No description available.

No description available.

Diarrheal disease caused by attaching and effacing pathogens, such as enteropathogenic E. coli (EPEC), is a worldwide health concern. As the second leading cause of diarrheal-related death in young children, new investigations into host defense against EPEC, as well as future therapeutics, is greatly needed. To elucidate the host immune responses to these enteric pathogens, the attaching and effacing (A/E) murine pathogen, Citrobacter rodentium, has been widely used. It is well understood that C. rodentium infection induces a robust Th1 response within the host. Yet how these pleiotropic IFNγ immune responses are initiated, propagated, and the accessory immune cell types involved remains poorly understood. In this thesis, I investigated how innate immune cell types such as natural killer cells, which are significant producers of IFNγ, mediate these Th1 directed responses. This work identified that both NK and NK-like innate lymphoid type 1 cells (ILC1s) are capable of producing IFNγ in response to C. rodentium, and NK cells rapidly increase in numbers within the colon during the early stages of infection. Depletion of these cell types causes a delayed Th1 CD4+ T cell response within the colon, resulting in increased bacterial load, and greater degree of colonic pathology at later time points. Additionally, depletion of these cells results in decreased CXCL9 chemokine expression in mice. I later determined that CXCL9 exhibited direct antimicrobial action against Citrobacter in vitro. Depletion of this chemokine in vivo, in the absence of adaptive immune responses, or its receptor CXCR3, results in increased mortality rates, elevated bacterial loads, greater degree of pathology, and deeper penetration of bacteria within the colonic crypts. These data indicate a potential direct antimicrobial role for this IFNγ-induced chemokine, independent of its known properties for the homing of T cells to the site of infection. These findings demonstrate the importance of accessory IFNγ-producing immune cells in not only mediating Th1 CD4+ T cells responses, but also other innate host defense mechanisms against A/E pathogens. / Thesis / Doctor of Philosophy (PhD)

The study of serial killer collaboration has received little attention in academia. While current explanatory theories of serial homicide can include subtypes of serial killers that operate alone, the study of collaborating serial killers has been neglected. In this paper, an integrated, explanatory theory of serial killer collaboration is proposed. The theory builds on concepts from social learning theory, the trauma control model, and relational self theory and aims to examine what interpersonal dynamics that characterize the partnerships of collaborating serial killers. Five cases of collaborating serial killers have been analyzed and compared with focus on individual life histories and how these are reflected in the interpersonal dynamics in serial killer collaboration. The study found that serial killer collaboration is fundamentally characterized by a mutual need for human connection and approval, and that sociocultural role expectations affect the interpersonal dynamics of collaborating serial killers in terms of dominance, victim-preference, victim-acquisition, and method of murder.

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Psychopathy and serial murder are 2 of society's most devastating and least understood tribulations. Even less is comprehended with regards to the differences in the way these ills are expressed between the genders. In this study, psychopathic personality traits are considered in a sample comparison of male and female serial murderers. Traits are measured using questions derived from Hare's Psychopathy Checklist Revised (PCL-R, 1991). A content analysis was performed to score the components for each subject, using known and accepted biographical and personal interview materials. Findings showed a distinct difference between the sexes, with females scoring lower than their male counterparts, indicating that factor structure of the PCL-R may need to be restructured in regards to females. Implications for public policy including the way female psychopathy is viewed and diagnosed are reviewed.

No description available.

No description available.

The Lyme disease spirochete Borrelia burgdorferi is the only known human pathogen that directly activates invariant natural killer T (iNKT) cells. The number and activation kinetics of iNKT cells vary greatly among different strains of mice. Here, we report the role of the iNKT cell response in the pathogenesis of Lyme disease using C57BL/6 (B6) mice, a strain with optimal iNKT cell activation that is resistant to the development of spirochetal-induced inflammation. During experimental infection of B6 mice with B. burgdorferi , iNKT cells localize to the inflamed heart where they are activated by CD1d-expressing macrophages. Activation of iNKT cells in vivo results in the production of IFNγ, which we demonstrate controls the severity of murine Lyme carditis by at least two mechanisms. First, IFNγ greatly enhances the recognition of B. burgdorferi by macrophages, leading to increased phagocytosis of the spirochete. Secondly, IFNγ activation of macrophages increases the surface expression of CD1d, thereby facilitating further iNKT activation. Collectively, our data demonstrate that in the resistant background, B6, iNKT cells modulate acute murine Lyme carditis through the action of IFNγ, which appears to self-renew through a positive feedback loop during infection. Inflammation during infection with B. burgdorferi is dependent on the ability of the spirochete to evade local mechanisms of clearance. Even though macrophages are the main infiltrating cell during Lyme carditis, the identification of a receptor capable of mediating phagocytosis of B. burgdorferi has been elusive. Here, we demonstrate that the integrin CR3 is able to mediate binding to the spirochete and facilitate phagocytosis in a complement-dependent and independent manner. Expression of CR3, but not CR4, in CHO cells markedly enhanced their capacity to interact with B. burgdorferi , in the absence and presence of complement opsonization. Furthermore, the interaction between CR3 and B. burgdorferi is dependent on the metal-ion-dependent adhesion site (MIDAS) and could be blocked with EDTA. Inhibition of CR3 with blocking antibody was able to completely abrogate phagocytosis of B. burgdorferi by the macrophage-like RAW264.7 cells and partially block uptake by bone marrow-derived macrophages (BMMs), a finding that was recapitulated with CD11b-deficient BMMs. We further show that activation with recombinant IFNγ increases the transcription of CD11b and CD18, which correlates with increased surface expression of CR3, and that the effect of IFNγ on the phagocytosis of B. burgdorferi is circumscribed to CR3 activity, because inhibition of CR3 is able to completely diminish the effect of IFNγ on the phagocytosis of the B. burgdorferi . Lastly, our results demonstrate that CR3 is a negative regulator of proinflammatory cytokine induction in macrophages responding to B. burgdorferi . Overall, our data demonstrate roles for CR3 in the binding, phagocytosis and proinflammatory cytokine elicited by B. burgdorferi and shed light on the role of IFNγ in mediating the clearance of the spirochete during Lyme disease.

Oncolytic viruses (OVs) are promising tumor-selective treatments, and the efficacy of OV therapies has been shown to depend heavily on the successful delivery and spread of these agents within the tumor mass to generate profound immunostimulatory effects. We have previously reported the potential of vanadium-based compounds such as vanadyl sulfate (VS) as immune-stimulatory enhancers of OV immunotherapy. These compounds, in conjunction with RNA-based OVs such as oncolytic VSVΔ51, improve viral spread and oncolysis, leading to long-term antitumor immunity and prolonged survival in resistant tumor models as previously reported. This effect is associated with a virus-induced antiviral type I IFN response shifting towards a type II IFN response. Here, the systemic impact and the relevant immunological changes following VS/VSVΔ51 combination therapy were investigated to understand the immunological mechanism of action leading to improved antitumor responses. We screened for the secretion of chemokines and cytokines in vivo to understand the mechanism of action regulating the recruitment of immune cells to the tumor in the CT26WT tumor model following treatment. Additionally, the antigen-specific immune response was investigated to further identify the relevant immunological changes following treatment with the VS+VSVΔ51 combination. Our data revealed that VS+VSVΔ51 combination therapy significantly increased the levels of IFN-γ and IL-6, and other key important pro-inflammatory cytokines and chemokines. Improved tumor antigen-specific T-cell responses were observed following the combined therapy. Supported by relevant immunological changes and as a proof of concept for the design of more effective therapeutic regimens, we found that local delivery of VSVΔ51 encoded with IL-12 or with other transgenes in combination with VS further improved therapeutic outcomes in a syngeneic CT26WT colon cancer model. We found that CD8+ T cells and Natural Killer (NK) cells play significant roles in establishing the therapeutic efficacy that we observed; Furthermore, engineering new and targeted therapeutic platforms to impact the antitumor immune response further improves the therapeutic benefits of the combined therapy.