Evaluation of the pathogenicity of GJB3 and GJB6 variants associated with nonsyndromic hearing loss

AbstractA number of genes responsible for hearing loss are related to ion recycling and homeostasis in the inner ear. Connexins (Cx26 encoded by GJB2, Cx31 encoded by GJB3 and Cx30 encoded by GJB6) are core components of gap junctions in the inner ear. Gap junctions are intercellular communication channels and important factors that are associated with hearing loss. To date, a molecular genetics study of GJB3 and GJB6 as a causative gene for hearing loss has not been performed in Korea. This study was therefore performed to elucidate the genetic characteristics of Korean patients with nonsyndromic sensorineural hearing loss and to determine the pathological mechanism of hearing loss by analyzing the intercellular communication function of Cx30 and Cx31 variants. Sequencing analysis of the GJB3 and GJB6 genes in our population revealed a total of nine variants, including four novel variants in the two genes. Three of the novel variants (Cx31-p.V27M, Cx31-p.V43M and Cx-30-p.I248V) and two previously reported variants (Cx31-p.V84I and Cx30-p.A40V) were selected for functional studies using a pathogenicity prediction program and assessed for whether the mutations were located in a conserved region of the protein. The results of biochemical and ionic coupling tests showed that both the Cx31-p.V27M and Cx31-p.V84I variants did not function normally when each was expressed as a heterozygote with the wild-type Cx31. This study demonstrated that two variants of Cx31 were pathogenic mutations with deleterious effect. This information will be valuable in understanding the pathogenic role of GJB3 and GJB6 mutations associated with hearing loss

Diffusive Capture Process on Complex Networks

We study the dynamical properties of a diffusing lamb captured by a diffusing lion on the complex networks with various sizes of $N$. We find that the life time $of a lamb scales as \sim N$ and the survival probability $S(N\to \infty,t)$ becomes finite on scale-free networks with degree exponent $\gamma>3$. However, $S(N,t)$ for $\gamma<3$ has a long-living tail on tree-structured scale-free networks and decays exponentially on looped scale-free networks. It suggests that the second moment of degree distribution $is the relevant factor for the dynamical properties in diffusive capture process. We numerically find that the normalized number of capture events at a node with degree$k$,$n(k)$, decreases as$n(k)\sim k^{-\sigma}$. When$\gamma<3$,$n(k)$still increases anomalously for$k\approx k_{max}$. We analytically show that$n(k)$satisfies the relation$n(k)\sim k^2P(k)$and the total number of capture events$N_{tot}$is proportional to$, which causes the $\gamma$ dependent behavior of $S(N,t)$ and $.Comment: 9 pages, 6 figure

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

THE POSSIBILITY OF CLASSIFYING V1 AND V2 SUB-TECHNIQUES OF A SINGLE IMU SENSOR THROUGH COMPARISON OF MOTION-SPECIFIC DATA(PITCH, YAW AND ROLL ANGLE VALUES-ORIENTATION ANGLE VALUE) IN XC SKI

The purpose of this study is to confirm whether the single IMU sensor module(LGE developing and providing for the experiments) that attached to the pelvis can distinguish the motion of the sub-techniques (V1, V2, V2A) with the accuracy of commercial XSENS(equipment consisting of 17 sensors) in freestyle(skate) xc skiing. Therefore, one elite male xc skier with eleven years experience was investigated by measuring the three-directional rotation angle for each of the three sub-techniques used in XC ski freestyle. Through this method, we could found not only the difference of motion patterns of each sub-techniques but also the possibility for replacement of multiple sensor system by a single IMU sensor module from LGE. Thus, it is expected that a single LGE IMU sensor module could be applied to repetitive and periodic sports such as XC ski

Simultaneous Multi-Vessel Subacute Stent Thromboses in Zotarolimus-Eluting Stents

Despite its low incidence, stent thrombosis (ST) is one of the most dreaded complications of percutaneous coronary intervention. Endeavor (Medtronics Europe SA) is a new zotarolimus-eluting stent (ZES) with a favorable safety profile that was reported in early and ongoing trials. However, few lethal stent thromboses related to this new drug eluting stent (DES) have been reported. We experienced a case of simultaneous subacute ZES thromboses, 6 days after stent implantations in the proximal left anterior descending artery and the proximal right coronary artery (RCA)

Very Late Stent Thrombosis after Drug-Eluting Stent Implantation in a Patient without Aspirin and Clopidogrel Resistance

Very late stent thrombosis (VLST) after implantation of drug-eluting stent is rare, but very fatal complication after percutaneous coronary intervention. We report a case of VLST of a sirolimus-eluting Cypher™ stent (Cordis, Johnson and Johnson) presenting as acute ST elevation myocardial infarction at 26 months after deployment with continued combined dual antiplatelet medication of aspirin and clopidogrel. The patient did not show anti-platelet resistance

Cystamine induces AIF-mediated apoptosis through glutathione depletion

AbstractCystamine and its reduced form cysteamine showed protective effects in various models of neurodegenerative disease, including Huntington's disease and Parkinson's disease. Other lines of evidence demonstrated the cytotoxic effect of cysteamine on duodenal mucosa leading to ulcer development. However, the mechanism for cystamine cytotoxicity remains poorly understood. Here, we report a new pathway in which cystamine induces apoptosis by targeting apoptosis-inducing factor (AIF). By screening of various cell lines, we observed that cystamine and cysteamine induce cell death in a cell type-specific manner. Comparison between cystamine-sensitive and cystamine-resistant cell lines revealed that cystamine cytotoxicity is not associated with unfolded protein response, reactive oxygen species generation and transglutaminase or caspase activity; rather, it is associated with the ability of cystamine to trigger AIF nuclear translocation. In cystamine-sensitive cells, cystamine suppresses the levels of intracellular glutathione by inhibiting γ-glutamylcysteine synthetase expression that triggers AIF translocation. Conversely, glutathione supplementation completely prevents cystamine-induced AIF translocation and apoptosis. In rats, cysteamine administration induces glutathione depletion and AIF translocation leading to apoptosis of duodenal epithelium. These results indicate that AIF translocation through glutathione depletion is the molecular mechanism of cystamine toxicity, and provide important implications for cystamine in the neurodegenerative disease therapeutics as well as in the regulation of AIF-mediated cell death

The effect of alpha lipoic acid in a porcine in-stent restenosis model

SummaryBackgroundThe aim of this study was to investigate the effect of alpha lipoic acid (α-LA) on a porcine in-stent restenosis (ISR) model.MethodsIn protocol 1, porcine vascular smooth muscle cells (PVSMC) were stimulated by granulocyte-colony stimulating factor (G-CSF) in the presence or absence of α-LA. MTT (3-[4,5-dimethylthiazole-2-yl] 2,5-diphenyl tetrazolium bromide) assay and western blotting were used to determine the cell growth inhibitory rate and anti-inflammatory effect associated with nuclear factor-κb (NF-κb) and extracellular signal-regulated kinase (ERK). In protocol 2, 28 days after balloon overdilation injuries, 24 bare metal stents were placed in coronary artery of 12 pigs. The pigs were randomly divided to receive control diet with or without α-LA (100mg/kg). In protocol 3, 8 control stents and 8 α-LA coated stents were randomly implanted in 2 coronary arteries of 8 pigs and follow-up coronary angiogram and histopathologic assessment were performed 4 weeks after stenting.ResultsProtocol 1. The proliferation of PVSMC was inhibited and protein expression of NF-κb and ERK were attenuated by α-LA pretreatment. Protocol 2. On histopathologic analysis, the neointimal area (4.0±1.0mm2 vs. 1.5±0.7mm2, p<0.001) and histopathologic area of stenosis (66.7±10.7% vs. 24.2±9.7%, p<0.001) were reduced in the α-LA feeding group compared to controls. Protocol 3. On histopathologic analysis, the neointimal area (3.9±0.8mm2 vs. 1.0±0.4mm2, p<0.001), and the histopathologic area of stenosis (67.1±8.8% vs. 17.4±10.0%, p<0.001) were reduced in the α-LA coated stent group compared to the control stent group.Conclusionsα-LA feeding and α-LA coated stents inhibit neointimal hyperplasia in porcine ISR, possibly through inhibiting the activation of NF-κb pathway and proliferation of PVSMC