Talking to Transform - Aesthetic Experiments in Conversational Inquiry

This dissertation is an investigation into conversation practices of transformative inquiry examples of which lie across philosophical, therapeutic, spiritual and pedagogical disciplines and include: Socratic dialogue, Community of Philosophical Inquiry, Philosophy for Children, Psychodrama, Psychoanalysis, Authentic Relating practices, Quaker Meetings, confessionals, dialogic pedagogies. My central claims are that these practices contain linguistic and paralinguistic techniques which: 1) perform functions of transformative inquiry 2) can perform these functions apart from the institutions, communities and ideologies typically tied to these techniques 3) can be aesthetically re-combined and re-deployed within artistic formats to expand the scope of these performative functions. I begin this study by a close investigation of a singular practice – Socratic dialogue – arguing how it was a live, performative practice which relied on techniques of questioning, clarifications, brachylogia, facilitation and role-play, and showing how these techniques moved in and out of play through interlocutory negotiations of power, desire and investment. The focus widens as I create a glossary of conversational techniques of transformative inquiry drawn from dozens of conversation practices. This glossary arranges techniques by their linguistic, paralinguistic and non-linguistic functions and analyzes how each technique performs transformative inquiry through the following variables: noticing, affective and conceptual clarity, opening and closing, expressivity, and focus. What follows is an analysis of Tino Sehgal’s This Progress which draws on the performative functions of the glossary to show how a contemporary work of art can utilize conversation techniques of transformative inquiry. I then conduct a more systematic analysis of how artworks can utilize techniques of transformative inquiry by examining: how conversation is deployed in artworks, how semantic determinacy or indeterminacy is negotiated, how determinate aspects can be notated or scored, questions of audienceship and witnessing, and how the transformative inquiry itself changes when conducted within a work of art. This leads into an extended study of my own art practice of developing conversation pieces for transformative inquiry, a practice which expands the reflexivity and reflectivity of transformative inquiry itself. I conclude with a brief investigation into how my own practice is para and pata-philosophical by examining key concepts of philosophical inquiry – expertise, techne, poiesis, eidos, immanence, logos, repetition

Epidermal growth factor and transforming growth factor-alpha decrease gamma interferon receptors and induction of intercellular adhesion molecule (ICAM-1) on cultured keratinocytes

The link between the epidermal keratinocytes of the skin and the activated T lymphocytes of the immune system is mediated by a variety of cytokines, including gamma interferon (IFN-Γ). We studied the influence of keratinocyte mitogens such as transforming growth factor-alpha (TGF-Α), epidermal growth factor (EGF), and somatomedin-C (SM-C) on the ligand binding of 32 P-labelled IFN-Γ to cultured keratinocytes derived from normal appearing adult human skin. Keratinocytes placed in a medium devoid of mitogens become growth arrested, and these quiescent cells expressed 2.4 times (28,900 versus 12,200 sites/cell) as many high affinity IFN-Γ receptors (Kd = 0.22 nM) compared to keratinocytes which were actively growing in medium containing TGF-Α (25 ng/ml) or EGF (10 ng/ml). The reduction in IFN-Γ receptor sites by TGF-Α/EGF was mitogen specific, as adding SM-C (500 ng/ml) did not have any effect on ligand binding, although it similarily stimulated keratinocyte growth. The reduction in IFN-Γ receptors was time dependent, occurring primarily after 24–48 hours of change in tissue culture conditions. The reduction in the number of high affinity IFN-Γ receptors by TGF-Α/EGF had immunobiological consequences, because quiescent keratinocytes in basal medium had an increased expression of HLA-DR and intercellular adhesion molecule-1 (ICAM-1) induced by IFN-Γ, compared to actively growing TGF-Α/EGF treated keratinocytes. These results suggest that rapidly proliferating keratinocytes exposed to TGF-Α/EGF but not SM-C are capable of altering their response to IFN-Γ by decreasing their number of cell surface high affinity receptors for IFN-Γ.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49881/1/1041500207_ftp.pd

The N-Glycans Determine the Differential Blood Clearance and Hepatic Uptake of Human Immunoglobulin (Ig)a1 and Iga2 Isotypes

Human immunoglobulin (Ig)A exists in blood as two isotypes, IgA1 and IgA2, with IgA2 present as three allotypes: IgA2m(1), IgA2m(2), and IgA2m(n). We now demonstrate that recombinant, chimeric IgA1 and IgA2 differ in their pharmacokinetic properties. The major pathway for the clearance of all IgA2 allotypes is the liver. Liver-mediated uptake is through the asialoglycoprotein receptor (ASGR), since clearance can be blocked by injection of excess galactose-Ficoll ligand and suppressed in ASGR-deficient mice. In contrast, only a small percentage of IgA1 is cleared through this pathway. The clearance of IgA1 lacking the hinge region with its associated O-linked carbohydrate was more rapid than that of wild-type IgA1. IgA1 and IgA2 that are not rapidly eliminated by the ASGR are both removed through an undefined ASGR-independent pathway with half-lives of 14 and 10 h, respectively. The rapid clearance of IgA2 but not IgA1 through the liver may in part explain why the serum levels of IgA1 are greater than those of IgA2. In addition, dysfunction of the ASGR or altered N-linked glycosylation, but not O-glycans, that affects recognition by this receptor may account for the elevated serum IgA seen in liver disease and IgA nephropathy

The Orphan Receptor CRF2-4 Is an Essential Subunit of the Interleukin 10 Receptor

The orphan receptor CRF2-4 is a member of the class II cytokine receptor family (CRF2), which includes the interferon receptors, the interleukin (IL) 10 receptor, and tissue factor. CRFB4, the gene encoding CRF2-4, is located within a gene cluster on human chromosome 21 that comprises three interferon receptor subunits. To elucidate the role of CRF2-4, we disrupted the CRFB4 gene in mice by means of homologous recombination. Mice lacking CRF2-4 show no overt abnormalities, grow normally, and are fertile. CRF2-4 deficient cells are normally responsive to type I and type II interferons, but lack responsiveness to IL-10. By ∼12 wk of age, the majority of mutant mice raised in a conventional facility developed a chronic colitis and splenomegaly. Thus, CRFB4 mutant mice recapitulate the phenotype of IL-10–deficient mice. These findings suggest that CRF2-4 is essential for IL-10–mediated effects and is a subunit of the IL-10 receptor

Targeted Therapies in Liver Fibrosis:Combining the Best Parts of Platelet-Derived Growth Factor BB and Interferon Gamma

Cytokines, growth factors and other locally produced mediators play key roles in the regulation of disease progression. During liver fibrosis, these mediators orchestrate the balance between pro- and antifibrotic activities as exerted by the hepatic cells. Two important players in this respect are the profibrotic mediator platelet derived growth factor BB (PDGF-BB) and the antifibrotic cytokine interferon gamma (IFNγ). PDGF-BB, produced by many resident and infiltrating cells, causes extensive proliferation, migration and contraction of hepatic stellate cells (HSCs) and myofibroblasts. These cells are the extracellular matrix producing hepatic cells and they highly express the PDGFβ-receptor. On the other hand, IFNγ is produced by natural killer cells in fibrotic livers and is endowed with pro-inflammatory, antiviral and antifibrotic activities. This cytokine attracted much attention as a possible therapeutic compound in fibrosis. However, clinical trials yielded disappointing results because of low efficacy and adverse effects, most likely related to the dual role of IFNγ in fibrosis. In our studies, we targeted the antifibrotic IFNγ to the liver myofibroblasts. For that, we altered the cell binding properties of IFNγ, by delivery of the IFNγ-nuclear localization sequence to the highly expressed PDGFβ-receptor using a PDGFβ-receptor recognizing peptide, thereby creating a construct referred to as Fibroferon (i.e. fibroblast-targeted interferon γ). In recent years, we demonstrated that HSC-specific delivery of IFNγ increased its antifibrotic potency and improved its general safety profile in vivo, making Fibroferon highly suitable for the treatment of (fibrotic) diseases associated with elevated PDGFβ-receptor expression. The present review summarizes the knowledge on these two key mediators, PDGF-BB and IFNγ, and outlines how we used this knowledge to create the cell-specific antifibrotic compound Fibroferon containing parts of both of these mediators

HIV-1 Inhibits Autophagy in Bystander Macrophage/Monocytic Cells through Src-Akt and STAT3

Autophagy is a homeostatic mechanism of lysosomal degradation. Defective autophagy has been linked to various disorders such as impaired control of pathogens and neurodegeneration. Autophagy is regulated by a complex array of signaling pathways that act upstream of autophagy proteins. Little is known about the role of altered regulatory signaling in disorders associated with defective autophagy. In particular, it is not known if pathogens inhibit autophagy by modulation of upstream regulatory pathways. Cells infected with HIV-1 blocked rapamycin-induced autophagy and CD40-induced autophagic killing of Toxoplasma gondii in bystander (non-HIV-1 infected) macrophage/monocytic cells. Blockade of autophagy was dependent on Src-Akt and STAT3 triggered by HIV-1 Tat and IL-10. Neutralization of the upstream receptors VEGFR, β-integrin or CXCR4, as well as of HIV-1 Tat or IL-10 restored autophagy in macrophage/monocytic cells exposed to HIV-1-infected cells. Defective autophagic killing of T. gondii was detected in monocyte-derived macrophages from a subset of HIV-1+ patients. This defect was also reverted by neutralization of Tat or IL-10. These studies revealed that a pathogen can impair autophagy in non-infected cells by activating counter-regulatory pathways. The fact that pharmacologic manipulation of cell signaling restored autophagy in cells exposed to HIV-1-infected cells raises the possibility of therapeutic manipulation of cell signaling to restore autophagy in HIV-1 infection