Some Aspects of the Interaction of Speaker and Hearer in the Construction of the Turn at Talk in Natural Conversation

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PI3K in juvenile myelomonocytic leukemia

Indiana University-Purdue University Indianapolis (IUPUI)Juvenile Myelomonocytic Leukemia (JMML) is rare, fatal myeloproliferative disease (MPD) affecting young children, and is characterized by expansion of monocyte lineage cells and hypersensitivity to Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) stimulation. JMML is frequently associated with gain-of-function mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase, Shp2. Activating Shp2 mutations are known to promote hyperactivation of the Ras-Erk signaling pathway, but Akt is also observed to have enhanced phosphorylation, suggesting a potential role for Phosphatidylinositol-3-Kinase (PI3K)-Akt signaling in mutant Shp2-induced GM-CSF hypersensitivity and leukemogenesis. Having demonstrated that Class IA PI3K is hyperactivated in the presence of mutant Shp2 and contributes to GM-CSF hypersensitivity, I hypothesized the hematopoietic-specific Class IA PI3K catalytic subunit p110δ is a crucial mediator of mutant Shp2-induced PI3K hyperactivation and GM-CSF hypersensitivity in vitro and MPD development in vivo. I crossed gain-of-function mutant Shp2 D61Y inducible knockin mice, which develop fatal MPD, with mice expressing kinase-dead mutant p110δ D910A to evaluate p110δ’s role in mutant Shp2-induced GM-CSF hypersensitivity in vitro and MPD development in vivo. As a comparison, I also crossed Shp2 D61Y inducible knockin mice with mice bearing inducible knockout of the ubiquitously expressed Class IA PI3K catalytic subunit, p110α. I found that genetic interruption of p110δ, but not p110α, significantly reduced GM-CSF-stimulated hyperactivation of both the Ras-Erk and PI3K-Akt signaling pathways, and as a consequence, resulted in reduced GM-CSF-stimulated hyper-proliferation in vitro. Furthermore, I found that mice bearing genetic disruption of p110δ, but not p110α, in the presence of gain-of-function mutant Shp2 D61Y, had on average, smaller spleen sizes, suggesting that loss of p110δ activity reduced MPD severity in vivo. I also investigated the effects of three PI3K inhibitors with high specificity for p110δ, IC87114, GDC-0941, and GS-9820 (formerly known as CAL-120), on mutant Shp2-induced GM-CSF hypersensitivity. These inhibitors with high specificity for p110δ significantly reduced GM-CSF-stimulated hyperactivation of PI3K-Akt and Ras-Erk signaling and reduced GM-CSF-stimulated hyperproliferation in cells expressing gain-of-function Shp2 mutants. Collectively, these findings show that p110δ-dependent PI3K hyperactivation contributes to mutant Shp2-induced GM-CSF hypersensitivity and MPD development, and that p110δ represents a potential novel therapeutic target for JMML

Dissecting Common Ground: Examining an Instance of Reference Repair

How participants to a joint activity come to develop a shared or mutual understanding of what they are perceiving has long been a problematic issue for philosophers, sociologists, and linguists. We examine the abstract model proposed by Clark and Marshall (1981) whereby speakers and hearers construct mutual knowledge and by which discrepancies in definite reference are repaired. We focus in particular on forms of demonstrative reference that depend upon physical co-presence. We examine an attested example of reference repair in the operating room of a teaching hospital. It involves learning to recognize pertinent structures within endoscopic surgeries, that is surgeries in which internal spaces are rendered visible by inserting a fiber-optic lens into the body of the patient. Clark and Marshall provide a useful vocabulary for discussing referential practices in this applied setting. We are left with some questions about how to interpret certain features of their model, however. We conclude that further theoretical framing is required before we develop a full appreciation of how reference and reference repair is accomplished in day-to-day interaction

La référence exophorique comme procédé interactif

Certaines unités utilisées dans la conversation, comme les démonstratifs thiset that, ont pour propriété de désigner, dans leurs emplois non anaphoriques, un objet à trouver dans le contexte environnant : cette « référence exophorique » est particulièrement intéressante à étudier lorsqu'on relie le verbal au non-verbal (positionnement, gestualité des protagonistes). L'orientation corporelle de l'interlocuteur ne paraît pas toujours congruente avec l'instruction qui lui est donnée verbalement par l'emploi du démonstratif, de trouver l’item désigné : dans quelle mesure ces situations sont-elles imputables à une erreur du destinataire, ou à une erreur du locuteur, qui par le déictique, enjoint à son partenaire de regarder ce qu’il ne peut voir, celui-ci ayant les yeux détournés de lui, ou même lui tournant le dos ? Charles Goodwin montre que ces comportements ne sont pas à interpréter en termes d'échec ou d’inconséquence, mais correspondent à l'accomplissement de tâches particulières, dans la construction du tour de parole