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Development and validation of a multiwavelength optical system for the dosimetry and therapeutic use of antimicrobial photodynamic therapy
No full textThe risk and burden of treating skin and soft tissue infections using antibiotic therapies is increasing due to the rising incidence of methicillin-resistant Staphylococcus aureus and other Gram-positive, multidrug-resistant bacteria. Antimicrobial photodynamic therapy (aPDT) has shown promise in treating skin infections without inducing new resistances. In this regard, it has recently been discovered that Gram-positive bacteria utilize a noncanonical method of synthesizing heme that results in the accumulation of coproporphyrin III (CPIII) instead of the usual protoporphyrin IX (PPIX). While CPIII and PPIX are both porphyrin molecules, and thus share many similar characteristics, the efficacy of properly utilizing CPIII as a photosensitizer is poorly understood. Thus, the first goal of this work was to gauge the maximum efficacy that can be achieved using CPIII-mediated aPDT. The optical parameters of the treatment were optimized and the resulting dose-responses for the aPDT of S. aureus were characterized. The results were then used to predict the treatment efficacy at different depths in the skin.
One of the major limiting factors in developing effective clinical PDT treatments is the lack of accurate and predictive dosimetry. Current measurement techniques do not provide accurate, real-time, and spatially-resolved monitoring of photosensitizer or oxygen concentrations in the target tissue without halting the treatment. To address this, the second goal of this work was to develop a combined treatment and dosimetry system that employs fluorescence imaging and spatial frequency domain imaging (SFDI), a modality that leverages patterned illumination to produce optical property maps, to monitor implicit and explicit dosimetry parameters. To enable the validation of the system, a new method of producing broadband, tissue optical phantoms was first developed. Phantoms made using this method were then used to determine the impact of sub-diffuse scattering on the accuracy of SFDI at different combinations of polarization and scattering phase function. Finally, the overall performance of the combined system was assessed, including its ability to produce quantitative fluorescence images. This system, along with the characterization of CPIII-aPDT, will allow for the development of effective alternatives to treating skin infections without antibiotics, helping to prevent further development of antibiotic-resistant bacteria
An Opportunity for Greater Professionalism in the United States Chaplain Corps
No full textDivinity School Doctor of Ministry in Integrative Chaplaincy Final ProjectsProfessionalism in the United States Navy Chaplain Corps is lacking. While there is ample work explaining and codifying what a chaplain should do and be, in practice the isolated nature of Naval Chaplaincy limits accountability. Autonomy creates individualism that fails to adhere to agreed upon principles.
When chaplains do work together, conflict is common, and resolution is often insufficient. Outside investigators resolve conflicts and chaplains are not involved in holding the community accountable. Time that is wasted by conflicts causes the Chaplain Corps to lose credibility and opportunity to care for others, thus impeding the mission of the Chaplain Corps.
This project explores actions that could be taken to minimize conflict, improve resolution, professionalism, and accountability in the United States Navy Chaplain Corps
Integrating Clinical Data and Genetic Variation to Understand Comorbidity Profiles and Generate Biologically Optimized Phenotypes
No full textCollectively, this work has centered around combining clinical and genetic information to provide insights about disease from various scopes of view. Specifically, it has addressed multimorbidity, comorbidity, and heritability through the development or employment of novel approaches that attempt to further the promise of precision medicine. We compared electronic health records across two major healthcare systems: Vanderbilt University Medical Center and Massachusetts General Brigham to establish multimorbidity networks that validated consistency across institutes despite regional differences in demographics and medical practice. We used this resource to explore comorbidities of schizophrenia to determine which ones were most likely to be easily modifiable due to a lack of shared genetic etiology. Thus, indicating other drivers such as adverse treatment effects, unhealthy behavior, or environmental factors. Then we looked at how to optimize heritability of various diseases through different phenotyping strategies using natural language processing of clinical notes in electronic health records. These showed promise in highlighting overlooked small effects of already known variants and provided potential for identifying previously unassociated single nucleotide polymorphisms. The current health care paradigm is centered around treating conditions through specialists in more of a piecemeal than holistic way and our work highlights the benefits of taking these complex relationships into account
Essays Relating to the Dynamics of Power and Policy Differences between States in the International System
No full textThis dissertation consists of three papers related to the differences in power {power gap} and policy preferences {alignment gap} between states in the international system. The first paper considers the issue of moral hazard that can arise in asymmetric alliances when both the power gap and the alignment gap between the two partners are significant. ln this paper; I demonstrate that the stronger ally in the relationship can manage the alliance to maintain its ideal interests by inducing costs on its protege, conditional on conflict initiation, much like a deductible in insurance terms. The second paper takes a broader view of the power and alignment gap implications, assessing their impact on international system structure. ln this paper, I argue that polarity, conventionally defined by the number of polar powers in the system, only accounts for the power gap between states, limiting the theoretical mechanisms used to explain state behavior. I propose a new structural concept and measure that captures both the capability and desire of major powers to oppose one another. I define this new measure, "polar tension", as the degree to which international policy space is contested. The implicit threat generated by this tension presents a new mechanism for interpreting state behavior. The third paper assesses the effects of polar tension on asymmetric alliances. I find that as polar tension rises, the protege states' alignment with its major power protectorate increases. The level of alignment depends on the prot6gd's prioritization of the common general interests, which corresponds with its selection into a bilateral or multilateral alliance. l find that states in multilateral alliances increase alignment as polar tension increases, while those in bilateral alliances do not. The dynamics associated with the power and alignment gap between nations drive behaviors at the state-to-state and system levels. By assessing these forces, this dissertation contributes to the rich literature on asymmetric alliances and international system structure, while presenting relevant international policy implications
Organizational Structure and Empowerment in Horizontal Grassroots Movements: Case Study of Karachi Bachao Tehreek
No full textThere is an increasing interest in horizontally structured grassroots organizations, but there is a lack of in-depth case study analyses of how such organizations function and evolve - especially in the geographic context of Pakistan. Using the case of Karachi Bachao Tehreek (KBT), which is a grassroots organization that includes activists and residents resisting evictions in Karachi, Pakistan, the thesis focuses on these research questions: the organizational structure of KBT; internal challenges related to empowerment of mutasireen (people affected by demolitions); and external challenges to grassroots organizing in Pakistan. I conducted 11 semi-structured, in-depth interviews with 13 members of KBT. The data were analyzed through grounded theory method and coding. While KBT claims to maintain a leaderless horizontal structure, I found that informal hierarchy emerges naturally in the absence of formal structure. KBT has been successful at empowering mutasireen through its internal structural aspects, such as by providing opportunity role structure and subgroup formations. The structure of committee subgroups also allows KBT to remain flexible and sustainable in a resource scarce and unpredictable environment. However, KBT also faces various challenges, including state violence, burnout and lack of funds. Due to major interpersonal conflicts, KBT has subsequently felt the need to restructure and become more formalized. This move towards formalization is consistent with resource mobilization theory. Through this restructuring, there is also potential for KBT to move towards the model of community organizing. Embedded in Pakistan’s context, the research provides important lessons on successful grassroots organizing practices along with the challenges that arise in this work. This research can help KBT and other organizations improve their organizing practices, and also fills an important gap in the literature of social movements and grassroots organizing in Pakistan. However, additional research is still required on grassroots organizational structure in different contexts, the challenges they face and how they maintain the balance between having an informal or formal structure
Investigation of Hippo Pathway in Proliferation, Repair, and Injury Response of the Retinal Pigment Epithelium
No full textThe retinal pigment epithelium (RPE) is a monolayer of pigmented cuboidal cells that separates the retina from the choroid and is crucial for vision. Defective RPE function and RPE atrophy can often cause age-related macular degeneration (AMD), one of the leading causes of blindness in the elderly population globally.
Although the healthy adult RPE maintains many properties of classic barrier epithelia, it does not retain the capacity to undergo cell turnover and self-renewal. Instead, the RPE supports tissue homeostasis via long-term survival. However, due to the growth of the eye and cell death throughout aging, RPE cell density often decreases over time. Furthermore, as the RPE ages, it undergoes functional and structural changes that often lead to RPE dysfunction and atrophy. There is evidence that the RPE has potential to self-repair and proliferate, but the molecular mechanisms driving this process are poorly understood. The Hippo signaling pathway plays an important role in the regulation of cell proliferation, differentiation, apoptosis, and tissue regeneration. This dissertation investigates the role of the Hippo signaling pathway in regulating RPE proliferation, repair, and injury response.
We investigated how Neurofibromin 2 (NF2) a known upstream regulator of the mammalian Hippo pathway, regulates RPE proliferation and optic fissure closure during eye development. Here, I demonstrate that NF2 promotes nuclear YAP localization in the ventral RPE, and results in overproduction of dorsal RPE cells and ectopic proliferation in the ventral RPE. I also interrogated whether I could use this approach of genetically disrupting Nf2 in the adult RPE to promote RPE repair and proliferation after injury. I demonstrate promising preliminary results that the RPE can proliferate after injury; however due to confounding challenges, I determined that NF2 is not a robust regulator of RPE proliferation in the adult tissue. However, the Hippo pathway is still a promising approach to investigate endogenous proliferation, as expression of YAP5SA results in proliferation in the RPE and decreased injury. Last, it has been previously shown that YAP is important for RPE fate and maintenance but can also play a role in epithelial-mesenchymal transition (EMT) of other tissues. In vivo, loss of Yap in the RPE results in loss of RPE characteristics and indication of EMT, but YAP is required for RPE EMT to occur in vitro. Thus, I interrogated whether YAP is critical for regulating RPE injury response and EMT after sodium iodate in vivo. Here, I determine that YAP appears to be important for promoting EMT in the RPE after injury, as haploinsuffiency and loss of Yap results in a dampened injury response
Design and evaluation of a lower-limb exoskeleton to augment human swimming
No full textWhile lower limb exoskeletons for aboveground locomotion have been developed, few attempts have been made to develop an exoskeleton to augment human swimming. The design of exoskeletons for aboveground activities has benefitted greatly from experimental efforts characterizing the kinematics and kinetics of motion; however, simple data characterizing the biomechanics of human finned swimming are not readily available. This work first presents the design and evaluation of an off-board robotic finned swimming testbed and describes experiments conducted to explore the exoskeletal joint-space requirements to augment the finned swimming motion. These data are subsequently used to inform the design of a lower limb exoskeleton to augment human finned swimming. The exoskeleton is first used as an unmanned robotic swimmer to verify and extend the kinematic and kinetic findings previously projected with the off-board actuation testbed. Specifically, the testbed with off-board actuation was limited in torque and power, and also required modeling to estimate resulting thrust, whereas the setup with onboard and enhanced actuation was better able to explore the range of torque and power associated with human finned swimming, and was also equipped to directly measure thrust. The resulting data characterizes the torque, speed, and power requirements of the finned flutter kicking motion and associated thrust production, which is essential for the design of a lower limb exoskeleton to assist or augment the human finned swimming. The exoskeleton was then implemented and evaluated on human participants to assess the quality and extent of augmentation. Two control methodologies are presented. The first enables a human user to implicitly control hip joint torque and power delivery, and the second allows a human to swim with little to no effort. For each, experimental results that demonstrate effective joint-level torque amplification and substantial thrust augmentation are presented. This work constitutes the first demonstration of a lower limb exoskeleton to augment to the thrust production of a human swimmer
Ultra-Low-Overhead Arbitrary-Waveform Generation as a Circuit Macro: Augmenting the Characterization of Radiation-Induced Transient Effects in Highly Scaled Integrated Circuits
No full textArbitrary waveform generators (AWGs) are not typically feasible as subsystems on integrated circuits due to their size and complexity, but they are versatile circuits that are broadly useful. The purpose of this work is to show that by prioritizing minimal overhead and designing for targeted performance, as necessary for the application, it is possible to create a reusable on-chip AWG circuit macro in a small form factor. To support this claim, details and results are provided for a proof-of-concept implementation in a 45nm partially depleted silicon-on-insulator process. The presented design is able to achieve a small size by eliminating the complicated calibration and filtering circuitry commonly used in contemporary designs, instead relying on intrinsic accuracy of the base circuits. The reliability and accuracy of the AWG are driven by careful design down to the layout level, including the development of a variant of the traditional common-centroid layout technique called distributed-centroid layouts (DCL), which addresses the importance of bias circuitry in mitigating process-induced mismatch. A custom simulation workflow was developed to investigate the effectiveness of this technique at the circuit level as compared to other designs from the literature. The proof-of-concept circuit was designed to improve the characterization of radiation-induced transient effects in highly scaled integrated circuits by providing built-in self-test and hardware-emulation capabilities to a custom photocurrent measurement circuit (PMC). Details of this specific application are explored in detail, along with experimental measurements made using flash x-ray and pulsed laser sources. Alternative AWG designs that might benefit a broader application space beyond radiation effects are also provided
Effects of Particle Hydrodynamic Behaviors on the Electrochemical Performance of Slurry Electrodes
No full textIn flowable slurry electrodes, charge is transferred from stationary electrodes to particle clusters through hydrodynamic interactions; however, so far little is known about the particle dynamic behavior under continuous flow. This dissertation aims to uncover new understandings about these behaviors and their effects on the electrochemical performance of flowable electrodes through numerical and experimental methods.
Using Stokesian dynamics, we explore the effects of conductive additive on the charging of a slurry electrode and present a unified expression for the dynamically varying electrical network of particles. The results suggest that at lower concentrations of activated carbon particles, the conductive additive enhances charge transfer by filling interstitial spaces and establishing contacts between carbon particles; however, at higher concentrations, the benefits are not as clear since direct contacts between particles dominate the charge transfer process.
Next, a novel microfluidic electrochemical flow capacitor (µ-EFC) platform was constructed using transparent materials to directly visualize particle hydrodynamics and measure electrochemical charging and discharging performance. It is found that as the flowrate varies, particle distribution along the channel height is significantly affected as particles tend to migrate away from the stationary electrodes where the shear is high; however, higher rates of shear also increase the number of interactions between particle clusters. These competing effects lead to a non-monotonic trend in the normalized charging and discharging current versus flowrate plot.
Finally, the µ-EFC design was iterated to include three-dimensional (3D) gold electrodes of varying lengths to directly visualize particle behavior in the boundary layer around stationary electrodes and the resulting electrochemical performance. These experiments revealed distinct particle flow behaviors at each 3D electrode length, and the electrochemical data is clearly affected by the inclusion of 3D electrodes. Specifically, the average resting charging current was increased by a factor of 4.8 and the discharging current was increased by a factor of 2.8.
These novel findings have significantly enhanced our understandings of the hydrodynamic effects on the electrochemical performance of flowable electrodes and pave the road for optimal operation of EFCs with slurry electrodes