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The Influence of Fatigue on Representations of Physical Effort in Humans
No full textWhen we experience fatigue, our valuation of the cost of effort increases, reducing our willingness to initiate or continue exertion. This interaction influences the decisions of healthy people daily, yet it is far more disruptive and debilitating in those with neurological conditions, including multiple sclerosis (MS). Despite knowledge of this, an understanding of how fatigue modulates our willingness to exert remains elusive. This thesis draws from two studies that seek to establish a mechanism by which fatigue affects our assessments of physical effort, and determine how this mechanism is affected in patients with MS.
In Aim 1, we use functional magnetic resonance imaging (fMRI) to investigate the neural mechanisms underlying the influence of cognitive fatigue on physical effort-based choice. Participants make choices for prospective physical effort in a baseline state and after experiencing repeated bouts of fatiguing cognitive exertion. This paradigm shows that feelings of fatigue increase with activity in right anterior insula (rIns), which is functionally connected to brain areas implicated in cognitive exertion.
In Aim 2, an effort association paradigm is used to detect differences in motor performance and assessments of physical effort between healthy individuals and patients with MS. Participants complete an effort assessment task in which they estimate their previous levels of exertion. Using hierarchical modeling on effort assessment data, we show that variability in motor performance predicts error in effort assessments, and that this relationship is mediated by disability due to MS.
These results, in combination with prior research on representations of physical effort, suggest that fatigue and motor performance can alter the perception of physical effort. We provide evidence for the existence of an effort valuation network that encodes the effects of
fatigue on decision-making across domains of exertion. Furthermore, we show that the perception of effort in patients with MS is compromised, and that this is related to deficiencies in motor control. We recommend that future investigations of effort perception, in the healthy and in patients with MS, should account for the impact of motor performance and fatigue on this process
Engineering CHO Cells for Enhanced Cell Growth and Protein Production
Get PDFLactate dehydrogenase (LDH) is one significant enzyme in the anaerobic metabolic pathway. The function of this enzyme is to catalyze the interconversion between pyruvate and lactate with the redox reaction of NAD+ and NADH. Lactate is known as a toxic metabolic product which will hamper cell growth significantly. In this project, we aimed to overexpress LDHB to favor the conversion from Lactate to pyruvate. We hypothesized both the removal and increment of pyruvate flux into flux would be beneficial to improve cell viability and thereby cell productivity. In addition, several LDHB isoforms have been made through site-directed mutagenesis to change LDHB’s cofactor preference from NAD(H) to NADP(H). NADP(H) is a critical cofactor which can facilitate lipid synthesis, which enables the expansion of endoplasmic reticulum. Cell density and glucose concentration are the two most crucial factors that can significantly affect the lactate consumption rate. Thus, in this study, the lactate concentrations were measured daily as well as cell density while the glucose concentrations were kept the same level among all diverse groups. The cells which overexpressed LDBH were expected to have higher cell density than the wild type cells and our results matched the expectation. All gene expressions were verified by Western Blot
End-Stage Kidney Disease and United States Hispanic-Latino Patients: Short-Term Trends, Healthcare Disparities, and Place-Based Factors Related to Kidney Transplantation Outcomes
Get PDFProblem Statement: The United States Latino-Hispanic population is often characterized as the “Awakening Giant'' due to its exponential growth in size and, with that, a seismic shift in economic and political power and influence. As the sleeping giant awakens in the twenty-first century, the identification of health-related patterns and trends among Hispanics remains a top public health research topic since the population’s health and aging-related needs are increasingly more pronounced. Chronic kidney disease and end-stage kidney disease (the fifth and last stage of chronic kidney disease) disproportionately impact racial-ethnic minority populations in the US, compared to non-Hispanic White patients.
Methods: This dissertation consists of three aims: 1) a systematic review summarizing the peer-reviewed evidence describing short-term outcomes post-kidney transplantation among US Hispanic and other racial-ethnic populations, 2) a retrospective cohort study assessing individual-level factors on rehospitalizations during the first year post-kidney transplantation across three US states, and 3) a retrospective cohort study assessing community-level (place-based) factors on rehospitalizations during the first year post-kidney transplantation, across the same three US states.
Results: Studies describe contemporary short-term outcome trends and disparities relating to kidney transplantation during the first year among Hispanics and other racial-ethnic populations in the US broadly and within three US states. The first dissertation aim identified sixteen peer-reviewed studies, where Hispanics were found to experience similar or more optimal post-transplantation outcomes in ten studies, albeit most results were statistically insignificant. The second dissertation aim (building on the first aim), assessed individual-level factors of 10,736 Californian, New Yorker, and Floridians’ post-transplantation rehospitalizations between 2017-2020. This study found that the recipient race and primary insurance type overall are associated with rehospitalizations during the first year after receiving a kidney transplantation. The third dissertation aim, assessed place-based factors on post-transplantation rehospitalizations during the first year. More specifically, we found that while majority statistically insignificant across time points, recipients living in higher median household income zip codes had lower expected rehospitalization rate ratios.
Conclusions: The ongoing peer-reviewed work and the results of the study results highlight potential points of intervention for addressing disparities of the post-transplantation period in the United States
Identity and Habit: Transcendental Empiricism, Freedom, and the Mechanization of Nature
Get PDFThis dissertation argues that we can use transcendental empiricism to account for the emergence of modern, Western modes of subjectivity. So-called “new materialism” suggests that at least some of our most ingrained ideas about nature and matter are at least partially false. That is, our notions of matter as dead, brute, and inert stuff are wrong insofar as matter partakes in some of the characteristics we usually reserve for human subjectivity, like affecting and being affected. Supposing that some of our ideas about matter and nature are wrong leaves open the question of how we got it so wrong. This dissertation attempts to answer this question by using the notion of habit to trace the emergence of some of our most basic ideas and assumptions about matter and subjectivity, e.g. identity, necessity, and free will. To this end, Chapter 1 traces Nietzsche’s “falsification thesis” to explore the extent to which subjectivity misunderstands its object and to show that even our most basic ideas, like that things are identical with themselves, are profoundly contestable. Chapter 2 examines an alternative conception of nature, using the Nietzschean notion of will to power, which resists common Western notions of nature and matter as dead, inert, and governed by an antecedent order of causality. Understanding nature in terms of will to power grounds habit insofar as a will can affect, be affected, and thereby interpret a world it repeatedly encounters. Chapter 3 follows Hume and Deleuze in accounting for the most basic forms of perception in terms of habit. This Chapter seeks to supplement their position insofar as it gives a positive account of our concepts of identity and necessity, which are entangled with the ideas of mechanical nature and free will. Chapter 4 elaborates the concept of virtual memory described in Chapter 3 to outline the mind’s constitutive relation to its outside – to its social, cultural, and political milieu. The dissertation concludes by considering the political and ethical implications of the mind’s inherent vulnerability in terms of reopening the question: “what is this?”
Prevalence of Epileptiform Activity in Stereoelectroencephalogram During Multi-Attribute Decision Making Task
Get PDFEpilepsy is characterized by recurrent, unprovoked seizures, often accompanied by interictal epileptiform discharges (IEDs) such as spikes and high-frequency oscillations (HFOs). This study investigates the modulation of epileptiform activity during cognitive engagement using stereoelectroencephalography (sEEG) in epilepsy patients performing a multi-attribute decision-making task. The analysis focused on the prevalence and temporal dynamics of HFOs and spikes during periods of cognitive task engagement versus rest periods. Results indicate a general pattern of reduced epileptiform activity during task engagement, suggesting a suppressive effect of cognitive tasks on epileptic brain activity. However, notable outliers were observed, particularly in patients whose epileptogenic zones overlapped with regions implicated in decision-making and cognitive control. These findings highlight the intricate relationship between cognitive engagement and epileptiform activity, underscoring potential mechanisms underlying cognitive modulation of epilepsy and offering implications for therapeutic strategies aimed at seizure control through targeted cognitive interventions
Disproportionate Aerosol Exposures in High Intensity Interval Training Gyms: A Needs Assessment Study
Get PDFThis study investigates the exposure to traffic-related air pollution (TRAP) in a High Intensity Interval Training (HIIT) gym located in an urban area, near a major highway. From March 2023 to January 2024, air quality measurements were taken at the Baltimore gym using QuantAQ Modulair® sensors and Observair BC monitors. Results showed mean concentrations of 11.22 µg/m³ for PM2.5 and significant peaks during high-traffic gym class times. Annual lung deposition estimates indicated substantial exposure to PM1, PM2.5, PM10, and black carbon (BC), posing health risks to gym participants and employees. These findings underscore the need for proprietor education, comprehensive environmental assessments and regulatory frameworks to mitigate health risks in HIIT gyms, especially those situated near high-traffic areas
Accessible Education for LUTO Patients: A Study of Multimodal Tools to Support Literacy and Emotional Wellbeing
Get PDFLower Urinary Tract Obstruction (LUTO) is a rare congenital condition that impairs fetal urinary and respiratory development due to urethral blockage, leading to urine retention, reduced amniotic fluid, and potential lung hypoplasia, kidney damage, and compression injuries (Capone et al., 2022; Haeri, 2015).
Current patient education materials often fail to adequately convey the condition’s severity and full implications, limiting understanding for patients and families. Existing materials are majorly text-based and not conducive to helping patients and families fully understand LUTO, despite studies showing that effective education is critical for parental comprehension (Denny et al., 2014; Żyrek et al., 2024). There is a clear need for improved resources to explain the condition, its implications, and available treatments.
This project developed and evaluated multimedia-based educational resources—including a 3D-animated video, a patient-focused webpage, and a printable handout—to improve comprehension of LUTO, its consequences, and treatment options. An IRB-approved study assessed their effectiveness through pre- and post-tests and participant surveys. Additionally, 3D-printed anatomical models were prototyped for tactile learning in clinical settings.
Results demonstrated that video-based education significantly improved knowledge retention compared to text-based materials, with a paired two-sample T-test confirming a statistically significant increase in post-test scores (p = 0.006). Participants also reported higher engagement and a preference for the video format. Survey feedback identified areas for improvement, such as accessibility enhancements.
This study reinforces the value of multimedia tools in patient education and suggests further research into optimizing materials for diverse learning needs
A comparison of measured and modeled chamber concentrations of VOCs using various well-mixed room models
Get PDFReliable estimation of airborne volatile organic compound (VOC) concentrations remains critical for occupational exposure assessment, especially in scenarios where direct measurements are limited. This study systematically evaluated multiple variants of well-mixed room (WMR) models, including those with general ventilation recirculation (GVR) and local exhaust ventilation (LEV), using a full-scale exposure chamber under controlled conditions. Acetone was employed as the model VOC due to its industrial relevance and measurable vapor-phase behavior. Model-predicted concentrations were derived through Monte Carlo simulations, incorporating variability in emission and ventilation parameters. Performance metrics including R2, NMSE, and fractional bias demonstrated high predictive accuracy for many WMR models. However, greater uncertainty was observed at lower airflow conditions and with poorly defined filtration efficiencies. These findings underscore the importance of robust parameter characterization in model performance. Our results support the use of probabilistic WMR modeling as a transparent, scalable tool for exposure assessment, offering practical value for occupational hygiene decision-making in the absence of comprehensive monitoring data
The role of P granule-enriched RNAs in C. elegans germ cell specification
No full textThe germ cells of sexually reproducing animals are essential for the propagation of a species. Therefore, it is critical to understand how they are specified. In animals with a preformed germline, like Drosophila and C. elegans, maternally deposited RNAs and proteins called germ granules are asymmetrically segregated during embryogenesis into the developing germ cells. It’s been hypothesized that germ granule-enriched RNAs encode factors essential for proper germline development. However, since a germ granule transcriptome has never been characterized, this model has not been tested. Recently, the C. elegans germ (P) granule protein MEG-3 was identified to bind hundreds of RNAs in vivo. I systematically characterized the expression pattern of 487 RNAs and found that only a minority of them contribute to specifying germ cell fate. Instead, our data support an alternative model for the role of germ granule RNAs: as structural scaffolds to maintain germ granule proteins in the germ cell lineage. The germ granule proteins, rather than most germ granule RNAs, have conserved roles in translational regulation and small RNA inheritance in the developing germline
The Role of Estrogen Receptor Mutations and Receptor Tyrosine Kinase Alterations in Driving Endocrine Therapy Resistance
No full textEstrogen Receptor-positive (ER+) breast cancer, the most common clinical subtype, is treated with anti-ER endocrine therapies as a first-line treatment. However, resistance to endocrine therapy develops in almost all patients with metastatic ER-positive breast cancer and remains an unmet medical need. In paired pre- and post-treatment patient biopsies, our collaborators identified a novel estrogen receptor variant of unknown significance, H524L. Our follow up investigation revealed that H524L is hyperphosphorylated, hyperactive, and drives an altered transcriptome. We also previously identified acquired mutations in the human epidermal growth factor receptor (HER2) and acquired alterations in the fibroblast growth factor receptor (FGFR), as a mechanism of resistance to endocrine therapies in approximately 7% of patients and 24% of patients respectively, and that these receptor tyrosine kinase (RTK) alterations lead to extensive transcriptional rewiring. We examined the mechanistic basis through which RTK alterations confer an endocrine resistant phenotype, using transcriptomic and epigenomic analysis. RTK alterations led to drastic genome-wide changes, and genome-wide ER chromatin binding revealed decreased global ER binding. We unexpectedly found that our FGFR alterations can translocate to the nucleus and are in the chromatin fraction. ER interactome investigation unveiled large differences in nuclear ER binding partners. Targeting ER with endocrine therapy in combination with BET inhibitors restores sensitivity RTK altered cell lines to endocrine therapy. Together, this data shows transcriptional rewiring underlies endocrine resistance driven by H524L and RTK alterations in breast cancer. This may play an important role in the clinical management of patients harboring these alterations