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Genetics and Treatment of Early Onset Alzheimer's Disease
No full textEarly-onset Alzheimer’s disease (EOAD) places a significant burden on families, caregivers, and patients. EOAD begins as young as 30 years old when patients are in the middle of their lives and disrupts their futures. The exact genetic background of EOAD remains a mystery, with just 10% of cases having known genetic causes from pathogenic APP, PSEN1, and PSEN2 mutations.1 We have conducted a literature review of the known genes implicated in EOAD, including APP, PSEN1, and PSEN2, as well as other candidate genes that have been seen in some individual families or cases of EOAD. Members of EOAD families with known mutations in APP, PSEN1, or PSEN2 can get genetic testing in preparation for their potential diagnoses. Identifying more genes whose mutations could be causative of EOAD is of public health importance because it will allow for more causative mutations available for testing, allowing individuals to prepare for the burden that will be placed on their families and caregivers. Notably, genes such as SORL1 are being identified in more and more EOAD families and are emerging as potential rare monogenic causes of EOAD. Many pathways are implicated in developing the hallmarks of disease – amyloid plaques and neurofibrillary tangles – and variants in genes across these pathways have been identified as potential risk variants. Treatments thus far have focused on amyloid plaques without large clinical benefit, creating a call for more focus on controlling the spread of neurofibrillary tangles. Identifying more implicated genes could provide the healthcare system and researchers with more information on the mechanism of disease and the ability to generate better treatments. Caregivers and families of patients feel most of the burden that comes with the diagnosis of EOAD. While patients suffer, they are the ones footing the healthcare bills and providing daily care while watching their loved ones deteriorate. Further research in this area will only serve to alleviate some of the stresses that come with the unanswered questions present in an Alzheimer’s disease diagnosis before the age of 60
Designing Zeolites for More Sustainable Natural Gas Utilization and Evaluating Metal-Support Interactions to Enhance Catalyst Stability
No full textHeterogeneous catalysis is crucial for sustainable and economical chemical processes. However, despite its long history, catalysts to-date are designed mostly via expensive trial and error, motivating continued interest in rational catalyst design. Towards this goal, this dissertation centers on two primary projects.
The first project focused on the design of metal-embedded zeolites for natural gas upgrading via methane dehydro-aromatization to benzene (MDA). Previous studies had shown that this reaction can be “intensified” by the use of microwave-assisted heating. However, while the highly efficient, direct heating of the metal site in a Fe-ZSM-5 catalysts via microwave energy resulted in strongly increased methane conversion, selectivity to the desired aromatics was much reduced due to the creation of intense metal hot spots, which leave the zeolite framework comparatively cold. Thus, we explored the design of SiC@Fe-ZSM-5 core@shell catalysts to reduce intra-catalyst temperature gradients by combining the activity of the metal-embedded zeolite with the high microwave susceptibility of SiC. We found that such rational catalyst structuring can indeed enable distinct temperatures of different catalyst components under microwave conditions, opening new avenues for process design.
We furthermore investigated the impact of different forms of coke on the activity of these catalysts. MDA requires high temperatures for methane activation, which results in severe coking and rapid catalyst deactivation. We were able to identify different types of coke formed over the different catalytic sites in the catalyst (metal vs Brønsted acid sites), potentially informing the development of more efficient catalyst regeneration processes.
The second, collaborative project focused on a fundamental understanding of metalsupport interactions—a key descriptor for catalyst stability. We developed a novel technique to directly measure force of adhesion between metal nanoparticles and supports and found that alloying metal nanoparticles results in an unexpectedly complex, nonlinear modification of the force of adhesion, which was explained by electron transfer between the two metals in the alloy and the underlying oxide support.
Overall, these projects yielded new insights that can aid the rational design of catalysts, and hence improve application of heterogeneous catalysts in terms of their performance in activity, selectivity, and stability
The Future that Never Was: Reactionary Fan Controversies and Affective Attachments to Speculative Fiction
No full textIn the past decade, speculative fiction media that feature diverse characters or storylines have been increasingly met with reactionary fan backlash in the form of review bombing, boycotts, doxxing, and death threats. This dissertation analyzes the communication of reactionary fans during controversies surrounding popular speculative fiction media to explore the motivating affective economies of contemporary reactionary social movements. Considering the connection between speculative fiction fans and reactionary groups, this dissertation poses the question: What is the relationship between the affective attachments fans have to speculative fiction media and the logics of violence/exclusion? While speculative fiction has been dismissed as escapist and nonpolitical, many of its authors, editors, and fans have long used the genre to advocate for their visions for the future. Through examining representative archival fanzines and professional speculative fiction magazines as well as reactionary fan discourse circulated via social media, this dissertation further theorizes revanchist nostalgia. Revanchist nostalgia not only aims to restore an imagined past but also to punish the ones who made that reclamation necessary. While different in scale and consequence, the affective economy of revanchist nostalgia is key to both fan controversies and broader reactionary incidents such as the 2017 Unite the Right rally and the 2021 insurrection at the US Capitol. Research on social movements often considers how affect is mobilized in support of progressive causes, but with this dissertation, I argue that both speculative fiction and affect are politically ambivalent and capable of being utilized to motivate reactionary and progressive causes. In considering reactionary fandoms in tandem with white supremacists, men’s rights activists, and other more explicitly political groups driven by revanchist nostalgia, this dissertation reads fandom as political and the political as fandom to demonstrate how reactionaries function as anti-fandoms that are motivated by hatred, disgust, and sadism toward others. Through considering extremist groups as (anti-)fandoms, this dissertation exposes the affective networks that bond reactionaries together, empower them to propagate their hateful rhetoric, and mobilize them against the increasing diversification in fan communities and beyond
SIN-Seg: A Joint Spatial-Spectral Information Fusion Model for Medical Image Segmentation
No full textIn recent years, the application of deep convolutional neural networks (DCNNs) to medical image segmentation has shown significant promise in computer-aided detection and diagnosis (CAD). Leveraging features from different spaces(i.e. multi-modalities, Euclidean, non-Euclidean, and spectrum spaces) has the potential to enrich the information available to CAD systems, enhancing both effectiveness and efficiency. However, directly acquiring the data across different spaces is often prohibitively expensive and time-consuming. Consequently, most current brain imaging segmentation techniques are confined to the spatial domain, which means just utilizing MRI or CT images. Our research introduces an innovative Joint Spatial-Spectral Information Fusion method that requires no additional data collection. We translate existing MRI data into a new domain to extract features from an alternative space. More precisely, we apply Discrete Cosine Transformation (DCT) to enter the spectrum domain, thereby accessing supplementary feature information from an alternate space. Recognizing that information from different spaces typically necessitates complex alignment modules, we also introduce a contrastive loss function for achieving feature alignment before synchronizing information across different feature spaces. Our empirical results illustrate the effectiveness of our model in harnessing additional information from the spectrum-based space and affirm its superior performance against influential state-of-the-art segmentation baselines
Examining Professionalism in Physician Assistant Education: Bridging the Gap Between Theory and Practice
No full textThis dissertation in practice addresses a practical issue: the failure of Physician Assistant (PA) students at The University of Pittsburgh Department of PA Studies fail to meet the program benchmarks of professionalism. The proposed change aims to impact the PAS Hybrid Program and will involve both students and preceptors. Assessment will employ qualitative methods to gauge the effectiveness of the intervention. The results will enhance comprehension of the intervention implications, thereby facilitating subsequent adjustments and broader implementation in the case of a successful intervention
Functional Characterization of RAD51 Paralog Cancer Associated Variants of Unknown Significance
No full textFor many individuals harboring a variant of uncertain functional significance (VUS) in a homologous recombination (HR) gene, their risk of developing breast and ovarian cancer is unknown. Integral to the process of HR are BRCA1 and regulators of the central HR protein, RAD51, including BRCA2, PALB2, RAD51C and RAD51D. Due to advancements in sequencing technology and the continued expansion of cancer screening panels, the number of VUS identified in these genes has risen significantly. While variant analysis is improving, there remains a struggle to keep up with demand. Understanding the effects of an HR variant can aid in preventative care and is critical for developing an effective cancer treatment plan. In this dissertation, we functionally screened 27 RAD51C ovarian cancer VUS, identifying two HRD variants. Modeling these and other previously analyzed HRD RAD51C ovarian cancer variants in the newly published BCDX2 cryoEM structure, we found a functionally deficient cluster within the critical Walker B region. Our study of RAD51C also uncovered two active translational start sites located at amino acid 1 and amino acid 10. The resulting protein isoforms and the M1 and M10 patient derived VUS were assessed and found to be functionally similar in their HR capabilities but showed differences in expression and possible cell type specificity. In all, these studies broaden our understanding of RAD51C and how its dysfunction can promote disease progression and response to therapy. These data have the potential to aid in more efficacious pathogenicity classification and improve patient care
Activity-dependent development of intrinsic network in the central nucleus of the inferior colliculus
No full textThrough experience, sensory circuits learn and adapt, optimizing their network organization in accordance to the external sensory inputs, to help the organism better recognize, better navigate and better survive in the world. How are these dynamic changes happen in the brain? This is the question constantly being pursued. In this thesis, I followed this everlasting pursuit by asking how is the fundamental architecture of the intrinsic synaptic connectivity of the central nucleus of the inferior colliculus (CNIC) shaped through experience.
In Chapter II, I investigated how the precise temporal pattern of prehearing spontaneous activity influences the prehearing establishment and post-hearing development of the CNIC intrinsic synaptic connectivity onto GABAergic neurons. I showed that the precise temporal pattern of prehearing spontaneous activity is required to prepare the CNIC intrinsic network into a configuration that permits acoustic experience-dependent network refinement to take place.
In Chapter III and IV, I investigated how acoustic experience influences the development and organization the CNIC intrinsic synaptic connectivity onto both GABAergic neurons and glutamatergic neurons. I showed that acoustic experience-dependent network refinement centers on GABAergic CNIC populations. Inhibition plays an essential role in shaping the CNIC intrinsic network configuration.
Based on the intrinsic synaptic connectivity, I proposed an inhibition-centered functional organization of the CNIC intrinsic network, in which inhibition not only sculpts, but also governs how the CNIC represents the acoustic world
Quantum Enhanced Sensing of Optomechanical Systems
No full textWith the advances in nanomechanical resonators in the past few years, the sensitivity of optomechanical system has been pushed so far that quantum noise becomes the dominant noise to be dealt with. Quantum enhanced sensing refers to various methods that can be used to fight against quantum noise. In this dissertation, several mechanisms and methods are experimentally demonstrated that can be used to surpass the sensitivity limit set by the quantum noise in optomechanical systems, pushing their sensing capability into untested realms of physics.
In the first part, I focus on optical lever detection. The optical lever is a centuries-old and widely used detection technique where the angle of reflected light is used to infer the tilting of a surface. It is as sensitive as interferometry, but its quantum limits have yet to be explored. In general, any precision optical measurement is accompanied by an optical force induced disturbance to the measured object, which is referred to as back action. Here we walk through the principle of back action evasion in optical lever detection and experimentally demonstrate it in the classical regime. In addition, the quantum efficiency of split photodetection used for readout is investigated and a method for improvement is experimentally demonstrated.
In the second part, I focus on a modified nonlinear mechanical SU(1,1) interferometer based on coupling two modes of a single nanomechanical string resonator for high-precision phase sensing. We walk through the theory, simulation, and experiment demonstrating parametric amplification and beam splitter interaction resulting from periodic stretching of the device frame that modulates the stress of the string resonator. These interactions correlate the mechanical noise and mix the states to yield a lower noise floor. We also propose a protocol to make full use of the squeezing in the presence of read out noise.
Lastly, I briefly go through the earlier work on the experimental realization of a new technique (ultra-low-voltage electron beam lithography) to create large-scale and complex two-dimensional quantum devices in LaAlO3/SrTiO3 heterostructure that is 10 000 faster compared to the previously used conductive atomic force microscopy
Investigation of immunologic and hepatic adverse effects of asparaginase
No full textAsparaginase is a highly effective antileukemic agent that has been used for over 5 decades but has several unique adverse effects, most commonly immunotoxicity and hepatotoxicity. These toxicities can lead to disruption of antileukemic treatment, leading to poorer outcomes. Therefore, investigation of the mechanisms underlying these toxicities and methods to prevent or treat them, could reduce morbidity and mortality associated with asparaginase. Using both human cohorts and murine models, we investigated the potential genetic and mechanistic modifiers of asparaginase immunotoxicity and hepatotoxicity. We performed genomic association studies to identify genetic loci underlying anti- asparaginase antibody formation and confirmed the association with Class II HLA-DRB*07:01 allele previously associated with asparaginase hypersensitivity reactions. We report the results of a clinical trial using anti-CD20 B-cell depletion to reduce anti-asparaginase antibodies. We investigated the mechanism of action of a novel small molecule inhibitor of a previously identified mechanism of asparaginase immunogenicity, showing its effectiveness as an immunosuppressant. Hepatotoxicity was investigated exclusively in murine models of asparaginase-induced liver injury. Our work showed that asparaginase-induced liver injury does not appear to be a direct hepatic insult from asparaginase but rather is associated with lipotoxicity, due to lipolysis of peripheral white adipose tissue and free fatty acid influx into the liver. Finally, our investigation at the single-cell level point to hepatocytes as the main cell types affected in liver injury, with similarities to other human steatotic liver diseases, posing interesting future questions on potential therapeutic interventions for asparaginase-induced liver injury. Taken together, this dissertation contributes original investigations and data towards our understanding of the pathophysiology and potential modifiers of asparaginase-induced immunotoxicity and hepatotoxicity
Teaching the Revision Processes to College Multilingual English Writers through Concept-based Language Instruction
No full textMultilingual college students often struggle with writing and revising for academic purposes. This dissertation explored the effectiveness of a Concept-Based Language Instruction (C-BLI) approach to teaching revision processes to college-level multilingual writers. Although a significant body of research exists on effective feedback on multilingual students’ writing, little is known about effective ways to support their development of revision skills, an essential part of the writing process. In this study, I designed and implemented C-BLI-informed tutoring sessions using a visual, conceptual tool called a Schema of an Orienting Basis of Action (SCOBA) (Gal’perin, 1989) to promote students’ development of revision skills and internalization of the concept of revision. Seven multilingual college students participated in the study. Data sources included audio recordings of tutoring sessions, interviews with the students, student essay drafts, and student-annotated SCOBAs. These data sources were analyzed qualitatively to understand students’ conceptual development and revision of writing. Overall, the quality of students’ revisions, conceptual understanding of revision, and revision practices improved. Students articulated their revision processes with greater specificity as the tutoring progressed and demonstrated strategic and creative uses of the mediational means (e.g., the SCOBA, the interactions with the writing tutor) to serve their unique trajectories of conceptual development. Findings also demonstrated the dynamic unity between cognitive and emotional processes; students’ emotional reactions to revision shaped their cognitive development and vice versa. This study contributes to research on teaching revision, suggesting that the C-BLI approach can effectively foster deeper conceptual understandings and practical applications of revision processes for college multilingual writers