In response to NIH initiatives to investigate sex as a biological variable in preclinical animal studies, researchers have increased their focus on male and female differences in neurotrauma. Inclusion of both sexes when modeling neurotrauma is leading to the identification of novel areas for therapeutic and scientific exploitation. Here, we review the organizational and activational effects of sex hormones on recovery from injury and how these changes impact the long-term health of spinal cord injury (SCI) patients. When determining how sex affects SCI it remains imperative to expand outcomes beyond locomotor recovery and consider other complications plaguing the quality of life of patients with SCI. Interestingly, the SCI field predominately utilizes female rodents for basic science research which contrasts most other male-biased research fields. We discuss the unique caveats this creates to the translatability of preclinical research in the SCI field. We also review current clinical and preclinical data examining sex as biological variable in SCI. Further, we report how technical considerations such as housing, size, care management, and age, confound the interpretation of sex-specific effects in animal studies of SCI. We have uncovered novel findings regarding how age differentially affects mortality and injury-induced anemia in males and females after SCI, and further identified estrus cycle dysfunction in mice after injury. Emerging concepts underlying sexually dimorphic responses to therapy are also discussed. Through a combination of literature review and primary research observations we present a practical guide for considering and incorporating sex as biological variable in preclinical neurotrauma studies.

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SummaryThe E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response – two findings that may be intrinsically linked through the concept of immunometabolism. Here, we combined bulk, single-cell, and spatial transcriptomics with cell-specific and spatially resolved metabolic analyses to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNAseq highlighted immunometabolic changes across the APOE4 glial transcriptome, specifically in subsets of metabolically distinct microglia enriched in the E4 brain during aging or following an inflammatory challenge. E4 microglia display increased Hif1α expression, a disrupted TCA cycle, and are inherently pro-glycolytic, while spatial transcriptomics and MALDI mass spectrometry imaging highlight an E4-specific response to amyloid that is characterized by widespread alterations in lipid metabolism. Taken together, our findings emphasize a central role for APOE in regulating microglial immunometabolism.

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The Horizon Simulation Framework is a modeling and simulation framework developed to verify system level requirements. In this thesis, the framework is extended to include the Dynamic position type that existed in the early development phase of the framework. The Dynamic position type is tested through the modeling and simulation of a sounding rocket. An active control system based on linear-quadratic regulator (LQR) control theory is implemented and tested in the simulation to determine the overall effect on altitude. A first order aerodynamics and aeroprediction model are created within the framework to allow for rapid changes early in the design process of the sounding rocket. The flight dynamics are compared to two different sounding rocket flights and the aeroprediction model is validated against public wind tunnel test data. iv ACKNOWLEDGMENTS I would like to thank my family for their continued support throughout my life. And thanks you to the wonderful Allison for editing this even if you didn't understand what was going on and for supporting me through this whole process. Thanks you to Dr. Mehiel for opening me to the world of modeling and simulation and guiding me through the process and helping me along the way. Thank you to Dr. Grieg for taking the time to advise CPSS and sit on my committee. I want to thank Damon Turner for his invaluable direction in this project. It would have been much more difficult without the resources you provided for me. Thank you Dr. Puig-Suari for taking the time out of your very busy schedule to serve on my committee. v