Browsing by Subject "Models, Biological"
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Item 4D Study of Thoracic Cancer Radiation Treatment(2007-05-22) Huang, Tzung-Chi; Zhang, GeoffreyRespiratory motion causes an added uncertainty in the radiation treatment of thoracic malignancies due to an increase in the normal tissue irradiated and an uncertainty in the radiation coverage of the tumor. This results in a potential increase in complications from treatment and may be insufficient to ensure coverage of the tumor. Reduction of the volume of normal tissue irradiation while maintaining tumor coverage is used to accomplish this goal. The application of 4D CT imaging to radiotherapy treatment planning is an active area of research with the goal to reduce the required normal tissue irradiation and improve the tumor coverage. Deformable image registration holds the key to link the information of two images at various phases. The major purpose of this study is to develop and validate the optical flow method (OFM), a method of deformable image registration by which the image content properties are utilized to generate a displacement vector between each voxel in the reference image to the target image for registration. With OFM, we were able to develop and validate an automated method for intrathoracic motion estimation from breath-hold and 4-D computed tomography imaging; demonstrate the path integration of a four-dimensional dose distribution onto the 3-D anatomy; develop an automated target delineation technique; and to develop and implement a method to quantify tumor response and normal tissue damage by comparison of pre- and post-treatment and 18F-FDG-PET scans, all of which constitute meaningful applications and represent substantial progress in radiation treatment.Item The Biological Role of Stochasticity from Molecules to Communities(2013-07-17) Kittisopikul, Mark Andrew; Ranganathan, Rama; Süel, Gürol M.; Alto, Neal; Rizo-Rey, JoséThe presence of stochasticity in biology engenders the question of the role of such randomness. While stochasticity may be an artifact of biochemical interactions, it could also be an actively regulated aspect of life. Here I investigate how noise may be encoded within the molecular interactions of a biochemical network and then examine how those consequences propagate to higher levels of organization including isogenic populations of cells and host-pathogen interactions. I particularly look into how this variability impacts the ability of populations to respond to their environments. I conclude that stochasticity is selectable property of life that adds robustness to biological processes during periods of uncertainty.Item Development of a Lipidomics Platform to Discover Enzymatic Activities of Mycobacterial Proteins of Unknown Function(2020-05-01T05:00:00.000Z) Pasko, Breanna Lauren; Alto, Neal; Shiloh, Michael; Sperandio, Vanessa; McDonald, JeffreyMycobacterium tuberculosis (Mtb), a facultative intracellular pathogen, is responsible for 10 million new cases of tuberculosis and 1.5 million deaths annually. Mtb infection can be acute but also lifelong. Indeed, despite the devastating global impact on health, how Mtb is able to adapt to the human body and survive for years is unknown. To better understand the physiology of Mtb infection, exploring the functions of individual proteins produced by Mtb is critical. Less than half of the proteins encoded in the M. tuberculosis genome have been fully characterized either directly through experimentation or indirectly through annotation. Many of these unknown genes likely encode proteins important for pathogenesis and adaptation to host responses. I created a novel method to facilitate the identification of novel substrates and products using direct infusion tandem mass spectrometry (DI-MS/MS) analysis of nonpolar metabolite fluctuations after transient and rapid protein overexpression. I studied 24 proteins using this lipidomic method. Of these, several demonstrate unique patterns of metabolites secondary to rapid induction of protein expression, and work towards identifying their specific enzymatic activities is ongoing. I selected one protein, Cor (Rv1829), for further characterization as it was recently shown to be fundamental to carbon monoxide (CO) resistance and pathogenesis of Mtb during host infection. To study Cor in vitro, I purified recombinant Cor from E. coli and used activity based metabolic profiling (ABMP) to measure changes in mycobacterial metabolites exposed to Cor. In the ABMP assay, exposure of mycobacterial metabolites to Cor led to consumption of acetyl phosphate and accumulation of phosphatidic acid (PA). I developed direct enzymatic assays for Cor activity, and confirmed the consumption of acetyl phosphate. To assess substrate binding, I used isothermal titration calorimetry (ITC) and demonstrated binding of Cor to acetyl phosphate. Additionally, Cor interacted directly with cardiolipin (CL), phosphatidylglycerol (PG), phosphatidylserine (PS), phosphatidylinositol (PI), and sulfatide on membrane lipid strips. I overexpressed Cor in M. smegmatis and Mtb and lipids were extracted and analyzed through DI-MS/MS to assess changes in lipid composition. I combined in vivo lipidomics and in vitro ABMP to biochemically characterize Cor and found that Cor is interacting with bacterial lipids. In vivo lipidomic analysis revealed an accumulation of PA and PG by 3 hours. Our findings suggest that Mtb Cor is interacting with lipids involved in the phospholipid biosynthesis pathway and modifying bacterial lipid composition by accumulating PG. These experiments provide mechanistic insight into the enzymatic function of Cor. Furthermore, the metabolomics and lipidomics approaches developed in this study can be broadly applied to study proteins of unknown function from other organisms.Item Lung Volume Predicts Survival and Diaphragm Plications on ILD Patients Undergoing Transplant Using Frustum Model(2017-01-17) Park, So-Youn; Wait, Michael; Pruszynski, Jessica; Ring, StevePURPOSE: To validate the frustum model for lung volumes in patients with interstitial lung disease (ILD) undergoing lung transplantation, and to test whether lung size by frustum model is associated with cumulative survival advantage and need for diaphragm plication following lung transplant. METHOD: This retrospective observational study consisted of 180 patients seen in the University of Texas Southwestern-affiliated hospitals during the period from May 2010 to May 2016. Patients receiving bilateral or single lung transplant for ILD with available pre and post-operative CT scans were included. Bilateral lung transplants were performed through thoracosternotomy and single lung transplants through a unilateral thoracotomy. Cardiopulmonary bypass was used in 48% of patients. The frustum equation for a truncated cone was used to calculate total lung volume with pre and post-operative CT and XR chest PA closest to surgery time. Lung height was defined as the distance from the first rib to the diaphragm on XR chest. Radius 1 and 2 were obtained with same landmarks on CT scan. Patients were stratified by post/pre transplant lung volume ratio >1 or ratio ≤ 1. Multivariate logistic regression analysis and Cox proportional hazards regression models were used for statistical analysis of diaphragm plication and overall survival. RESULTS: Of the total 180 patients included, 39 (22%) had lung volume ratio ≤1 and 141 (78%) had ratio > 1. To validate the frustum model, a Pearson Correlation Coefficient was used to assess correlation between plethysmography TLC and frustum volume (n =251, r=.85, p <.01). Multivariate analysis for diaphragm plication included lung ratio, BMI, and smoking status. Lung volume ratio was a significant predictor of diaphragm plication (ratio >1 OR 7.19, p <.05). Multivariable Cox regression model for survival included lung ratio, diabetes, dyslipidemia, reintubation, and post-operative pneumonia. The only significant predictors were lung ratio (ratio ≤1HR 1.79, p <.05) and reintubation (HR 3.43, p<.01). CONCLUSION: The frustum model is a valid method for evaluating lung volumes in transplantation. The study suggests that lung volume confirms previous observations of a survival advantage to larger donor size in ILD. However, larger lung size may require diaphragm plication.Item [News](1985-05-20) Weeter, Deborah