Metabotropic glutamate receptor 1 acts as a dependence receptor creating a requirement for glutamate to sustain the viability and growth of human melanomas.

Metabotropic glutamate 1 (mGlu) receptor has been proposed as a target for the treatment of metastatic melanoma. Studies have demonstrated that inhibiting the release of glutamate (the natural ligand of mGlu1 receptors), results in a decrease of melanoma tumor growth in mGlu1 receptor-expressing melanomas. Here we demonstrate that mGlu1 receptors, which have been previously characterized as oncogenes, also behave like dependence receptors by creating a dependence on glutamate for sustained cell viability. In the mGlu1 receptor-expressing melanoma cell lines SK-MEL-2 (SK2) and SK-MEL-5 (SK5), we show that glutamate is both necessary and sufficient to maintain cell viability, regardless of underlying genetic mutations. Addition of glutamate increased DNA synthesis, whereas removal of glutamate not only suppressed DNA synthesis but also promoted cell death in SK2 and SK5 melanoma cells. Using genetic and pharmacological inhibitors, we established that this effect of glutamate is mediated by the activation of mGlu1 receptors. The stimulatory potential of mGlu1 receptors was further confirmed in vivo in a melanoma cell xenograft model. In this model, subcutaneous injection of SK5 cells with short hairpin RNA-targeted downregulation of mGlu1 receptors resulted in a decrease in the rate of tumor growth relative to control. We also demonstrate for the first time that a selective mGlu1 receptor antagonist JNJ16259685 ((3,4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone) slows SK2 and SK5 melanoma tumor growth in vivo. Taken together, these data suggest that pharmacological inhibition of mGlu1 receptors may be a novel approach for the treatment of metastatic melanoma.

Seabed geoacoustic characterization with a vector sensor array.

This paper proposes a vector sensor measurement model and the related Bartlett estimator based on particle velocity measurements for generic parameter estimation, illustrating the advantages of the Vector Sensor Array (VSA). A reliable estimate of the seabed properties such as sediment compressional speed, density and compressional attenuation based on matched-field inversion (MFI) techniques can be achieved using a small aperture VSA. It is shown that VSAs improve the resolution of seabed parameter estimation when compared with pressure sensor arrays with the same number of sensors. The data considered herein was acquired by a four-element VSA in the 8-14 kHz band, during the Makai Experiment in 2005. The results obtained with the MFI technique are compared with those obtained with a method proposed by C. Harrison, which determines the bottom reflection loss as the ratio between the upward and downward beam responses. The results show a good agreement and are in line with the historical information for the area. The particle velocity information provided by the VSA increases significantly the resolution of seabed parameter estimation and in some cases reliable results are obtained using only the vertical component of the particle velocity.

A new direction for myosin.

Members of the myosin superfamily of actin-based motor proteins were previously thought to move only towards the barbed end of the actin filament. In an extraordinary reversal of this dogma, an abundant and widespread unconventional myosin known as myosin VI has recently been shown to move towards the pointed end of the actin filament - the opposite direction of all other characterized myosins. This discovery raises novel and intriguing questions about the molecular mechanisms of reversal and the biological roles of this 'backwards' myosin.