Dementia affects 50 million people around the world, with 10 million new cases every year. The hunt for causes and therapies of dementia causing neurodegenerative diseases (NDDs) have gone hand in hand. An important direction for therapeutic development is to combat the aberrant amyloid aggregation of intrinsically disordered proteins (IDPs). The consensus in the field is that oligomeric intermediates formed during amyloid aggregation are the disease-causing species via their lipid membrane interactions. The heterogeneity and transient nature of intermediates have stymied efforts to study structures, membrane interactions and the mechanism by which therapies act. To this end, this dissertation has three objectives, (i)understand structural features and membrane interactions of intermediates; (ii)develop methods to isolate oligomers from cells in their native forms; (iii)develop efficient therapeutic delivery solutions. First, we employ NMR spectroscopy to resolve atomic scale structural features of a synthetic preparation of pre-fibrillar α-synuclein (αS)-intermediate, an IDP implicated in Parkinson’s disease. We find that the αS-intermediate displays a fold very similar to the fibril, although with distinct lipid interactions and side-chain arrangements. This observation is interesting in the context of the anti-parallel transition to parallel cross β-sheets which is perceived as an important step in initiating amyloid aggregation. Next, to establish accurate structure-function correlations, we propose the use of silica nanobowls to scavenge and purify membrane bound amyloid aggregates from neuronal cultures. We demonstrate with amyloid-β (Aβ) aggregates, an IDP implicated in Alzheimer’s disease, that atleast their aggregation driving domains are conserved by this method and the amount of non-amyloid contaminants is minimal. Lastly, to address the concern of minimizing side-effects and increasing efficiency of therapeutic delivery, we explore the use of magnetically modified nanobowls for targeted delivery to neurons. The three projects in this work advance the understanding of the pathological interaction of amyloid oligomers and membranes and aid in efforts to study and modulate oligomers in their native environments.
Flapping wing insects benefit from a compliant thorax that provides elastic energy exchange and resiliency to wing collisions. In this thesis, we present a flapping wing robot that uses an underactuated, compliant, transmission inspired by the insect thorax. We developed a novel fabrication method that combines carbon fiber (CF) laminate and soft robotics fabrication techniques for transmission construction. The transmission design is optimized to achieve desired wingstroke requirements and to allow for independent motion of each wing. We validate these design choices in benchtop tests measuring transmission compliance and kinematics. We integrate the transmission with laminate wings and two types of actuation, demonstrating elastic energy exchange and limited lift-off capabilities Lastly, we tested collision mitigation through flapping wing experiments that obstructed the motion of a wing. These experiments demonstrate that an underactuated compliant, transmission can provide resilience and robustness to flapping wing robots.
Medical imaging requires the perturbation of biological tissues with external radiation. Clinically, acoustic and optical methods (e.g., ultrasonography, fluorescence imaging) are attractive because they are non-ionizing and offer real-time acquisition with high resolution. Photoacoustic imaging is an emerging hybrid modality that combines the contrast of optics with the penetration of ultrasound. This dissertation presents novel strategies for the detection of aberrant biomarkers through the application of high-frequency ultrasonography, optical methods (i.e., visible/near-infrared absorbance, fluorescence, scattering) and photoacoustic imaging, with primary focuses in periodontal disease and protease detection. First, the preclinical field of photoacoustic imaging is reviewed across various disease areas for image-guided therapy, surgery, and drug delivery. The second chapter describes research advances in photoacoustic imaging specifically for drug delivery. The third chapter reviews progress to date in photoacoustic imaging for dental and oral health applications. In the fourth chapter, the clinical value of high-resolution ultrasonography is demonstrated for noninvasive and chairside measurement of anatomic periodontal metrics in a pilot case control study. Next, this work is extended to imaging the periodontal pocket in a healthy human case study using photoacoustic imaging with a food-grade contrast agent. Chapter six describes the application of a modality-independent algorithmic method for reducing motion artifacts that commonly arise during 3D photoacoustic/ultrasound imaging of the oral environment. Chapter seven describes the chemical development of a modular and activatable contrast agent that produces photoacoustic and fluorescent signal upon proteolytic cleavage by leveraging the intramolecular coupling of dye-peptide conjugates. This work is validated with trypsin as a model protease and subcutaneous photoacoustic imaging of the probe in mice. In chapter eight, the design is honed for targeting proteolytic gingipains secreted by the periodontal pathogen, Porphyromonas gingivalis, with demonstrated photoacoustic imaging of the gingipain-activated probe in ex vivo swine jaws and fluorescent activation in gingival crevicular fluid samples collected from human subjects with periodontal disease. In chapter nine, the dissertation concludes with a foray into the characterization of protein aggregates associated with Alzheimer’s disease. It is demonstrated that multispectral nanoparticle tracking analysis can utilize light scattering at multiple wavelengths to measure the nanoscale distribution of amyloid-β aggregates (size and concentration) in vitro, without interfering dyes and in real time.
Traditionally, most autism assessment instruments are based on medical models and designed to identify social communication deficits and behavioral abnormality in an individual. However, as more autistic narratives reveal the insider views of autists, some scholars and autistic activists support the neurodiversity model and assert the acceptance of autism as difference and diversity instead of deficits or impairment. With this conceptual shift, it is appropriate to rethink the validity of current autism assessment practice. Adopting contemporary validity theories, which emphasizes the ontological definition of an attribute, response process, and ethical consequences of measurement, this study examined how autism has been defined, how the definitions of autism affect the way autism is understood and assessed, and how autism assessment affects the way people define autism. Also, as a case study, the current form of Social Communication Question was revalidated following Wilson’s (2004) Four Building Block approach. The interview conducted with autistic adults and autistic people’s caregiver to examine the response process revealed how these people interpret the items in SCQ and how autism assessment tools like SCQ have affected the way they conceptualize autism and establish their self-identities.
This dissertation contains three essays studying topics in applied microeconomics. The first chapter studies the formation and the spread of crisis-driven racial animus during the coronavirus pandemic. Exploiting plausibly exogenous variation in the timing of the first COVID-19 diagnosis across US areas, we find that the first local case leads to an immediate increase in local anti-Asian animus, as measured by Google searches and Twitter posts that include a commonly used derogatory racial epithet. This rise in animus specifically targets Asians and mainly comes from users who use the epithet for the first time. These first-time ch-word users are more likely to have expressed animosity against non-Asian minorities in the past, and their interaction with other anti-Asian individuals predicts the timing of their first ch-word tweets. Moreover, online animosity and offline hate incidents against Asians both increase with the salience of the connection between China and COVID-19; while the increase in racial animus is not associated with the local economic impact of the pandemic. Finally, the pandemic-driven racial animus we documented may persist beyond the duration of the pandemic, as most racist tweets do not explicitly mention the virus.The second chapter investigate if primary care physician (physician henceforth) and patient concordance in terms of socio-economic status (SES) reduces the SES inequality in health. We exploit variations in SES concordance between physicians and patients that are induced by plausibly exogenous clinic closures. We find that SES concordance lowers low-SES patients' mortality while high-SES patients' mortality does not depend on their physicians' SES. Together, these effects translate to a 23% reduction in the SES-mortality gradient. Mortality reductions related to cardiovascular conditions are especially pronounced. We study patients' health behavior and physicians' treatment choices to explain how SES concordance reduces patient mortality. Low-SES patients with low-SES physicians receive more care at the intensive margin; making more office visits per year and receiving more services per visit. In addition, they are more likely to be prescribed Statins, adhere to diabetes check-up visits, and are less likely to have avoidable hospitalizations due to COPD, relative to comparison groups.The third chapter asks: how does employer reputation affect the online labor market? We investigate this question using a novel dataset combining reviews from Glassdoor.com and job applications data from Dice.com. Labor market institutions such as Glassdoor.com crowd-sources information about employers to alleviate information problems faced by workers when choosing an employer. Raw crowd-sourced employer ratings are rounded when displayed to job seekers. By exploiting the rounding threshold, we identify the causal impact of Glassdoor ratings using a regression discontinuity framework. We document effects from both labor demand and supply sides at equilibrium. We find that displayed employer reputation affects employer’s ability to attract workers, especially when the displayed rating is sticky. Employers respond to the rounding threshold by posting more new positions and re-activating more job postings. The effects are the strongest for firms that are private, smaller, and less established, suggesting that online reputation is a substitute for other types of reputation.
First-generation college students may experience a mismatch between their cultural backgrounds, which tend to emphasize interdependent cultural norms (i.e., group achievements, connection with others, and taking actions that foster fitting in) and universities, which tend to emphasize independent cultural norms (i.e. individual achievements, separation from others, and taking actions aimed at standing out). This cultural mismatch can create stress and lower sense of belonging for first-generation college students, which may prevent them from completing their degree. This dissertation investigates whether a targeted intervention that depicts stress as common and impermanent lowers their stress and increases their sense of belonging during the transition to college compared to first-generation college students who were given an intervention that depicts stress as something to ignore and compared to continuing-generation students who received both of these conditions. Surprisingly, it was the condition which encouraged students to ignore stress that reduced first-generation college student stress compared to multiple comparison groups both immediately following the intervention and one month later. Qualitative analysis revealed that the way in which first-generation college students related to stress was consistent with a cultural emphasis on hard independence (i.e. self-reliance and resilience).
I. A mild and affordable method for C–S couplings under environmentally responsible micellar aqueous conditions with low nickel loadings is presented. The scope includes various heterocycles and API-related structures. Moreover, the practicability was demonstrated by a gram-scale synthesis with low residual nickel in the products detected after standard purification. Opportunities to use the aqueous medium for tandem, 1-pot applications are also demonstrated.II. Introducing the use of nanomicelles in transaminase-catalyzed chemoenzymatic reactions enables a faster reaction rate and minimizes enzymatic inhibition. Furthermore, it allows chem- and bio-catalytic reactions to run in a single reaction vessel without switching solvents. An anti-dementia drug (S)-rivastigmine is synthesized efficiently with this new technology.III. A green chemistry-based synthesis of lapatinib was developed. A streamlined 5- step synthesis in 3 pots was carried out in water and ethanol as the only solvents. This unprecedented method represents an opportunity for shifting from petroleum-based solvents to green solvents. Additionally, a less precious metal catalyst was involved using mild reaction conditions with less reaction time.IV. Fluorinated compounds are one of the most important categories in pharmaceuticals. A convenient method has been developed for the synthesis of difluorocyclopropenes and difluorocyclopropanes using commercially available TMSCF2Br in the absence of solvents. Complex alkenes and alkynes can readily undergo [2+1] cycloaddition to difluorocarbene with extraordinarily low E Factors.
Political discourse is inherently abundant with metaphors, which speakers use to reframe complex issues to the public in more concrete, familiar, and approachable terms. As research has shown (Charteris-Black, 2004, 2005; Lakoff, 2002, 2004, 2010; Musolff, 2000), the different ways of metaphorically framing a subject can influence reasoning and decision-making. Thus, metaphors hold vast potential for manipulating the public by groups of authority. In the last twenty years, Europe has seen a rise in far-right parties entering government and securing seats in European Parliament. These parties have become powerful forces in Europe’s political landscape, garnering more voter support and polarizing public debate. This study explores the metaphorical expressions used by the German right-wing populist party, Alternative für Deutschland (AfD), to conceptualize relevant political issues before and after the 2017 federal election, in which they secured 12% of the seats, making them the third biggest party in the 19th German Bundestag. Building on two approaches, Conceptual Metaphor Theory (Lakoff & Johnson, 1980) and Critical Metaphor Analysis (Charteris-Black, 2004, 2005), this study not only identifies and analyzes the conceptual metaphors and source domains utilized in the AfD’s discourse on topics such as Europe and the state of the European Union, the Bundestag, and immigration, but also examines shifts in metaphor usage over time. Consequently, this work argues that an analysis of the metaphorical depictions illuminates the underlying ideological foundations of the party and provides insights to better understand the role of such rhetoric in persuasion and manipulation in the political sphere.
This dissertation investigates several instances of the micro-communication landscape across the spectrum of hazards, from the quotidian to the exotic, by offering a deeper understanding into the communication process via retransmission and communication dynamics. Chapter 2 focuses on hazard communication during quotidian and atypical hazards in the context of the National Weather Service's use of Twitter from 2009-2021. We investigate several micro-structural, content, and style related message features to understand the properties that make a message more likely to be retransmitted. Chapter 3 looks into communication occurring in the range of exotic and atypical end of the spectrum by studying public-health communicators on Twitter during the first eight months of the unfolding coronavirus disease 2019. Finally, Chapter 4 focuses solely on the exotic end of this spectrum in an investigation of 17 communication networks during the unfolding events of the 2001 World Trade Center Disaster. We model 17 dynamic radio networks to understand the role that the social mechanisms of preferential attachment, Institutionalized Coordinator Roles, and conversational inertia play in the communication process of a disrupted environment. This dissertation provides a holistic overview of hazard communication across this spectrum, providing into the kinds of micro-communication strategies and processes that are unfolding. We hope it inspires future research in this area of critical importance.