The 5' half of the EWS gene has recently been described to be fused to the 3' regions of genes encoding the DNA-binding domain of several transcriptional regulators, including ATF1, and ERG, in Members of the Ets family form a novel class of sequencespecific DNA-binding proteins which are implicated in developmental processes, in the response of cells to extracellular signals, and in cellular transformation (for reviews, see references 23 and 70). They are characterized by an 85-amino-acid region of similarity, the Ets domain, which is essential for sequence-specific binding to DNA (20,28,30,37,50,64,69,73). DNA sequences bound by several Ets family members have been analyzed in detail and found to include about 10 nucleotides centered over a central GGAA core sequence (11,18,50,67,78). These sequences when multimerized upstream of a minimal promoter or when present in the context of natural viral and cellular promoters/enhancers mediate transcriptional regulation by Ets proteins (8,30,55,56,71,74,79). Consistent with these properties, specific transcriptional activation domains have been mapped in Ets-1, 39,59

Our data indicate that methylated H3K4 can act as a chromatin mark reflecting the original meaning of "epigenetic."

SummarySomatic activating mutations of BRAF are the earliest and most common genetic abnormality detected in the genesis of human melanoma. However, the mechanism(s) by which activated BRAF promotes melanoma cell cycle progression and ⁄ or survival remain unclear. Here we demonstrate that expression of BIM, a pro-apoptotic member of the BCL-2 family, is inhibited by BRAF fi MEK fi ERK signaling in mouse and human melanocytes and in human melanoma cells. Trophic factor deprivation of melanocytes leads to elevated BIM expression. However, re-addition of trophic factors or activation of a conditional form of BRAF V600E leads to rapid inhibition of BIM expression. In both cases, inhibition of BIM expression was dependent on the activity of MEK1 ⁄ 2 and the proteasome. Consistent with these observations, pharmacological inhibition of BRAF V600E or MEK1 ⁄ 2 in human melanoma cells (using PLX4720 and CI-1040 respectively) led to a striking elevation of BIM expression. Re-activation of BRAF fi MEK fi ERK signaling led to phosphorylation of BIM-EL on serine 69and its subsequent degradation. Interestingly, endogenous expression of BIM in melanoma cells was insufficient to induce apoptosis unless combined with serum deprivation. Under these circumstances, inhibition of BIM expression by RNA interference provided partial protection from apoptosis. These data suggest that regulation of BIM expression by BRAF fi MEK fi ERK signaling is one mechanism by which oncogenic BRAF V600E can influence the aberrant physiology of melanoma cells.

Three straight-bladed vertical axis turbine designs were simulated using ThreeDimensional (3D) transient Computational Fluid Dynamics (CFD) models, using a commercial Unsteady Reynolds Averaged Navier-Stokes (URANS). The turbine designs differed in support strut section, blade-strut joint design and strut location to evaluate their effect on power output, torque fluctuation levels and mounting forces. Simulations of power output were performed and validated against Experimental Fluid Dynamics (EFD), with results capturing the impacts of geometrical changes on turbine power output. Strut section and blade-strut joint design were determined to significantly influence total power output between the three turbine designs, with strut location having a smaller but still significant effect. Maximum torque fluctuations were found to occur around the rotation speed corresponding to maximum power output and fluctuation levels increased with overall turbine efficiency. Turbine mounting forces were also simulated and successfully validated against EFD results. Mounting forces aligned with the inflow increased with rotational rates, but plateaued due to reductions in shaft drag caused by rotation and blockage effects. Mounting forces perpendicular to the inflow were found to be 75% less than forces aligned with the inflow. High loading force fluctuations were found, with maximum values 40% greater than average forces.

Ride control systems are essential for comfort and operability of high-speed ships, but it remains an open question what is the optimum ride control method. To investigate the motions of a 112 m high-speed catamaran fitted with a ride control system a 2.5 m model was tested in a towing tank. The model active control system comprised two transom stern tabs and a central T-Foil beneath the bow. Six ideal motion control feedback algorithms were used to activate the model scale ride control system and surfaces in a closed loop control system: heave control, local motion control and pitch control, each in a linear and nonlinear version. The responses were compared with the responses with inactive control surfaces and with no control surfaces fitted. The model was tested in head seas at different wave heights and frequencies and the heave and pitch Response Amplitude Operators (RAOs), Response Phase Operators (RPOs) and acceleration response were measured. It was found that the passive ride control system reduced the peak heave and pitch motions only slightly. The heave and pitch motions were more strongly reduced by their respective control feedback. This was most evident with nonlinear pitch control which reduced the maximum pitch RAO by around 50% and the vertical acceleration near the bow by about 40% in 60 mm waves. These reductions were influenced favorably by phase shifts in the model scale system which effectively contributed both stiffness and damping in the control action. Nomenclature CLα Control surface lift coefficient derivative (dCL/dα) Fr Froude number based on hull waterline length g Gravitational acceleration (m/s 2) H Model heave at LCG (m, positive up) H* Dimensionless model heave at LCG (heave/wave amplitude) l Length of model waterline (m) LCG Longitudinal Centre of Gravity LST Stern tab lift force (N) LTF T-Foil lift force (N) P Model pitch about LCG (radian, positive bow down) P* Dimensionless model pitch at LCG (pitch/wave slope) SST Stern tab planform area (m 2) STF T-Foil planform area (m 2) ST0 Stern tab initial angle of attack (radian, positive producing upward lift) TF0 T-Foil initial angle of attack (radian, positive producing upward lift) U Model forward speed (m/s) xST Distance between centre of pressure of the stern tabs and LCG (m) xTF Distance between centre of pressure of the T-Foil and LCG (m) αST Stern tabs angular deflection (radian, positive producing upward lift) αSTd Control system demand stern tabs angular deflection (radian, positive producing upward lift) αTF T-Foil angular deflection (radian, positive producing upward lift) αTFd Control system demand T-Foil angular deflection (radian, positive producing upward lift) ζ Wave amplitude (m) λ Wave length (m) ρ Water density (kg/m 3) ω0 Wave frequency in fixed coordinate (radian/s) ωe Wave encounter frequency (radian/s) ωe* Dimensionless wave encounter frequency