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The Role of the Unfolded Protein Response on Sleep and Cognition in Aging and Alzheimer’s Disease
No full textThe maintenance of protein homeostasis, or proteostasis, is crucial for the proper functioning of cells. Proteostasis refers to the cycle of synthesizing, folding, transporting, and degrading proteins. The main site of protein synthesis within the cell is the endoplasmic reticulum (ER). When protein folding load is excessive, proteostasis is disrupted and ER stress ensues. Activation of the unfolded protein response (UPR) pathway acts to reduce ER stress and restore proteostasis. However, with age the UPR becomes less efficient, or even maladaptive, contributing to sleep deficits and cognitive impairments. As the number of aged individuals in the population grows due to the advances of modern medicine, so does the incidence of age-related disorders. Age is a major risk factor for the development of Alzheimer’s disease (AD). Cognitive dysfunction and sleep deficits are prominent features of AD, coupled with protein dyshomeostasis in the form of protein aggregates such as Aβ plaques. Further, protein synthesis is necessary for memory formation, and disruptions in proteostasis can have direct consequences for cognition in both age and disease. Given this, it remains unclear if there is a causal link between proteostasis, sleep quality, and cognition across aging and disease. In the following dissertation, we use a mouse model of aging and a mouse model of Alzheimer’s disease to determine if reducing ER stress via increasing protein chaperone levels, either systemically via intraperitoneal PBA injections or locally via hippocampal microinjections with an AAV-BiP, improves both sleep quality and memory. Our results suggest that chaperone treatment consolidates sleep in a wildtype mouse model of aging and improves learning in both a mouse model of aging and AD. Chaperone treatment reduces ER stress in both models and leads to an increase CREB activity which is linked to improved cognition. Further, chaperone treatment in a mouse model of AD led to the increase of XBP1s and ADAM10, which are associated with the non-amyloidogenic cleavage of APP. The implications of these results could have an impact on the development of therapies to improve healthspan in the growing aged population and inform the development of potential treatments for Alzheimer’s disease
Applying Next Generation Sequencing to Investigate the Dynamics of Clinical Infections
No full textInfectious diseases continue to be leading causes of morbidity and mortality around the world. Hospital acquired infections are one of the major public health concerns today. This work explores how we apply next generation sequencing to understand hospital-acquired infections in the clinical setting, using advanced sequencing techniques from the research setting. In our first study, we investigated a possible Mycobacterium chelonae point outbreak of two patients in a local hospital. We performed hybrid assembly, pangenome and single nucleotide variant analysis, and found that the two strains of Mycobacterium chelonae were not genetically similar and thus were contracted from the environment separately. We defined genetic identity by establishing the divergence between genome assemblies from sequencing error through whole genome sequencing a single strain of Vibrio campbellii 39 separate times. In our second study, we investigated the association between the gut microbiome composition and bloodstream infection in critically ill patients through whole genome and metagenomic sequencing. We found that bloodstream infection species were present in the gut of half the subjects and were the dominant gut taxa in 10% of bloodstream infection episodes. Whole genome sequencing of available bloodstream infection isolates confirmed strain-level identity between gut and blood organisms in 5 of 6 episodes where the species were present in the gut. Using sequence comparison and temporal analysis, our findings suggest that the gut was a likely source of bloodstream infection in 7 of 9 episodes where the species was dominant in the gut. We concluded that translocation of dominant gut organism may contribute to bloodstream infection in some critically ill patients; thus, sequencing of the gut microbiome may provide data on the frequency and clinical correlates of bloodstream infection. Overall, our methods were able to distinguish genetic similarity between organisms both between and within subjects and shed light on the origin and dynamics of hospital-acquired infections. Our studies lay the foundations for using next generation sequencing to better understand and track the dynamics of hospital acquired infections
The Effect of Confinement on T-Lymphocyte Upstream Migration Under Shear Flow
No full textTo maintain homeostasis and fight infections, leukocytes must exit the bloodstream and reach sites of inflammation. The leukocyte adhesion cascade has evolved to perform this function. One step is migration on the endothelium. CD4+ T-lymphocytes migrate upstream on intracellular adhesion molecule-1 (ICAM-1). In this thesis, we explore the potential of this upstream migration to direct T cells confined within microcontact printed and microfluidic devices. In the first aim, we explore the microcontact printing conditions to confine T cells within printed ICAM-1 patterns and support upstream migration. We determined directly inking and printing a 50:50 mixture of ICAM-1 and vascular adhesion molecule-1 (VCAM-1) provides optimal conditions without creating any noticeable topological features. In the second aim, we seeded T cells on stripes oriented in the direction of flow and tested upstream migration. We discovered that confinement on stripes has the potential to inhibit upstream migration. T cells on 50μm stripes migrated primarily downstream. Full upstream migration was restored on stripes 200μm wide. Characterization of T cell migration determined that this behavior was a factor of the width of the patterned stripe. The edge of the printed stripe has a greater inhibition of upstream migration beyond that of the stripe width. In the third aim, we further investigated the phenomenon of induced downstream migration based on width of confinement by seeding T cells and observing migration under flow in microfluidic devices. Microfluidic channels with widths of 25μm and 50μm both resulted in downstream migration of T cells, confirming the discovery aim 2 across device architecture. Full upstream migration was restored in microfluidic channels 200μm wide. Characterization of T cell behavior within these devices determined that the downstream migration is regulated by the width of the channel. Interactions with the microfluidic wall has minimal additional inducement of downstream migration. The determination of T cell behavior dependent on the width of confinement discovered in this thesis may be applied to the creation of microfluidic devices to control and direct T cells for potential applications in immunotherapy
Development of MUSTANG-2: A Microwave Squid Multiplexed TES Array for 90 GHz Imaging
No full textGalaxy clusters provide rich astrophysical laboratories, enabling studies of the most energetic events since the Big Bang. The myriad of important astrophysical phenomena present in high energy events such as galaxy mergers and active galactic nuclei, include shocks, cold fronts, and interactions of gas within the envelope of the cluster’s dark matter potential. The study of galaxy cluster physics yields a fundamentally unique opportunity to probe the properties of cluster dynamics and the intracluster medium (ICM). High-resolution observations of pressure substructure in the ICM with the second generation Multiplexed SQUID/TES Array at Ninety GHz (MUSTANG-2) provide a powerful probe into the dynamical state of these clusters. MUSTANG-2 contains a 223-pixel bolometer array with a microwave SQUID multiplexed (µMUX) readout system, which combines the sensitivity of TES detectors with the multiplexing capability of Microwave Kinetic Inductance Detectors (MKIDs). The µMUX readout system has been demonstrated to multiplex 400 bolometers with no degradation in noise performance. Arrays of thousands of polarization sensitive TES detectors can be read out on a single feedline by tuning each SQUID on the µMUX to a slightly different resonance frequency. Thousands of resonators can be fabricated onto a single layer, coupled to one feedline and then amplified by a cryogenic HEMT amplifier. MUSTANG-2 will not only dramatically aid in increasing our understanding of high-energy astrophysical phenomena and their relationship to cosmological parameters, but also significantly advance the technology readiness level of highly multiplexed detector arrays
Collation Model for Oversize Ms. Codex 243: Leticha / del magnio filosefo Aristotile.
Get PDFItalian compendium of Aristotle\u27s Nichomachean ethics. Written in Italy, ca. 1500.https://repository.upenn.edu/sims_models/1096/thumbnail.jp
18F-FDG-PET/CT in Radiation Therapy-Induced Cerebellar Inflammation
Get PDFABSTRACT
Background
18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18FDG- PET/CT) is used in the clinical diagnosis and management of oncologic and inflammatory pathologies. It may also have utility in detecting tissue damage induced by radiotherapy (RT) used to treat various types of cancer. The aim of the present study was to use 18FDG-PET/CT to evaluate the effect of RT on the uptake of 18FDG by the cerebellum.
Methods Thirty patients with head and neck cancer (HNC) were included in this retrospective study. The patients were treated with photon, proton, or combined photon/proton RT, in addition to chemotherapy. All patients received 18FDG- PET/CT imaging pre-treatment and 3 months post-treatment. The global mean standardized uptake value (SUVmean) of the cerebellum was determined for every patient by global assessment of 18FDG activity using OsiriX MD software. A two-tailed paired t-test was used to compare global SUVmean pre- and post-RT.
Results The pre-treatment and post-treatment global SUVmean for the photon group were 5.26 and 5.51 (p: 0.42), respectively. As for the proton only group, the pre- and post-treatment global SUVmeans were 7.06 and 6.05, respectively. In the combined RT group, the pre- and post-treatment global SUVmeans were 6.14 and 6.19 respectively (p: 0.92). The differences between the pre- and post-treatment values failed to reach statistical significance for any of the treatment groups but it should be noted that there was a trend of increased 18FDG uptake in the cerebellum following photon therapy. This trend was not clear in the combined group. As for the proton group, p-value was not calculated as only two patients were included.
Conclusion
Although not statistically significant, the results showed an incremental increase in global SUVmean following treatment with photon RT likely reflecting the presence of mild radiation-induced inflammation in the cerebellum
Dialect on Trial: Raciolinguistic ideologies in perceptions of AAVE and MAE codeswitching
Get PDFIt is known that listeners map speakers’ voices to racial categories and that such identification can have harmful social, political, and economic consequences for African American Vernacular English (AAVE) speakers (Baugh 2003, Grogger 2009, Rickford and King 2016). While this work has focused on the production of linguistic cues used to perceive speakers’ race, recent research on the white listening subject (Flores and Rosa 2015) has advocated investigating listeners’ raciolinguistic ideologies, regardless of whether speakers command standardized or stigmatized varieties (Rosa and Flores 2017). This paper explores social perceptions of a bidialectal African American speaker when he uses African American Vernacular English (AAVE) compared to Mainstream American English (MAE). The speaker, a 32-year-old African American professor from California, recorded AAVE and MAE versions of a (2 minute) passage accounting his weekend activities, made to resemble an alibi in a criminal justice proceeding. Utilizing a matched-guise design, 116 undergraduate participants were randomly assigned to hear the account spoken in either AAVE or MAE, without background information about the speaker. A majority of participants identified the speaker as Black, as having less than a college degree, and as coming from a lower/working-class background, though listeners hearing the AAVE guise were more likely to perceive the speaker as Black and less educated than those in the MAE guise. Further, participants in the AAVE condition perceived the speaker as more likely to be involved in a gang compared to the MAE condition. That the speaker’s codeswitching resulted in racialized differences in some ratings (e.g., race, education, gang status), but not in others (e.g., class, credibility, trustworthiness) raises questions about whether codeswitching can ameliorate the well-established consequences of anti-Black stereotypes for AAVE speakers. Regardless of the presence or absence of AAVE features, ideologies attached to Black voices can still yield associations with legible Black tropes
X-Ray Scattering Investigations Into Nanoporous Gold\u27s Kinetic Behavior During Dealloying And Coarsening For Applications In 3d Energy Storage
No full textThe ever-increasing presence of catastrophic climate events around the globe signify the effects of the last century’s climb from below 300 ppm to over 400 ppm of atmospheric carbon. Materials Science and Engineering offers us an exit strategy. In this dissertation, we aim to connect three of the primary aspects of Materials Science and Engineering – synthesis, processing, structure, and performance – with fundamental X-ray scattering studies on dynamic processes in nanoporous gold, the model system for a class of materials called nanoporous metals, which have applications in fossil-fuel curbing technologies such as catalysis, energy storage and conversion, and mechanical-to-electrical energy harvesting. In the first part of the dissertation, we connect materials synthesis and underlying structure by (i) developing a novel, eco-friendly free corrosion dealloying synthesis route to nanoporous gold and comparing its structure to that of nanoporous gold created by conventional free corrosion in concentrated nitric acid, and (ii) using real-time X-ray scattering techniques to study the microstructural evolution and kinetic behavior of nanoporous gold during synthesis by electrolytic dealloying. In (i), we use a chelating agent to sequester copper ions as they are removed from a parent Au-Cu alloy in a neutral electrolyte. Without a chelating agent, these Cu ions would react to form a passive surface film that would prevent dealloying from proceeding in neutral electrolyte. In (ii), we study the microstructure and crystal structure of nanoporous gold simultaneously during electrolytic dealloying in perchloric and nitric acids; here, we discover that a passive silver chloride (AgCl) film grows on its surface in perchloric acid, whereas no film growth was observed in nitric acid. This passive film slows down dealloying kinetics and ultimately results in a smaller characteristic size as AgCl blocks the surface diffusion of gold adatoms. In the second part of the dissertation, we use real-time X-ray scattering techniques to study the coarsening behavior of nanoporous gold during thermal processing, thereby connecting materials processing and underlying structure. We find that during heat treatment, the characteristic size of nanoporous gold departs from the conventional t1/4 power law for surface diffusion coarsening, slowing down to t1/20 within 2 hours of heating at 200 oC. Using new insight gleaned from this study on nanoporous gold’s behavior during thermal treatment, we connect material structure and material performance in the last part of this dissertation. Here, we fabricate and electrochemically test novel aperiodic 3D energy storage devices (3D nanocapacitors and 3D batteries) that use nanoporous gold as a current-collecting scaffold. Our aperiodic 3D nanocapacitor outperforms its 2D counterpart by 4x in terms of capacitance, and our aperiodic 3D battery is the first demonstration of its kind. These devices have the potential to outpace the energy and power density of conventional 2D energy storage technologies
The Ebb And Flow Of Revolution: A History Of Emotions In Early Nineteenth-Century Colombia
Get PDFThis dissertation explores the ways in which emotions shaped people’s understandings of the troubled times they were living in. It focuses on northern South America – present-day Colombia, Ecuador, and Venezuela – between 1808 and 1830. These years saw both the collapse of the Spanish Monarchy’s rule over the region and the rise of new republican nations. Such an outcome was far from being inevitable or from being one desired by all. The dissertation is both a history of emotions that focuses on early nineteenth-century northern South America and a history of the region’s independence process studied from the perspective of emotions. Throughout the dissertation, I reflect on how emotions shaped people’s notions of reality and their conceptions of the past and the future. The dissertation poses two main arguments. First, I argue that emotions are a constitutive part of cognition. Emotions shaped the meanings people gave to the world around them at the same time that emotions helped express and impute meaning to people’s actions. Second, the dissertation demonstrates that the emotions that circulated during these years, particularly intense fear and confusion, gave form to the republican and national projects that emerged at the time. It claims that independence and the onset of republicanism did not bring about a critical break from the monarchical and colonial past. Widespread feelings of dread and uncertainty led many of the region’s residents to seek stability and safety at the expense of their aspirations for social and political reform. The dissertation carries out a microscopic analysis of a series of events, such as earthquakes, volcanic eruptions, panic attacks, and funeral rites, in order to grasp the prevailing emotions of the time as well as to get a sense of the different ways in which people understood, experienced, and expressed emotions
Caucasus In Motion: Dynamic Wordhood And Morpheme Positioning In Armenian And Beyond
No full textThis dissertation explores the syntactic and morphological properties of a class of mobile verb markers in Modern Armenian. The most prominent case discussed in the literature is the Eastern Armenian auxiliary, which obligatorily attaches to focused constituents, displays second-position effects in focus-neutral contexts, or attaches to the main verb in verb-only contexts (Kahnemuyipour & Megerdoomian, 2017). By looking at an understudied variety of Erzurum Armenian and cross-dialectally, I show that (i) mobile markers are also found in a subset of Western varieties, and (ii) that the auxiliary is not the only mobile marker attested in Modern Armenian. In fact, every high morpheme on the clausal spine can become mobile depending on the dialect.
I provide a syntactic analysis of the clause structure in Erzurum Armenian. Building off the recent literature, I posit information-structure-motivated movement of focused constituents to a high FocP, as well as movement of the closest syntactic element in the Comment to a high FinP. Under this analysis, given/backgrounded information is dislocated to TopP. I add to the typology of Second Position by claiming that Modern Armenian shows both (i) a high focus position and (ii) second-position effects within the comment.
I further use the articulated left periphery to analyze the placement of mobile verb markers. The mobility is derived syntactically via head movement to FinP or FocP. Moreover, accounting for cross-dialectal variation in Erzurum and other varieties which includes variable morpheme positioning and morpheme doubling calls for adopting a decomposed view on head movement. Under this approach, head movement is split into a syntactic operation of head chain formation and a separate operation that selects the locus of chain pronunciation, determined dynamically using an algorithm operating on the chain (Arregi & Pietraszko, 2021). I propose that the decision to extend the head chain should also be determined dynamically in the context of structurally adjacent heads