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Multi-scale Representations of Functional Movement - Quantitative Analysis of Upper Extremity Movement Severity and Dissimilarity after Stroke
Get PDFThis work is embargoed by the author and will not be publicly available until December 2025.The upper extremity is a highly motor abundant, non-linear, and non-periodic system of muscles and joints, with the ability to produce a vast variety of movements. From reaching for a toothbrush in the morning to pulling up the covers at night, our arms and hands are a significant part of how we interact with the world. Central Nervous System (CNS) injuries such as lesions consequent to stroke are a leading cause of disability, often accompanied by hemiparetic impairment and functional limitations in the ability to reach to grasp, transport, and release objects. Upper extremity impairment severity differs vastly from person to person, persistently affecting about 80% of persons six months past the stroke event. For stroke rehabilitation, upper limb kinematic assessments have increasingly been used as primary or secondary outcome measures. The experience of disability consequent to stroke is highly individual, and therefore rehabilitative interventions must also be informed by an individual's movement capacities, compensatory strategies, and motor deficits. Without a model for translating movement capacities into individualized therapies, rehabilitative interventions are at best estimations of how the underlying neural structures will respond and produce movement. It has been difficult to reach a consensus on which movements can best represent the motor capacities of the upper extremity, and which kinematic metrics contribute to a comprehensive standardized representation of the multi-joint upper limb. A quantitative and universal summary index of upper extremity multi-joint movement would be a valuable tool for assessing limb coordination, compensatory mal-adaptations, and recovery. Such indices are already validated in the assessment of the lower extremities, such as the Gait Deviation Index (GDI) which evaluates dissimilarities between an individual's performance and reference data sets. In this dissertation, I described the use of reaching as a representative functional task that is a feature of many upper extremity movements relevant to Activities of Daily Living (ADLs). I described a data segmentation technique that is sensitive to task-specific movement features and identifies segments that demonstrate spatially and temporally matched progression of movement between limb segments. This method, informed by gait measures such as the GDI, was applied to clinically produced three-dimensional movement data in persons with stroke to identify segments that reproduced movement behaviors evident in healthy reference movement. Other experiments were conducted to quantify multi-joint coordination and age-related differences in bilateral synergistic movement. From these experiments, I observed that characteristic movement initiation behaviors are preserved with mild movement impairment and inter-joint coordination is disrupted with severe movement impairment. Further, I found this methodology coupled with wearable acceleration sensors to be sensitive to age-related differences in inter-limb and intra-limb coordination during tasks requiring symmetric and asymmetric bilateral movements. This methodology presents the ability to objectively quantify synergies, parts of movement where multiple joints and limb segments synchronize and optimize movement. These findings were combined to create the Reach Severity and Deviation Index (RSDI), a proposed summary score that is adaptable to other movements and body regions, and translates well to the clinical setting without modifying measurement modalities and allows the potential for remote at-home use to improve compliance with rehabilitative practice.2025-12-1
The Constitutional Political Economy of Deficits and Public Debt
Get PDFThis dissertation provides an economic explanation for the United States' deficit and public debt. Unlike most economic and political economy explanations, this dissertation provides a constitutional political economy perspective. Chapter one is based on a review essay of Olivier Blanchard's recent book Fiscal Policy under Low Interest Rates, forthcoming in Journal of Public Finance and Public Choice. In the essay, I critique Blanchard's conclusion that, when interest rates are low, politicians can use public debt and deficit finance to increase welfare for all individuals. Specifically, I argue that Blanchard's conclusion assumes a particular type of political process—one under which politicians have incentives to use public debt and deficits in a way that improves the welfare for all. While such a political system is possible, another political system under which politicians have incentives to increase the welfare for only some individuals—which would subsequently reduce the welfare for others—is also possible. I conclude that without an examination of the political process governing politicians, Blanchard's conclusion is dubious at best. Chapter two heeds the call of chapter one by examining the political systems that have caused the increase in public debt and deficits since the 1980s. While this has already been done in the political economy of deficits and public debt literature, I offer an alternative perspective. Rather than attributing the increase in deficits and public debt to politicians' actions given rules of time-and-place, I attribute the increase in deficits and public debt to politicians' actions because of a change in the fiscal constitution—the rules constraining politicians' use of the federal budget. Using this alternative perspective, I argue that the Congressional Budget Impoundment and Control Act of 1974 is why public debt and deficits have increased since the 1980s. This is because the Act changed the fiscal constitution: it removed the president's constraint on each congressperson's propensity to use deficit and public debt finance, and, as such, unleashed the fiscal commons. Chapters three and four build on chapter two by examining the incentives for politicians and interest groups, respectively, to support increases in public debt and deficits. Constitutional exchange does not merely happen without incentives for the parties to the exchange—politicians and interest groups. In chapter three, I argue that politicians have incentives to use public debt and deficits because it allows them to maximize the net present value of their future returns—i.e., gain more political power. Specifically, it allows them to gain more power through the use of rent extraction. In chapter four, I argue that dominant interest groups have incentives to support deficits and public debt because it creates fiscal illusion—which allows them to gain power over non-dominant interest groups with the least amount resistance
THE EVOLUTION OF THE D2 DOPAMINE RECEPTOR: ITS UNIQUE PROPERTIES AND ALTERNATIVE SPLICING IN THE VERTEBRATE BRAIN, THE AVIAN SONG SYSTEM, AND POSSIBLE FUNCTIONS OF THE CONSERVED MIR-9 SITES
Get PDFThe D2 dopamine receptor has roles in the regulation of physiology and behavior and is also involved in the pathophysiology and treatment of psychiatric diseases. Alternative splicing of Drd2 pre-mRNA produces D2 long “D2L”, and D2 short “D2S” receptors by exon skipping of exon 6. This splice choice alters cytoplasmic loop 3 of the D2 protein, and affects the rates of D2 endocytosis and cytoplasmic processing. Here it is shown that Drd2 exon 6 originated prior to the duplication and divergence of D2 and D3 dopamine receptor genes. The exon 6 homolog inherited by the Drd3 gene has not been well conserved and is not skipped during RNA splicing in any tetrapod species. Moreover, skipping of Drd2 exon 6 was not detectable in the brains of primitive aquatic vertebrates, nor in the primitive species of each tetrapod class. But Drd2 exon 6 was found to be skipped in the more derived species of each tetrapod class, suggesting that alterations of cytoplasmic loop 3 of the D2 receptor have been associated with adaptive radiations. Additional Drd2 mRNA isoforms were found in passeriform birds. In zebra finch (a passeriform bird), all Drd2 mRNA isoforms (including the passeriform-specific D2L-50 and D2S-50 variants) were present at higher levels in the anterior forebrain pathway of the song system than in any other brain area except the ventral striatum (which likely is also involved in song learning). These isoforms were relatively abundant in whole brain tissues of many other passerine species, but were rare or undetectable in all non-passerine bird species tested. This suggests that the -50 variants may help to facilitate song learning in passerine birds. Finally, in addition to exon 6, another unique property of Drd2 is the presence of a conserved miR-9 recognition site in the 3’ untranslated region. The functions and expression patterns of Drd2 are complex. A simpler case may be present in the Clock gene, which has multiple conserved miR-9 sites. Here it is shown that miR-9 expression and Clock expression were positively correlated with each other in two different vertebrate species and tissues. The evolutionary conservation of multiple miR-9 sites in the Clock mRNA must increase the turnover of Clock mRNA, but it evidently does so without altering the circadian expression pattern of Clock. That miRNAs encoded the turnover rates of targeted mRNAs rather than their expression patterns may prove to be a general paradigm for the interactions of many miRNAs with their target genes
Risk Based Prioritization of Organic Chemicals within the Chesapeake Bay Watershed
Get PDFDetection of chemicals of emerging concern (CECs) in aquatic systems is raising concern about exposure limits and environmental health. New Approach Methodologies (NAMs), which include a range of molecular and computational techniques, are being developed to help reduce animal-intensive toxicity testing with risk-based prioritization approaches. Certain NAMs are aimed at translating concentration data into risk assessment by comparing target chemical concentrations to a range of available toxicity data, including high-throughput bioassays and whole-organism toxicity endpoints, to prioritize “high risk” chemicals. This thesis applies such a geographic-based chemical prioritization approach to forecast risk in tributaries of the Chesapeake Bay and identify problematic contaminants for further research. Our study encompasses two distinct geographic scales: a micro-scale analysis focusing on a Potomac River tributary, assessing the impact of a local wastewater treatment plant (WWTP) and combined sewer overflows (CSOs); and a macro-scale analysis across multiple Chesapeake Bay tributaries, evaluating urban and agricultural land-use contributions to contaminant risk. In the micro-scale study, we identified several “high risk” chemicals that exceeded toxicity thresholds, especially psychotropic compounds. We found the highest potential risk near the WWTP and CSO outfalls at the Potomac River tributary; however, the risk levels dramatically decreased in the mainstem Potomac River, likely due to its greater flow. In the macro-scale study, we also identified several “high risk” chemicals that exceeded toxicity thresholds. We found greater chemical concentrations, especially hormone and pesticide compounds, with highest potential risk at sites where land-use was predominantly agricultural. These results support the need for further organism-specific and landscape studies to research the biological effects of “high risk” chemicals and risk correlations to agricultural land-use and WWTP sources
Exploratory Proteomic Analysis of Transgenic Alzheimer’s Disease Mouse Model Treated with Young Blood Plasma
Get PDFAlzheimer’s disease (AD) is a progressive neurodegenerative disorder
characterized by the accumulation of amyloid plaques and tau tangles. Studies suggest
that treatment using young blood plasma in transgenic AD mice is associated with
enhanced synaptic activity, increases in neuronal proteins, and behavioral improvements.
This exploratory proteomic study used liquid chromatography–mass spectrometry (LCMS)
to analyze the composition of blood plasma for the identification of proteins that
may contribute to synaptic and behavioral changes. Plasma samples were collected from
AD-type (rTg4510 h-Tau P301/CaMKII) and wild-type (WT) mice treated with saline or
young blood plasma. A bottom-up approach was used to identify proteins by assessing
fragmentation output from LC-MS and cross-referencing values with validated mouse
protein databases. 4 proteins were significantly differentiated between AD plasma and
AD saline groups including up-regulation of MDH2 and down-regulation of KNG1,
KCNB1, and KRT15. Pathway analysis of these results suggest disruptions in brain
energy metabolism and blood coagulation may induce chronic immune activation that
coincide with AD progression. This study also reveals the need for additional research on
blood coagulation mechanisms and its involvement in AD as well as a potential
biomarker for diagnosis. By targeting these specific proteins and downstream pathway,
future studies may gain a better understanding of the molecular mechanisms that underlie
AD
Between the Lost and the Forgotten
No full textThis thesis has been embargoed for 10 years. It will not be available until April 2032 at the earliest.In a far-distant future, where humans possess the technology to link their minds directly to an immersive virtual universe, most Americans have permanently fled to this alternate reality, leaving a crumbling world and their withering bodies behind. Meanwhile, those who cannot afford access to this integrated simulation are forced to build and sustain their own makeshift systems—economic, social, and political—to survive outside the new technocratic order. For years, these groups, nicknamed “The Lost” and “The Forgotten,” have coexisted in an uneasy truce, living in two different words though their physical bodies sit only miles from each other. All that will change, however, when a young Forgotten woman named Zinya Feniks, hoping to follow in her deceased parents’ footsteps, gains employment with the Lost. Through her work, she’ll slowly discover a series of clues hinting at the dark truth behind her parents’ deaths, and as she unravels that mystery, she’ll need to contend with the shadowy power hidden deep within the Lost’s frame-perfect world, one hell-bent on destroying everything she’s ever known.2032-04-2
TARGETING CEACAM5/6 WITH A NOVEL DUAL SPECIFIC ANTIBODY-DRUG CONJUGATE AS A THERAPEUTIC STRATEGY IN GASTROINTESTINAL CANCERS
Get PDFBackground: Carcinoembryonic antigen cell adhesion molecule (CEACAM) family members 5 and 6 are tumor-associated antigens frequently upregulated in epithelial cancers, including pancreatic ductal adenocarcinoma (PDAC), where they contribute to invasion, metastasis, survival, resistance to chemotherapy, and immune escape. CT109 is a novel humanized antibody with dual specificity for both CEACAM5 and 6, mediated by binding to a shared glycoepitope. CT109 exhibits a high affinity to both CEACAMs. To further develop CT109, in vitro and in vivo characterization of antibody-drug conjugates (ADCs) was performed. Methods: Immunoblots were performed against recombinant CEACAM5 and 6 and lysates of PDAC and CRC cell lines to assess the specificity of CT109. For CT109 cognate epitope characterization, PNGase F treatment, mutation of N-linked and glycosylation sites (Asn>Gln) was performed on recombinant CEACAM6-Fc expressed in HEK293T. Immunohistochemistry (IHC) was also performed to establish expression prevalence in epithelial cancers and confirm target expression specificity in tissues. Internalization kinetics were assessed by pHrodo conjugation and flow cytometry in two PDAC cell lines. For CT109 antibody-drug conjugates (ADCs), IC50 values were determined in the antigen-expressing PDAC line, BxPC-3, and non-expressing line, PANC-1. Effects of CT109-SN-38 and CT109-MMAF in vivo were evaluated in a heterotopic BxPC-3 xenograft model. Results: CT109 bound to both cell surface and recombinant CEACAM5 and CEACAM6 on immunoblots. CT109 exhibited remarkably high tissue specificity in IHC and high expression prevalence in PDAC and colorectal cancer (CRC). CT109 was internalized in antigen-expressing, but not in non-expressing, PDAC cells with a half-maximal localization to low pH compartments after 2.3-9.6 hours. In vitro, the CT109-SN-38 and auristatin ADCs exhibited robust dose and antigen-dependent cell killing. In vivo, CT109-SN-38 mediated specific tumor-killing, resulting in reduced tumor growth rates and volumes (through day 50, p = 0.02) and reduced tumor burden below baseline in a subset of mice (3/10 mice in the high dose group). Conclusions: CT109, an anti-CEACAM5/6 antibody with a unique glycoepitope, bound to a high proportion of CRC and PDAC lines and tumors. However, binding to CEACAMs 5 and 6 does not compromise specificity in IHC, with a vast majority of normal tissues exhibiting no expression. In a small subset of epithelial tissues, expression was barely detectable and relegated to the epithelial lumen in normal tissues. While GPI-linked proteins such as CEACAM 5 and 6 are canonically viewed as slow or non-internalizing antigens, CT109 was nonetheless internalized. As SN-38, monomethyl auristatin (MMA) F, and MMAE conjugates, CT109 ADCs mediated a dose and antigen-dependent cytotoxic effect in vitro. CT109-SN-38 similarly exhibited a dose-dependent effect in reducing tumor growth in a heterotopic PDAC tumor xenograft model, with regression observed in the subset of mice receiving the ADC. Further preclinical and clinical development of CT109-SN-38 is warranted
Effects of Rearing Conditions on Behavior and Neuropathology in h-TAU Transgenic Alzheimer’s-Type Mice
Get PDFAlzheimer’s disease (AD) is a progressive and currently incurable form of dementia that affects nearly 5.8 million Americans (CDC, 2021). It results in brain atrophy and neuronal death, which with time results in severe memory impairment and loss of ability to function. Activities of daily living (ADLs) and meaningful interactions with others are primarily affected, even in the early stages of the disease. There are numerous variables that exacerbate the progression of Alzheimer’s disease. Some of those variables include isolation and the lack of environmental enrichment. Those burdened with AD are often secluded at home or in a nursing center and there has been extensive research regarding loneliness and isolation in both human and mice models. Contrarily, socialization and environmental enrichment has not been studied substantially. Enriched housing has been shown to have a positive effect on AD progression and could be a promising area of research against Alzheimer’s disease (Griñán-Ferré et al., 2018). This study aims to investigate the effects of rearing conditions on behavioral and neuropathological differences in hTau transgenic Alzheimer’s-type mice.
rTg 4510 and 4510 -/- mouse models, which are models of AD were employed in this study. Mice were either reared in Block Party housing or standard cages for a duration of four months, in order to allow for appropriate neurodegeneration to appear in the transgenic subjects. All mice underwent various behavioral testing to assess cognitive deficits. Western blots were used to analyze tau protein and p-Tau concentration.
Based on the results of this study, Block Party housing did not ameliorate the pathogenesis of Alzheimer’s Disease. Furthermore, it seems to lead to some negative outcomes for mice housed in this type of paradigm. Nevertheless, these findings have important implications for understanding the behavioral and molecular changes associated with Alzheimer’s disease in mice
Surviving NIBRS: Restoring America’s Unreported Homicides and Exploring the Influences for Law Enforcement’s Declining Cooperation in Crime Reporting
Get PDFFBI adoption of the National Incident Based Reporting System (NIBRS) in 2021 as the mandatory reporting standard for crime data resulted in an unprecedented decline in police reporting to the federal government. Only 57 percent of the nation’s homicides were reported that year. This study obtained more than 6,000 unreported homicides from local and state police agencies using Freedom of Information Act and Open Record Act requests. The study compares FBI data and the study’s augmented dataset for accuracy and completeness using the National Vital Statistics System as a reference. This study also used a 3,134-county regression analysis to explore the socioeconomic factors associated with police decisions to participate, or to decline participation, in the more complex NIBRS program
Double F’s and Effeminists: Effeminism in Berkeley and New York City, 1969-1976
No full textThe Effeminists were a group of gay men who left the gay liberation movement to align themselves with radical feminists. Their work is controversial, but also provides important challenges and insights for the study of gay liberation history and its shortcomings. Through reviewing their publications, we see that the effeminists provided unique and generative interrogations of gay male misogyny that still provide insights about gay men’s politics today. In studying effeminism, we are reminded not only that
gay liberation was not a perfect political project, and that its shortcomings continue to be relevant to our political situation, but also that theoretical debates about the origins of homophobia and its relation to sexism are not concluded