accelerating cavity as well as the output microtron current. The loading current has been used to calculate the frequency deviations caused by the incremental loading in the accelerating cavity coupled with the magnetron. Further computations using the 2-D simulation show noticeable phase oscillation of the accelerated bunch leaving the microtron on the macro-pulse front. The phase oscillation is in agreement with the measured one and affects the lasing in the microtron-based FEL. Optimization of the microtron regimes allows one to minimize the effect. As a result, the terahertz microtron-based FEL provides radiated macro-pulse energy up to 0.2 mJ tunable in the range of 0.85-3 THz with good stability. Results of the simulation and the measurements are presented in this article

Intrinsically Stretchable Three Primary Light-Emitting Films Enabled By Elastomer Blend For Polymer Light-Emitting Diodes

Intrinsically stretchable light-emitting materials are crucial for skin-like wearable displays; however, their color range has been limited to green-like yellow lights owing to the restricted stretchable light-emitting materials (super yellow series materials). To develop skin-like full-color displays, three intrinsically stretchable primary light-emitting materials [red, green, and blue (RGB)] are essential. In this study, we report three highly stretchable primary light-emitting films made from a polymer blend of conventional RGB light-emitting polymers and a nonpolar elastomer. The blend films consist of multidimensional nanodomains of light-emitting polymers that are interconnected in an elastomer matrix for efficient light-emitting under strain. The RGB blend films exhibited over 1000 cd/m2 luminance with low turn-on voltage (Von) and the selectively stretched blend films on rigid substrate maintained stable light-emitting performance up to 100% strain even after 1000 multiple stretching cycles

Integrative genome-scale metabolic analysis of Vibrio vulnificus for drug targeting and discovery

Chromosome 1 of Vibrio vulnificus tends to contain larger portion of essential or housekeeping genes on the basis of the genomic analysis and gene knockout experiments performed in this study, while its chromosome 2 seems to have originated and evolved from a plasmid.The genome-scale metabolic network model of V. vulnificus was reconstructed based on databases and literature, and was used to identify 193 essential metabolites.Five essential metabolites finally selected after the filtering process are 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine (AHHMP), D-glutamate (DGLU), 2,3-dihydrodipicolinate (DHDP), 1-deoxy-D-xylulose 5-phosphate (DX5P), and 4-aminobenzoate (PABA), which were predicted to be essential in V. vulnificus, absent in human, and are consumed by multiple reactions.Chemical analogs of the five essential metabolites were screened and a hit compound showing the minimal inhibitory concentration (MIC) of 2 μg/ml and the minimal bactericidal concentration (MBC) of 4 μg/ml against V. vulnificus was identified

Clinical Experience of an Iontophoresis Based Glucose Measuring System

Currently finger pricking is the common method of blood glucose measurement in patients with diabetes mellitus. However, diabetes patients have proven to be reluctant to check their glucose profiles regularly because of the discomfort associated with this technique. Recently, a non-invasive and continuous Reverse Iontophoresis based Glucose Monitoring Device (RIGMD) was developed in Korea. The study was conducted during the period November 2003-January 2004 on 19 in-patients. Glucose measurements were performed using RIGMD between 10 a.m. and 4 p.m. Concurrent plasma glucose levels were checked hourly and subsequently compared with RIGMD data. The mean error of RIGMD measurements was -3.45±52.99 mg/dL with a mean absolute relative error of 20±15.16%. Measurements obtained by RIGMD were correlated with plasma glucose levels (correlation coefficient; 0.784 (p<0.05)) and this correlation was independent of time of data collection. However, after excluding confounding variables this correlation coefficient exhibited a tendency to increase. 98.9% of the results were clinically acceptable by Clarke error grid analysis. We concluded that RIGMD does not have the reliability and accuracy required to wholly replace conventional methods. However, further technical advancements that reduce its shortcomings would make this device useful for the management of diabetes