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Thymic stromal lymphopoietin (TSLP) is produced primarily but not exclusively by epithelial cells. It has been shown to induce the production of Th2 cytokines and inflammation in allergic disease. Since Th2 cytokines have been shown to be detrimental to the anti-tumor immune response, we hypothesized that TSLP promotes the development of a permissive microenvironment for breast cancer, which facilitates the growth and metastasis of primary tumors and that it does so, in part, by inducing the development of a Th2-mediated immune response. Using the 4T1 mouse breast cancer model, we used wild type (WT) and TSLP receptor deficient (TSLPR-/-) mice to compare primary tumor growth, metastasis to the lungs and brain, cytokine profiles and 4T1-directed lysis. Some of these parameters were also examined in mice treated with an anti-TSLP neutralizing antibody. We showed that in TSLPR-/- mice, primary tumor establishment, growth and metastasis to the lungs were reduced, compared to WT mice. Unexpectedly, we observed that metastasis to the brain was increased. When mice were treated with anti-TSLP neutralizing antibody, the only significant effect that we observed was a reduction in metastasis to the lung in WT mice. We also studied TSLP expression in a human invasive breast cancer microarray (TMA). Both the normal breast epithelial cells and breast cancer cells stained positively for TSLP, but it appears that it might be more highly expressed in the breast cancer tissue. Taken together, our data support the hypothesis that TSLP promotes the development of a permissive microenvironment for breast cancer. However, the role of TSLP appears to be complex since the absence of TSLP responsiveness resulted in a greater level of metastasis to the brain.

Oil and gas exploration in Northern Canada uses explosive-based seismic techniques to locate hydrocarbon reserves beneath waterbodies not frozen to the bottom. The use of explosives in, or near, waterbodies has the potential to harm fishes, primarily through instantaneous pressure changes (IPCs) generated from the detonations. These IPCs can damage soft tissues through the rapid compression and expansion of the swimbladder as the pressure wave passes. In Canada, a document entitled Guidelines for the Use of Explosives In or Near Canadian Fisheries Waters recommends that peak pressures not exceed 100 kPa for the protection of fish, however damage has been reported below this level. To simulate seismic exploration and examine potential pathological changes surrounding the current Guideline, fish across different developmental stages and with varying degrees of swimbladder presence were exposed to a variety of explosive based IPC levels in field experiments. Early life stages of rainbow trout (Oncorhynchus mykiss) including eyed eggs, sac fry, and juveniles were caged and exposed to discrete detonations from 0 to 280 kPa in the Mackenzie Delta, NWT. These fish were subsequently examined for both gross pathological and histological changes to cranial structures as well as swimbladder, kidney, liver and gill tissue. Results showed changes in both the area and circumference of the cranial region of eyed eggs, as well as swimbladder, ocular and kidney damage in juveniles. Additionally, caged adult swimbladder bearing lake trout (Salvelinus namaycush) and non-swimbladder bearing slimy sculpin (Cottus cognatus) were exposed to explosive based IPCs ranging in peak pressure from 0 to 127 kPa at the Experimental Lakes Area, Ontario. Fish were later examined grossly and blood, liver, kidney, intestine, and spleen were examined to determine the presence of any traumatic based pathological changes. Results indicated the occurrence of swimbladder hemorrhage in lake trout exposed to IPCs near the current Guideline level. Finally, a risk assessment for lake trout of the Mackenzie Delta exposed to IPCs was undertaken; to examine the potential for adverse risk to individuals and populations, and the likelihood of populations being unable to recover. Based on the findings of the aforementioned studies, the recommended Guideline level is not protective of early life stages of rainbow trout and furthermore represents the threshold at which damage to the swimbladder in adult lake trout does not occur, as such, a re-examination of the recommended Guideline level is warranted.

Septoria tritici blotch (Stb) is a major foliar disease of wheat worldwide caused by the fungal pathogen Mycosphaerella graminicola. This project mapped the chromosomal locations of Stb resistance, which will be useful for wheat cultivar enhancement. In the first study of this project, Stb resistance and grain yield quantitative trait loci (QTL) were identified in a winter wheat doubled-haploid (DH) population produced from the cultivars Pastiche (resistant) and Torfrida (susceptible). A genetic map of the population was constructed using 104 microsatellite and 202 DArT markers. Separate disease and yield field trials were conducted in north-western Europe to measure natural Stb infection and grain yield, respectively. A resistance QTL from Pastiche was identified (QStb.jic-2A) that reduced flag leaf pycnidial density by 31.2% compared to the population mean. A second QTL from Pastiche (QYld.jic-2A) co-localized with QStb.jic-2A, and conferred an increase in grain yield of approximately 2.0% (0.19 t ha-1). The second study determined the map location of the third multiple-isolate resistance gene in the hexaploid landrace Salamouni. A population was developed using the resistant DH line 98S05B*13 (Salamouni/Katepwa) crossed to the susceptible cultivar Katepwa. The parent 98S05B*13 was found to contain the resistance gene Stb14 on chromosome 3BS, therefore, to minimize the effect of this gene, individual plants of the F2 population were selected for self-pollination based on presence or absence of Stb14 using flanking microsatellite markers. The Stb14(+) F2:3 families were screened with M. graminicola isolate MG96-36. Bulked segregant analysis identified a possible linkage to the gene of interest on chromosome 3AS. Polymorphic microsatellite markers on 3AS were used to construct a linkage group. The markers barc321 and barc12 were found to flank the resistance gene at genetic distances of 1.9 and 2.5 cM, respectively. This position on 3AS has not been previously linked to Stb resistance and this gene will be designated StbSm3. The third population was developed to fine map the isolate-specific resistance gene Stb14 located on chromosome 3B of Salamouni. A large population of 84 fixed recombinant F4 families was developed using the co-dominant microsatellite markers flanking Stb14. Attempts to identify clearly polymorphic molecular markers within the interval containing Stb14 were unsuccessful.

<p> Vegetable production is an important sector of the organic food industry in the Pacific Northwest USA. Significant acres of organic vegetable crops, particularly processing green pea and sweet corn, are grown in the semi-arid Columbia Basin of central Washington and north central Oregon, where Pythium damping-off can cause losses in early spring when cool and wet soil conditions are conducive to the disease. In this study, 37 certified organic fields were surveyed in the Columbia Basin for <i>Pythium</i> species, from which 305 isolates were baited and identified to 19 species. Pathogenicity tests of isolates of each species on pea in cool and wet soil conditions revealed isolates of 9 species were pathogenic, with differences in virulence among species and among isolates within species. <i>Pythium ultimum</i> (24.6% of the 305 isolates), <i>P. irregulare</i> group 1 (15.1%), and <i>P. abappressorium </i> (4.9%) were the most prevalent pathogenic species. Real-time PCR assays detected <i>P. ultimum</i>in 100% of the 37 fields compared to 78% for <i>P. abappressorium,</i> and 57% for <i>P. irregulare</i> group 1. </p><p> Given the lack of highly effective seed treatments for damping-off control in organic production, organic seed and drench treatments were evaluated in five pea field trials in the Columbia Basin, and two pea trials plus one sweet corn trial in maritime western Washington in 2011-12. Nordox seed treatment and seed priming demonstrated the greatest potential for damping-off control. Pea seed priming with 16 h of seed soaking + 10 h of air drying optimized priming for rapid emergence. In two field trials in 2012, combining Nordox seed treatment with seed priming using biochar as an alternative to air-drying, was promising for damping-off control. </p><p> Seed exudates produced during germination are measured using electrical conductivity (EC). The EC levels of 17 pea seed lots (six cultivars) significantly affected emergence and susceptibility to Pythium damping-off. A negative linear relationship was demonstrated between EC level and emergence, with a stronger regression at higher inoculum levels of <i>P. ultimum.</i> Measuring the EC of pea seed lots, and quantifying <i>Pythium</i> inoculum in soil using real-time PCR assays may enable organic pea growers to assess accurately the risk of damping-off.</p>

The normal lung with its air-filled alveoli is designed primarily to function in gas-exchange. Pulmonary edema, particularly in its alveolar flooding phase, is life-threatening because it interferes with this gas-exchange function. An important safety factor against alveolar flooding is the pulmonary interstitium that has a high compliance to accommodate edema fluid. We tested the hypothesis that if we decreased the compliance of the interstitium by experimental fibrosis, lung edema would be redistributed from the interstitium and predominantly flood alveoli. To study this, severe left lung fibrosis was produced in six dogs with radiation and bleomycin. Twenty-four months later, hydrostatic edema was induced by fluid infusion and lungs were studied pre- and post-edema with computed tomography (CT) scanning. Gravimetry and morphology were used to assess the amounts and distribution of edema between fibrotic left and control right lungs. Fibrosis, pre-edema, produced a 11-fold decrease in lung volume and a 2.2-fold increase in tissue density. We found, by CT and gravimetry, that similar amounts of water accumulated per unit volume in control and fibrotic lungs. Morphometry and semi-quantitative light microscopic grading showed a two-fold rise in the volume fractions of connective tissue and alveolar edema, and a 50% reduction of air and of interstitial edema in the fibrotic lobes. By electron microscopy, the interstitial edema in the fibrotic lungs was randomly distributed, whereas in the controls it was found primarily around extra-alveolar vessels and airways, not in the alveolo-capillary septa. We conclude that fibrosis profoundly affects the distribution of edema in the lung.

The pathophysiological origins of airway hyperresponsiveness (AHR) in asthma are unknown. The objectives of this thesis were to establish an association between AHR in an animal model of asthma and altered contractility of airway smooth muscle (ASM) and to elucidate changes in contractile signalling that could account for any observed differences in ASM contractility. The Fisher strain of rat is spontaneously hyperresponsive to methacholine inhalation challenge relative to Lewis rats. These inbred rat strains provide a model with which to study genetically-determined variations in airway smooth muscle that may underlie AHR. Fisher rats were found to be also hyperresponsive to serotonin (5-HT) in vivo compared to Lewis rats, indicating that their AHR is not agonist specific the narrowing capacity and velocity of contraction of Fisher intraparenchymal airways in cultured explants were also greater than explanted. Lewis intraparenchymal airways in response to 5-HT. In addition, 5-HT stimulated higher Ca2+ transients in Fisher than Lewis ASM, in parallel with their rank order of intraparenchymal airway responsiveness. These results suggest that ASM contractility may be determined by the extent of Ca2+ mobilization in airway myocytes. To examine the mechanism of enhanced intracellular Ca2+ mobilization in Fisher ASM, the role of the inositol (1,4,5)trisphospbate (Ins (1,4,5)P 3) pathway in determining interstrain differences in ASM Ca2+ was studied. 5-HT produced higher levels of Ins (1,4,5)P3 in Fisher than Lewis ASM. This appeared to be caused by a lower expression and activity in Fisher ASM of the type I and II 5-phosphatases which inactivate Ins (1,4,5)P3. Inhibition of 5-phosphatase activity increased Ins (1,4,5)P3-mediated Ca2+ release in ASM from both strains of rat, equalizing Ca2+ signals between Lewis and Fisher ASM. Since Ins (1,4,5)P3 receptor sensitivity to Ins (1,4,5)P 3 was found to be similar between the two rat strains, the differences in 5-phosphatas

The injury-induced alterations in sulfated proteoglycans (PG) were studied, in neointima, developed in response to a selective deendothelialization of the aorta, of normocholesterolemic rabbits. Light microscopic radioautography and size exclusion chromatography revealed differences in PG between neointima not covered by regenerated endothelium, and reendothelialized neointima or normal aorta. These differences included radioautographic reaction, concentration, size distribution and composition. Further studies were conducted to examine the putative role of the altered PG in lipoprotein (LP) sequestration and lipid accumulation during atherogenesis. LP-PG complexes were isolated by anti apo-B affinity column, from intima-medial tissues from normal and injured aortas. These complexes contained low density and very low density LP, chondroitin sulfate PG and hyaluronic acid. It appeared that endothelial injury enhanced the formation of LP-PG complexes, particularly in areas covered by regenerated endothelium. The uptake and degradation of LP-PG complexes, derived from normal (LP-NPG) or injured aortas (LP-IPG), by arterial smooth muscle cells (SMC) and blood monocyte-derived macrophages (BMDM) were also examined. LP-PG complexes stimulated LP binding, internalization and degradation by SMC and BMDM. Both cell types showed a higher affinity for LP-IPG than LP-NPG. The uptake of LP-PG complexes was mediated mainly by the LDL receptor pathway and phagocytosis. The scavenger receptor played a minor part in the uptake of LP-PG complexes. Data from this study provide evidence that endothelial injury could trigger alterations in neointimal PG, which in turn, facilitate LP accumulation both extracellularly and intracellularly during atherogenesis.

The production of contrastive stress was studied in normal-hearing and severely and profoundly hearing-impaired children. A picture description task was used to elicit utterances. Contrastive stress was assigned by changing one element in the second and third pictures in sets of three pictures. Stress production was assessed perceptually and acoustically. The normal-hearing and the severely hearing-impaired children were judged to have consistently stressed the element that was changed in the pictures. Some of the profoundly hearing-impaired subjects were judged to have stressed the changed element more often than chance but some did not perform above chance. Acoustic measurements indicated that only the normal-hearing speakers significantly varied both duration and fundamental frequency when stressing words while some of the hearing-impaired children varied only duration. These findings were interpreted as indicating that profoundly hearing-impaired speakers had difficulty producing recognizable contrastive stress and showed deviations in the duration and fundamental frequency of their utterances.