A. James Clark School of Engineering
Permanent URI for this communityhttp://hdl.handle.net/1903/1654
The collections in this community comprise faculty research works, as well as graduate theses and dissertations.
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Item Metabolic Profiling of Brain Microvascular Endothelial Cells: Investigating the Role of Sex, Stress, APOE Genotype, and Exercise in Alzheimer's Disease Risk(2024) Weber, Callie; Clyne, Alisa M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Alzheimer’s disease (AD) is the 7th leading cause of death in the United States, yet there are still no effective treatments to prevent or slow the progression of the disease. AD develops from a combination of genetic and lifestyle risk factors including female sex, elevated stress hormone exposure, the apolipoprotein (APOE) ε4 genotype, and a sedentary lifestyle. In order to better identify the manifestations of AD, it is vital to understand how each of these risk factors impact brain health and lead to neurological dysfunction associated with AD. Brain microvascular endothelial cells (BMEC) line the blood vessels of the brain and have specialized tight junctions designed to strictly regulate nutrient and waste transfer between the blood and the brain. Two of the early indicators of AD development are breakdown of the tight junctions and whole brain glucose hypometabolism. Since BMEC form the first line of defense for the brain against neurotoxic compounds in the blood and are responsible for glucose transport to the rest of the brain, the overarching goal of this thesis is to understand how female sex, elevates stress hormone exposure, the APOE ε4 genotype, and a sedentary lifestyle induce breakdown of tight junction proteins and glucose hypometabolism in BMEC. I first demonstrate that female sex exacerbates endothelial dysfunction in response to high levels of a stress hormone, Angiotensin II (AngII). Specifically, I show that in response to AngII, female endothelial cells increase oxidative stress and inflammatory responses while male endothelial cells do not. Next, I used CRISPR/Cas9 to generate a set of induced pluripotent stem cells (iPSC) homozygous for the APOE ε3 and ε4 genotype and differentiated them into BMEC (hiBMEC). Using the hiBMEC I showed the APOE ε4 genotype induces barrier deficiencies that are partially mediated through reduced levels of protein deacetylase Sirtuin 1 (SIRT1), and that the APOE ε4 genotype causes glucose hypometabolism through decreased insulin signaling. Finally, by adding serum from sedentary and exercise trained individuals to genotype-matched hiBMEC, I show that APOE ε3 and ε4 hiBMEC have divergent responses to treatment with serum from sedentary and exercise trained individuals. Treatment with exercise trained serum increases SIRT1 and glycolytic enzymes compared to sedentary serum, while exercise trained serum decreases SIRT1 and glycolytic enzymes in APOE ε4 hiBMEC compared to sedentary serum. The work described in this thesis gives a fundamental, mechanistic understanding to the roles of female sex, stress hormone exposure, the APOE ε4 genotype, and a sedentary lifestyle in BMEC dysfunction and hypometabolism, giving insight into how these factors contribute to AD development and progression.Item CORTICAL REPRESENTATIONS OF INTELLIGIBLE AND UNINTELLIGIBLE SPEECH: EFFECTS OF AGING AND LINGUISTIC CONTENT(2023) Karunathilake , I.M Dushyanthi; Simon, Jonathan Z.; Electrical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Speech communication requires real-time processing of rapidly varying acoustic sounds across various speech landmarks while recruiting complex cognitive processes to derive the intended meaning. Behavioral studies have highlighted that speech comprehension is altered by factors like aging, linguistic content, and intelligibility, yet the systematic neural mechanisms underlying these changes are not well understood. This thesis aims to explore how the neural bases are modulated by each of these factors using three different experiments, by comparing speech representation in the cortical responses, measured by Magnetoencephalography (MEG). We use neural encoding (Temporal Response Functions (TRFs)) and decoding (reconstruction accuracy) models which describe the mapping between stimulus features and the cortical responses, which are instrumental in understanding cortical temporal processing mechanisms in the brain.Firstly, we investigate age-related changes in timing and fidelity of the cortical representation of speech-in-noise. Understanding speech in a noisy environment becomes more challenging with age, even for healthy aging. Our findings demonstrate that some of the age-related difficulties in understanding speech in noise experienced by older adults are accompanied by age-related temporal processing differences in the auditory cortex. This is an important step towards incorporating neural measures to both diagnostic evaluation and treatments aimed at speech comprehension problems in older adults. Next, we investigate how the cortical representation of speech is influenced by the linguistic content by comparing neural responses to four types of continuous speech-like passages: non-speech, non-words, scrambled words, and narrative. We find neural evidence for emergent features of speech processing from acoustics to linguistic processes at the sentential level as incremental steps in the processing of speech input occur. We also show the gradual computation of hierarchical speech features over time, encompassing both bottom-up and top-down mechanisms. Top-down driven mechanisms at linguistic level demonstrates N400-like response, suggesting involvement of predictive coding mechanisms. Finally, we find potential neural markers of speech intelligibility using a priming paradigm, where intelligibility is varied while keeping the acoustic structure constant. Our findings suggest that segmentation of sounds into words emerges with better speech intelligibility and most strongly at ~400 ms in prefrontal cortex (PFC), in line with engagement of top-down mechanisms associated with priming. Taken together, this thesis furthers our understanding on neural mechanisms underlying speech comprehension and potential objective neural markers to evaluate the level of speech comprehension.Item Effects of Aging on Cortical Representations of Continuous Speech(2022) Karunathilake, I.M Dushyanthi; Simon, Jonathan Z.Understanding speech in a noisy environment is crucial in day-to-day interactions, and yet becomes more challenging with age, even for healthy aging. Age-related changes in the neural mechanisms that enable speech-in-noise listening have been investigated previously; however, the extent to which age affects the timing and fidelity of encoding of target and interfering speech streams are not well understood. Using magnetoencephalography (MEG), we investigated how continuous speech is represented in auditory cortex in the presence of interfering speech, in younger and older adults. Cortical representations were obtained from neural responses that time-locked to the speech envelopes using speech envelope reconstruction and temporal response functions (TRFs). TRFs showed three prominent peaks corresponding to auditory cortical processing stages: early (~50 ms), middle (~100 ms) and late (~200 ms). Older adults showed exaggerated speech envelope representations compared to younger adults. Temporal analysis revealed both that the age-related exaggeration starts as early as ~50 ms, and that older adults needed a substantially longer integration time window to achieve their better reconstruction of the speech envelope. As expected, with increased speech masking, envelope reconstruction for the attended talker decreased and all three TRF peaks were delayed, with aging contributing additionally to the reduction. Interestingly, for older adults the late peak was delayed, suggesting that this late peak may receive contributions from multiple sources. Together these results suggest that there are several mechanisms at play compensating for age-related temporal processing deficits at several stages, but which are not able to fully reestablish unimpaired speech perception.Item RESILIENCE OF NETWORKED INFRASTRUCTURE WITH EVOLVING COMPONENT CONDITIONS: A PAVEMENT NETWORK APPLICATION(2016) Asadabadi, Ali; Miller-Hooks, Elise; Civil Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)This thesis deals with quantifying the resilience of a network of pavements. Calculations were carried out by modeling network performance under a set of possible damage-meteorological scenarios with known probability of occurrence. Resilience evaluation was performed a priori while accounting for optimal preparedness decisions and additional response actions that can be taken under each of the scenarios. Unlike the common assumption that the pre-event condition of all system components is uniform, fixed, and pristine, component condition evolution was incorporated herein. For this purpose, the health of the individual system components immediately prior to hazard event impact, under all considered scenarios, was associated with a serviceability rating. This rating was projected to reflect both natural deterioration and any intermittent improvements due to maintenance. The scheme was demonstrated for a hypothetical case study involving Laguardia Airport. Results show that resilience can be impacted by the condition of the infrastructure elements, their natural deterioration processes, and prevailing maintenance plans. The findings imply that, in general, upper bound values are reported in ordinary resilience work, and that including evolving component conditions is of value.