The Genetic, Molecular, And Cellular Bases Of Unidentified Primary Immunodeficiencies

The immune system is inseparable from every part of human biology. From cell intrinsic mechanisms of pathogen recognition to multi-cellular interactions over vast ranges of time and space, the immune system is both essential for protection from infection and central to the pathogenesis of many diseases. Thus understanding it has long been a focus of biomedical research. While in vitro molecular, biochemical, and cellular techniques as well as complex genetically modified animal models have been developed, these approaches still only approximate true human disease and in vivo human biology. Primary immunodeficiencies are inborn genetic defects of immunity and present rare opportunities to observe, study, and understand how genetic perturbations impact human immunity directly. I therefore clinically and genetically analyzed three patient families with unidentified primary immunodeficiencies. Using whole exome sequencing coupled with in vitro and in vivo biochemical and cellular assays, I identified two novel genetic etiologies of primary immunodeficiency. I first identified de novo missense mutations in GNAI2, the gene encoding the ubiquitously expressed heterotrimeric G-protein Gαi2, in 2 families with life-threating multi-organ system autoimmunity and immunodeficiency to mucocutaneous infections. Gαi2 is essential for chemokine mediated leukocyte migration as well as regulating development, inflammation, and metabolism in the immune system and beyond. The heterozygous dominant gain-of-function patient proteins impaired chemokine signaling and chemotaxis in addition to augmenting T cell activation by constitutively activating costimulatory pathways and reducing the requirement for T cell costimulation. I also identified homozygous missense mutations in IFIH1, the gene encoding the cytosolic pattern recognition receptor of dsRNA MDA5, in the third family of study. The affected individual presented with recurrent severe respiratory infections with RNA viruses including human rhinovirus, coronaviruses (HKU1, OC43, NL63), influenza virus, and respiratory syncytial virus. The mutant protein lost the ability to bind dsRNA and failed to initiate antiviral interferon-β and pro-inflammatory NF-κB responses. Using gene knockdown and gene editing in immortalized and patient derived cell lines, I demonstrated an essential role for MDA5 in restricting rhinovirus infection in human respiratory epithelium. Thus this work demonstrates the power of human genetics to identify disease causing mutations in rare individuals and reveal how the immune system uses molecules involved in cell migration, activation, and nucleic acid sensing to robustly protect us from virus infections without causing autoimmunity

Examining Visitor Attitudes Toward the Proposed Greater Canyonlands National Monument: A Visitor Survey in Utah’s Indian Creek Corridor

In August of 2012, the Outdoor Industry Association (OIA) sent a letter that was backed by over 100 outdoor retailers to President Barack Obama

Pathological Personality Traits and Social Behaviour: Informant and Within-Person Variability Perspectives

The link between personality pathology and social functioning is well established in past research. As such, this study sought to contribute to the literature on the new alternative DSM-5 model for personality disorders, by examining how the dimensional pathological personality traits embedded within the model (viz. antagonism, disinhibition, negative affectivity, detachment, and psychoticism) relate to patterns in social behaviour, using the interpersonal circumplex as the model of social behaviour. The current study recruited 240 university students (‘targets’), who gave ratings of their own personality, nominated informants who provided parallel ratings of the targets’ personality, and completed an intensive repeated measures in naturalistic settings (IRM-NS) procedure to measure their social behaviour in naturally-emerging social interactions over a period of 10 days. A total of 147 cases with data from all three study components were gathered, and 204 targets completed the IRM-NS procedure. The relations between personality and social behaviour were examined from two perspectives. The first perspective compared the predictive validity of self- versus informant-reported traits in accounting for general trends in social behaviour. Much of the previous literature has suggested that informant-reports are particularly useful for understanding maladaptive personality traits and their connection to outcomes such as social functioning (e.g., Klein, 2003; Miller et al., 2005; Ready et al., 2002; Ro et al., 2017). A series of partially latent structural equation modelling (SEM) analyses were used to compare the utility of self- and informant-reports in predicting mean-level aggregations of the target’s behaviour from the IRM-NS procedure. These analyses showed that across all the personality traits examined, self-reported personality was a superior predictor of social behaviour, compared to informant-report personality. Moreover, each of the pathological personality traits was associated with a predominant interpersonal theme, and correlational agreement between the target and informants reached only modest levels, with informants reporting that the targets had lower levels of the pathological personality traits than did targets themselves. The second perspective examined how well the pathological personality traits could predict patterns of within-person variability in social behaviour. Within-person variability refers to the range in behaviour an individual exhibits across different interactions and over time; it concerns whether they tend to behave similarly in different interactions or are prone to demonstrating many different interpersonal styles. Past research suggests that higher levels of within-person variability represent dysfunction (Côté et al., 2012; Kopala-Sibley et al., 2013; Moskowitz & Zuroff, 2004, 2005; Russell et al., 2007). Multiple regression analyses were conducted with the pathological personality traits as predictors of various indices of within-person variability. Detachment and antagonism emerged as the most consistent predictors of within-person variability. However, the traits often did not collectively account for more variance than mean-level social behaviour scores, and the traits accounted for only modest amounts of explained variance in the within-person variability scores. This study contributes to the literature through its use of an ecologically valid measure of social behaviour, direct comparison of the validity of self and informant-reported personality traits, and examination of whether the pathological personality traits are better able to predict within-person variability in social behaviour than the predictors used in past examinations. The limitations of this study and directions for future research are discussed

A Social-Ecological Approach to Understanding the Structure, Function, and Challenges Faced by Fisheries

Fisheries throughout the world play many important roles, and they are also subject to many pressures. The tension between roles and pressures is increasing, and as a result, many fisheries are being utilized to, or over their capacity, which ultimately threatens their sustainability. To address these challenges, this dissertation provides insights and tools to help us better understand fisheries and the challenges they face. The first study explores the impacts of an earlier spring runoff in Montana. Earlier runoff has resulted in lower and warmer summer flows, which is stressing coldwater species like trout. This stress is affecting fishing quality, and the state of Montana, along with outfitters and guides, are altering fishing practices to reduce resource impacts. As runoff trends continue, August, the once-coveted month offering high quality angling opportunities, will be fraught with unfavorable conditions and fishing restrictions. The second study presents an innovative method for developing social-ecological models. I show how this approach can illustrate the breadth and interconnectedness of a social-ecological system and explore the components and interactions affecting a system’s sustainability. Using a collaboratively developed model of the Kenai fishery, I identified how the nature of salmon (migratory) and their habitat (large and unpredictable) leads to uncertainty about effective management strategies. This uncertainty, in addition to a large and diverse set of people using the fishery, creates conflicting management visions, which ultimately paralyze the governance system. The third study evaluates how fire and post-fire flooding can affect a fishery. Through stakeholder interviews and a literature review, I identified fish populations that are the most vulnerable to long-term fire-related impacts. Vulnerable populations are isolated, lack quality habitat alternatives, and have low abundance. Applying this to the Kenai, I concluded that early-run Chinook salmon are the most vulnerable to fire, and if impacted, early-run Chinook have the greatest potential to severely impact the broader fishery through a chain of negative interactions. Collectively, this dissertation provides insights and tools to help us better understand fisheries and the challenges they face

Factors Associated with Distress in Caregivers of People with Personality Disorders

The present study investigated a variety of stressors experienced by caregivers of people with personality disorders, how these stressors relate to each other and psychological distress, and caregivers’ intentions to seek help, using the Stress Process Model (Pearlin, Mullan, Semple, & Skaff, 1990). Caregivers (N = 106) completed an online survey; 85% of the sample supported a loved one with borderline personality disorder and over 90% of the care-receivers had additional acute psychopathology. Partial Least Squares Path Modelling revealed that caregivers who were male, younger, or residing with their loved one were more likely to experience stressors. Salient primary stressors, or those arising from the needs of the care-receiver, included the caregivers’ worry and care-receivers’ level of instrumental demands and interpersonal problems. Important secondary stressors, or impacted areas of the caregivers’ lives outside the caregiving relationship, included strains in the caregivers’ schedules, family relationships, and health, as well as reduced mastery and caregiving esteem. The model supported a trajectory through which demographic characteristics and experiences of stigma and problems with services increase the likelihood of experiencing primary stressors, which, in turn, are predictive of higher secondary stressors. Higher levels of stressors increase the risk of experiencing psychological distress. Additional preliminary analyses revealed that caregivers reported higher intentions to seek emotional and informational support, rather than instrumental, as well as a preference for formal, rather than informal, informational support. The present study has implications for understanding the broader impact of personality disorders, developing strategies to better support caregivers, and clarifying the way caregiving stressors give rise to outcomes such as psychological distress

From Darwin to Dracula: A study of literary evolution

Argues that, without the publication of Charles Darwin\u27s Origin of Species, Bram Stoker\u27s novel Dracula and Oscar Wilde\u27s novel The Picture of Dorian Gray would not have been written with their distinct style and themes, as evolution clashes with degeneration and female power (and the sexuality derived from that power) clashes with the new science. Stoker and Wilde combine the science of the late 19th century with the characters of their imaginations. Natural and sexual selection plays a part in these characters\u27 core development. The mixture of sexuality, science and power in these two novels all combine to formulate what is known as Victorian sexology