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Physiological changes in GTP levels in live cells have never been considered a regulatory step of RAC1 activation because intracellular GTP concentration (determined by chromatography or mass spectrometry) was shown to be substantially higher than the in vitro RAC1 GTP dissociation constant (RAC1-GTP Kd). Here, by combining genetically encoded GTP biosensors and a RAC1 activity biosensor, we demonstrated that GTP levels fluctuating around RAC1-GTP Kd correlated with changes in RAC1 activity in live cells. Furthermore, RAC1 co-localized in protrusions of invading cells with several guanylate metabolism enzymes, including rate-limiting inosine monophosphate dehydrogenase 2 (IMPDH2), which was partially due to direct RAC1-IMPDH2 interaction. Substitution of endogenous IMPDH2 with IMPDH2 mutants incapable of binding RAC1 did not affect total intracellular GTP levels but suppressed RAC1 activity. Targeting IMPDH2 away from the plasma membrane did not alter total intracellular GTP pools but decreased GTP levels in cell protrusions, RAC1 activity, and cell invasion. These data provide a mechanism of regulation of RAC1 activity by local GTP pools in live cells., Changes in intracellular GTP levels are not considered as a regulatory event in RAC1 activation in live cells since total GTP levels are substantially higher than the RAC1 GTP dissociation constant determined in vitro. Here, the authors demonstrate that the availability of free GTP in live cells controls the activity of RAC1 and cell invasion.

Signal transduction pathways post-translationally regulating nucleotide metabolism remain largely unknown. Guanosine monophosphate reductase (GMPR) is a nucleotide metabolism enzyme that decreases GTP pools by converting GMP to IMP. We observed that phosphorylation of GMPR at Tyr267 is critical for its activity, and found that this phosphorylation by ephrin receptor tyrosine kinase EPHA4 decreases GTP pools in cell protrusions and levels of GTP-bound RAC1. EPHs possess oncogenic and tumor-suppressor activities, although the mechanisms underlying switches between these two modes are poorly understood. We demonstrated that GMPR plays a key role in EPHA4-mediated RAC1 suppression. This supersedes GMPR-independent activation of RAC1 by EPHA4 resulting in a negative overall effect on melanoma cell invasion and tumorigenicity. Accordingly, EPHA4 levels increase during melanoma progression and inversely correlate with GMPR levels in individual melanoma tumors. Therefore, phosphorylation of GMPR at Tyr267 is a metabolic signal transduction switch controlling GTP biosynthesis and transformed phenotypes.

Resistance to the proteasome inhibitor bortezomib (BTZ) represents a major obstacle in the treatment of multiple myeloma (MM). The contribution of lipid metabolism in the resistance of MM cells to BTZ is mostly unknown. Here we report that levels of fatty acid elongase 6 (ELOVL6) were lower in MM cells from BTZ-nonresponsive vs BTZ-responsive patients and in cultured MM cells selected for BTZ resistance compared with parental counterparts. Accordingly, depletion of ELOVL6 in parental MM cells suppressed BTZ-induced endoplasmic reticulum (ER) stress and cytotoxicity, whereas restoration of ELOVL6 levels in BTZ-resistant MM cells sensitized them to BTZ in tissue culture settings and, as xenografts, in a plasmacytoma mouse model. Furthermore, for the first time, we identified changes in the BTZ-induced lipidome between parental and BTZ-resistant MM cell lines underlying a functional difference in their response to BTZ. We demonstrated that restoration of ELOVL6 levels in BTZ-resistant MM cells resensitized them to BTZ largely via upregulation of ELOVL6-dependent ceramide species, which was a prerequisite for BTZ-induced ER stress and cell death in these cells. Our data characterize ELOVL6 as a major clinically relevant regulator of MM cell resistance to BTZ, which can emerge from the impaired ability of these cells to alter ceramide composition in response to BTZ.

Oncogenic transcription factor FOXQ1 has been implicated in promotion of multiple transformed phenotypes in carcinoma cells. Recently, we have characterized FOXQ1 as a melanoma tumor suppressor that acts via repression of N-cadherin gene, and invasion and metastasis. Here we report that FOXQ1 induces differentiation in normal and transformed melanocytic cells at least partially via direct transcriptional activation of MITF gene, melanocytic lineage-specific regulator of differentiation. Importantly, we demonstrate that pigmentation induced in cultured melanocytic cells and in mice by activation of cAMP/CREB1 pathway depends in large part on FOXQ1. Moreover, our data reveal that FOXQ1 acts as a critical mediator of BRAF(V600E)-dependent regulation of MITF levels, thus providing a novel link between two major signal transduction pathways controlling MITF and differentiation in melanocytic cells.

Opposite lineage-specific regulation of tumor progression by the same transcription factor is an understudied phenomenon. Here, we report that levels of a carcinoma oncogenic transcription factor FOXQ1 are decreased during melanoma progression. Moreover, in melanoma cells, FOXQ1 suppresses the same processes it activates in carcinoma cells: epithelial-to-mesenchymal transition, invasion, and metastasis. We identify that lineage-specific tumor suppressor or oncogenic functions of FOXQ1 in large part depend on its ability to repress or activate expression of the same gene (N-cadherin, (CDH2)) in melanoma or carcinoma cells, respectively. Mechanistically, we demonstrate that FOXQ1 interacts with nuclear β-catenin and TLE proteins, and that repression of CDH2 by FOXQ1 occurs in the presence of TLE and absence of nuclear β-catenin, levels of which are lower in human melanomas than carcinomas. Accordingly, FOXQ1-dependent phenotypes can be manipulated by altering nuclear β-catenin or TLE proteins levels. Our data identify a novel melanoma suppressor and establish a unique mechanism underlying inverse lineage-specific transcriptional regulation of transformed phenotypes.

Although antioxidants promote melanoma metastasis, the role of reactive oxygen species (ROS) in other stages of melanoma progression is controversial. Moreover, genes regulating ROS have not been functionally characterized throughout the entire tumor progression in mouse models of cancer. To address this question, we crossed mice-bearing knock-out of Klf9, an ubiquitous transcriptional regulator of oxidative stress, with two conditional melanocytic mouse models: Braf(CA) mice, where Braf(V600E) causes premalignant melanocytic hyperplasia, and Braf(CA)/Pten(−/−) mice, where Braf(V600E) and loss of Pten induce primary melanomas and metastases. Klf9 deficiency inhibited premalignant melanocytic hyperplasia in Braf(CA) mice but did not affect formation and growth of Braf(CA)/Pten(−/−) primary melanomas. It also, as expected, promoted Braf(CA)/Pten(−/−) metastasis. Treatment with antioxidant N-acetyl cysteine phenocopied loss of Klf9 including suppression of melanocytic hyperplasia. We were interested in a different role of Klf9 in regulation of cell proliferation in Braf(CA) and Braf(CA)/Pten(−/−) melanocytic cells. Mechanistically, we demonstrated that BRAF(V600E) signaling transcriptionally upregulated KLF9 and that KLF9-dependent ROS were required for full-scale activation of ERK1/2 and induction of cell proliferation by BRAF(V600E). PTEN depletion in BRAF(V600E)-melanocytes did not further activate ERK1/2 and cell proliferation, but rendered these phenotypes insensitive to KLF9 and ROS. Our data identified an essential role of KLF9-dependent ROS in BRAF(V600E) signaling in premalignant melanocytes, offered an explanation to variable role of ROS in premalignant and transformed melanocytic cells and suggested a novel mechanism for suppression of premalignant growth by topical antioxidants.

Ferroresonance is a non-linear vibrational phenomenon that is generated by the electrical interaction of the inductance compon ent with the capacitor component of a certain capacitance as the device of the inductance component such as a transformer is saturated due to the degradation, the wavef orm distortion of current and voltage, and the oscillation of overcurrent and overvoltage in a system. Recently, ferroresonance was generated from the waveform distortion of current and voltage, or the overvoltage or undervoltage phenomenon caused by the nature of an electrical power system and design technology of the transformer in the three phase transformer system. Hence, in general, ferroresonance analyzed by converting to the LC equivalent circuit. However, in general, the aforementioned analytical method only applies to the resonance phenomenon that is generated by the interaction of the capacita nce of bussbar and grounding, and switching as the capacitor component with PT and the transformer as the inductance component in a system. Subsequently, the condition where ferroresonance was generated since overvoltage was supplied as line voltage to the phase voltage and thus the iron core is saturated due to the interconnection between grounded and ungrounded systems could not be analyzed when single phase PT was connected in a △/Y connection system. In this st udy, voltage swell in the confi guration of grounded circuit of a step-up transformer with the △-△ connection linked to PT for control power and the ferroresonance generated by overvoltage when the line voltage of the △-△ connection was connected to the phase voltage of the grounded Y-Y connection were analyzed using PSCAD / EMTDC through the failure case of the transformer caused by ferroresonance in the system with the △-△ /Y-Y connection, and subsequently, the preventive measure of ferroresonance was proposed.

Polyamine inhibition for cancer therapy is, conceptually, an attractive approach but has yet to meet success in the clinical setting. The aryl hydrocarbon receptor (AHR) is the central transcriptional regulator of the xenobiotic response. Our study revealed that AHR also positively regulates intracellular polyamine production via direct transcriptional activation of 2 genes, ODC1 and AZIN1, which are involved in polyamine biosynthesis and control, respectively. In patients with multiple myeloma (MM), AHR levels were inversely correlated with survival, suggesting that AHR inhibition may be beneficial for the treatment of this disease. We identified clofazimine (CLF), an FDA-approved anti-leprosy drug, as a potent AHR antagonist and a suppressor of polyamine biosynthesis. Experiments in a transgenic model of MM (Vk*Myc mice) and in immunocompromised mice bearing MM cell xenografts revealed high efficacy of CLF comparable to that of bortezomib, a first-in-class proteasome inhibitor used for the treatment of MM. This study identifies a previously unrecognized regulatory axis between AHR and polyamine metabolism and reveals CLF as an inhibitor of AHR and a potentially clinically relevant anti-MM agent.

When the ground fault on the power side occurs on distribution system interconnected with distributed generations, the abnormal current is generated in the neutral conductor by the connection type and the iron core structure of transformers for the interconnection of distributed power supplies due to the unbalanced voltage of the system, and subsequently the false operation of the protective relay on the load side occurs. Herein, this paper proposes the method to correct errors in the phase current to prevent the false operation of the protective relay by applying p-q theory and presents the simulation result of the error correction algorithm using PSCAD/EMTDC.

A portable electronic nose system has been fabricated and characterized using an oxide semiconductor gas sensor array and artificial neural network. The sensor array consists of such thick-film oxide semiconductor sensing materials as Pd-doped WO3, Pt-doped SnO2, TiO2–Sb2O5–Pd-doped SnO2, TiO2–Sb2O5–Pd-doped SnO2+Pd-coated layer, Al2O3-doped ZnO and PdCl2-doped SnO2. The portable electronic nose system consists of an Intel 80c196kc as CPU, an EEPROM and an LCD for displaying gas concentrations, etc. As an application, the system has been used to identify 26 CO/HC car exhausting gases and the identification has been successfully demonstrated.

Ozone sensing properties of In2O3-based semiconductor thick films have been investigated. The In2O3 sensing layer is quite sensitive to ozone, but the rapid saturation in sensitivity cannot be obtained. The addition of Fe2O3 (3 wt.%) into In2O3 and the high temperature firing of the mixed powder give rise to a remarkable improvement in response and recovery, although the sensitivity decreases. The sensing layer fired at 1300°C and operated at 550°C shows excellent properties such as fast response, stable sensitivity, and rapid recovery. In addition to it, the sensor shows a good linearity with ozone concentration and a good reproducibility. The preliminary results clearly demonstrated that the sensor was successfully applied for the ozone detection of parts per billion range.

We have fabricated an electronic nose system using a thin film oxide semiconductor micro gas sensor array which shows only 65 mW of power consumption at an operating temperature of 300°C. Principal component analysis and neural network pattern recognition analysis were used to identify 12 gas samples (CH3SH, (CH3)3N, C2H5OH and CO gases in the concentration range of 0.1–100 ppm) or six flavor samples (carrot, green onion, woman's perfume (eau de cologne), man's perfume (eau de toilette), 25% liquor (Korean soju) and 40% liquor (whisky)). Good separation among the gases with different concentrations or flavor samples was obtained using the principal component analysis. The recognition probability of the neural network was 100% for each of the 5 trials of 12 gas samples and 93% for each of 10 trials of 6 flavor samples.

We have investigated abnormal current-voltage characteristics of an oxide semiconductor and have developed a novel method of detecting reducing gases utilizing the self-heating mechanism of the sensing layer without an additional heater. Planar-type sensors based on WO 3 -doped SnO 2 were fabricated using a screen-printing technique. The applied voltage across the sensing layer caused heating of the sensing layer and the current abruptly varied upon exposure to a gas, mainly as a result of surface reactions. A fascinating aspect of the gas sensing scheme is that no additional heater is necessary for detection. The new sensing method has been applied to C 2 H 5 OH gas in this preliminary work.

In order to identify CH3SH, (CH3)3H, C2H5OH and CO gases in the concentration range of 0.1 to 100 ppm, a gas recognition system using a gas sensor array and neural-network pattern recognition has been fabricated. The sensor array consists of such thin film oxide semiconductor sensing materials as 1 wt% Pd-doped SnO2, 6 wt% Al2O3-doped ZnO, WO3 and ZnO. The principal component analysis and the neural-network pattern recognition analysis were used for the discrimination of gas species and concentrations. Good separation among gases and concentrations was obtained using the principal component analysis. The recognition probability of the neural-network was 100% for each 5 trials of 12 gas samples.

The gas-sensing properties of copper phthalocyanine (CuPc) thin films have been measured for NO 2 concentrations of 1 to 10 parts per million (ppm). The CuPc films thermally evaporated on glass substrates appear to have an α-form polycrystalline structure. Most measurements of gas sensitivity are done with heat-cleaned sensing elements to reduce the instability of CuPc resistance. We have established unambiguously that a significant enhancement of detectivity can be accomplished by converting the resistance to a normalized figure, i.e., the relative resistance. Good sensitivity to as low as 1 ppm has been reproducibly achieved.

Highly sensitive and mechanically stable micro gas sensors have been made using microfabrication and micromachining techniques. The sensing material used to detect offensive CH 3 SH gas is 1 wt.% Pd-doped, 2000A˚thick SnO 2 deposited by r.f. magnetron sputtering. The optimum operating temperature of the sensor is 250°C, and the corresponding heater power is about 55 mW. Excellent thermal insulation of the membrane is achieved by the use of a double-layer structure of 0.2 μm thick silicon nitride and 1.4 μm thick phosphosilicate glass (PSG) prepared by low-pressure chemical-vapour deposition (LPCVD) and atmospheric-pressure chemical-vapour deposition (APCVD), respectively. The sensors are mechanically stable enough to endure at least 43 200 heat cycles between room temperature and 350°C.

We have investigated the sensing properties of Al 2 O 3 -doped ZnO for combustion control in lean-burn conditions. Planar-type sensing elements made of heater, electrode and sensing layer were formed on an alumina substrate using a screen-printing technique. Our exhaust-gas sensor exhibits significant resistance changes even under lean conditions, apparently due to the simultaneous functioning of bulk and surface conduction mechanisms. Utilizing the sensor for the feedback control of a domestic boiler, we have demonstrated that the system can be successfully operated at the best combustion conditions.

The Korea Atomic Energy Research Institute (KAERI) began to construct the 1 kJ Nd:glass laser facility. The KAERI laser facility (KLF) is designed to deliver 1 kJ at n-sec and 50 TW at p-sec to target chamber for high energy density plasma physics.

In order to identify CH/sub 3/SH, (CH/sub 3/)/sub 3/, C/sub 2/H/sub 5/OH and CO gases in the concentration range of 0.1 to 100 ppm, a gas recognition system using a gas sensor array and neural network pattern recognition has been fabricated. The sensor array consists of such thin film oxide semiconductor sensing materials as 1 wt.% Pd-doped SnO/sub 2/, 6 wt.% AI/sub 2/O/sub 3/-doped ZnO, WO/sub 3/ and ZnO. The principal component analysis and the neural-network pattern recognition analysis were used for the discrimination of gas species and concentrations. Good separation among gases and concentrations was obtained using the principal component analysis. The recognition probability of the neural-network was 100% for each five-trial of twelve gas samples.

We have fabricated and examined an ammonia gas sensor with high sensitivity using thick-film technology. The sensing material of the gas sensor is FeO/sub x/-WO/sub 3/-SnO/sub 2/ oxide semiconductor. The sensor exhibits resistance increase upon exposure to low concentration of ammonia gas. The resistance of the sensor is decreased, on the other hand, for exposure to reducing gases such as ethyl alcohol, methane, propane and carbon monoxide. We have proposed and investigated a novel method for detecting ammonia gas quite selectively by using a sensor array with two sensing elements which contains an ammonia gas sensor and a compensation element. The compensation element is a Pt-doped WO/sub 3/-SnO/sub 2/ gas sensor which shows an opposite direction of resistance change in comparison with the ammonia gas sensor upon exposure to ammonia gas. Excellent selectivity has been achieved using the sensor array with two sensing elements.

An adaptive array system is a candidate to increase the channel capacity by rejecting interference. However adaptive array systems are hard to remove all the interference when the incident signals are coherent with a desired signal. In this paper, we propose a modified Duvall beamformer, which performs spatial smoothing using spatial interpolation technique to maintain the degree of freedom. The proposed algorithm can minimize the loss in the degree of freedom due to spatial smoothing by forming subarrays with interpolated signals. Simulation results show that the proposed algorithm can remove all the interference while the conventional beamformer cannot.

A frequency domain partially adaptive algorithm, called a censoring adaptive array (CAA) algorithm, is proposed to reduce the computational complexity of a frequency domain adaptive array. The CAA algorithm uses a cell averaging constant false alarm rate (CA-CFAR) processor to adapt only those weights that correspond to the frequency bins expected to contain interference. The false alarm rate also adapts according to the environment. Furthermore, a censoring spatial smoothing is proposed to combine the CAA algorithm with a spatial smoothing technique. The performances of the proposed algorithms are compared with conventional algorithms using computer simulation.