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FEASIBILITY STUDY OF TOWER DESIGN AND VIBRATION SUPPRESSION FOR AN ANTARCTIC INFRARED TELESCOPE
No full textThere is increasing interest to develop a dedicated near-infrared (NIR) observatory in Antarctica due to the advantages of a colder, darker sky in the NIR band and because the turbulent ground layer, responsible for seeing, is limited to the first 30 m above the ice shelf. A telescope mounted atop a 25 to 30 m tower will have enhanced performance by operating at the top of the boundary layer and unprecedented sensitivity due to the Antarctic climate.
Cryoscope is one such telescope and will be mounted atop a 30 m tower at Dome C, Antarctica. This presents a challenge for image stability since vibration-induced image motion must be less than 0.1 arcsec while the tower is subjected to 10 m/s wind buffeting. Seven tower designs were assessed using structural analysis programs to determine each tower’s stability and natural frequency from wind loads determined using ASCE Standards 7-16 and wind data from Dome C. Power law analysis was conducted to evaluate the relationships between stability and mass if a tower was linearly scaled. Furthermore, in case the tower designs provide insufficient stability, vibration isolation mounts are explored to provide additional compensation, mainly damping mounts and friction mounts. In addition, we hold in reserve the possibility of active cancellation of forces on the telescope by applying torques with direct drive motors in response to forces measured by rotary flexures and encoders incorporated into the bearing mounts. The primary purpose of this work is to assess the feasibility and degree of difficulty of designing a 30 m tower for Antarctica with sufficient stability through passive and active mitigation methods while considering construction and transportation constraints
DESIGN OPTIMIZATION OF FIBER-REINFORCED COMPOSITE LAMINATES WITH MANUFACTURING CONSTRAINTS
No full textFiber reinforced composites have been widely used in many industries due to their relatively low mass and excellent mechanical properties. Although significant advances have been made in the manufacturing of composites, existing design tools are not well-suited to leverage these advances. This thesis looks to advance design optimization methods for structural composites and stacked composite laminates on two fronts: (i) to provide composite designers effective tools for systematic integration of manufacturing constraints in the design, and (ii) to explore the benefits of optimizing variable stiffness on different objectives including stiffness and strength.
Current studies on the design of stacking sequences in variable stiffness laminates mainly focus on optimizing fiber orientation in the form of discrete patches, either constant on the entire layer of a structural panel or rapidly varying across a layer, the former sacrificing design freedom and structural performance and the latter leading to overly complex and potentially unmanufacturable designs. We propose an integration of Heaviside Projection Method (HPM) with Discrete Material Optimization (DMO) to provide formal control over the length scale and interaction of structural features, holes, and patches of constant orientation, hence providing designers with more flexibility in balancing structural performance and design manufacturability. Extensions of the methodology beyond composites will also be demonstrated, including optimizing the arrangement of discrete objects within a geometric envelope, exhibiting strong similarities to classical packing problems.
In contrast to laminate stacking, Automated Fiber Placement (AFP) technologies, such as tow steering, enable manufacturing of composites with curvilinear fiber paths, increasing design freedom yet imposing restrictive manufacturing constraints. Here we consider the topology optimization of such structural composites and introduce manufacturing constraints on fiber paths, including limits on path curvature and divergence to prevent fiber overlaps and gaps. Various design constraints and objectives are considered, including various failure modes related to strain and stress states
Strategies to Reduce Serious Infections in High-Risk Solid Organ Transplant Recipients
No full textSolid organ transplant (SOT) recipients endure frequent serious infections owing to multifactorial immunosuppression. This population, however, contains subgroups with distinctive immunodeficiencies including persons with HIV (PWH) and those with poor vaccine responses for whom infection risks may differ. This dissertation focuses on identifying high-risk phenotypes and strategies to reduce infections including immunosuppressive optimization and targeted prophylaxis.
The first work analyzes data from the HOPE in Action trials of HIV-donor-to-HIV-recipient SOT (Chapter 2) to elaborate the profile of donors with HIV. Certain coinfections (hepatitis B, syphilis, cytomegalovirus) were more prevalent among donors with HIV. Most donors were taking effective antiretroviral therapy (ART); 20% showed severe immunosuppression. Although HIV drug resistance mutations were frequent, resistance that might evade standard recipient ART was rare (2%). Overall, a minority of donors appeared high-risk for opportunistic infection transmission, though prophylaxis can be optimized.
The second work analyzes a national registry of 1225 PWH undergoing kidney transplant (HIV+ KT) (Chapter 3) evaluating the relationship between corticosteroid maintenance and organ rejection, treatment of which predisposes to infection. Early steroid withdrawal (ESW) varied widely among centers (0-90%), and was associated with increased rejection (18.4% vs 12.3% at one year; aHR:1.02.1.39.1.90, p=0.03); graft failure and mortality were not increased. Tailoring ESW to lower alloimmune risk PWH may mitigate the HIV+ KT infection-rejection cycle.
The final work (Chapter 4) is a clinical trial evaluating immunoprotection phenotypes following third SARS-CoV-2 mRNA vaccination in high-risk KT recipients. Preceding negative SARS-CoV-2-spike antibody (anti-RBD) after two-dose vaccination was strongly associated with poor responses to third doses; 45% remained seronegative, none showed Omicron variant neutralization. Immunogenicity varied considerably; 9% showed negative global (anti-RBD/T cell) responses, associated with high-dose mycophenolate use, while 40% showed global positive response; SARS-CoV-2-spike-specific CD4+ T cell expansion appeared necessary, but not sufficient for anti-RBD response. Breakthrough infections occurred in 16%, concentrated among poor anti-RBD responders, emphasizing need for alternative vaccine strategies to improve post-transplant COVID-19 immunoprotection.
These findings reinforce complementary roles of observational and trials datasets in understanding infection risks in SOT subpopulations. The COVID-19 pandemic highlights needed rigor for evaluating immunodeficiencies in generating personalized strategies to prevent serious post-transplant outcomes
THE LONG AND SHORT OF IT: GENOME ASSEMBLY AND EPIGENETICS WITH THIRD-GENERATION SEQUENCING
No full textThis dissertation focuses on methods development for "third-generation" (long-read) sequencing technologies. With an emphasis on nanopore sequencing, this work discusses strategies and applications for genome assembly of both non-model organisms and humans. The methods described here make extensive use of hybrid genome assembly methodologies for generating chromosome level gapless genomes as well as native oxford nanopore sequencing for investigating epigenetics. We use these approaches to evaluate the following non-model organisms: the tobacco hornwom moth (Manduca sexta) and the ruby-throated hummingbird (Archilochus colubris). Lastly, we apply these methodologies to the human genome to generate the first gapless telomere to telomere assembly of a human genome and provide a framework with which to investigate the most elusive regions of the human genome, granting insights into epigenetic regulation
HOUSING DISCRIMINATION AND HEALTH: EXPLORING THE RELATIONSHIP BETWEEN STRUCTURAL RACISM AND MENTAL HEALTH AMONG BLACK AMERICAN ADULTS
No full textStructural racism contributed to the construction of housing environments for Black American populations. Housing discrimination is one form of structural racism. Discriminatory housing policies and practices that have limited people of color from
healthy housing environments include redlining and gentrification. To advance equitable health and combat oppressive systems, research must consider how structural racism
in the form of housing discrimination, both past and present, influence mental health among Black adults. This dissertation used multiple methodologies and data sources to understand the influence of redlining and gentrification on Black mental health. A scoping review was conducted to synthesize existing evidence of the mental health implications of housing discrimination (e.g., redlining and gentrification) among an adult Black population. Geospatial analyses were conducted to characterize gentrification in Metro
Detroit and examine the spatial relationship between historical redlining and gentrification. Principal component analysis in conjunction with regression models were used to examine the influence of the housing environment on posttraumatic stress disorder (PTSD) among Black adults in Detroit, Michigan. Results showed that redlining and gentrification often have a negative impact on the mental health of Black adults and that measurement of these exposures lack consistency. Within Metro Detroit, gentrification is happening slowly and further away from the urban city center. Although most of the metropolitan area experienced historical redlining, findings from the spatial analysis suggested that the relationship
between gentrification and historical redlining only occurred on a local scale. Findings did not support a relationship between the housing environment and PTSD among an
adult Black sample. Overall, redlining and gentrification created housing environments that are often more harmful to Black mental health. Given that these influences occur over space and time, public health should consider historical influences on contemporary health and the use of geospatial methods to better understand and improve mental health among Black populations
Fatigue in Heart Failure: A Secondary Data Analysis of the Atherosclerosis Risk in Communities (ARIC) Study
No full textFatigue in HF is prevalent and distressing and may have prognostic implications. We currently have a limited understanding of fatigue in HF and limited interventions to for treatment. This study aimed to identify unique subtypes of general and exertional fatigue, describe the sociodemographic, clinical, and cardiac structural and functional characteristics of each subtype, and determine the association of fatigue subtype with clinical and patient-reported outcomes in those with prevalent HF in the Atherosclerosis Risk in Communities (ARIC) study.
We included those with prevalent HF at visit 5 of the ARIC study, of Black or White race, and provided fatigue surveys (n=1,065). The sample was 54% female, 38% Black, 89% HF with preserved ejection fraction (HFpEF), with a mean age of 77 ± 5.5 years. Using latent class analysis of general and exertional fatigue scales, we identified 4 subtypes of fatigue: high general/high exertional fatigue, moderate general/moderate exertional fatigue, high general/ow exertional fatigue, and low/no fatigue.
Compared to low/no fatigue, high general/high exertional fatigue was associated with cardiometabolic risk and sociodemographic factors. Moderate general/moderate exertional fatigue was associated with coronary heart disease and atrial fibrillation. High general/low exertional fatigue was associated with female sex and increased depressive symptoms. One measure of diastolic dysfunction was associated with high general/high exertional fatigue (OR = 1.8; 95% CI = 1.12, 2.91) and moderate general/exertional fatigue (OR = 1.4; 95% CI = 1.10, 1.96).
High general/high exertional fatigue was associated with worse physical (Beta = -8.6; p<0.001) and mental (Beta = -14.0; p<0.001) quality of life (SF-12 scale). Moderate general/moderate exertional, as well as high general/low exertional fatigue were associated with worse physical quality of life (Beta = -5.9, p<0.001; Beta = -2.5, p=0.032, respectively). High general/high exertional fatigue was associated with higher hazard of HF admission (HR = 2.1; 95% CI: 1.3, 3.6) and death (HR = 2.3; 95% CI: 1.0, 5.0).
These findings suggest that there may be non-cardiac and other unknown driving mechanisms of general and exertional fatigue in HF that require further study. Standardized fatigue assessment in HF clinical care may supplement the assessment of HF severity in improving outcomes
POSE ESTIMATION AND SHAPE ABSTRACTION FROM A PROBABILISTIC AND GEOMETRIC PERSPECTIVE
No full textIn recent years, we have witnessed great progress in how intelligent machines perceive the environment. To humans, perception is understanding the surroundings by interpreting sensing (e.g. vision, haptics, language) into semantic primitives, which are logistically understandable and mutually communicable. For machines, in their current form, perception can be defined as a process of formalizing a mathematical representation of the environment, from which higher-level tasks can be efficiently planned, modeled, and solved. Nowadays, most artificial intelligence (AI) systems rely on data-driven neural networks to establish versatile implicit representations. However, the learned representations are, to a large degree, task-specific, cumbersome, and weak in generalizability. Moreover, a learned representation is closed within itself, i.e., rarely interpretable and communicable to human beings or other AI systems. This dissertation focuses on achieving interpretable visual perception through geometric analysis and probabilistic modeling.
In achieving the goal, this thesis targets two fundamental visual perception problems: pose estimation and shape abstraction. For the first problem, the author proposes a geometry-guided probabilistic model to realize an accurate and robust point cloud registration, which is the basis for understanding the pose relationship between visual inputs. Furthermore, the author proposes an unconstrained optimization method on a matrix Lie group to estimate the rigid transformation efficiently. Next, the methodology is extended to extract compact geometric primitive-based abstractions from visual inputs. This task goes beyond pose estimation and further includes the shape-level description of the visual input. Geometric primitives called superquadrics are studied and utilized as the basis for perceiving the environment. The primitive-based shape abstraction is concise and fully analytical in mathematics, which makes it a desirable standard messenger connecting perception and higher-level tasks such as segmentation, robot grasping, collision detection, motion planning, and physical simulation. Furthermore, the approach is learning-free, inherently generalizable, and interpretable, yet still possesses competitive expressiveness compared to learning-based representations
REGULATION OF STRAND SCISSION IN DNA TOPOISOMERASE II: BIOCHEMICAL, COMPUTATIONAL, AND STRUCTURAL STUDIES
No full textType II topoisomerases are essential enzymes that generate transient breaks in chromosomes to pass one double-stranded DNA segment through another, supporting a number of critical processes including DNA replication, transcription, and chromosome segregation. In addition to their cellular utility, type IIA topoisomerases are targets of clinically validated antibacterial and anti-cancer agents. The most commonly used class of topoisomerase antagonists are compounds known as ‘poisons,’ which stabilize cleaved-DNA intermediates and convert the enzyme into a genotoxic agent. To better understand the action and selection mechanisms of various poison compounds, I performed biochemical analyses with a series of eukaryotic type IIA topoisomerase variants that impart drug resistance. I also determined the first structure of a human topoisomerase II breakage-reunion region in complex with oligonucleotide DNA and a fluoroquinolone compound. This structure revealed a unique mode of binding compared to previously published structures, identified interactions which may account for specificity of individual fluoroquinolone compounds for human topo II, and highlights molecular contexts that may be useful in the development of novel topoisomerase poisons for chemotherapeutic treatments. To better understand mechanisms that underlie poison sensitivity, I characterized the in vitro activities of human topoisomerase IIβ (hTOP2β) variants sensitized to etoposide poisoning and uncovered a mechanistic interplay between elevated sensitivity to poison compounds and the innate cleavage propensity of the enzyme in the absence of drug. Computational analyses helped to delineate some of the mechanisms underlying breakage-reunion dysfunction and were subsequently used to identify cancer cell samples harboring DNA-damaging hTOP2β variants, highlighting the potential of the enzyme to act as a clastogen capable of maintaining or driving cellular transformation. To better understand how topoisomerases are fundamentally regulated to prevent unwanted breaks, I performed biochemical analyses showing that the ATPase elements of type IIA topoisomerases are not required for strand passage activity, but that their presence moderates aberrant cleavage activity by the enzyme’s DNA binding and cleavage elements. These data lend support to a longstanding hypothesis in the field that the ATPase elements of type II topoisomerases may have been acquired in the course of evolution to suppress erroneous DNA damage by the enzyme
AN ANALYSIS OF PERCEIVED DISCRIMINATION AND ALLOSTATIC LOAD AMONG LATINO SUBGROUPS AND THE INFLUENCES OF OPTIMISM AND ETHNIC IDENTITY
No full textAbstract
Statement of the Problem: Chronic exposure to discrimination and its association with heightened stress response is considered one of the underlining mechanisms through which perceived discrimination affects one’s physical health. US Latinos are underrepresented in studies exploring the effects of discrimination exposure on physical health outcomes and whether resilience and coping can minimize these potentially harmful effects. This study aims to better understand Latino subgroup differences in response to discrimination and the effect of culturally relevant resilience and coping resources.
Methods: Data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and its Sociocultural Ancillary Study (SCAS) was analyzed to examine the association between four aspects of personal discrimination and allostatic load (AL) scores derived from 16 different biomarkers involved in stress response. The analytical sample comprised 5312 Latinos, including Dominicans (N= 529), Central Americans (n=548), Cubans (n=775), Mexicans (n=2079), Puerto Ricans (n=879), and South Americans (n= 346). First, an AL latent measurement model was assessed and fitted to a proposed 6-factor hierarchical CFA model. Next, group discrimination direct and indirect effects on AL through self-reported ethnic identity and the association between optimism, group discrimination perception, and AL were examined.
Results: Puerto Ricans consistently reported the highest and Cubans reported the lowest discrimination scores across all personal domains. AL was highest among Puerto Ricans compared to Dominicans, Central Americans, Mexicans, and South Americans. Perceived discrimination was not associated with higher AL scores for any of the six Latino groups in fully adjusted models. Higher levels of group discrimination perception were associated with significantly higher AL while controlling for covariates and as well as Latino group membership. The relationship between group discrimination and ethnic identity was significant and in the hypothesized positive direction; however, indirect AL effects through ethnic identity were not significant. As hypothesized, higher levels of optimism were associated with lower perceptions of group discrimination and significantly lower AL.
Conclusion: Understanding how stress arising from racialized experiences impacts Latino health can inform nurse-led interventions to mitigate the harmful effects of discrimination exposure. Findings support a biopsychosocial approach to discrimination research among Latinos that can address health behaviors
Silicosis Trails: Law, Medicine, and the Corrosion of the Laboring Body in Turkey
No full textThis dissertation ethnographically explores how a state-led expansion of access to medical care for workers in Turkey shapes occupational health litigation in courts. It investigates how the embeddedness of law and governance in medical field fashions disease ontology and patient experience by producing diagnostic uncertainties. The arch of the dissertation’s argument lays out the trajectories through which claims on behalf of workers that their ill health is caused by work conditions come to be articulated and adjudicated in the movement between medicine and law in the context of Turkey’s Health Transformation Program of 2003. It asks when legal rights have been expanded for workers to claim compensation for occupational diseases, why are so few cases decided in favor of workers? This dissertation argues that the underrecognition of occupational diseases stems from the divergences between the medical and legal understandings of the cause-effect relationships that establish the etiology of diseases. Instead of attributing these divergences between medicine and law to the epistemic cultures of each field separately, this dissertation illustrates how the intersection of different ways of defining causation leads to volatility in diagnostic knowledge across medical, bureaucratic, and legal institutions.
Based on eighteen months of multi-sited ethnographic research in occupational diseases hospitals, courts, workplaces and households, this dissertation moves anthropological engagements with disease ontology and patient experience beyond the patient's bedside. It brings out the signal role of the role of law in conceptualizing occupational disease as produced within specific health systems. In the case of occupational health litigation in Turkey, this dissertation demonstrates how disease ontology depended not only upon negotiation between subfields of medicine but also on expert testimonies in courts and reviews by bureaucratic institutions. The major contribution of this research is to show how the embeddedness of law and governance in medical uncertainty can deflect state and employer responsibility for occupational diseases and cast worker suffering as agentless and intractable