Nosetip Bluntness Effects on Transition at Hypersonic Speeds: Experimental and Numerical Analysis

The existing database of transition measurements in hypersonic ground facilities has established that the onset of boundary layer transition over a circular cone at zero angle of attack shifts downstream as the nosetip bluntness is increased with respect to a sharp cone. However, this trend is reversed at sufficiently large values of the nosetip Reynolds number, so that the transition onset location eventually moves upstream with a further increase in nosetip bluntness. This transition reversal phenomenon, which cannot be explained on the basis of linear stability theory, was the focus of a collaborative investigation under the NATO STO group AVT-240 on Hypersonic Boundary-Layer Transition Prediction. The current paper provides an overview of that effort, which included wind tunnel measurements in three different facilities and theoretical analysis related to modal and nonmodal amplification of boundary layer disturbances. Because neither first and second-mode waves nor entropy-layer instabilities are found to be substantially amplified to initiate transition at large bluntness values, transient (i.e., nonmodal) disturbance growth has been investigated as the potential basis for a physics based model for the transition reversal phenomenon. Results of the transient growth analysis indicate that stationary disturbances that are initiated within the nosetip or in the vicinity of the juncture between the nosetip and the frustum can undergo relatively significant nonmodal amplification and that the maximum energy gain increases nonlinearly with the nose radius of the cone. This finding does not provide a definitive link between transient growth and the onset of transition, but it is qualitatively consistent with the experimental observations that frustum transition during the reversal regime was highly sensitive to wall roughness, and furthermore, was dominated by disturbances that originated near the nosetip. Furthermore, the present analysis shows significant nonmodal growth of traveling disturbances that peak within the entropy layer and could also play a role in the transition reversal phenomenon

Nosetip Bluntness Effects on Transition at Hypersonic Speeds: Experimental and Numerical Analysis Under NATO STO AVT-240

The existing database of transition measurements in hypersonic ground facilities has established that the onset of boundary layer transition over a circular cone at zero angle of attack shifts downstream as the nosetip bluntness is increased with respect to a sharp cone. However, this trend is reversed at suciently large values of the nosetip Reynolds number, so that the transition onset location eventually moves upstream with a further increase in nosetip bluntness. This transition reversal phenomenon, which cannot be ex- plained on the basis of linear stability theory, was the focus of a collaborative investigation under the NATO STO group AVT-240 on Hypersonic Boundary-Layer Transition Predic- tion. The current paper provides an overview of that e ort, which included wind tunnel measurements in three di erent facilities and theoretical analysis related to modal and nonmodal ampli cation of boundary layer disturbances. Because neither rst and second- mode waves nor entropy-layer instabilities are found to be substantially ampli ed to ini- tiate transition at large bluntness values, transient (i.e., nonmodal) disturbance growth has been investigated as the potential basis for a physics-based model for the transition reversal phenomenon. Results of the transient growth analysis indicate that disturbances that are initiated within the nosetip or in the vicinity of the juncture between the nosetip and the frustum can undergo relatively signi cant nonmodal ampli cation and that the maximum energy gain increases nonlinearly with the nose radius of the cone. This nding does not provide a de nitive link between transient growth and the onset of transition, but it is qualitatively consistent with the experimental observations that frustum transition during the reversal regime was highly sensitive to wall roughness, and furthermore, was dominated by disturbances that originated near the nosetip

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

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

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