Discriminating transcriptional changes that drive disease pathogenesis from nonpathogenic and compensatory responses is a daunting challenge. This is particularly true for neurodegenerative diseases, which affect the expression of thousands of genes in different brain regions at different disease stages. Here we integrate functional testing and network approaches to analyze previously reported transcriptional alterations in the brains of Huntington disease (HD) patients. We selected 312 genes whose expression is dysregulated both in HD patients and in HD mice and then replicated and/or antagonized each alteration in a Drosophila HD model. High-throughput behavioral testing in this model and controls revealed that transcriptional changes in synaptic biology and calcium signaling are compensatory, whereas alterations involving the actin cytoskeleton and inflammation drive disease. Knockdown of disease-driving genes in HD patient-derived cells lowered mutant Huntingtin levels and activated macroautophagy, suggesting a mechanism for mitigating pathogenesis. Our multilayered approach can thus untangle the wealth of information generated by transcriptomics and identify early therapeutic intervention points.

A conjugate heat transfer analysis methodology has been defined and applied to an Air Force film cooled turbine vane consisting of 648 cooling holes. An unstructured computational mesh was used to model both the fluid and metal sides of the turbine vane. A summary of the numerical methods employed by Code Leo is provided along with a description of the coupling procedure employed between the fluid and heat conduction computations. Numerical simulations were conducted at multiple mesh resolutions to assess accuracy and repeatability. A detailed review is presented for the numerical solution obtained from a fine mesh consisting of 24 million elements (8 million solid, 16 million fluid) covering all 648 film holes. Results showed that cooled air from the film holes formed a protective layer around the airfoil surfaces and endwalls as intended. Low metal temperatures were present not only on the external surfaces exposed to hot gas, but also around the entrances to the film cooling holes. Cooled air was also observed to pile up along the pressure surface at mid-span. Solution convergence was achieved in approximately 15,000 iterations and 100 hours elapsed time on a dual-socket Intel E5504 workstation. The combination of fast turnaround time with accurate metal temperature prediction will enable conjugate heat transfer analysis to be easily incorporated into routine design processes to better address durability goals.

Conjugate heat transfer analysis was conducted on a 648 hole film cooled turbine vane using Code Leo and compared to experimental results obtained at the Air Force Research Laboratory Turbine Research Facility. An unstructured mesh with fully resolved film holes for both fluid and solid domains was used to conduct the conjugate heat transfer simulation on a desktop PC with eight cores. Initial heat flux and surface metal temperature predictions showed reasonable agreement with heat flux measurements but under prediction of surface metal temperature values. Root cause analysis was performed, leading to two refinements. First, a thermal barrier coating layer was introduced into the analysis to account for the insulating properties of the Kapton layer used for the heat flux gauges. Second, inlet boundary conditions were updated to more accurately reflect rig measurement conditions. The resulting surface metal temperature predictions showed excellent agreement relative to measured results (+/− 5 degrees K).