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As a new pediatric dummy family, the Q-family, is suggested for the European childsafety regulations (R44) and the updated EuroNCAP, it needed to be tested andcompared to the older pediatric dummy family, Hybrid III, used in testing at Autolivtoday.In this study, tests were performed with the Q6 and the Hybrid III 6-year-old. Bothdummies were subjected to eight sled tests using a EuroNCAP acceleration pulse. The sled represented the interior of a Volvo V70, with integrated booster cushions mounted onto the car body through a rigid fixture. Standard belt were used for all tests, except one where pretensioning was used. Static tests investigated how the chest deflection on Q6 was affected by the shoulder belt geometry. Large difference in belt interaction was observed between the dummies. The beltslipped off the Hybrid III’s shoulder for all tests except one, while the belt on the Qdummy’swas hard to provoke off the shoulder. The overall kinematic behavior, beforethe belt slipped off the Hybrid III’s shoulder, were similar for both dummies. Differences in chest deflection on the Q6, depending on the belt geometry, were observed in both the dynamic and the static tests; a shoulder belt geometry closer to theneck resulted in minor displacement than a mid-shoulder belt geometry. After testing, five different damages were observed on the Q6.

<ol> Då en ny familj av barnkrockdockor, Q-familjen, är föreslagen för det europeiskalagkravet som reglerar barnsäkerhet (R44), uppstod ett behov av att testa och jämföradessa mot den äldre familjen av barnkrockdockor som används vid testning på Autoliv idag, Hybrid III. I den här studien utfördes tester på Q6 och Hybrid III 6 år. Båda dockorna utsattes föråtta stycken slädtest i en accelerationspuls enligt EuroNCAP. Släden representerade enVolvo V70 med integrerade barnkuddar som monterats i riggen via en stel fixtur. I alla test utom ett användes standardbälten (i undantagsfallet användes försträckare). Statiska tester gjordes för att undersöka hur Q6 påverkades av olika geometrier på axelbältet. Stora skillnader observerades mellan dockornas bältesinteraktion. Bältet gled av HybridIII:s axel i alla test förutom ett, medan det istället var svårt att provocera av bältet från Q-dockans axel. Innan Hybrid III gled ur bältet var dockornas kinematik liknande. I både statiska och dynamiska tester observerades skillnader i bröstintryckning på Q6, beroende på bältesgeometrin; en geometri där axelbältet var placerat nära nackenresulterade i en mindre intryckning än då axelbältet var placerat mitt på axeln. Efte ravslutad testning upptäcktes fem skador på Q6. </ol>

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La variation de la diversité des communautés d’hôtes réservoirs peut modifier le risque de maladies impliquant ces espèces. En particulier, l’introduction d’une espèce potentiellement réservoir est susceptible d’augmenter le risque de maladie, en agissant comme un réservoir supplémentaire et/ou en amplifiant la circulation des agents pathogènes chez les réservoirs autochtones. L’objectif du travail de thèse est de quantifier la contribution, d’une espèce introduite, le tamia de Sibérie (Tamias sibiricus barberi), au risque d’une maladie multi-hôtes, la borréliose de Lyme, due à des bactéries appartenant au complexe d’espèces Borrelia burgdorferi sensu lato et transmises par des tiques, principalement Ixodes ricinus en Europe. Dans un premier temps, nous avons testé si le tamia est un réservoir compétent pour la maladie de Lyme en milieu naturel, c'est-à-dire s’il est capable de transmettre B. burgdorferi sl aux tiques I. ricinus et de maintenir l’infection. Le tamia est fortement infesté par les tiques et infecté par les bactéries et il peut transmettre B. burgdorferi sl aux tiques. Nos résultats ne montrent pas clairement que le tamia peut maintenir l’infection. Une des deux composantes du risque de la maladie de Lyme pour l’homme est le risque acarologique, c'est-à-dire la densité de nymphes infectées en quête d’hôtes. Dans un deuxième temps, nous avons calculé la contribution du tamia au risque acarologique et l’avons comparé à celles du campagnol roussâtre (Myodes glareolus) et du mulot sylvestre (Apodemus sylvaticus), réservoirs avérés de B. burgdorferi sl. Puis, nous avons étudié la variation temporelle de la contribution du tamia et testé si sa présence influençait la contribution des réservoirs rongeurs natifs. Pour calculer la contribution au risque, nous avons utilisé deux approches, l’une basée sur des captures des rongeurs, et l’autre sur l’identification des espèces hôtes sur lesquelles se sont gorgées les tiques. Le tamia produit plus de nymphes infectées à l’affût que le campagnol et le mulot. La contribution du tamia varie entre années suivant la densité de tamias et intra-années suivant la disponibilité en tiques. Sa plus forte infestation par I. ricinus et infection par B. burgdorferi sl, que les rongeurs natifs, peuvent être expliquées par sa plus forte exposition aux tiques. En conclusion, le tamia semble un réservoir compétent pour B. burgdorferi sl, avec une forte contribution au risque acarologique et une amplification possible de la circulation des pathogènes dans les communautés natives. Sa présence peut augmenter le risque pour la borréliose de Lyme chez l’homme en augmentant la prévalence d’infection des nymphes, mais pas les densités de nymphes à l’affût.

The variation of the composition of host communities can modify the risk of diseases involving these species. In particular, the introduction of a potentially reservoir species may increase the disease risk, by acting as an additional reservoir or by amplifying the circulation of pathogens in the native reservoirs. We quantified the…

Advisors/Committee Members: Vourc'h, Gwenaël (thesis director).

▼ Using the theory of Michael White, Hans-Georg Gadamer, and Charles Gerkin, this thesis discusses how and why narrative therapy techniques work and how they could be applied in group or parish settings. It further explores using theory developed by Charles Gerkin regarding how spiritual reflective practice could be utilised in the narrative process to help people process their life experiences for hope and resilience. In examining similar and difference theoretic framings in Gadamer and White, the thesis discusses and develops a process for purposeful listening. This method of listening, unlike listening-to someone or listening-for information, involves an immediate “presentness” with others. It creates a context of openness for new insights to come and be explored openly. A special kind of questioning enables horizons to expand and new learning to be experienced either within a group or in pastoral care settings. This listening recognises biases and people’s historic realities and interpretations while fostering new interpretations that expand people’s horizons and bring new understandings. In Gadamer’s writing we find the theoretical understanding of human communication – what works and why it works. While in White we have practical applications of theory based on narratives and ways to use communication to bring healing and new interpretations of life experiences. Finally, Gerkin provides a spiritual component that assists people in connecting the bigger narrative of God to their individual faith to foster healing and hope. The thesis concludes with suggestions for training for pastoral care providers as facilitators of this process and ways in which this communication methodology could be utilised in a parish setting.

▼ This thesis considers the practice of Bible translation from the perspective of contemporary translation studies and provides a fresh translation and accompanying commentary of aspects of Paul's Letter to the Romans. The emergence of functionalism, particularly skopos theory, in the latter part of the 20th century is seen as a key moment in the development of translation theory. The thesis argues that it has significant advantages over source text orientated approaches which have traditionally dominated Bible translation practice. An essential history documents this evolution of theoretical developments in translation study. The advantages of skopos theory over equivalence-based approaches are discussed with particular reference to Bible translation theory and the work of E. A. Nida. The functionalist approach increases the range of possible translations, with this thesis adopting a foreignising purpose in a new translation of Romans 1:1-15, 15:14-16:27. The foreignising approach owes its origins to F. Schleiermacher (popularised more recently by L. Venuti among others) and involves rendering a text so as to preserve or heighten the sense of otherness of the source text, thereby retaining something of the foreignness of the original. An accompanying commentary is provided to explain the translator's choices.

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Polysaccharides are important structural components of bacterial capsule and cell walls. Polysaccharide-specific antibodies are an important component of serologic memory capable of protecting against infection by pathogenic microorganisms. An understanding of the biology and function of polysaccharide specific B cells is necessary for formulation of vaccines designed to induce polysaccharide specific memory and longlived antibody production. The goal of this dissertation was to examine the development of naïve DEX-specific B cells and examine their capacity to generate memory and longlived plasma cells in response to polysaccharide [alpha] 1->3-dextran (DEX), which is expressed by the opportunistic pathogens Enterobacter cloacae, Histoplasma capsulatum and Aspergilillus fumigatus. In the first study we examined the development of DEX-specific B cells in naïve mice and the ability of DEX-expressing microorganisms to promote development of DEX-specific memory B cells. In naive mice DEX-specific B cells preferentially enriched in MZ and B1b B cell populations. Challenge with DEX or DEX-expressing microorganisms resulted in the activation of MZ B cells and rapid production of peak titers of DEX-specific antibodies followed by the formation of long-lived DEX-specific B1b B cells capable of sustaining DEX-specific antibody production for up to 150 days. DEX-specific B1b B cells provided enhanced production of DEX-specific antibodies after secondary challenge in a manner independent of germinal center and T cell help, but instead dependent upon their capacity to self-renew. In the second study we investigated the ability of DEX to induce the formation of long-lived plasma cells. We examined the biology of DEX-specific plasma cells induced in response to DEX demonstrating that DEX did not generate long-lived plasma cells, but instead the generation of short-lived plasmablast and plasma cells, which were dependent upon DEX persistence. This study demonstrated an essential role for polysaccharide persistence in the maintaining long-lived polysaccharide-specific antibody production. Collectively these findings demonstrated that polysaccharides are capable of generating long-lived memory B cells and that maintenance of DEX-specific antibody production was dependent upon persistence of DEX, which continually stimulated the generation of short-lived plasmablast and plasma cells.

ix, 127 p. : ill., digital, PDF file

Microbiology

Joint Health Sciences

Antibody Memory Persistance Dextran Polysaccharide B cells

UNRESTRICTED

Advisors/Committee Members: Kearney, John F., Burrows, Peter D.<br>, Lorenz, Robinna G.<br>, Elson, Charles O.<br>, Schroeder, Harry W.<br>, Weaver, Casey T..

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Mammalian antimicrobial peptides, including cathelicidins and defensins, play an important role in host defense via direct antimicrobial activity as well as immune regulation. The cathelin-related antimicrobial peptide (mCRAMP) is the only identified mouse cathelicidin and the orthologue of human LL-37. We show that all mouse B cell subsets, including follicular, marginal zone, B1a, and B1b cells, as well as CD4+ and CD8+ T cells produce mCRAMP directly ex vivo. In addition, mCRAMP-deficient B cells produced less IgG1 antibody in vitro in response to CD40L or LPS plus IL-4 when compared to WT B cells. The addition of recombinant mCRAMP at the time of mCRAMP-deficient B cell activation restored the level of IgG1 production to WT levels. mCRAMP-deficiency had no effect on proliferation, survival, or class switch recombination, but resulted in a decrease in the amount of IgG1 mRNA. Surprisingly, mCRAMP-deficient mice immunized with TNP-OVA absorbed in Alum resulted in an enhanced TNP-specific IgG1 response when compared to WT B6 mice. ELISpot and PCR analysis revealed increased numbers of TNP-specific IgG1-secreting splenic B cells and increased CD4+ T cell IL-4 expression in mCRAMP-deficient mice. Taken together, B cells express and respond to mCRAMP positively in vitro while in vivo mCRAMP appears to also indirectly regulate B cell antibody production through regulation of T cell cytokine production.

1 online resource (vii, 86 p. : ill., digital, PDF file)

Microbiology

Joint Health Sciences

antibody B cell antimicrobial peptide

UNRESTRICTED

Advisors/Committee Members: Kearney, John F., Briles, David E.<br>, Burrows, Peter D.<br>, Klug, Christopher A.<br>, Schroeder, Harry W..

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Fc receptor-like 2 (FCRL2) is a transmembrane protein with immunomodulatory potential that is preferentially expressed by memory B cells in humans. It has two consensus immunoreceptor tyrosine-based inhibitory motifs (ITIM) in addition to a putative immunoreceptor tyrosine-based activation motif (ITAM) sequence in its cytoplasmic domain. We have confirmed the cellular distribution of FCRL2 and analyzed its functional potential to show that coligation with the B cell receptor (BCR) leads to tyrosine phosphorylation of its ITIM motifs and subsequent SHP-1 recruitment to facilitate inhibition of BCR signaling. Mutational analysis indicates that the tyrosine residues in both inhibitory motifs of FCRL2 are required for complete inhibition of BCR signaling, while tyrosines in the putative activation motif are dispensable for signal modulation. These findings suggest a negative immunomodulatory function for FCRL2 in the regulation of memory B cells.

1 online resource (ix, 80 p. : ill., digital, PDF file)

Microbiology

Joint Health Sciences

Fc receptor B cell signal transduction inhibition receptor

UNRESTRICTED

Advisors/Committee Members: Cooper, Max D., Burrows, Peter<br>, Davis, Randall<br>, Frank, Stuart<br>, Justement, Louis.

▼  Vår uppsats har haft två huvudsyften, dels att jämföra den information om kundnöjdhet som SL presenterar på sin hemsida gällande våren 2010 mot vår egen kundnöjdhetsundersökning, samt även att beskriva säkerhetsarbetet som har ägt rum inom trygghetsavdelningarna på SL och MTR. Som kompletterande syfte och mot bakgrund att SL hävdar att kundnöjdheten bland resenärer ständigt ökar vill vi inom uppsatsgruppen med hjälp av egna frågor säkerställa om resenärer som nyttjar tunnelbanan upplevt att det har blivit positiva förändringar inom säkerheten, renheten och tidshållningen. Författarna har använt sig utav ett antal olika modeller om tjänstekvalitet såsom kund-leverantör-modellen samt teorin om lärande organisationer av Lewitt och Marsch och ytterligare en teori av Walsch och Ungson vilken behandlar organisationsminnen. För att försäkra sig om att vi har valt samma tillvägagångsätt har den intervjuande gruppen använt sig utav samma enkätunderlag som SL överlämnar ute bland resenärer i Stockholms Tunnelbana. Intervjuerna har varit av kvalitativ karaktär och själva enkätundersökningen bar spår av kvantitativt inslag. Genom analys av empirin har gruppen kommit fram till att de data som erhölls i viss mån kunde relateras till de svar som SL fått i sina undersökningar. Dock inte fullt ut pga en för oss känd anledning och det är att antalet respondenter i enkätundersökningen hos SL var betydligt större än i vår egen. Likaså har gruppen genom analys kommit fram till att vissa aspekter, såsom säkerhet och tidshållning, enligt det kvinnliga könet förbättrats de senaste åren. Samtidigt som utfallet av enkätsammanställningen på den manliga sidan visar att män i åldern 19-30 år inte upplevde några förbättringar inom tidshållningen, renheten eller säkerheten.

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VH replacement occurs through RAG-mediated secondary recombination to change unwanted IgH genes. In this dissertation, I focused on studying the molecular mechanism that regulates VH replacement in human immature B cells. In part I, our results show that VH replacement is regulated by B cell antigen receptor (BCR) mediated signaling. Using the human EU12 μHC+ cells as an experimental model system, crosslinking BCR with F(ab’)2 anti-IgM antibodies results in BCR internalization, cell proliferation arrest, and induction of VH replacement. Pretreatment of human EU12 μHC+ cells with the protein tyrosine kinase inhibitor Genistein, Syk kinase inhibitors, and a Src kinase inhibitor blocks BCR-mediated signaling events and inhibits VH replacement. Inhibition of PI3K kinase enhances VH replacement, conversely, activation of PI3K by anti-CD19 antibodies inhibits BCR signaling induced VH replacement. Furthermore, analyses of large numbers of IgH sequences reveal that the VH replacement products are highly enriched in different autoimmune diseases and anti-viral responses. In part II, we further dissect BCR-mediated signaling events in EU12 μHC+ immature B cells compare to that in human Daudi and Ramos mature B cells. EU12 μHC+ cells have features of human bone marrow immature B cells. After 30 minutes of treatment with anti-IgM antibodies, almost 100% of EU12 μHC+ cells lost their surface BCR, in contrast, Daudi and Ramos cells only partially lost their surface BCR. After BCR internalization, restimulation of EU12 μHC+ cells with anti-IgM antibodies results in normal level of Erk1/2 activation, but with delayed Syk phosphorylation, reduced Ca2+ mobilization, and decreased FoxO1 phosphorylation. Thus, internalization of BCR on EU12 μHC+ immature B cells attenuates BCR signaling with selective effects on downstream signaling events, which may favor receptor editing. Taken together, the results presented in this dissertation provide the first evidence that VH gene replacement is regulated by BCR signaling on immature B cells. Complete internalization of BCR receptor specifically changes BCR-mediated signaling events in immature B cells.

1 online resource (xii, 150 p. : ill., digital, PDF file)

Microbiology;

Joint Health Sciences;

immature B cells VH replacement B cell receptor

UNRESTRICTED

Advisors/Committee Members: Zhang, Zhixin (Jason), Burrows, Peter D.<br>, Kearney, John F.<br>, Kubagawa, Hiromi<br>, Justement, Louis B..

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Acute myeloid leukemia (AML) comprises approximately 25% of newly diagnosed cases of leukemia each year. The constitutive activation of the classical NF-κB signaling pathway has been observed in up to 70% of AML cases, and could be due to mutations upstream involving the PI3K-Akt cascade, which is also constitutively active in a majority of cases. In mice, constitutive activation of Akt either through deletion of the negative regulator of PI3K-Akt, PTEN, or by expression of Myr-Akt induces rapid stem cell loss along with a lethal, transplantable myeloproliferative disorder and AML. These studies show that constitutive Akt and NF-κB signaling distinguish leukemiainitiating cells from normal hematopoietic stem cells (HSC). Although constitutive activation of NF-κB is observed in AML, it is unknown whether NF-κB signaling alone is sufficient to promote leukemogenesis and to what extent NF-κB signaling plays a role in HSC biology. This study used retroviral overexpression of activated IKKβ (IKKβSS/EE) to induce constitutive classical NF-κB signaling and an inducible conditional knockout mouse model (Mx1-Cre;NemoF/F) to efficiently repress classical NF-κB signaling to address these questions. Activation of NF-κB induced a loss of HSC over 10 weeks likely due to a loss of self-renewal potential because an increase in apoptosis or HSC mobilization to iii the spleen was not observed. Persistent NF-κB activation also promoted differentiation and a transient increase in monocytes at the expense of B-cell lymphopoiesis. In compar-ison to activated Akt phenotypes, constitutive NF-κB signaling did not induce progres-sion to MPD or AML. Conversely, repression of NF-κB resulted in the loss of one of the earliest non-self-renewing MPP subsets, whereas the stem cell compartment was unaf-fected, likely due to either a block in differentiation or an increase in apoptosis, which was observed systemically. Overall, these results show that constitutive NF-κB signaling is not sufficient to initiate AML, and that other genetic changes likely occur prior to acti-vation of constitutive NF-κB signaling. In addition, the repression of NF-κB suggests a fundamental requirement for NF-κB in the survival and maintenance of MPPs.

1 online resource (x, 92 p. : ill., digital, PDF file)

Microbiology;

Joint Health Sciences;

NF-κB hematopoietic stem cell self-renewal

UNRESTRICTED

Advisors/Committee Members: Klug, Christopher A., Benveniste, Etty<br>, Justement, Louis B.<br>, Kabarowski, Janusz H.<br>, Lopez, Richard D..

▼ This thesis deals with the conversation between the interpretations of Paul‘s letters and modern European thought. It is a narrative of an oft-neglected relationship; but, more than that, it tries to push this negotiation further than where it is now. Thus, in this project, I intend to play with the many possibilities that poststructuralist theory provides for alternative interpretations of biblical texts, and to uncover the ways that the Bible can offer new solutions to the challenges of modern thought. My study will focus on three issues: power, religion, and gender. I believe that the debates around these three topics have been crucial to the European self-definition. Besides, Paul has been present in the European discourse on politics, law, and sexuality. His letters have been interpreted only based on a certain kind of normativity at the expense of many alternative readings. The reception of Paul, in turn, provided some ground for further discussions on European identity. In chapter one, I draw on the complications of physical portraits of Paul to indicate the problems in offering a finalized clear picture of his message. Obsession with portraying the Apostle is not dissimilar to the recurrent reference to him in the works of European intellectuals since the Enlightenment. Paul has thus been involved in the construction of European identity. This does not mean that he has always conformed to what Europe wants. Rather, he has challenged the binary identities that European normativity has built. It is precisely in these moments that the arbitrariness of European discourse is betrayed. Relying on Judith Butler‘s theories on gender normativity, I try to spot the ways that identity was established through the reiteration of modern categories that may be far from what the text says. In the following chapters, I investigate three passages that signal Paul‘s challenge to modern normative identities. In the next chapter, I deal with the interpretation of Romans 13, where Paul tells the Roman Church to be subjected to political authorities. This chapter has troubled the interpreters because it is far from what is expected from Paul – promotion of justice in face of brutal regimes. I demonstrate that the readers of Romans 13 lost touch with Paul‘s ethos soon after his death. Relying on Hans Blumenberg‘s description of ―secularization by eschatology‖ at the time of the composition of the New Testament toward the end of the first century CE – i.e. the relegation of the end matters to the transcendental –, I argue that Paul was preaching in the context of what I call the ―daily messianic‖. My formulation of the ―daily messianic‖ consists of what continental philosophers, from Martin Heidegger to Michel Foucault, Jacques Derrida, and Giorgio Agamben see as a rupture within the worldly (i.e. ―secular‖) matters. This mode, which had subsumed Paul‘s discourse, was permeated by ―care‖ and ―anxiety; it was beyond calculation or metaphysical description; it was where the distinction between the body and the soul did not make sense;…

▼ This thesis argues that Satan is essentially a literary figure and that he is best understood in the context of narrative. This study furthermore establishes what the literary figure of Satan can contribute to the understanding of evil and how his portrayal has changed as we move into the 21st century. I suggest that the interdisciplinary reading of theology and literature offers the best approach to the character of Satan. The focus of the study lies on novels from the last 100 years, focusing on the implications of the historic, philosophical and theological changes in the late modern landscape on the figure of Satan. Underlying this study are three primary aspects: Firstly, the literary character of Satan raises the question of the nature of evil. Satan has long been cast as evil personified and this work tries to explore the relationship between the abstract concept of evil and the character of Satan: in an attempt to asses whether evil has a face. The literary figure of Satan can be seen as one approach to the abstract concept of evil that is a reality in human life but that cannot be understood in its being, only through expression. Secondly, the diabolical appears as part of any story; the powers of creation and destruction are connected. The figure of Satan is ambivalent and despite all its destructive elements, the character appears as the driving force behind the story. I want to show how Satan can be understood to be the facilitator of the story. Finally, any narrative is based on relation, and Satan is essentially a relational character. We can speak of a ‘mutual dependency’: Satan needs the human mind – we embody him, we give him his form, but equally are we in need of a scapegoat for all that is dark and undiscovered in us. The character of Satan is therefore personal and relational, best approached in the context of the story, with its inherent relationship between form and content.With this work, I am trying to establish a dialogue between theology and literature through the character of Satan, who transgresses boundaries and facilitates discussion, and therefore is by definition a truly interdisciplinary character. In my introduction I will examine the origins of the satanic figure in the theology of Christianity, starting with the Serpent in Genesis 3:1 and its development into a powerful character in myth and story. I also place the focus of this work on the inderdisciplinary reading of Satan, set against the conceptual approach of systematic theology. Part one of this work will shed some light on the dwelling place of the character, discussing the role of Satan as a symbol (of evil) and the difficulties connected to the definitions of Satan. Beginning with the Scriptures and then further elaborating the function of Satan in the story, I will focus on the relation between Satan and the text. Part two discusses six aspects of satanic characters in recent or contemporary novels, focusing on the function that the satanic image can contribute to the discussion of evil in the post-modern…

▼ This thesis deals with the conversation between the interpretations of Paul‘s letters and modern European thought. It is a narrative of an oft-neglected relationship; but, more than that, it tries to push this negotiation further than where it is now. Thus, in this project, I intend to play with the many possibilities that poststructuralist theory provides for alternative interpretations of biblical texts, and to uncover the ways that the Bible can offer new solutions to the challenges of modern thought. My study will focus on three issues: power, religion, and gender. I believe that the debates around these three topics have been crucial to the European self-definition. Besides, Paul has been present in the European discourse on politics, law, and sexuality. His letters have been interpreted only based on a certain kind of normativity at the expense of many alternative readings. The reception of Paul, in turn, provided some ground for further discussions on European identity. In chapter one, I draw on the complications of physical portraits of Paul to indicate the problems in offering a finalized clear picture of his message. Obsession with portraying the Apostle is not dissimilar to the recurrent reference to him in the works of European intellectuals since the Enlightenment. Paul has thus been involved in the construction of European identity. This does not mean that he has always conformed to what Europe wants. Rather, he has challenged the binary identities that European normativity has built. It is precisely in these moments that the arbitrariness of European discourse is betrayed. Relying on Judith Butler‘s theories on gender normativity, I try to spot the ways that identity was established through the reiteration of modern categories that may be far from what the text says. In the following chapters, I investigate three passages that signal Paul‘s challenge to modern normative identities. In the next chapter, I deal with the interpretation of Romans 13, where Paul tells the Roman Church to be subjected to political authorities. This chapter has troubled the interpreters because it is far from what is expected from Paul – promotion of justice in face of brutal regimes. I demonstrate that the readers of Romans 13 lost touch with Paul‘s ethos soon after his death. Relying on Hans Blumenberg‘s description of ―secularization by eschatology‖ at the time of the composition of the New Testament toward the end of the first century CE – i.e. the relegation of the end matters to the transcendental –, I argue that Paul was preaching in the context of what I call the ―daily messianic‖. My formulation of the ―daily messianic‖ consists of what continental philosophers, from Martin Heidegger to Michel Foucault, Jacques Derrida, and Giorgio Agamben see as a rupture within the worldly (i.e. ―secular‖) matters. This mode, which had subsumed Paul‘s discourse, was permeated by ―care‖ and ―anxiety; it was beyond calculation or metaphysical description; it was where the distinction between the body and the soul did not make…

▼ This thesis examines the hogbacks and hammerhead crosses of Viking Age Strathclyde and Northumbria. Both are Insular forms of carved stone sculpture often found in Christian contexts. This thesis aims to highlight the significance of these carved stones within a contemporary landscape dominated by a complex historical and archaeological narrative, with the overall aim of ascribing them functions, beyond those of funerary. The approach this thesis takes is theoretical in its construct, both methodologically and analytically, and is grounded in the phenomenological principles of Maurice Merleau-Ponty. It is hoped that this thesis will break down the perceived barrier imposed on research by the modern Scotland-England border, thus potentially alleviate the implied disconnect between Viking Age Strathclyde and Northumbria. While acknowledging the current art-historical work, this thesis archaeologically reappraises hogbacks and provides an original and detailed archaeological treatise of hammerhead crosses. Additionally, this thesis espouses a conceptual framework for approaching, analysing and interpreting carved stones, which considers the idea of what makes space become a place. This framework involves the adoption of a reflexive phenomenological approach to the recording of carved stone monuments in the landscape, and, in approaching material, the adoption and adaption of the concepts of hybrid practice, supervenience, Deleuzian difference, common difference, the third space, and art and agency. In integrating these approaches and concepts, the idea of place-making emerges, discerned via non-dialectical interrelationships between people, material, and space. It is conceptualised here in abstract form as the person/object/place framework. In applying this framework to postulate the functions of hogbacks and hammerhead crosses in the landscape, the following, non-mutually exclusive, themes are considered: commemorative space, economic space, biblical space, mythological space, political space, and sacred space. Considering these themes in the application of the conceptual framework to approaching notable carved stones gives rise to the concept of functional landscapes. These abstract landscapes emerge and are understood through a network of functional places, developing out of particular carved stone monuments inhabiting specific spaces. Ascribing functions to Viking Age carved stones allows for interpretation beyond the traditional and uncritical narrative that hogbacks and hammerhead crosses are simply Viking ‘calling cards’ or gravestones. Furthermore, in considering the Christian context and syncretic nature of many hogbacks, this thesis challenges the common idea that their origins and models often lie solely in Scandinavian paganism and culture.

▼ The feminist theological literature highlights certain weaknesses in the traditional (Western) Christian understanding of eschatology, death and the concept of time. Many feminist theologians reject the linear time concept and the idea of final, fixed eschatology in which death is an enemy to be conquered and flourishing is postponed and reserved to another time and space. However, an alternative convincing vision for a concept of time in which eschatology and death have a place and meaning that is congruent with the feminist concerns and priorities is yet to be developed. My thesis aims to explore and suggest a workable concept of time from a feminist theological perspective with a reference to feminist eschatology and the role and meaning of death.

▼ Understanding evil spiritual forces is essential for Christian theology. Evil has typically been studied either from a philosophical perspective or through the lens of ‘spiritual warfare’. The first seldom considers demonology; the second is flawed by poor methodology. Furthermore, warfare language is problematic, being very dualistic, associated with violence and poorly applicable to ministry. This study addresses these issues by developing a new model for conceptualizing and counteracting evil using ‘non-warfare’ biblical metaphors, and relying on contemporary metaphor theory, which claims that metaphors are cognitive and can depict reality. In developing this model, I examine four biblical themes with respect to alternate metaphors for evil: Creation, Cult, Christ and Church. Insights from anthropology (binary oppositions), theology (dualism, nothingness) and science (chaos-complexity theory) contribute to the construction of the model, and the concepts of profane space, sacred space and sacred actions (divine initiative and human responsibility) guide the investigation. The role of the Holy Spirit in maintaining the boundaries of divine reality is emphasized, and the ontology of evil minimized (considered quasi-real). This model incorporates concentric circles, evil being considered peripheral to godly reality. I suggest metaphors of cleansing, ordering, separating and limiting evil and discuss potential applications of this model.

▼ This thesis considers the practice of Bible translation from the perspective of contemporary translation studies and provides a fresh translation and accompanying commentary of aspects of Paul's Letter to the Romans. The emergence of functionalism, particularly skopos theory, in the latter part of the 20th century is seen as a key moment in the development of translation theory. The thesis argues that it has significant advantages over source text orientated approaches which have traditionally dominated Bible translation practice. An essential history documents this evolution of theoretical developments in translation study. The advantages of skopos theory over equivalence-based approaches are discussed with particular reference to Bible translation theory and the work of E. A. Nida. The functionalist approach increases the range of possible translations, with this thesis adopting a foreignising purpose in a new translation of Romans 1:1-15, 15:14-16:27. The foreignising approach owes its origins to F. Schleiermacher (popularised more recently by L. Venuti among others) and involves rendering a text so as to preserve or heighten the sense of otherness of the source text, thereby retaining something of the foreignness of the original. An accompanying commentary is provided to explain the translator's choices.

▼ This thesis presents a theological theory of translation which suggests that a Protestant poetics such as Yeats’ may be reformed in translation into a Catholic poetics such as Bonnefoy’s, and links the latter’s poetics with the phenomenological theology of Jean-Luc Marion, most particularly with ideas about the idol and icon. What translation of a literary text of this high order achieves is a theological transformation, where Catholic or Protestant poetics derive from the culturally conditioned religious elements which Yeats and Bonnefoy inherit. Such a transformation is effected by a process whereby the Protestant source text (Yeats’) is unravelled, and strands of the poem which are important to the translator are taken and redeveloped in line with his own insights (here Bonnefoy’s) in a process which brings the two poets together, rather than being about Steiner’s act of aggression. This is a crucially important process for translation, because it asserts that translations are, effectively, new works of art, since they offer a response to the original poem which is no longer about giving the reader the literal sense of the source text, but is about developing the poet’s original insights, enriching her ideas. Moreover, such ideas are of key importance theologically. Yeats’ use of images parallels what Marion calls the idol, whereas Bonnefoy’s use of images aims both to decipher idols and to present us with the icon instead. Indeed, it is the combination of a literary and a theological sense of the original source, and some personal experience of the original act, which gives birth to the poem (for Bonnefoy). This allows the creation of a new work of art, where poets communicate at the most intimate level, and motivates Bonnefoy to create a metanarrative for his anthology collection where the character of Yeats becomes more perceptive and less divided by the complexities of fury”: he reforges Yeats’ poems as a sacerdotal poet with a vision of the sacramental.

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B lineage cells are major players in the adaptive immune system. Pax5 is essential for B lineage cell development and function. Pax5 controls B lineage cell developmental progression by regulating expression of many B lineage specific genes and the B lineage specific VH to DJH recombination; and the meantime, Pax5 also represses the transcription of lineage- and developmental stage- inappropriate genes to restrict the B lineage developmental pathway. It is not clear how Pax5-mediated function can be regulated to fulfill its role in different biological reactions. In this dissertation, we focused on the study of the molecular regulation of Pax5-mediated functions. In part I, our results showed that Pax5-mediated transcriptional activation can be dramatically elevated by overexpression of histone acetyltransferase p300. We found that p300 directly interacts with Pax5 and acetylates multiple lysine residues within the Nterminal regions of the Pax5 protein. Mutation of the lysine 67, 87, 89, 103, or 142 residues into alanine diminished p300 mediated enhancement of Pax5 function in activation of Luc-Cd19 reporter gene expression. Moreover, mutations of lysine 67, 87/89 in Pax5 impaired Pax5-mediated activation of endogenous Pax5 target genes in Pax5-/- mouse pro B cells, indicating that acetylation of Pax5 provides an important regulation for Pax5-mediated biological functions during B lineage cell development. In part II, to understand how Pax5 mediates global effects during B cell development, we analyzed the nuclear sub-localization of Pax5. It has long been hypothesized that transcription in cells occurs on the discrete loci associated with the nuclear matrix inside the nucleus. We found that most endogenous Pax5 in human or mouse B lineage cells associates with the nuclear matrix. In addition, Pax5 co-localizes with the basal transcriptional machinery. We found that the partial homeodomain and its flanking regions contain signals to target Pax5 to the nuclear matrix. Deletion of the partial homeodomain of Pax5 compromises Pax5-mediated transcriptional activation of many target genes. These results indicate that the association with the nuclear matrix is essential for Pax5 to fully activate endogenous B lineage specific genes. Taken together, the results presented in this dissertation uncovered two novel mechanisms that regulate Pax5-mediated transcription function.

x, 138 p. : ill., digital, PDF file

Microbiology

Joint Health Sciences

Pax5 p300 acetylation nuclear matrix

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Advisors/Committee Members: Zhang, Zhixin, Justement, Louis B. <br>, Klug, Christopher A. <br>, Burrows, Peter B. <br>, Raman, Chander.

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Zinc oxide eugenol sealers have been used clinically for several years. Glass ionomer sealers were introduced due to their adhesion to the dental hard tissues and excellent sealing ability. During the process of endodontic treatment a post, core and final restoration is required for tooth restoration. Recently fiber reinforced composite posts have become more popular because of their mechanical properties and esthetics. However, fiber posts have to be adhesively cemented into root canal which can be affected by the endodontics sealers. The purpose of this study was to evaluate the effect of eugenol and non-eugenol containing sealers on the retention of fiber posts and to evaluate the apical sealing ability of both sealers. Forty extracted human single rooted teeth were instrumented to simulate the conventional root canal therapy and divided into two groups (n=20); one was obturated with gutta-percha and zinc oxide eugenol and the other was obturated with gutta-percha and glass ionomer sealer. Gutta-percha was removed and a standardized post space was prepared. The fiber posts were cemented in each group either, with Rely X Unicem or Panavia F 2.0 and ED Primer II system. Each root was sectioned in to three parts. A push-out test and SEM evaluation were applied for all groups. Bond strengths were analyzed using three-way ANOVA for the combination of the cement, sealer and sections. The results showed no statistically significant difference in bond strength within the two resin luting systems and the tooth sections. For microleakage, the apical third section of each root was covered with a nail polish. The specimens were immersed into 50% silver nitrate dye and cleared. The maximum dye penetration was measured and compared using T-test analysis. There was a statistically significant difference among the two sealers. Zinc oxide eugenol showed (2.07±0.36) and glass ionomer sealer (1.5± 0.269).

M.S.

x, 58 p. : ill., digital, PDF file.

Prosthodontics and Biomaterials

Dentistry

Endodontic sealers fiber post push-out bond test resin cements

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Advisors/Committee Members: Burgess, John O., Cakir, Deniz <br>, Rahemtulla, Firoz G. <br>, Coar, T. Madelyn <br>, Litaker, Mark Stephan.

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One primary distinction separating the innate and the adaptive branches of the immune system is the numbers of ways in which a cell can recognize foreign antigens. The innate immune system evolved a mechanism for pattern recognition. Here, highly conserved repeat units that are frequently expressed by pathogens are recognized by the innate effector cells. The adaptive immune system has evolved a strategy of random gene recombination to create a diverse repertoire of cells able to recognize the virtually limitless possibilities of antigens expressed by pathogens. This process occurs in developing B cells and T cells. The mature peripheral B cell repertoire can create a greater antibody repertoire via somatic mutation in their immunoglobulin genes. The germinal center is a structure central to this process. Germinal center B cells interact intimately with T follicular helper cells and follicular dendritic cells. It is thought that these cellular contacts provide signals that determine the fate of the germinal center B cells. This dissertation demonstrates how several different cellular mechanisms contribute to the selection and the fate of germinal center B cells. Chapter one provides evidence that the Mucosal Addressin Cell Adhesion Moelcule-1 (MAdCAM-1) is necessary for proper placement of cells in the germinal center. Loss of MAdCAM-1-dependent cellular interactions leads to depolarization of the germinal center and also to an acceleration of the germinal center reaction. Together the data support the hypothesis that MAdCAM-1 expression on follicular dendritic cells supports the cellular interactions in the germinal center and regulates the numbers of germinal center B cells. In the second chapter, I report that when there is an abundance of B cells with related B cell receptors, the cells undergo intra-clonal competition. This presents a situation in which the clonally related B cells lack the proper antigen dependent signals that direct them to undergo efficient affinity based selection. This resulted in failure to form high affinity antibody secreting cells. These studies demonstrate that preventing the development of a large number of clonally related B cells is necessary to retain the ability to support the development a high affinity antibody response.

xv, 77 p. : ill., digital, PDF file

Microbiology

Joint Health Sciences

B Cell MAdCAM-1 Affinity Maturation FDC

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Advisors/Committee Members: Chaplin, David D., Burrows, Peter D.<br>, Carter, Rober H.<br>, Kearney, John F.<br>, Weaver, Casey T..

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Type I IFN is a known pro-inflammatory cytokine that is associated with the development of systemic lupus erythematosus (SLE). At the level of B-cell regulation, current literature primarily attributes the formation of autoantibodies at the post-germinal center stage when type I IFN is known to promote plasmablast differentiation. However, our findings here point to a type I IFN effect at the pre-germinal stage. Type I IFN promotes T-dependent antibody response, activation-induced cytidine deaminase (AID) expression, germinal center formation, all of which are processes before the onset of plasmablast differentiation. We have determined a subset of splenic transitional B-cells, that is known as the precursors to the development of marginal zone (MZ) B-cell population, and are termed marginal zone B-cell precursors (MZPs), whose trafficking from the MZ border to the inner follicle (FO) is promoted by type I IFN. MZPs are more efficient antigen-presenting cells than MZ or FO B cells. Type I IFN up-regulates expression of CD69 and down-regulates expression of S1P1 to promote migration of MZPs into the inner follicle to interact with CD4 T-cells. Together, these observations suggest a novel pathway by which type I IFN can promote the presentation of antigen to CD4 T-cells by MZPs to initiate germinal center reaction prior to type I IFN induction of plasmablast differentiation.

1 online resource (x, 200 p. : ill., digital, PDF file)

Pathology

Joint Health Sciences

UNRESTRICTED

Advisors/Committee Members: Mountz, John D., Lorenz, Robin<br>, Clemens, Thomas<br>, Justement, Louis<br>, Raman, Chander<br>, Weaver, Casey.

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Glioblastoma (GBM) is an incurable tumor of the central nervous system (CNS). Over the past 50 years, little progress has made in improving the quality of life and median lifespans of patients who are diagnosed with this devastating disease. However, new insights into the aberrant signaling pathways at the root of GBM pathology are providing new targets for next generation cancer therapies. Two signaling pathways that are commonly upregulated in GBM are NF-kB and STAT3. Importantly, tumor models in which NF-kB and STAT3 signaling are inhibited have demonstrated the importance of these pathways to GBM growth and proliferation. Therefore, better understanding of the regulation of these pathways is required so that therapies can be designed against them in the future. We have found that the peptidyl prolyl isomerase Pin1 plays an important role in the regulation of both the NF-kB and STAT3 pathways. Through an interaction with the NF-kB protein p65, we found that Pin1 enhances the activation of NF-kB, as measured by pS276 p65. Furthermore, we found that this enhanced NF-kB signaling results in the differential expression of NF-kB-regulated genes, including the upregulation of the angiogenic factor IL-8. We also determined that the mechanism through which Pin1 enhanced IL-8 expression was by increasing the recruitment of active p65 to the IL-8 promoter. Finally, using a migration assay, we found that Pin1 enhanced the migration of cells stimulated with TNFa, suggesting an NF-kB-mediated mechanism. We have also determined that Pin1 acts as a positive regulator of the JAK2/STAT3 pathway. Pin1 enhanced STAT3 activity in whole-cell lysates, as measured by pY705 and pS727 STAT3. Pin1 also increased the levels of total and pS727 STAT3 in the nucleus, and this led to increased recruitment of STAT3 to the promoter of an important STAT3 target, SOCS3. SOCS3 mRNA and protein expression was also increased by Pin1. Finally, using an invasion assay, we found that Pin1 decreases the invasive properties of unstimulated glioma cells. On the whole, this project has made new discoveries as to the role of Pin1 in NF- kB and STAT3 signaling. We hope that his work, in combination with innovations in GBM cell targeting and delivery, will eventually lead to benefits in GBM therapy.

1 online resource (viii, 115 p. : ill., digital, PDF file)

Cell Biology;

Joint Health Sciences;

NF-kB STAT3 Pin1 IL-8 SOCS3

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Advisors/Committee Members: Benveniste, Etty (Tika) N., Benos, Dale<br>, Chang, Chenbei<br>, Fuller, Gerald<br>, Nabors, L. Burton<br>, Schwiebert, Lisa.

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Type I diabetes (T1D) is an autoimmune disease in which β cells are destroyed by the immune system; however, role of infections in type I diabetes (T1D) pathogenesis is unclear. Reports suggesting that childhood Group A Streptococcal (GAS) infections protected against T1D prompted us to study how antibodies to N-acetyl-D-glucosamine (GlcNAc), which are induced by GAS infection, influenced T1D development. We found that GlcNAc-specific antibodies reacted with β cell secretory granules, and neonatal NOD mice immunized with GAS or given GAS-immune sera were protected from spontaneous diabetes. Monoclonal GlcNAc-specific IgM blocked activation and effector responses to islet antigens by diabetogenic T cells. Immunization with GAS inhibited BDC2.5 T cell activation in pancreatic lymph nodes, and passive transfers of monoclonal GlcNAc-specific antibodies to neonatal NOD.Rag-2 KO recipients delayed diabetes induced by BDC2.5 Tg splenocyte transfer. To understand how neonatal exposure to environmental antigens, such as GAS, shapes humoral responses in adulthood, we utilized a novel flow cytometric method to identify and phenotype ultra-low frequency GlcNAc-specific B cells in wildtype C57BL/6 mice. After secondary re-challenge in adulthood, neonatal immunization with GAS led to increased production of GlcNAc-specific antibodies with distinct idiotype reactivities compared to those generated in mice given PBS as neonates, suggesting that the clonal composition of the GlcNAc-specific B cell repertoire was altered by early exposure to GAS. Boosted GlcNAc-specific antibody titers occurred when mice were immunized within 3-14 days of age, indicating a window in neonatal life in which the B cell repertoire is shaped by antigen exposure. Taken together, these findings indicate that GlcNAc-specific B cells, when activated by microorganism-associated antigens during a defined time in neonatal life, can protect against T1D through the production of self-reactive antibodies that impede diabetogenic CD4 T cell activation.

PhD

1 online resource (viii, 152 pages) :illustrations

Ph.D.University of Alabama at Birmingham2012.

Microbiology

Joint Health Sciences

Antibodies B cells Group A Streptococci N-acetyl-D-glucosamine Neonatal immunity Type I diabetes

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Advisors/Committee Members: John F. Kearney, Chaplin, David D. Justement, Louis B. Nahm,Moon Tse, Hubert M..

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Insulin resistance commonly occurs following injuries or critical illness independent of previous diabetic status. The development of insulin resistance and hyperglycemia is associated with increased mortality and morbidity in critically ill patients. However, the molecular mechanisms underlying the acute insulin resistance following injuries remain poorly understood. With an animal model of trauma and hemorrhage, we have previously demonstrated the rapid development of insulin resistance in liver, and a critical role of TNF? in hemorrhage-induced defects in insulin signaling following resuscitation. However, hepatic insulin signaling is impaired prior to a significant increase in plasma TNF?, suggesting the initial development of hemorrhage-induced hepatic insulin resistance may be TNF? independent. By inhibiting the activity of TNF? or reactive oxygen species (ROS), our current studies further demonstrated that elevated ROS is responsible for the initial development of hepatic insulin resistance following hemorrhage, while TNF? has a dominant role later, following resuscitation. The mechanisms by which ROS induces the rapid development of hepatic insulin resistance were next investigated. Both Inhibitory-?B kinases (IKK) and c-Jun Nterminal kinase (JNK) can be activated by ROS and inhibit insulin signaling, potentially by increasing serine phosphorylation of insulin receptor (IR) or insulin receptor substrates (IRSs). Activation of hepatic IKK and JNK was observed as early as 15 minutes after trauma and hemorrhage, which was concomitant with the rapid impairment of hepatic insulin signaling. The important roles of IKK and JNK in the early development of hemorrhage-induced insulin resistance were further demonstrated by direct inhibition of the IKKs (IKK? and ?) and JNK1 with adenovirus-mediated expression of dominant negative mutants of IKKs and JNK1 in liver. Using two approaches of Kupffer celldepletion, we further demonstrated that the early development of hemorrhage-induced hepatic insulin resistance and activation of IKK and JNK are Kupffer cell independent. Thus, acute activation of IKK and JNK likely occurs within hepatocytes where they directly interact with IR or IRS proteins and inhibit insulin signaling. In conclusion, our studies provide mechanistic insights into the acute onset of hepatic insulin resistance following injury. IKK and JNK are potential therapeutic targets for treating hyperglycemia in the Intensive Care Unit.

1 online resource (xii, 199 p.) :ill., digital, PDF file.

Joint Health Sciences

Acute insulin resistance, Injury, Liver, TNF?, Serine kinase, Kupffer cell

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Advisors/Committee Members: Joseph L. Messina, Additional advisors: Jeonga Kim, John D. Mountz, Alexander Pereboev, Selvarangan Ponnazhagan..

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Despite the controversy regarding the adverse effects of exposure to higher folate concentrations on health outcomes particularly cancer, there has been paucity of research to understand the biological mechanisms affected by such exposures in relation to the risk of developing pre-cancer or cancer. We have recently addressed this concern by demonstrating that higher plasma folate concentrations were not associated with greater risk of being diagnosed with higher grades of cervical intraepithelial neoplasia (CIN 2+) especially in women with sufficient plasma vitamin B12 concentrations. Higher plasma folate was also associated with a pre-cancer protective level of peripheral blood mononuclear cells (PBMC) long interspersed nuclear elements-1 (LINE-1) methylation, a validated surrogate marker of global DNA methylation status. However, it is unknown whether these results could be reproduced using homocysteine (Hcy), a functional indicator of both folate and vitamin B12 status and whether genetic polymorphisms in the folate metabolic pathway (FMP) may have an effect on these associations in a population of women exposed to FA fortification program. The objectives of this research were to determine the 1) association between Hcy and risk of CIN 2+, 2) the association between MTHFR C677T, TS 3'UTR 6bp deletion and DHFR 19bp deletion polymorphisms and the risk of CIN 2+, 3) modifying effects of plasma folate and vitamin B12 on the association between the genetic polymorphisms and the risk of CIN 2+, 4) the association between the genetic polymorphisms and pre-cancer/cancer associated epigenetic biomarkers and DNA damage markers, 5) modifying effects of plasma folate and vitamin B12 on the association between the genetic polymorphisms and these biomarkers. Higher Hcy was associated with increased risk of CIN 2+ and a lower degree of PBMC LINE-1 methylation. Women with MTHFR 677CT or TT genotype and lower plasma folate were at a reduced risk for CIN 2+ and had lower degree of PBMC LINE-1methylation compared to women with MTHFR 677CT or TT genotype and higher plasma folate. In conclusion, even in the FA fortification era, not all women have adequate folate status to overcome the adverse effects of higher Hcy and MTHFR C677T. PBMC LINE-1 methylation is a useful marker to assess the risk of CIN 2+ in individuals having MTHFR C677T polymorphism.

PhD

1 online resource (xiii, 126 p.) :ill., digital, PDF file.

Nutrition Sciences

Health Professions

cervical intraepithelial neoplasia (CIN) DNA methylation folate folic acid fortification genetic polymorphisms

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Advisors/Committee Members: Chandrika J. Piyathilake, Piyathilake, Chandrika J. Azuero,Andres Deluca,Maria Edberg, Jeffrey C. Eto,Isao.

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The role of human leukocyte antigen (HLA)-A and HLA-B supertypes in control-ling human immunodeficiency virus type 1 (HIV-1) infection in African-Americans re-mains poorly understood. We examined the effects of HLA class I supertypes on the out-comes of HIV-1 clade B infection among 338 African-American adolescents and women from Reaching for Excellence in Adolescent Care and Health and HIV Epidemiology Re-search Study cohorts. In addition, we investigated HLA-B58 supertype (B58s) and its constituent alleles in relation to control of HIV-1 clade A (202 Rwandans) and C infec-tion (423 Zambians). Our analysis of clade B-infected African-Americans demonstrated associations of certain previously or newly implicated HLA class I alleles (A*32, A*36, A*74, B*14, B*3501, B*45, B*53, B*57, Cw*08, Cw*12, and Cw*18) with one or more of the HIV-1 outcomes. B58s (P < 0.0001) and B62s (P = 0.01) were associated with more favorable outcomes, whereas B7s (P < 0.001) and B44s (P = 0.02) were associated with less favor-able ones. The unfavorable effect of B*1510 (P = 0.04) masked an otherwise protective effect of other alleles in B27s (P = 0.03). HLA-A supertypes exerted no appreciable in-fluence. With notable exceptions, we observed broad homogeneity of allelic effects with-in specific HLA-B supertypes in the context of clade B HIV-1 infection. The associations of B supertypes (B58s, B7s) were largely explained either by well known constituent al-leles or by previously unimplicated B alleles grouped together within a supertype (B44s, B62s). The frequencies of HLA-B genotypic supertypes correlated positively with viral load (VL) (r = 0.63, P = 0.027) and negatively with CD4+ T-cells (r = -0.62, P = 0.03). Multilevel linear analysis of VL heterogeneity between the genotypic supertypes sug-gested that B58s and B*57 in particular contributed disproportionately to the explainable VL variation. We detected no significant advantage for B58s as a whole in native Afri-cans with clade A or C, due to contrasting influences of favorable B*57 and unfavorable B*5802. Taken as a whole, we demonstrated the dominant role of HLA-B alleles and su-pertypes in HIV-1 clade B-infected African-Americans and further dissected the contri-butions of individual class I alleles and their population frequencies to the supertype ef-fects across the spectrum of viral clades in North America and Sub-Saharan Africa.

xii, 120 p. : ill., digital, PDF file

Epidemiology

Public Health

HLA HIV Allele African Supertype Control

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Advisors/Committee Members: Kaslow, Richard A., Shrestha, Sadeep<br>, Tang, Jianming<br>, Wilson, Craig M.<br>, Zhang, Kui.

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Study Type: Cohort, between and within group comparison. Objective: To determine the efficacy of the 15-second lateral step-up (15-SLSU) test for comparing hip function between patients treated with two different intramedullary nailing (IMN) approaches for femur fractures. In addition, to determine whether the 15-SLSU detects differences in hip function between the surgical and non-surgical limb of subjects treated with IMN. Background: Historically, two surgical approaches have been used for IMN of femur fractures. Determining tests that can detect whether various surgical approaches result in differences in hip function is important for making decisions about treatment. Methods and Measures: Subjects were recruited from an on going prospective randomized study based on the surgical approach, piriformis or trochanteric. Each subject completed the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and were rated on the Injury Severity Score (ISS). At a follow-up greater than one year post-operatively, subjects performed the 15-SLSU. Results: When comparing scores on the 15-SLSU between the groups, no significant difference was found. One significant finding was a 3.39 repetition [t(27)=5.193, p<0.01] difference in the 15-SLSU mean scores between the injured and uninjured side when scores from the two groups were pooled together. No difference was found between the two groups on the WOMAC and ISS. Conclusion: With this sample size, the 15-SLSU did not detect differences between the two approaches. The 15-SLSU did demonstrate differences between the surgical and non-surgical sides for all the subjects in this study. Since differences were shown between the sides and the 15-SLSU is easy to perform, the 15-SLSU may be a useful outcome measure to include when assessing function following IMN of femur fractures.

D.Sc.P.T.

viii, 21 p. : ill., digital, PDF file.

Physical Therapy

Health Professions

trochanteric piriformis intramedullary nailing 15 second lateral set up femur fractures functional outcomes

UNRESTRICTED

Advisors/Committee Members: Ogard, William K., Graham, Cecilia L.<br>, Braswell, Jennifer J.<br>, Stannard, James P.<br>, Davis, Richard Drew.

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The marginal zone (MZ) in the spleen provides a critical defense against bloodborne pathogens. Specialized MZ macrophages (MZM) identified previously based on scavenger receptor (MARCO) or C-type lectin (SIGN-R1) expression, play an essential role in the capture of bacteria whereas MZ B lymphocytes are rapidly activated to produce protective antibodies. Contact between MZM and MZ B cells has been suggested, however the functional role of the interaction is not clear. The goal of this dissertation is to understand the development of the marginal zone and the functional importance of the interaction between MZ B cells and MZM. In the first study, we examined the role of CD19 in MZ development. In CD19-/- mice where MZ B cells are missing, SIGN-R1+ MZM are lost and CD11c DC distribute abnormally in the MZ. The lack of MZ B cells could be an intrinsic defect in B cells and/or a secondary defect in the extrinsic MZ microenvironment. Adoptively transferred B cells from normal mice are able to reconstitute MZ B cells in CD19-/- mice and further restore MZM distribution and MZ DC distribution. Thus, MZ B cells are required for generation of the normal MZ microenvironment, but the deficiency of MZ B cells in CD19-/- mice is caused by an intrinsic defect in B cell signaling. In the second study, we examined the cross-talk between MZ B cells and MZM. We found that SIGN-R1+ MZMs constitute a subset of the MARCO+ MZMs and that MARCO+ MZMs exist in mice lacking MZ B cells. Secondly, the continuous presence of MZ B cells is required to maintain SIGN-R1+ MZMs. Finally, MZ B cells obtain certain types of Ag exclusively through their interaction with SIGN-R1+ MZMs during the initial exposure to Ag. Therefore, MZ B cells regulate expression of molecules on macrophages involved in antigen transfer to B cells. Collectively these findings demonstrate that CD19 intrinsic signaling is required for the generation of MZ B cells, that MZ B cells are required for maintenance of a normal MZ environment and finally that MZ B cells and MZMs collaborate together during the initial host response to blood-borne pathogens.

1 online resource (viii, 104 p. : ill., digital, PDF file)

Microbiology;

Joint Health Sciences;

Marginal Zone Marginal Zone B cells (MZ B cells) Marginal Zone Macrophages (MZM) CD19 SIGN-R1 host defense

UNRESTRICTED

Advisors/Committee Members: Justement, Louis B., Chaplin, David D.<br>, Kearney, John F.<br>, Klug, Christopher A.<br>, Smith, Phillip D..

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B cell development, maturation and proliferation are all strictly regulated processes. Disruption of the regulatory network at any step would lead to immune disorders. The regulatory system of B cells can be considered as two layers: a general homeostasis regulation system and a specificity-based control system. General regulation of B cell homeostasis is mastered by BLyS (B Lymphocyte Stimulator) and several other BLyS family cytokines, which serve as a crucial survival factor for which transitional and mature B cells compete. Specificity-based control is achieved via B cell antigen receptors (BCRs), which serve as a determinant of whether an antigen-specific B cell will survive negative and positive selection and successfully mature. As one would expect, mechanisms that can regulate either BLyS levels or BCR signaling strength can impact B cell destiny and the shape of adaptive immune system. In this work, we uncovered two new mechanisms that contribute to B cell regulation: Fcγ receptors boosting soluble BLyS levels, and enhancing BCR signaling. (1) Both IgG and CRP, immune system opsonins, induced rapid and significant shedding of membrane-bound BLyS on human myeloid cells. The shed BLyS promotes long-term (days) B cell survival. Furthermore, using direct anti-receptor mAb cross-linking, we demonstrated that this effect was preferentially mediated by FcγRI compared to FcγRIIA. (2) We identified FcγRIIC as a second FcγR on human B cells besides FcγRIIB. Its expression is determined by a single nucleotide polymorphism in amino acid codon 13 in its first extracellular domain. This SNP encodes either a stop codon or an open reading frame (allele frequency 0.12). In transduced cells, co-ligation of FcγRIIC and BCR led to FcγRIIC tyrosine phosphorylation, as well as enhanced B cell activation, reflected by amplified global tyrosine phosphorylation and increased phosphorylation of a series of key molecules in the BCR signaling cascade, and enhanced calcium flux. Therefore, in carriers of the open reading frame allele, FcγRIIC is expressed on B cells and would set up a new activation threshold, potentially slanting B cells towards hyper-activation. Keywords: FcγR, BLyS, BCR, autoimmunity, polymorphism

1 online resource (x, 111 p. : ill., digital, PDF file)

Cell Biology;

Joint Health Sciences;

FcγR BLyS BCR autoimmunity polymorphism

UNRESTRICTED

Advisors/Committee Members: Kimberly, Robert, Burrows, Peter<br>, Frank, Stuart<br>, Justement, Louis<br>, Serra, Rosa.