Investigation of Hypersonic Laminar Heating Augmentation in the Stagnation Region

Laminar stagnation region heating augmentation is investigated in the AEDC Tunnel 9 at Mach 10 by performing high frequency surface pressure and heat transfer measurements on the Orion CEV capsule at zero degree angle-of-attack for unit Reynolds numbers between 0.5 and 15 million per foot. Heating augmentation increases with Reynolds number, but is also model size dependent as it is absent on a 1.25-inch diameter model at Reynolds numbers where it reaches up to 15% on a 7-inch model. Heat transfer space-time correlations on the 7-inch model show that disturbances convect at the boundary layer edge velocity and that the streamwise integral scale increases with distance. Therefore, vorticity amplification due to stretching and piling-up in the stagnation region appears to be responsible for the stagnation point heating augmentation on the larger model. This assumption is reinforced by the f(exp -11/3) dependence of the surface pressure spectrum compared to the f(exp -1) dependence in the free stream. Vorticity amplification does not occur on the 1.25- inch model because the disturbances are too large. Improved free stream fluctuation measurements will be required to determine if significant vorticity is present upstream or mostly generated behind the bow shock

Transition Within a Hypervelocity Boundary Layer on a 5-Degree Half-Angle Cone in Air/CO_2 Mixtures

Laminar to turbulent transition on a smooth 5-degree half angle cone at zero angle of attack is investigated computationally and experimentally in hypervelocity flows of air, carbon dioxide, and a mixture of 50% air and carbon dioxide by mass. Transition N factors above 10 are observed for air flows. At comparable reservoir enthalpy and pressure, flows containing carbon dioxide are found to transition up to 30% further downstream on the cone than flows in pure air in terms of x-displacement, and up to 38% and 140%, respectively, in terms of the Reynolds numbers calculated at edge and reference conditions

Biased Multicomponent Reactions to Develop Novel Bromodomain Inhibitors

BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo BET inhibitors has prompted a need for structurally dissimilar ligands as probes of bromodomain function. Using fluorous-tagged multicomponent reactions, we developed a focused chemical library of bromodomain inhibitors around a 3,5-dimethylisoxazole biasing element with micromolar biochemical IC50. Iterative synthesis and biochemical assessment allowed optimization of novel BET bromodomain inhibitors based on an imidazo[1,2-a]pyrazine scaffold. Lead compound 32 (UMB-32) binds BRD4 with a Kd of 550 nM and 724 nM cellular potency in BRD4-dependent lines. Additionally, compound 32 shows potency against TAF1, a bromodomain-containing transcription factor previously unapproached by discovery chemistry. Compound 32 was cocrystallized with BRD4, yielding a 1.56 Å resolution crystal structure. This research showcases new applications of fluorous and multicomponent chemical synthesis for the development of novel epigenetic inhibitors

Structure-Guided DOT1L Probe Optimization by Label-Free Ligand Displacement

The DOT1L lysine methyltransferase has emerged as a validated therapeutic target in MLL-rearranged (MLLr) acute leukemias. Although S-adenosylmethionine competitive inhibitors have demonstrated pharmacological proof-of-principle in MLLr-leukemia, these compounds require further optimization to improve cellular potency and pharmacokinetic stability. Limiting DOT1L inhibitor discovery and ligand optimization have been complex biochemical methods often using radionucleotides and cellular methods requiring prolonged culture. We therefore developed a new suite of assay technologies that allows comparative assessment of chemical tools for DOT1L in a miniaturized format. Coupling these assays with structural information, we developed new insights into DOT1L ligand binding and identified several functionalized probes with increased cellular potency (IC50 values ∼10 nM) and excellent selectivity for DOT1L. Together these assay technologies define a platform capability for discovery and optimization of small-molecule DOT1L inhibitors

Transition Within a Hypervelocity Boundary Layer on a 5-Degree Half-Angle Cone in Air/CO_2 Mixtures

Laminar to turbulent transition on a smooth 5-degree half angle cone at zero angle of attack is investigated computationally and experimentally in hypervelocity flows of air, carbon dioxide, and a mixture of 50% air and carbon dioxide by mass. Transition N factors above 10 are observed for air flows. At comparable reservoir enthalpy and pressure, flows containing carbon dioxide are found to transition up to 30% further downstream on the cone than flows in pure air in terms of x-displacement, and up to 38% and 140%, respectively, in terms of the Reynolds numbers calculated at edge and reference conditions

BTN3A2 Expression in Epithelial Ovarian Cancer Is Associated with Higher Tumor Infiltrating T Cells and a Better Prognosis

BTN3A2/BT3.2 butyrophilin mRNA expression by tumoral cells was previously identified as a prognostic factor in a small cohort of high grade serous epithelial ovarian cancer (HG-EOC). Here, we evaluated the prognostic value of BT3.2 at the protein level in specimen from 199 HG-EOC patients. As the only known role of butyrophilin proteins is in immune regulation, we evaluated the association between BT3.2 expression and intratumoral infiltration of immune cells by immunohistochemistry with specific antibodies against BT3.2, CD3, CD4, CD8, CD20, CD68 and CD206. Epithelial BT3.2 expression was significantly associated with longer overall survival and lower risk of disease progression (HR = 0.651, p = 0.006 and HR = 0.642, p = 0.002, respectively) and significantly associated with a higher density of infiltrating T cells, particularly CD4+ cells (0.272, p<0.001). We also observed a strong association between the relative density of CD206+ cells, as evaluated by the ratio of intratumoral CD206+/CD68+ expression, and risk of disease progression (HR = 1.355 p = 0.044, respectively). In conclusion, BT3.2 protein is a potential prognostic biomarker for the identification of HG-EOC patients with better outcome. In contrast, high CD206+/CD68+ expression is associated with high risk of disease progression. While the role of BT3.2 is still unknown, our result suggest that BT3.2 expression by epithelial cells may modulates the intratumoral infiltration of immune cells

Computational and Experimental Investigation of Supersonic Convection on a Laser Heated Target

This research concerns the development and validation of simulation of the beam-target Interaction to determine the target temperature distribution as a function of time for a given target geometry, surface radiation intensity and free stream flow condition. The effect of a turbulent supersonic flow was investigated both numerically and experimentally. Experiments were In the Virginia Tech supersonic wind tunnel with a Mach 4 nozzle, ambient total temperature, total pressure of 1.1 x 10⁶ Pa and Reynolds number of 5 x 10⁷/m. The target consisted of a 6.35 mm stainless steel plate painted flat black. The target was irradiated with a 300 Watt continuous beam Ytterbium fiber laser generating a 4 mm Gaussian beam at 1.08 micron 10 cm from the leading edge where a 4 mm turbulent boundary layer prevailed. An absorbed laser power of 65, 81, 101, 120 Watts was used leading to a maximum heat flux between 1035 to 1910 W/cm². The target surface and backside temperatures were measured using a mid-wave infrared camera. The backside temperature was also measured using eight type-K thermocouples. Two tests are made, one with the flow-on and the other with the flow-off. For the flow-on case, the laser is turned on aft.er the tunnel starts and the flow reaches a steady state. For the flow-off case, the plate is heated at the same power but without the supersonic flow. The cooling effect is seen by subtracting the flow-on temperature from the flow-off temperature. This temperature subtraction is useful in canceling the bias errors such that the overall uncertainty is significantly reduced. The GASP conjugate heat transfer algorithm was used to simulate the experiments at 81 and 65 Watts. Most computations were performed using the Spalart-Allmaras turbulence model on a 280,320 cell grid. A grid convergence study was performed. Compared to the 65 Watt case, the 81 Watt case displays more asymmetry and a region of increased cooling is found upstream. The increased asymmetry was also seen on the backside by both the thermocouple and infrared temperature measurements. The computation underpredicts the surface temperature by 7% for the flow-off case. For both thef 65 and 81 Watt cases, cooling is underpredicted at the surface near the center. For all power settings, convective cooling significantly increases the time required to reach a given temperature