VictorJuiz/thesis huggingface dataset:
Establishing Relations between BOLD Variability, Age, and Cognitive Performance
Keywords: Brain variability
aging
cognition
fMRI

Neuroscientists have long known that brain function is inherently variable. Functional magnetic resonance imaging (fMRI) research often attributes blood oxygen level-dependent (BOLD) signal variance to measurement-related confounds. However, what is typically considered “noise” variance in data may be a vital feature of brain function that reflects development, cognitive adaptability, flexibility, and performance. In the present thesis, we examine how brain signal variability (measured with a modified BOLD time series standard deviation (SDBOLD)) relates to human aging and cognitive performance in a series of studies. In Study 1, we examined brain variability during fixation baseline periods. We found that not only was the SDBOLD pattern robust, its unique age-predictive power was more than five times that of meanBOLD (a common measure of BOLD activity), yet revealed a spatial pattern virtually orthogonal to meanBOLD. Contrary to typical conceptions of age-related neural noise, young adults exhibited greater brain variability overall. In Study 2, we found that younger, faster, and more consistent performers exhibited significantly higher brain variability across three cognitive tasks, and showed greater variability-based regional differentiation compared to older, poorer performing adults. SDBOLD and meanBOLD spatial patterns were again orthogonal across brain measures. Study 3 demonstrated experimental condition-based modulations in SDBOLD. SDBOLD was an effective discriminator between internal (lower variability) and external (higher variability) cognitive demands, particularly in younger, high performing adults. Finally, to gauge the extent that brain variability can be incrementally manipulated within a single cognitive domain, Study 4 examined parametric modulations in SDBOLD on a face processing task in a young-only sample. Results indicated that SDBOLD can be robustly manipulated through experimental control, and that this manipulation linearly follows performance trends across conditions. These studies help establish the age- and performance-relevance of BOLD variability. We thus argue that the precise nature of relations between aging, cognition, and brain function is incompletely characterized by using mean-based brain measures exclusively.
Integrating Patients into Integrated Healthcare: Perspectives from Individuals Coinfected with Tuberculosis and HIV
Keywords: tuberculosis
HIV
coinfection
qualitative methods
service integration
patient perspectives

Background: Tuberculosis (TB) and human-immunodeficiency virus (HIV) infections are intertwined through complex biological and social pathways that affect over one million people worldwide. Mitigation of the co-epidemic is undermined by a failure to integrate TB and HIV healthcare services as a result of critical clinical, operational and social challenges. The social challenges of TB/HIV coinfection and integrated care are least understood. Objectives: This research examines the social contexts of TB/HIV illness and related healthcare from the perspective of patients coinfected with TB and HIV. Methods: The study was set within a constructivist-interpretivist theoretical framework. Non-participant field observations and semi-structured in-depth interviews were held with 40 coinfected adults (24 women, 16 men) and 8 healthcare workers at 3 ambulatory clinics in KwaZulu-Natal, South Africa, providing varying models of TB and HIV care. Subjective meanings of illness and healthcare were analyzed in relation to patients’ social contexts. Findings and Interpretations: Coinfection exposes patients to a double and unequal form of social stigma around TB and HIV. Affected individuals construct dual identities and negotiate selective disclosure of TB over HIV in order to manage this double stigma. Their experiences with stigma are bound by social, structural and gendered inequalities, and mediate their decisions to disclose, access and adhere to medical care. Coinfection also exposes patients to pluralistic, disparate and fragmented forms of healthcare delivery. Experiences with stigma and with distinct cultures of TB and HIV care affect their decisions for integrated healthcare. While integration may allow for some technical and clinical efficiency, it may also heighten some patients’ social burden of illness as a result of HIV disclosure and stigmatization. Conclusion: Integration efforts should consider the social contexts of TB/HIV coinfection, social consequences of patients’ health decisions, and paradigms within which such efforts are set in the design and execution of successful interventions.
Destabilization of IL-8 mRNA by Anthrax Lethal Toxin: Demonstration of the Requirement for TTP and Examination of its Cellular Interactions
Keywords: Anthrax lethal toxin
mRNA destabilization
Tristetraprolin

Control of mRNA stability is an important aspect in the regulation of gene expression. A well studied signal for rapid transcript decay in mammalian cells is the AU-rich element (ARE), which is found in the 3’ untranslated region (UTR) of many labile transcripts. These sequence elements confer destabilization of transcripts by binding to AU-binding proteins (AUBPs) that can recruit cellular decay enzymes. The stability of ARE-containing mRNAs can be regulated by extracellular stimuli, which allows for cells to adapt to the changing environment. AREs are found in many transcripts that encode for inflammatory genes, including TNF, GM-CSF, and IL-8. Pathogens evolve and devise mechanisms to subvert the immune response of the host to aid in its infection. Bacillus anthracis is one such infectious agent that can disable numerous arms of the host immune response. Its secreted toxin, anthrax lethal toxin (LeTx), causes the accelerated decay of the IL-8 mRNA. IL-8 is a dual function cytokine and chemokine that can recruit and activate neutrophils at the site of infection. Through the inactivation of MAPK pathways, LeTx activity causes the destabilization of IL-8 transcripts through its ARE. In this thesis, I show that an AUBP, TTP, is dephosphorylated by LeTx and MAPK inhibitors, and knock-down of its expression stabilized IL-8 transcripts. LeTx activity also increased the colocalization of TTP to P-bodies, cytoplasmic sites concentrated with RNA decay enzymes. This suggests that the post-translational modification of TTP induced by LeTx led to its enhanced destabilization function. Identified TTP-associated proteins, non-muscle myosin heavy chain 9 (myosin-9) and HSC-70, were examined for their role in IL-8 transcript decay. Knock-down of each protein led to a slower rate of IL-8 mRNA destabilization. However, treatment of LeTx continued to mediate accelerated destabilization of IL-8 in these siRNA-transfected cells. This suggests that LeTx, myosin-9, and HSC-70 modulate the destabilization function of TTP independently.
Things Rank and Gross in Nature: Psychological, Physiological and Neuroimaging Investigations of Sociomoral Disgust
Keywords: disgust
emotion
moral

Much like unpalatable foods, filthy restrooms and bloody wounds, sociomoral transgressions are often described as “disgusting”. This linguistic similarity suggests that there is a link between sociomoral disgust and more rudimentary forms of disgust associated with toxicity and disease. Critics have argued, however, that such references are purely metaphorical, or that sociomoral disgust may be limited to transgressions that remind us of more basic disgust stimuli. My aim was to provide more direct evidence that sociomoral transgressions do genuinely evoke disgust, and to explore factors that may influence how much disgust is evoked. I first searched for similarity in the facial expressions evoked by gustatory distaste (elicited by unpleasant tastes), physical disgust (elicited by photographs of contaminants), and moral disgust (elicited by unfair treatment in an economic game). I found that all three states evoked activation of the levator labii muscle region of the face, characteristic of an oral-nasal rejection response and consistent with an origin of sociomoral disgust in oral disgust. I next investigated whether individual differences in the tendency to experience physical disgust are related to variability in sociomoral judgement and emotion. In two different populations, heightened sensitivity toward physical disgust was related to more severe sociomoral judgements. A complementary neuroimaging study showed overlap between the neural correlates of physical disgust and sociomoral judgement, as well as highlighting brain regions that may underlie sociomoral hypersensitivity. Finally, I tested the idea that perceived differences in the causal stability of sociomoral transgressions may specifically affect levels of disgust. Although it was not possible to dissociate disgust from anger, the transgressions that were presented did evoke reliable self-reports of disgust. Taken together, these findings converge to support the conclusion that sociomoral transgressions can in fact elicit disgust, and accordingly that references to the disgusting nature of wrongdoing reflect biological reality rather than metaphor.
Essays on the Allocation of Talent, Skills and Inequality, and Life-cycle Effects of Health Risk
Keywords: Health Risk
Earnings Inequality
Life-cycle Model
Cognitive Skills
Physical Skills
College Field Choice

This dissertation consists of three essays. The first essay studies how health risk affects individuals' economic decisions due to changes in productivity, required medical expenditures, available time and survival probabilities implied by changes in health status. It assesses the role of these four channels in determining labour supply, asset accumulation and welfare using a life-cycle model calibrated to the U.S. economy. I find that all channels and the interactions between them have large implications for the macroeconomic variables studied. Health has larger effects for the non-college than college educated, explaining a significant fraction of the difference in labour supply, degree of reliance on government transfers and asset accumulation across education groups. Improving non-college health outcomes to approach those of college graduates results in large welfare gains, higher labour supply, and significantly lower reliance on government welfare programs. The second essay studies the evolution of wage inequality in the United States between 1980 and 2002 in a framework that accounts for changes in the employment of physical and cognitive skills and their returns. I find that within education-gender groups, average employed cognitive skills have remained constant, while average physical skills have declined. The returns to high levels of cognitive skills have increased dramatically, while returns to low levels of cognitive skills and physical skills have remained approximately constant. Skills account for approximately half of the increase in the college wage premium, and for a small but growing fraction of residual wage inequality. The final essay studies the sorting decisions of students with different levels of analytical and verbal skills into college fields of study. I build a model where each field tests and perfectly reveals to potential future employers only the students' skill that is intensively required in that field. Students' expected wages after graduation are a function of their revealed skill levels and firms' expectations of the unrevealed skills given the chosen field. I show how the size of each field and the average talent it attracts depend on the average skill levels, on skill dispersion and on the degree of correlation between skills in the student population.
Are There Age Differences in Shallow Processing of Text?
Keywords: aging
reading comprehension
eye movements
error detection
shallow processing

There is growing evidence that young adult readers frequently fail to create exhaustive textbased representations as they read. Although there has been a significant amount of research devoted to age-related effects on text processing, there has been little research concerning this so-called shallow processing by older readers. This dissertation uses eye tracking to explore age-related effects in shallow processing across different levels of text representations. Experiment 1 investigated shallow processing by older readers at the textbase level by inserting semantic anomalies into passages read by participants. Older readers frequently failed to report the anomalies, but no more frequently than did younger readers. The eye-fixation behaviour revealed that older readers detected some of the anomalies sooner than did younger readers, but had to allocate disproportionately more processing resources to looking back to the anomalies to achieve comparable levels of detection success as their younger counterparts. Experiment 2 examined age-related effects of shallow processing at the surface form by inserting syntactic anomalies into passages read by older and younger adults. Older readers were less likely to detect syntactic anomalies when first encountering them relative to younger readers and engaged in increased regressive fixations to the anomalies. However, older readers with high iii reading comprehension skill were able to use their familiarity with text content to increase their likelihood of syntactic anomaly detection. Experiment 3 investigated the role of aging on shallow processing of the temporal dimension of the situation model. No age-related differences reporting the anomalies were found. The eye-fixation behaviour revealed that older readers with high working memory capacity detected some anomalies sooner than did younger readers; however, they had to allocate increased processing resources looking back to the anomalies to achieve comparable levels of detection as younger readers. Together, the results demonstrate that older readers are susceptible to shallow processing, but no more so than younger readers when they can rely on their linguistic skill or their existing knowledge to help reduce processing demands. However, older readers appear to require additional processing time to achieve comparable levels of anomaly detection as younger readers.
A Study of Corticotropin-releasing Factor-catecholamine Interactions in the Reinstatement of Cocaine Seeking in Rats
Keywords: Corticotropin-releasing factor
Noradrenaline
Dopamine
Relapse
Drug Self-administration
Cocaine
Stress
Yohimbine

It has been well established that the stress-related neurochemical systems corticotropin-releasing factor (CRF), noradrenaline (NA), and dopamine (DA) mediate stress-induced reinstatement of drug seeking. The three series of experiments presented in this dissertation constitute a further exploration of the role these neurochemical circuits play in reinstatement by providing the first direct exploration of whether central CRF and catecholamine (NA and DA) systems interact to influence reinstatement of cocaine seeking. The primary objective of the first series of experiments was to determine whether NA and CRF systems interact to mediate reinstatement of cocaine seeking and, if so, to determine the direction of this interaction. Results showed that central administration of NA induced reinstatement and up-regulated the expression of c-fos mRNA, a marker of neuronal activation, in brain regions involved in footshock-induced reinstatement. Pretreatment with a CRF antagonist blocked NA-induced reinstatement. In contrast, pretreatment with the α2-adrenoceptor agonist, clonidine, failed to block CRF-induced reinstatement. Taken together, these findings suggest a functional interaction between NA and CRF systems in mediating stress-induced reinstatement of cocaine seeking, whereby activation of CRF receptors occurs subsequent to, and downstream of, the sites of action of NA. A second series of experiments examined the role of D1- and D2-like receptors in CRF-induced reinstatement. Pretreatment with the D1- or D2-like receptor antagonists, SCH23390 and raclopride, respectively, dose-dependently blocked CRF-induced reinstatement of cocaine seeking. Taken together with previous findings, these results suggest that CRF-induced reinstatement of cocaine seeking likely involves DAergic signaling via D1- and D2-like receptors, subsequent to activation of CRF receptors. The final series of experiments investigated the neuropharmacology of yohimbine-induced reinstatement, focusing on the roles of α2-adrenoceptors, D1- and D2-like receptors. These experiments were prompted by an unexpected finding in the first series of experiments, in which a CRF antagonist failed to interfere in yohimbine-induced reinstatement of cocaine seeking. Results showed that pretreatment with the α2-adrenoceptor agonist, clonidine, or raclopride, prior to tests for yohimbine-induced reinstatement failed to influence responding. In contrast, pretreatment with SCH23390 blocked yohimbine-induced reinstatement. Taken together, these findings suggest that yohimbine may act through system(s) other than NA to have its effects.
Investigation of the Effects of Inhibiting N-glycosylation in Cancer
Keywords: N-glycosylation
Cancer
Chemical Biology

Glycosylation, the addition of sugar moieties to nascent proteins, is one of the most common posttranslational modifications. Glycosylation regulates protein structure, function and localization. Most cell surface proteins and secreted proteins are glycosylated by the addition of Asparagine(N)-linked glycans (N-glycans). Aberrant N-glycosylation is a well-accepted feature of malignancy and is a potential prognostic marker for some types of cancer. For example, increased expression of complex N-glycans has been detected in cancers of breast, colon and has been correlated with reduced survival of the patients. Therefore, understanding the role of N-glycosylation in malignancy could be beneficial for developing novel therapeutic and prognostic strategies. To examine the role of N-glycosylation in malignancy, we applied chemical biology and genetic approaches. First, we conducted a high throughput screen to identify compounds that could block L-PHA-induced cell death. Our screen identified the cardiac glycoside Na+/K+-ATPase inhibitors as novel inhibitors of N-glycosylation. Further analysis of N-glycans consistently confirmed that inhibition of Na+/K+-ATPase impairs the N-glycosylation, as well as migration and invasion. Interestingly, other studies have shown antimetastatic effects of cardiac glycosides in patients. Thus, our high throughput screen identified Na+/K+-ATPase inhibition as a novel strategy to target the N-glycosylation pathway. In addition, we used a genetic approach to investigate the role of N-acetylglucosaminyltransferase I (GlcNAc-TI/Mgat1) in malignancy. Knockdown of GlcNAc-TI decreased the cell-surface expression of complex N-glycans. By confocal microscopy, knockdown of GlcNAc-TI decreased cell surface expression of β1 integrins and increased their localization around the nucleus. Moreover, GlcNAc-TI knockdown decreased the migration and invasion of malignant cells. Next, we investigated the effect of GlcNAc-TI in an orthotopic xenograft mouse model of metastasis. GlcNAc-TI knockdown significantly decreased the lung colony formation of the highly metastatic PC3N7 human prostate cancer cell line in mice. Our results suggest an important role for GlcNAc-TI in tumor metastasis. Interestingly, breast cancer patients with lower expression levels of Mgat1 had lower risk of disease relapse after therapy. Thus, GlcNAc-TI plays an important role in cancer progression and metastasis and GlcNAc-TI inhibitors could have therapeutic benefits for cancer patients. Moreover, expression levels of GlcNAc-TI could be used as a prognostic marker in patients with cancer.
Atmospheric Modernism: Rare Matter and Dynamic Self-world Thresholds
Keywords: Woolf, Virginia
Lawrence, D.H.
London
Atmosphere
Spatial Perception
Body Imagery
Modernism
Meynell, Alice
Chiang, Yee
Markino, Yoshio
Hyde, William
Fog
Rarity
Density
Self-World Thresholds
Air
Subject/Object Boundaries
Reader Response
Gestalt Effects
Conrad, Joseph
Fitzgerald, F. Scott

Defining rarity as a relative quality in matter roughly opposite to density, this dissertation focusses on the way material qualities of molecular gases, such as semi-opacity, permeation, and blending, inform modernist representations of embodied spatial experience. In modernist writing, rare matter—including air, fog, smoke, and haze—functions as an active component of the sensory environment, filling up the negative space that sets off subjects from objects, and characters from settings. Representing matter across the full range of the rarity-density spectrum allows modernist writers to challenge the ontological status of such boundaries, and to develop dynamic spatial models of the self-world threshold. The Introduction defines rare matter and examines its function as a sensory medium that can alternately define and blur subject/object boundaries. Interpreting dynamic thresholds as products of authorial activism, I argue that modernist narratives disrupt the normative constructions of the self-world boundary that prevailed in biomedical discourse around the turn of the century. Chapter 1, seeking to expand the scope of modernist object studies to include rare matter, analyzes illustrated books about London to demonstrate the increased cultural visibility of the atmosphere in the modernist period. Visual and verbal gestalt effects, modelled on the hermeneutic oscillation between looking at and looking through the fog, foreground the materiality of the atmosphere that fills up three-dimensional space, pressing up against the thresholds of the body and disrupting fixed distinctions between subjects and their surroundings. Chapter 2 shows how D. H. Lawrence harnesses the properties of rare matter to construct dynamic representations of the self-world boundary. In his early novels and his criticism, the oscillation between self-diffusion and self-differentiation expresses characters’ psychological responsiveness to changing interpersonal and ontological pressures. Chapter 3 demonstrates how Virginia Woolf takes advantage of rare attributes like permeation, fluid motion, and variable particle spacing to model process-oriented communities that incorporate dynamic shifts between social autonomy and collective identity. The Conclusion examines rare imagery in modernist scenes of narration, arguing that dynamic self-world thresholds help to articulate a responsive form of reader-text interaction that allows for the alternation of independent and collaborative reading practices.