Posttraumatic stress disorder (PTSD) and substance use disorder (SUD) frequently co-occur. Comorbid PTSD+SUD confers heightened risk of other mental health concerns, suicidality, mortality, and functional impairment. Current treatments for comorbid PTSD+SUD show inconsistent results, highlighting the need for a more comprehensive understanding of the associations between PTSD and SUD symptoms. The current dissertation aimed to characterize the associations between PTSD and SUD using structural equation modelling among three different samples with differing clinical severity and presentation: (1) concurrent disorders sample with a high prevalence of PTSD; (2) an in-patient sample seeking treatment for PTSD; and (3) a subclinical sample of healthcare workers and public safety personnel. Data were extracted from multiple clinical databases across different studies to evaluate the associations between PTSD symptoms and alcohol/cannabis/substance use-related problems. Furthermore, the role of underlying mechanisms such as dissociation and emotion dysregulation, which are associated with both PTSD and SUD, were analyzed. All analyses used a structural equation modelling framework to represent the complex clinical presentation of comorbid PTSD+SUD analytically. A relatively consistent pattern of results was observed across the three samples. Global PTSD symptoms were significantly associated with cannabis-related problems, alcohol-related problems, and other illicit substance-related problems. Among PTSD symptoms, the reactivity symptom cluster (characterized by symptoms of hypervigilance, irritability, reckless behaviour, problems with concentration and sleep disturbances) was significantly associated with alcohol/cannabis/substance-related v problems across among the three samples. Furthermore, underlying mechanisms such as dissociation and emotion dysregulation significantly mediated the relations between PTSD symptoms and alcohol/cannabis/substance-related problems. Overall, the current results contribute to the limited literature examining the associations between PTSD and SUD symptoms. Lastly, the current results have important clinical implications for identifying efficacious treatment targets for comorbid PTSD+SUD. / Dissertation / Doctor of Philosophy (PhD) / Psychological distress following a traumatic event, known as traumatic stress, is often associated with problematic alcohol and/or substance use. The co-occurrence of these two confers a heightened risk of other mental health problems. As such, studying how these phenomena are associated with one another and what about each thing is more important to the association is important to understand. The purpose was to examine the connection between these phenomena among three different groups of people: two treatment-seeking groups and non-treatment seeking group one group. Traumatic stress was associated with problematic substance use in all three groups. In addition, other factors like mentally escaping from your body and having difficulties with regulating your emotions explained how traumatic stress and problematic substance use were connected to each other. These findings can help clinicians hone their treatment programs to better help individuals struggling with traumatic stress and problematic substance use.

T cells play an important role in adaptive immune system against viral infections, while premature aging and dysfunction of T cells induced by unrepaired DNA damages are always non-negligible snags during the long-term of fighting with chronic viral infections, such as Hepatitis B virus (HBV), Hepatitis C virus (HCV) or Human Immunodeficiency Virus (HIV) infection. In this dissertation, we investigated the role of topological DNA damage in reprogramming telomeric DNA damage responses (DDR), mitochondrial metabolisms, and T cell functions using CD4+ T cells derived from individuals with chronic viral infections or healthy subjects treated with topoisomerase inhibitors. The healthy human T cells were treated with camptothecin (CPT) for mitochondrial topoisomerases I (Top1mt) or ICRF-193 or etoposide (ETP) for topoisomerases IIα (Top2α) as models. We found a significant suppression of Top2α and Top1mt protein levels and enzymatic activity in CD4+ T cells in chronically HCV/HIV-infected patients compared to age and gender-matched healthy subjects, along with an accumulation of the topoisomerase cleavage complex (Topcc) in genomic DNA as well as mitochondrial DNA (mtDNA). Mechanistically, topoisomerase inhibition in healthy CD4+ T cells caused topological DNA damage, telomere attrition, mitochondrial metabolic disorder and T cell apoptosis or dysfunction via inducing Topcc accumulation, PARP1 cleavage and failure in DNA repair, thus recapitulating T cell dysregulation in the setting of chronic viral infections. In addition, T cells from virally infected subjects with lower topoisomerase levels were vulnerable to the inhibitor-induced cell apoptosis, indicating an important role for Top2α and Top1mt in preventing DNA topological disruption and cell death. These results demonstrate that accumulation of Topcc and topoisomerase deficiency lead to unrepaired DNA damage and render virally infected patients’ T cells prone to senescence and apoptosis, thus contributing to mitochondrial metabolic disturbance or dysfunction in CD4+ T cell during chronic HCV or HIV infection. This study reveals a novel mechanism by which topoisomerase deficiency promotes telomeric DNA or mtDNA damage and premature T cell aging, and provides a new therapeutic target for restoring the DNA topologic machinery protecting T cells from unwanted DNA damage and to maintain immune competence.

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Borderline personality disorder (BPD) is a severe and debilitating mental disorder that is over-represented within the criminal legal system (CLS), with 15-29.5% of individuals in the CLS meeting criteria. However, little research has examined mechanisms leading to criminal involvement within this population. Potential mechanisms include positive/negative emotion dysregulation and internalized shame, which (aside from positive emotion dysregulation) have been linked to criminal involvement in other populations. Research has yet to examine these constructs as mechanisms explaining criminal involvement among individuals with BPD. This study examined positive/negative emotion dysregulation and internalized shame as mechanisms of the relationship between BPD and criminal involvement. Adults (N = 93) currently incarcerated in jail who are identified as having a current or prior mental health concern were invited to participate in the study. Measures include the addiction severity index (ASI) examining criminal involvement, the original and positive versions of the difficulties in emotion regulation scale (DERS; DERS-P), and the internalized shame scale (ISS). At the bivariate level, BPD symptoms were significantly correlated with negative emotion dysregulation (total score) and several subscales (clarity, goals, impulse, strategies), as well as internalized shame and criminal involvement. Negative emotion dysregulation and internalized shame were unrelated to criminal involvement, and there was no evidence of mediation through these constructs. These bivariate results are consistent with other literature, but future research is needed to examine relevant variables that could explicate the relationship between BPD symptoms and criminal involvement.