The social organization of conversational narrative : a methodological contribution to linguistic discourse analysis via conversational analysis

This thesis examines stories bold in natural conversation with an interest in discovering and describing social features of conversational discourse. Sociology has begun to develop a strong interest in narrative structures, and this interest parallels the current interest in discourse and seeks to make the sociological enterprise of conversational analysis relevant to discourse analysis, particularly in relation to narrative. The data for this study were collected over a period of four years (1979-83). Approximately 19 hours of tape-recorded conversations recorded in a variety of situations were collected. After a lengthy period of listening to the tapes, instances where stories are told were isolated and transcribed, and structural features of prefacings, tellings, and responses were subjected to formal analysis. The analytical techniques used in this study were first developed by Harvey Sacks and his students. The contribution of this study is to provide the discourse analyst with a set of well-defined discovery procedures for describing ethnographic features which influence discourse. The ethnographic interest has two distinctive features; (1) it is oriented to members' practices, and (2) it is 'micro' in character, oriented to a close reading of interactions in context. In the analytical chapters (3-6), the thesis explores how characters may be formulated in the narratives and what kinds of interactional work gets done (Chapter 3), the interactional importance of collateral information in narrative telling sequences (Chapter 4), how narratives get generated from prior ongoing talk (Chapter 5), and narrative response types and preferences (Chapter 6). Throughout the thesis an interest is maintained in relating the findings of the study with current findings in discourse analysis. The thesis concludes with a chapter summarising its original contribution and relating the methodology and findings of the study to recent methodologies and findings in discourse analysis.Arts, Faculty ofSociology, Department ofGraduat

TOWARDS A MODEL OF CO-MANAGEMENT OF PROVINCIAL PARKS IN ONTARIO A Rationale for Co-Management

Abstract I Resume This paper explores to what extent First Nations communities participate in the planning and management of Ontario parks, and if the current process is successful. The study is also designed to show how First Nations' concems, needs and interests can be better reflected in provincial park planning and design practices. A key claim ofthis study is that First Nations communities have been inadequately involved with the land-use planning and design issues which have confronted govemment-run parks in traditional First Nations territories. eet article examine la degre d'implication des communautes autochtones dans la planification et I'administration des pares de l'Ontario et evalue Ie fonctionnment de ceux-ci dans la situation actuelle. On propose aussi de montrer comment mieux inb §grer les preoccupations, les besoins et les intert~ts des Premieres Nations au pratiques de planification et de gestion des pares provinciaux. Une affirmation centrale de cette etude est que les communautes autochtones n'ont pas ete impliquees autant qu'elles auraient dQ I'etre la gestion des problemes de planification et de conception auxquels sont confrontes les pares se trouvent sur leurs territoires mais administres par l'Etat. This paper is about a new kind of thinking, a new kind of architecture, if you will: an architecture of culture and mind. For First Nations people, this architecture of culture and mind will have a familiar ring to it, for it is really an ancient architecture and way ofthinking deeply entrenched in Aboriginal traditions. There is little written about this new architecture and how it is grounded in these ancient traditions. This paper is intended to introduce the reader to the foundation upon which contemporary environmental planning and design must rest, at least from an Aboriginal perspective. The purpose of this study is to investigate to what extent First Nations communities participate in the planning and management of parks, and if the current process is successful. This study shows how First Nations' concems, needs and interests can be reflected in park planning and design practices. Specifically, this study examines the present relationship between Ojibwe First Nations and the Ontario Parks management systems in a contemporary context

Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation

Hypoxia regulates autophagy and nucleotide-binding oligomerization domain receptor, pyrin domain containing (NLRP)3, two innate immune mechanisms linked by mutual regulation and associated to IBD. Here we show that hypoxia ameliorates inflammation during the development of colitis by modulating autophagy and mammalian target of rapamycin (mTOR)/NLRP3 pathway. Hypoxia significantly reduces tumor necrosis factor α, interleukin (IL)-6 and NLRP3 expression, and increases the turnover of the autophagy protein p62 in colon biopsies of Crohn's disease patients, and in samples from dextran sulfate sodium-treated mice and Il-10 -/- mice. In vitro, NF-κB signaling and NLRP3 expression are reduced through hypoxia-induced autophagy. We also identify NLRP3 as a novel binding partner of mTOR. Dimethyloxalylglycine-mediated hydroxylase inhibition ameliorates colitis in mice, downregulates NLRP3 and promotes autophagy. We suggest that hypoxia counteracts inflammation through the downregulation of the binding of mTOR and NLRP3 and activation of autophagy.Hypoxia and HIF-1α activation are protective in mouse models of colitis, and the latter regulates autophagy. Here Cosin-Roger et al. show that hypoxia ameliorates intestinal inflammation in Crohn's patients and murine colitis models by inhibiting mTOR/NLRP3 pathway and promoting autophagy

Hypoxia Reduces the Transcription of Fibrotic Markers in the Intestinal Mucosa

Intestinal fibrosis, characterized by excessive deposition of extracellular matrix proteins, is a common and severe clinical complication of inflammatory bowel disease (IBD). However, the mechanisms underlying fibrosis remain elusive, and currently, there are limited effective pharmacologic treatments that target the development of fibrosis. Hypoxia is one of the key microenvironmental factors influencing intestinal inflammation and has been linked to fibrosis. In the present study, we sought to elucidate the impact of hypoxia on fibrotic gene expression in the intestinal mucosa. Methods:Human volunteers, IBD patients, and dextran sulphate sodium-treated mice were exposed to hypoxia, and colonic biopsies were collected. The human intestinal epithelial cell line Caco-2, human THP-1 macrophages, and primary human gut fibroblasts were subjected to hypoxia, and changes in fibrotic gene expression were assessed. Results:Human volunteers subjected to hypoxia presented reduced transcriptional levels of fibrotic and epithelial-mesenchymal transition markers in the intestinal mucosa. IBD patients showed a trend towards a decrease in tissue inhibitor of metalloproteinase 1 protein expression. In mice, hypoxic conditions reduced the colonic expression of several collagens and matrix metalloproteinases. Hypoxic Caco-2 cells, THP-1 cells, and primary gut fibroblasts showed a significant downregulation in the expression of fibrotic and tissue remodelling factors. Conclusions:Stabilization of hypoxia-inducible factors might represent a novel therapeutic approach for the treatment of IBD-associated fibrosis

Modeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip

Abstract Diabetic retinopathy (DR) is a microvascular disorder characterized by inner blood-retinal barrier (iBRB) breakdown and irreversible vision loss. While the symptoms of DR are known, disease mechanisms including basement membrane thickening, pericyte dropout and capillary damage remain poorly understood and interventions to repair diseased iBRB microvascular networks have not been developed. In addition, current approaches using animal models and in vitro systems lack translatability and predictivity to finding new target pathways. Here, we develop a diabetic iBRB-on-a-chip that produces pathophysiological phenotypes and disease pathways in vitro that are representative of clinical diagnoses. We show that diabetic stimulation of the iBRB-on-a-chip mirrors DR features, including pericyte loss, vascular regression, ghost vessels, and production of pro-inflammatory factors. We also report transcriptomic data from diabetic iBRB microvascular networks that may reveal drug targets, and examine pericyte-endothelial cell stabilizing strategies. In summary, our model recapitulates key features of disease, and may inform future therapies for DR

Activating the synthesis of progerin, the mutant prelamin A in Hutchinson-Gilford progeria syndrome, with antisense oligonucleotides.

Hutchinson-Gilford progeria syndrome (HGPS) is caused by point mutations that increase utilization of an alternate splice donor site in exon 11 of LMNA (the gene encoding lamin C and prelamin A). The alternate splicing reduces transcripts for wild-type prelamin A and increases transcripts for a truncated prelamin A (progerin). Here, we show that antisense oligonucleotides (ASOs) against exon 11 sequences downstream from the exon 11 splice donor site promote alternate splicing in both wild-type and HGPS fibroblasts, increasing the synthesis of progerin. Indeed, wild-type fibroblasts transfected with these ASOs exhibit progerin levels similar to (or greater than) those in fibroblasts from HGPS patients. This progerin was farnesylated, as judged by metabolic labeling studies. The synthesis of progerin in wild-type fibroblasts was accompanied by the same nuclear shape and gene-expression perturbations observed in HGPS fibroblasts. An ASO corresponding to the 5' portion of intron 11 also promoted alternate splicing. In contrast, an ASO against exon 11 sequences 5' to the alternate splice site reduced alternate splicing in HGPS cells and modestly lowered progerin levels. Thus, different ASOs can be used to increase or decrease 'HGPS splicing'. ASOs represent a new and powerful tool for recreating HGPS pathophysiology in wild-type cells

Noncoding copy-number variations are associated with congenital limb malformation

PurposeCopy-number variants (CNVs) are generally interpreted by linking the effects of gene dosage with phenotypes. The clinical interpretation of noncoding CNVs remains challenging. We investigated the percentage of disease-associated CNVs in patients with congenital limb malformations that affect noncoding cis-regulatory sequences versus genes sensitive to gene dosage effects.MethodsWe applied high-resolution copy-number analysis to 340 unrelated individuals with isolated limb malformation. To investigate novel candidate CNVs, we re-engineered human CNVs in mice using clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing.ResultsOf the individuals studied, 10% harbored CNVs segregating with the phenotype in the affected families. We identified 31 CNVs previously associated with congenital limb malformations and four novel candidate CNVs. Most of the disease-associated CNVs (57%) affected the noncoding cis-regulatory genome, while only 43% included a known disease gene and were likely to result from gene dosage effects. In transgenic mice harboring four novel candidate CNVs, we observed altered gene expression in all cases, indicating that the CNVs had a regulatory effect either by changing the enhancer dosage or altering the topological associating domain architecture of the genome.ConclusionOur findings suggest that CNVs affecting noncoding regulatory elements are a major cause of congenital limb malformations