AAD-2004, a potent spin trapping molecule and microsomal prostaglandin E synthase-1 inhibitor, shows safety and efficacy in a mouse model of ALS

While free radicals and inflammation constitute major routes of neuronal injury occurring in neurodegenerative diseases, neither antioxidants nor nonsteroidal anti-inflammatory drugs (NSAIDs) have shown significant efficacy in human clinical trials. To explore the possibility that concurrent blockade of free radicals and PGE2-mediated inflammation might constitute a safe and effective therapeutic approach to certain neurodegenerative diseases, we have developed 2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobezoic acid (AAD-2004) as a derivative of aspirin. AAD-2004 completely removed free radicals at 50 nM as a potent spin trapping molecule and inhibited microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 230 nM. Oral administration of AAD-2004 blocked free radical formation, PGE2 formation, and microglial activation in the spinal motor neurons of SOD1G93A mice. As a consequence, AAD-2004 reduced autophagosome formation, axonopathy, and motor neuron degeneration, improving motor function and increasing life span. In these assays, AAD-2004 was superior to ibuprofen or riluzole. Gastric bleeding was not induced by AAD-2004 even at a dose 400-fold higher than that required to obtain maximal therapeutic efficacy in SOD1G93A mice. Targeting both mPGES-1 and free radicals may be a promising approach to reduce neurodegeneration in ALS and possibly other neurodegenerative diseases

PKCε-mediated ERK1/2 activation involved in radiation-induced cell death in NIH3T3 cells

AbstractProtein kinase C (PKC) isoforms play distinct roles in cellular functions. We have previously shown that ionizing radiation activates PKC isoforms (α, δ, ε, and ζ), however, isoform-specific sensitivities to radiation and its exact mechanisms in radiation mediated signal transduction are not fully understood. In this study, we showed that overexpression of PKC isoforms (α, δ, ε, and ζ) increased radiation-induced cell death in NIH3T3 cells and PKCε overexpression was predominantly responsible. In addition, PKCε overexpression increased ERK1/2 activation without altering other MAP-kinases such as p38 MAPK or JNK. Co-transfection of dominant negative PKCε (PKCε-KR) blocked both PKCε-mediated ERK1/2 activation and radiation-induced cell death, while catalytically active PKCε construction augmented these phenomena. When the PKCε overexpressed cells were pretreated with PD98059, MEK inhibitor, radiation-induced cell death was inhibited. Co-transfection of the cells with a mutant of ERK1 or -2 (ERK1-KR or ERK2-KR) also blocked these phenomena, and co-transfection with dominant negative Ras or Raf cDNA revealed that PKCε-mediated ERK1/2 activation was Ras–Raf-dependent. In conclusion, PKCε-mediated ERK1/2 activation was responsible for the radiation-induced cell death

Eco-Friendly Synthesis of Water-Glass-Based Silica Aerogels via Catechol-Based Modifier

Silica aerogels have attracted much attention owing to their excellent thermal insulation properties. However, the conventional synthesis of silica aerogels involves the use of expensive and toxic alkoxide precursors and surface modifiers such as trimethylchlorosilane. In this study, cost-effective water-glass silica aerogels were synthesized using an eco-friendly catechol derivative surface modifier instead of trimethylchlorosilane. Polydopamine was introduced to increase adhesion to the SiO2 surface. The addition of 4-tert-butyl catechol and hexylamine imparted hydrophobicity to the surface and suppressed the polymerization of the polydopamine. After an ambient pressure drying process, catechol-modified aerogel exhibited a specific surface area of 377 m(2)/g and an average pore diameter of approximately 21 nm. To investigate their thermal conductivities, glass wool sheets were impregnated with catechol-modified aerogel. The thermal conductivity was 40.4 mWm(-1)K(-1), which is lower than that of xerogel at 48.7 mWm(-1)K(-1). Thus, by precisely controlling the catechol coating in the mesoporous framework, an eco-friendly synthetic method for aerogel preparation is proposed

Evaluation of an immunochromatographic assay for the detection of anti-hepatitis A virus IgM

<p>Abstract</p> <p>Background</p> <p>Hepatitis A virus (HAV) is a causative agent of acute hepatitis, which is transmitted by person-to-person contact and via the faecal-oral route. Acute HAV infection is usually confirmed by anti-HAV IgM detection. In order to detect anti-HAV IgM in the serum of patients infected with HAV, we developed a rapid assay based on immunochromatography (ICA) and evaluated the sensitivity of this assay by comparing it with a commercial microparticle enzyme immunoassay (MEIA) that is widely used for serological diagnosis.</p> <p>Results</p> <p>The newly developed ICA showed 100% sensitivity and specificity when used to test 150 anti-HAV IgM-positive sera collected from infected patients and 75 negative sera from healthy subjects. Also, the sensitivity of ICA is about 10 times higher than MEIA used in this study by determining end point to detect independent on infected genotype of HAV. In addition, the ICA was able to detect 1 positive sample from among 50 sera from acute hepatitis patients that had tested negative for anti-HAV IgM using the MEIA.</p> <p>Conclusion</p> <p>Conclusively, ICA for the detection of anti-HAV IgM will be very effective for rapid assay to apply clinical diagnosis and epidemiological investigation on epidemics due to the simplicity, rapidity and specificity.</p

Echovirus 30 Induced Neuronal Cell Death through TRIO-RhoA Signaling Activation

BACKGROUND: Echovirus 30 (Echo30) is one of the most frequently identified human enteroviruses (EVs) causing aseptic meningitis and encephalitis. However the mechanism underlying the pathogenesis of Echo30 infection with significant clinical outcomes is not completely understood. The aim of this investigation is to illustrate molecular pathologic alteration in neuronal cells induced by Echo30 infection using clinical isolate from young patient with neurologic involvement. METHODOLOGY/PRINCIPAL FINDINGS: To characterize the neuronal cellular response to Echo30 infection, we performed a proteomic analysis based on two-dimensional gel electrophoresis (2-DE) and MALDI-TOF/TOF Mass Spectrophotometric (MS) analysis. We identified significant alteration of several protein expression levels in Echo30-infected SK-N-SH cells. Among these proteins, we focused on an outstanding up-regulation of Triple functional domain (TRIO) in Echo30-infected SK-N-SH cells. Generally, TRIO acts as a key component in the regulation of axon guidance and cell migration. In this study, we determined that TRIO plays a role in the novel pathways in Echo30 induced neuronal cell death. CONCLUSIONS/SIGNIFICANCE: Our finding shows that TRIO plays a critical role in neuronal cell death by Echo30 infection. Echo30 infection activates TRIO-guanine nucleotide exchange factor (GEF) domains (GEFD2) and RhoA signaling in turn. These results suggest that Echo30 infection induced neuronal cell death by activation of the TRIO-RhoA signaling. We expect the regulation of TRIO-RhoA signaling may represent a new therapeutic approach in treating aseptic meningitis and encephalitis induced by Echo30

Anatomic variations of the T2 nerve root (including the nerve of Kuntz) and their implications for sympathectomy

AbstractObjective: The aim of this study was to clarify the anatomic variations of the intrathoracic nerve of Kuntz, and this should help delineate the resection margins during video-assisted thoracic sympathectomy. Methods: Sixty-six thoracic sympathetic chains of 39 adult Korean cadavers were dissected on both sides of the thorax in 27 cadavers (54 sides) and on one side in 12 cadavers (12 sides). Results: The intrathoracic nerve was observed in 45 (68.2%) sides and was present bilaterally in 48.1% of cadavers. No intrathoracic nerve or ascending ramus communicans arising from the second thoracic nerve was observed in only 5 (7.6%) sides. The diameter of the intrathoracic nerve was 1.25 ± 0.55 mm on average. The arising point of the intrathoracic nerve from the second thoracic nerve was 7.3 mm on average from the sympathetic trunk. Presence of the stellate ganglion was noted in 56 (84.8%) sides, and 6 (9.1%) sides showed a single large ganglion formed by the stellate and the second thoracic sympathetic ganglia. The second thoracic sympathetic ganglion was most commonly located (50%) in the second intercostal space. Conclusion: The anatomic variations of the intrathoracic nerve of Kuntz and the second thoracic sympathetic ganglion were characterized in human cadavers. It is hoped that this study will help to improve the recurrence of symptoms caused by the intrathoracic nerve in an upper thoracic sympathectomy for hyperhidrosis.J Thorac Cardiovasc Surg 2002;123:498-50

Position and Thickness Optimization of Ribs for Ventilation Covering Using the Micro Genetic Algorithm with an Interpolated Smooth Objective Function

Structures with supporting ribs are adopted in many fields of engineering. These ribs are attached to the main plate or shell to increase stiffness and reduce the stresses of a structure. Currently, much research in structural optimization has been devoted to size or thickness optimizations. In this study, the discrete positions of the ribs of a structure are optimized in addition to their thicknesses. The objective function, which is the total weight of a structure, is a continuous function with respect to the thickness of the ribs. However, it is a stepwise function of a dimensionless variable, which represents the set of positions of the ribs. Because of this stepwise objective function, the gradient method of optimization is not applicable. Therefore, we applied the micro genetic algorithm (MGA), which does not need derivatives of the objective function. To accelerate the rate of convergence, the stepwise objective function is interpolated to a smooth artificial objective function that does not alter the optimal solution

Inactivation Patterns of p16/INK4A in Oral Squamous Cell Carcinomas

The p16/INK4A is one of the major target genes in carcinogenesis and its inactivation has frequently been reported in other types of tumors. The purpose of this study is to evaluate inactivation patterns of p16/INK4A in oral squamous cell carcinoma. Six different oral cancer cell lines, SCC-4, SCC-9, SCC-15, SCC-25, KB, and SNUDH- 379 were examined for inactivation of p16/INK4A genes. In the analysis of p16/INK4A gene inactivation, PCR amplification, direct sequencing, and methylation-specific PCR methods were adopted for evaluation of homozygous deletion, point mutation, and promoter hypermethylation, respectively. Homozygous deletion was detected in SCC-25 and SCC-9. SCC-15 showed hypermethylated promoter region within p16/INK4A gene. It is suggestive in the present study that inactivation patterns of p16/INK4A were mainly homozygous deletion, promoter methylation rather than point mutation in oral squamous cancer cell lines, so treatment modalities of oral squamous cell carcinoma should be focused on these types of inactivation