This research is aimed at examining experimentally and analytically the behavior of reinforced concrete bridge pier caps strengthened with externally bonded reinforcement. In the experimental study, nine full-scale reinforced concrete bridge pier caps were built, externally strengthened with stainless steel reinforcement, and ten tested to failure. Load, deflection, and strain measurements were collected and two potential failure mechanisms were identified. In the analytical part of this work, mechanics-based equations were developed for calculating the shear strength of these types of structural elements when a diagonal shear crack is formed under loading. In addition, a combined strut-and-tie/truss model is proposed for determining the strength of reinforced concrete bridge caps with externally bonded reinforcement. Results from both experimental and analytical studies were compared and design recommendations are made for future adoption in bridge and building codes and specifications.

Sickle cell disease is a hereditary blood disorder caused by a point mutation in the gene encoding hemoglobin. This mutation causes hemoglobin molecules to polymerize during de-oxygenation of erythrocytes producing rod-shaped polymers that bend and distort the red blood cell membrane, making it more rigid and “sickled”. This sickling causes red blood cells to lose their flexibility and ability to navigate small capillaries and also enhances the production of pro-inflammatory membrane-derived microparticles, leading to chronic inflammation and many complications such as peripheral artery disease, stroke, myocardial infarction, vasculitis and even death. Sphingolipids are a class of lipids containing a backbone of sphingoid bases and are integral components of erythrocyte and microparticle membranes. Many of these lipids are known to mediate biological processes, but their expression, distribution and orientation in erythrocytes during sickle cell disease has never been explored. Sphingomyelin, the most abundant sphingolipid in the red blood cell membrane is hydrolyzed by sphingomyelinase to produce ceramide, which has been shown to alter membrane dynamics and enhance microvessel formation. Additionally, ceramide can be further metabolized to form sphingosine and sphingosine 1-phosphate, which is a bioactive ligand for 5 known G-protein coupled receptors present on most blood and vascular cells that modulates cell motility, proliferation, migration and phenotype. Prior to this work, it was not understood how sphingolipid metabolism contributes to vascular inflammation in sickle cell disease. Together, this body of work has elucidated key enzymatic and lipidomic alterations in sphingolipid metabolism (i.e. the activation of acid sphingomyelinase on red blood cells) that result in the production of sphingolipid-rich erythrocyte-derived microparticles, which enhance inflammatory cell activation. Our work has elucidated novel pharmacological targets to reduce microparticle generation and subsequent vascular inflammation in sickle cell disease.

Sickle cell disease is a genetic disorder that affects 100,000 Americans and millions more worldwide. Although the sickle mutation affects one protein, which is only expressed in a single cell type, it has profound detrimental effects on nearly every organ system in the body. Young children with sickle cell disease have an 11\% chance of suffering a major stroke event by the age of 16, and a 35\% chance of developing ÒsilentÓ strokes that often result in significant learning and mental disabilities. Clinical investigations suggest that stroke development in people with sickle cell disease results from luminal narrowing of the carotid and cerebral arteries due to excess matrix deposition and fragmentation of the elastic lamina; however, the underlying cellular mechanisms that initiate arterial remodeling in sickle cell disease remain relatively unknown. Cathepsins K and V are members of the cysteine family of proteases and represent two of the most potent elastases yet identified in humans. Furthermore, the role of Cathepsins has been well established in other cardiovascular remodeling diseases, such as atherosclerosis. Due to the compelling histological similarities between vasculopathy in sickle cell disease and atherosclerosis, we tested the hypothesis that the unique inflammatory milieu, in conjunction with the biomechanical vascular environment of sickle cell disease upregulates cathepsin K and V activity in large artery endothelial cells, ultimately leading to arterial remodeling and stroke. Currently, there are few therapeutic options for the prevention of stroke in sickle cell disease; those that do exist carry significant health risks and side effects. Together, this body of work has generated a more mechanistic understanding of how the sickle milieu stimulates the endothelium to initiate arterial remodeling, which has enabled us to identify important pathways (JNK, NF$\kappa$B) downstream of inflammatory and biomechanical stimuli and validate new therapeutic targets within the JNK pathway to establish preclinical proof of efficacy for the prevention of arterial remodeling in sickle cell disease.

Macroscopic changes in the urban environment and in the built transportation infrastructure, as well as changes in household demographics and socio-economics, can lead to spatio-temporal variations in household travel patterns and therefore regional travel demand. Dynamics in travel behavior may also simply arise from the randomness associated with values, perceptions, attitudes, needs, preferences and decision-making process of the individual travelers. Most urban travel behavior models and analysis seek to explain variations in travel behavior in terms of characteristics of the individuals and their environment. Spatial extents and temporal variation in an individual’s travel pattern may represent a measure of the individual’s spatial appetite for activity and the variability-seeking nature on his/her travel behavior. The objective of this dissertation effort is to develop a methodology to predict activity participation using revealed spatial extents and temporal variability as variables that represent the spatial appetite and variability-seeking nature associated with individual household. Activity participation is defined as a set of activities in which an individual or household takes part, to satisfy the sustenance, maintenance and discretionary needs of the household. To accomplish the goals of the dissertation, longitudinal travel data collected from the Commute Atlanta Study are used. The raw Global Positioning Systems (GPS) data are processed to summarize trip data by household travel day and individual travel day data. A methodology was developed to automatically identify the activity at the end of each trip. Methods were then developed to estimate travel behavior variability that can represent the variability-seeking nature of the individual. Existing methods to estimate activity space were reviewed and a new Modified Kernel Density area method was developed to address issues with current methods. Finally activity participation models using structural equation modeling methods were developed and the effects of the variability-seeking nature and spatial extent of activities were applied to the models. The variability-seeking nature was presented in the activity participation model as a latent variable with coefficient of variation of trips and distance as indicator variables. The dissertation research found that inclusion of activity space variables can improve the activity participation modeling process to better explain travel behavior.

The prediction of an atomistic system's macroscopic observables from microscopic physical characteristics is often intractable, either by theory or computation, due to the intrinsic complexity of the underlying dynamical rules. This complexity can be simplified by identifying key mechanisms that drive behavior and considering the system in a reduced representation that captures these mechanisms. Through theory, this thesis examines complex relationships in structured assembly and reaction mechanisms that occur when effective interactions are applied to mesoscale structures. In the first part of this thesis, the structure and assembly of soft matter systems are characterized while varying the interpenetrability of the constituent particles. The nature of the underlying softness allows these systems to be packed at ever higher density, albeit with an increasing penalty in energy. Stochastic equations of motion are developed in which mesoscopic structures are mapped to single degrees of freedom through a coarse-graining procedure. The effective interactions between these coarse-grained sites are modeled using stochastic potentials that capture the spatial behavior observed in systems governed by deterministic bounded potentials. The second part of this thesis presents advancements in time-dependent transition state theory, focusing on chemical reactions that are induced by oscillatory external forces. The optimal dividing surface for a model driven reaction is constructed over a transition state trajectory. The stability of the transition state trajectory is found to directly dictate the reaction rate, and it is thus the fundamental and singular object needed to predict barrier-crossing rates in periodically driven chemical reactions. This thesis demonstrates that using minimalist models to examine these complex systems can provide valuable insight into the dynamical mechanisms that drive behavior.

Aging is a complex process by which a combination of environmental, genetic and stochastic factors generate whole-system changes that modify organ and tissue function and alter physiological processes. Over the last few decades, many genetic and environmental modulators of aging have been found to be highly conserved between humans and a diverse group of model organisms. Yet, an integrative understanding of how these environmental and genetic variables interact over time in a whole organism to modulate the systemic changes involved in aging is lacking. The goal of this thesis project is to advance a systems perspective of aging by providing the experimental tools and conceptual framework for dissecting the regulatory connection between environmental inputs, molecular outputs and long term aging phenotypes in Caenorhabditis elegans, an experimentally tractable multi-cellular model for aging. Specifically, this work advances the quantitative imaging toolsets available to biologists by developing and refining microfluidic, hardware, computer vision, and software integration tools for high-throughput, high-content imaging of C. elegans. As a result of these technological advances, new roles for the TGF-beta and serotonin signaling pathways in encoding environmental food signals to influence longevity were uncovered and quantitatively characterized. Moreover, this work develops and integrates new microfluidic technologies with off-chip support systems to establish a platform for long-term tracking of the health and longevity trajectories of large numbers of individual C. elegans. The capabilities of this platform have the potential to address many important questions in aging including addressing environmental determinants of aging, the sources of inter-individual variability, the time course of aging-related declines and the effects of interventional strategies to improve health outcomes. Together, the toolsets for quantitative imaging and the long-term culture platform permit the large-scale investigation of both the internal state and long-term behavioral and health outputs of an important multicellular model organism for aging.

Electrospun nanofibers represent a class of versatile scaffolds for tissue engineering applications owing to their ability to mimic the nanoscale features of the native extracellular matrix (ECM). In addition, nanofibers produced by electrospinning can be readily collected as uniaxially aligned assemblies to recapitulate the architecture of the ECM in tissues with anisotropic characteristics, such as tendon-to-bone insertions, tendons, and nerves. This dissertation focuses on the design, fabrication, functionalization, and assessment of various types of scaffolds consisting of aligned nanofibers, which can be used to augment regeneration in tissues with anisotropic structures. Briefly, for tendon-to-bone insertion repair, I assessed the capability of aligned nanofibers with a gradient in mineral content to induce spatially graded osteogenesis of adipose-derived mesenchymal stem cells (ASCs). I also developed an alternative approach to the production of a gradient in the density of osteoblasts. The graded pattern of osteoblasts generated using both approaches could mimic their distribution in the native tendon-to-bone insertion. To further enhance the stiffness of the scaffolds, a new solution was developed to coat the scaffold with a thicker mineral layer. In a third project, a novel method of generating crimp in aligned nanofibers was developed. A solvent plasticizer was employed to release the residual stress retained in the nanofibers during electrospinning, which led to the generation of crimp. Finally, the outgrowth of neurites derived from embryoid bodies (EBs) was studied using aligned nanofibers as the substrates. Depending on the strength of adhesion between nanofibers and neurites, two patterns of outgrowth--parallel and perpendicular (to the alignment)--were observed. Maturation of neurons derived from dissociated EBs was also investigated, as characterized by their extracellular action potential and the ability to form neuromuscular junctions with co-cultured muscle cells.

Understanding the origin of life requires understanding the origin of translation, which in turn, requires understanding the origin of the ribosome. Ribosomes are complex structures consisting of hundreds of thousands of atoms. Here, we describe how we organized ribosomal structures and information into a broad database, RiboZones. We also describe a new visualization web app, RiboVision. RiboZones and RiboVision are productivity tools that lower the learning curve for ribosomal research. RiboZones makes the ribosome more accessible. RiboVision especially helps create beautiful publication ready figures in a fraction of the labor and time previously required. It is only through the creation of RiboZones and RiboVision through which the rest of this dissertation became feasible. We constructed a high-quality sequence alignment of ribosomal sequences for both the LSU and the SSU rRNA. Each ribosomal sequence is complete, allowing detailed, low background statistics to be computed. The sequence alignment broadly samples the tree of life according to available data. The alignment was adjusted for maximum agreement with 3D superimpositions of multiple ribosomal structures. We defined a nucleotide-level definition of the common core of the ribosome, as the RNA that is present in 95% of the sequences in our alignment. Multiple versions of the common core were created, including the universal common core, the prokaryotic common core, and domain specific common cores. The definition allows statistics to be computed for various use-cases. For example, with RiboVision visualization technology, it is possible to see which helices are optional, in which of the three domains of life, and what the minimum helical length is for each helix. We discovered that ribosomal RNA grows mostly by helix extension and helix insertion. When a helix is inserted, it minimally perturbs the underlying helix. We call this pattern ‘insertion fingerprints’. Insertion fingerprints are found throughout the common core and the eukaryotic expansion segments. Insertion fingerprints were used to divide the ribosomal RNA into units called ancestral expansion segments (AES’s). AES’s make ideal structural, functional, and evolutionary units. The AES’s are arranged into the first complete experimentally testable model of ribosomal evolution. The model can be refined over time as new information is discovered.

This research provides quantitative data to aid engineers in the selection of various attributes to facilitate fit-up during I-girder bridge construction. Concepts and procedures for explicit calculation of locked-in forces due to cross-frame detailing are developed and discussed. Fit-up forces are evaluated and discussed for a suite of bridge cases analyzed in this research. Bridge cases with difficult fit-up are highlighted. Recommendations for erection procedures are provided to facilitate fit-up. The research investigates and recommends beneficial staggered cross-frame framing arrangements that are applicable to straight skewed bridges, framing arrangements with liberal offsets around bearing lines at interior pier in continuous spans bridges, and the use of staggered versus lean-on cross-frame arrangements in straight skewed bridges. The research also addresses the impacts of cross-frame detailing methods, that is, the “fit condition” of the structure, on cross-frame forces, girder elevations, girder layovers, girder stresses, and vertical reactions in the completed bridges.

Reverse electrodialysis (RED) is a technique that can capture electrical potential from mixing two water streams of different salt concentration through permselective ion exchange membranes. Effective design of ion exchange membranes through structure optimization is critical to increase the feasibility of salinity gradient power production by RED. In this work, we present the preparation of organic-inorganic nanocomposite cation exchange membranes containing sulfonated polymer, poly (2,6-dimethyl-1,4-phenylene oxide), and sulfonated silica (SiO2-SO3H). The effect of silica filler size at various loading concentrations on membrane structures, electrochemical properties, and the RED power performance is investigated. The membranes containing bigger-sized fillers (70 nm) at 0.5 wt% SiO2-SO3H exhibited a relatively favorable electrochemical characteristic for power performance: an area resistance of 0.85 Ω cm2, which is around 9.3% lower than the resistance of the membranes with smaller filler particles. The power performance of this nanocomposite cation exchange membrane in a RED stack showed 10% higher power output compared with the membranes containing small particle size and achieved the highest gross power density of 1.3 W m-2. Thus, further optimized combination of material properties and membrane structure is a viable option for the development of effective ion exchange membrane design, which could provide desirable electrochemical performance and greater power production by RED.